CINP - Antidepressant Medications

Antidepressant medications and othertreatments of depressive disorders: a CINPTask Force report based on a review of evidence

Members of the Task Force :

Norman Sartorius1 (Chairperson), Thomas C. Baghai2, David S. Baldwin4, Barbara Barrett5,

Ursula Brand6, Wolfgang Fleischhacker7, Guy Goodwin8, Heinz Grunze2,3, Martin Knapp5,

Brian E. Leonard9, Jeffrey Lieberman10, Yoshibumi Nakane11, Roger M. Pinder12,

Alan F. Schatzberg13, Jaromır Svestka14

This text was written by :

Thomas C. Baghai2, David S. Baldwin4, Barbara Barrett5, Pierre Baumann15,

Kareem Ghalib16, Guy Goodwin8, Heinz Grunze2,3, Martin Knapp5, Brian E. Leonard9,

John C. Markowitz17, Frank Padberg2, Roger Pinder12 and Norman Sartorius1.

Substantial contributions to some of the chapters were made by Ursula Brand6, Max Fink18,

Toshiaki Furukawa19, Konstantinos N. Fountoulakis20, Peter Jensen16, Shigenobu Kanba21,

Anita Riecher-Rossler22.

The text was edited by :

Thomas C. Baghai2, Heinz Grunze2,3 and Norman Sartorius1

The names of the persons who produced the first draft of the chapters are given in the table

of contents.

Website : www.cinp-antidpressant-task-force.de

Address for correspondence : Thomas C. Baghai, M.D., Department of Psychiatry and

Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstr. 7, D-80336 Munich,

Germany.

Tel. : +49-89-5160-5711 Fax : +49-89-5160-5718

E-mail : [email protected]

With copy to :

Norman Sartorius, M.D., Ph.D., Chairperson of CINP Task Force, 14 chemin Colladon,

1209 Geneva, Switzerland.

Tel. : +41-22-788 23 31 Fax : +41-22-788 23 34


Heinz Grunze, M.D., School of Neurology, Neurobiology and Psychiatry,

Newcastle University, UK.

Tel. : +44-191-28-25765 Fax : +44-191-222-6162


Affiliations :1 14 chemin Colladon, 1209 Geneva, Switzerland2 Dept. of Psychiatry and Psychotherapy, Ludwig-Maximilians-University Munich, Nussbaumstr. 7,

D-80336 Munich3 School of Neurology, Neurobiology and Psychiatry, Newcastle University, Leazes Wing, Royal,

Victoria Infirmary, Queen Victoria Road, Newcastle upon Tyne NE1 4LP, United Kingdom

International Journal of Neuropsychopharmacology (2007), 10, S1–S207. Copyright f 2007 CINPdoi:10.1017/S1461145707008255

SUPPLEMENT

CINP

4 University Dept. of Psychiatry, Royal South Hants Hospital, Graham Road, Hampshire SO14 0YG,

UK.5 London School of Economics and Political Science, Houghton Street, London WC2A 2AE,

UK.6 EUFAMI (European Federation of Associations of Families of Mentally Ill People), Tagermoosstrasse

22, D-78462 Konstanz, Germany.7 Dept. of Psychiatry, Innsbruck University Clinics, Anichstrasse 35, A-6020 Innsbruck, Austria8 Dept. of Psychiatry, University of Oxford, Warneford Hospital, Oxford OC3 7JX, UK.9 National University of Ireland, Galway, University Road, Galway, Ireland.10 Dept. of Psychiatry, College of Physicians and Surgeons, Columbia University,

New York State Psychiatric Institute, 1051 Riverside Drive – Unit #4, New York, N.Y. 10032,

USA11 Dept. of Neuropsychiatry, Nagasaki, University School of Medicine, Japan12 Pharma Consultant, Vughterstraat 123D, 5211GA ’s-Hertogenbosch, The Netherlands.13 Dept. of Psychiatry and Behavioral Sciences, Stanford University School of Medicine,

401 Quarry Road, Third Floor, Stanford, CA 94305-5717, USA.14 Psychiatric Clinic, Medical Faculty of MU, Jihlavska 20, 639 00 Brno-Bohunice, Slovenia.15 University Department of Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne, Switzerland16 Child and Adolescent Psychiatry, Columbia and Cornell Universities, New York Presbyterian

Hospital, 525 East 68th Street, New York, NY 10021, USA.17 Columbia and Cornell Universities, New York Presbyterian Hospital, 525 East 68th Street,

New York, NY 10021, USA.18 St. James, New York, NY 11780-0457, Department of Psychiatry, School of Medicine, Stony Brook

University, Long Island, New York, NY, USA19 Dept. of Psychiatry and Cognitive-Behavioral Medicine, Nagoya City University Graduate School of

Medical Sciences, Nagoya 467-8601 Japan.20 3rd Department of Psychiatry, Arisotle University of Thessaloniki, 55132 Aretsou Thessaloniki,

Greece.21 Yamanashi-ken Nakakomagun, Tomahocho Shimogatou 1110, 409-3898 Japan.22 Psychiatrische Poliklinik, Universitatsspital Basel, 4031 Basel, Switzerland.

Received 21 February 2007; Reviewed 31 March 2007; Revised 8 August 2007 ;

Re-revised 5 November 2007 ; Accepted 5 November 2007

Contents

Antidepressant medications and other treatments of depressive disorders: a CINP Task Force report based

on a review of evidence. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S1

1 Foreword (Brian E. Leonard). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S4

2 Note from the Editors (Thomas C. Baghai, Heinz Grunze, Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . S4

3 Introduction (Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S5

4 Method used to produce the review (Barbara Barrett, Ursula Brand, Heinz Grunze, Martin Knapp) . . . . . S9

4.1 Consensus process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S9

4.2 Data sources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S11

4.3 Additional sources of information. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S12

4.4 Limitations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S12

5 Diagnosis and epidemiology (Thomas C. Baghai, Heinz Grunze, Norman Sartorius) . . . . . . . . . . . . . . . . . .S14

5.1 Diagnosis of depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S14

5.2 Features of particular relevance to the treatment of depressive disorders . . . . . . . . . . . . . . . . . . . . . . .S16

5.3 Epidemiology of depressive disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S26

6 Standards of care (Heinz Grunze). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S27

6.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S28

6.2 Access to mental health services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S30

6.3 Enhanced care . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S30

S2 CINP Antidepressant Task Force 2007

7 Goals of treatment : response, remission, recovery (Heinz Grunze). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S31

7.1 Acute treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S32

7.2 Continuation and maintenance treatment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S35

7.3 Managing side effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S37

8 Mechanisms of action and future directions in the development of antidepressants

(Thomas C. Baghai, Pierre Baumann, Brian E. Leonard, Roger Pinder) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S38

8.1 The development of antidepressants based on the monoamine hypothesis of depression. . . . . . . . . .S38

8.2 Developments leading to new understanding of the mechanism of action of antidepressants . . . . . .S39

8.3 The role of pharmacogenetics in understanding how antidepressants work. . . . . . . . . . . . . . . . . . . . .S44

9 Pharmacological treatment options (Thomas C. Baghai, Pierre Baumann, Konstantinos N.

Fountoulakis, Toshiaki Furukawa, Guy Goodwin, Heinz Grunze, Peter Jensen, Shigenobu Kanba,

Brian E. Leonard) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S45

9.1 The use of medication in the acute treatment of depressive disorders. . . . . . . . . . . . . . . . . . . . . . . . . .S45

9.2 Continuation and maintenance therapy with antidepressants, mood stabilizers and other

medication . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S81

10 Specific age- and gender-related conditions (Thomas C. Baghai, Kareem Ghalib, Heinz Grunze,

Frank Padberg, Anita Riecher-Rossler). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85

10.1 Gender-related differences (Heinz Grunze, Anita Riecher-Rossler) . . . . . . . . . . . . . . . . . . . . . . . . . . . .S85

10.2 Age-related differences (Thomas C. Baghai, Kareem Ghalib, Frank Padberg). . . . . . . . . . . . . . . . . . . .S87

11 Suicidality and antidepressants : depression and suicide (Heinz Grunze) . . . . . . . . . . . . . . . . . . . . . . . . . . .S98

12 Other treatments for depression (Thomas C. Baghai, Max Fink, John C. Markowitz,

Frank Padberg) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S103

12.1 Psychotherapy (John C. Markowitz) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S103

12.2 Electroconvulsive therapy (Thomas C. Baghai, Max Fink) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S104

12.3 Other non-pharmacological treatments (Thomas C. Baghai, Frank Padberg) . . . . . . . . . . . . . . . . . . .S106

13 Antidepressant drugs in the treatment of anxiety disorders (David Baldwin) . . . . . . . . . . . . . . . . . . . . . . .S110

14 Health economics : the cost of illness (Barbara Barrett, Martin Knapp) . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S110

14.1 Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S110

14.2 The broad costs of depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S111

14.3 Methodology : economic evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S112

14.4 Economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S113

14.5 Evidence on the cost-effectiveness of antidepressants and care management . . . . . . . . . . . . . . . . . . .S117

14.6 Economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S117

14.7 Implications : economic evidence for pharmacological treatment options . . . . . . . . . . . . . . . . . . . . . .S118

14.8 Economic evidence for psychological treatment options . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S119

15 Conclusions and implications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S121

16 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S122

17 Statement of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S122

18 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S123

19 Annexes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S179

19.1 Annex 1: Opinions and suggestions that could not be fully accommodated in the review

(Thomas C. Baghai, Max Fink, Heinz Grunze, David Healy, Ulrich Hegerl,

Florence Thibaut, Florence Thibaut, Markus Kosel, Min-Soo Lee, Shigenobu Kanba,

Norman Sartorius) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S179

19.2 Annex 2: Additional information on the types of economic evaluation (Barbara Barrett,

Martin Knapp). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S181

19.3 Annex 3: Additional information on electroconvulsive therapy (Thomas C. Baghai, Max Fink). . . .S184

19.4 Annex 4: Additional information on transcranial magnetic stimulation (Frank Padberg) . . . . . . . . .S189

19.5 Annex 5: Additional information on vagus nerve stimulation (Frank Padberg) . . . . . . . . . . . . . . . . .S190

19.6 Annex 6: Additional information on acupuncture (Thomas C. Baghai). . . . . . . . . . . . . . . . . . . . . . . .S191

19.7 Annex 7: Additional information on chronotherapeutics : light and wake therapy

(Klaus Martiny) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . S192

19.8 Annex 8: Additional information on psychotherapy (John C. Markowitz) . . . . . . . . . . . . . . . . . . . . .S193

CINP Antidepressant Task Force 2007 S3

19.9 Annex 9: Additional information on antidepressant drugs in the treatment of anxiety disorders

(David Baldwin) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S196

19.10 Annex 10: List of regional meetings and countries represented . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S197

19.11 Annex 11: Suggestions concerning the organization of national review meetings . . . . . . . . . . . . . . .S198

19.12 Annex 12: Additional information on the European Federation of Associations of Families

of People with Mental Illness (EUFAMI) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S198

19.13 Annex 13: List of Advisors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S199

20 Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .S205

1 Foreword

According to the World Health Organization, de-

pression is one of the most debilitating disorders af-

fecting humankind. The social and economic costs of

chronic ill health resulting from untreated or in-

adequately treated depression are considerable and

frequently underestimated.

The CINP established the Task Force on Anti-

depressant Medications in 2004 to examine all aspects

of therapy with antidepressant drugs. This was con-

sidered necessary as, despite the availability of effec-

tive antidepressants for the past 50 years, a substantial

minority of depressed patients either remains un-

treated or under treated. As the only international

organization devoted to the promotion of research,

education and the applications of neuropsycho-

pharmacology to the clinic, the main task of the CINP

is to extend the knowledge of the drugs that are

available with the aim of improving the management

of mental disorders. The purpose of this Task Force

document was not to produce an academic mono-

graph nor a set of guidelines, but to provide mental

health and other professionals with comprehensive

and objective information about the different aspects

of the use of antidepressants important in clinical

practice.

The Task Force consisted of 15 experts in psy-

chiatry, psychopharmacology, public health, econ-

omics and family care. The majority of its members are

senior members of the CINP. The Task Force was also

advised to rely in the course of its work on advisors

in different countries selected because of their out-

standing expertise in the matters covered by the re-

view. The report presented here was approved by the

Executive Committee and the Council of the CINP at

its meeting in Chicago in July 2006.

As a service to those engaged in mental health care

and to ensure maximum impact, the Task Force re-

view is being published as a supplement to the CINP’s

journal, the International Journal of Neuropsycho-

pharmacology. In addition, the information will later

be made available on the CINP website. To facilitate

access to the review for non-English-speakers, we also

intend for it to be published in Chinese, French, Rus-

sian and Spanish.

It is the intention of the CINP to provide, in the fu-

ture, other task force publications dealing with other

major groups of medications used for the treatment

of mental disorders. We hope in this way to enhance

the effectiveness of the CINP as a major international

organization committed to improving knowledge

worldwide of the appropriate use of psychotropic

drugs for the optimal treatment of psychiatric dis-

orders.

BRIAN E. LEONARD

President, CINP

January 2007

2 Note from the Editors

This review is the result of the work of many. The

names of those who contributed the first drafts of the

text are given in the table of contents : in their present

form, however, the chapters often differ significantly

from their original version. This is because they have

been revised – often more than once – to do justice to

the numerous comments and suggestions concerning

additional evidence received from the Advisory

Group and the members of the CINP Task Force. In

selecting the members of the Advisory Group the Task

Force made every effort to include experts from dif-

ferent countries and with outstanding expertise in a

manner that was to make it possible to obtain advice

and guidance in the relevant areas of knowledge and

disciplines. Their contribution is acknowledged in the

acknowledgements chapter 16. In addition, we would

like to express our thanks for the particularly useful

comments and suggestions, as well as additional ma-

terials, contributed by Profs. Baumann, Blier, Burrows,

Dunn, Furukawa, Halaris, Kutcher, Remschmidt and

Moller.


The method used to produce the first draft of the

chapters of this review and the sources of data used

are described in chapter 4.1. What makes this effort

different from similar documents are the steps that

were taken after the review of the literature was com-

pleted. First, as soon as the Task Force approved the

text, the review was submitted for comments and re-

view to an advisory group composed of experts from

the countries the world over. At the same time the re-

view was translated into Chinese, French, Russian and

Spanish, and these versions of the text were then pre-

sented to experts in regional meetings held in Caracas,

Munich, Paris, Shanghai and St. Petersburg. Present at

each of these meetings were experts from the host

country and from other countries that use the same

language or share scientific traditions. The participants

in these meetings undertook to organize national

meetings in their countries to review the materials

presented and to examine the facts in the light of the

experience, special circumstances and evidence that

may not have been available in international data-

bases. The national meetings have been taking place

during the year 2007 and will continue in 2008. The

results of these meetings will be examined by the

CINP and may be published, possibly together with

results of new studies that become available or of

studies that have been missed by those who drafted

the chapters, by the members of the Advisory Group

and the CINP Task Force. It would have been desir-

able to make the regional meetings coincide with

CINP regional meetings : this however was not poss-

ible because of the need to complete the production of

the review within a year which imposed serious time

constraints on the work plan. However, the regional

and national meetings included a number of members

of the CINP.

After lengthy discussions and some hesitation the

Task Force decided to supplement the description

of antidepressant medications with chapters that pro-

vide information about the diagnosis of depression

(chapter 5.1) and its epidemiology (chapter 5.3), as

well as about principles of caring for people with de-

pression (chapter 6) and treatment that can be used in

combination with antidepressants or alone (chapters

9.1 and 12). In view of the many discussions and

differences of opinion over whether to include de-

scription of other treatment methods, the Task Force

finally decided to provide a brief description of these

methods in the text of the review and to place more

detailed information in the annexes (19.3–19.8). An

important argument in this respect was that the main

task of the Task Force was to produce a review of

evidence (and experience) and not guidelines for

treatment that should be produced at the national or

even subnational level, taking evidence as well as local

circumstances into account.

In reviewing the evidence, we paid particular

attention to results obtained in randomized control

trials of antidepressant medications. The results of

these trials are important, and their statistical signifi-

cance is often put forward as being sufficient for

recommendations about clinical practice. A statisti-

cally significant difference, however, is not always

equal to a clinically meaningful difference; nor is the

evidence obtained in research the only evidence to

consider in making treatment decisions. For that rea-

son, this review was developed in consultation with

leading mental health experts, representatives of fam-

ily organizations and specialists in medical disciplines

other than psychiatry. These consultants generously

provided advice, spoke from experience and contri-

buted information published in non-English lan-

guages. We hope that this intensive process of

consultation has helped the review to reflect evidence

from research as well as from experience and clinical

wisdom.

T. C. BAGHAI, H. GRUNZE AND N. SARTORIUS

on behalf of the CINP Task Force

Munich, Geneva, January 2007

3 Introduction

The criteria used to assess whether a problem is of

public health importance (and therefore should be a

priority for health services) include the prevalence of

the problem, the severity of its consequences, the

likelihood that it will remain stable or grow if un-

attended and the availability of effective means of

intervention to resolve or significantly reduce the

problem.

Depressive disorders satisfied the first three criteria

long ago. These disorders are among the most fre-

quent mental illnesses, and their prevalence matches

that of many serious physical illnesses given priority

in public health action. The consequences of de-

pression, if left untreated, are grave and include in-

creased morbidity and mortality from various

physical illnesses as well as significant impairment

that produces more disability than many common

chronic disorders such as diabetes and chronic col-

lagenoses. Reports of the World Health Organization

(WHO) show that depressive disorders rank very high

in number of life years lost due to illness, premature

death and disability. Depressive disorders also sig-

nificantly increase the risk of suicide and of suicidal

attempts.


Depressive illness is likely to become even more

prevalent in the decades to come for a variety of rea-

sons. These include increased life expectancy both

among the general population in many countries (with

a concomitant increase in groups that are at particu-

larly high risk for depressive disorders1) and among

people with chronic physical illness often ac-

companied by depressive disorders (e.g. chronic gas-

trointestinal disorders, cardiovascular disorders and

stroke) ; greater numbers of iatrogenic mental dis-

orders, including depression ; and, in both developed

and developing countries, continuously increasing

levels of stress that parallel the weakening of social

support. WHO has predicted that unipolar depression

alone will be the second most important contributor to

disability by the year 2020, not only in Europe and

northern America, but worldwide (World Health

Organization, 2001).

The fourth criterion for public health importance,

and for consequent action, is the availability of an

effective intervention that can reduce or eliminate the

problem and is suitable for widespread application.

Until recently that criterion had not been satisfied for

the majority of mental disorders. Although public

health authorities succeeded in preventing some

mental disorders (e.g. cretinism in areas where iodine

deficiency was eliminated, and of progressive paral-

ysis in areas where infection with syphilis was

brought under control), treatment of mental disorders

was, by and large, not very effective. Electro-

convulsive therapy (ECT) helped in treating people

with certain forms of depressive disorders and

schizophrenia, but the number of those who could not

benefit from ECT vastly surpassed the numbers of

those who could. Thus this intervention did not fit

the criterion of wide applicability. Psychotherapy

helped many, but the number of experts qualified to

apply it were – and still are – small in most parts of

the world. Psychotherapeutic strategies and tech-

niques have become sufficiently well defined to be

candidates for study in undergraduate medical edu-

cation and in-service training of non-psychiatrists.

Moreover, psychotherapies may have widespread

utility, even in countries in which the purchase

and regular distribution of medications are different

(Bolton et al., 2003).

The introduction of antidepressant medications

changed the public health importance of depressive

disorders and their priority in health care services. In

addition, recognizing that depressive disorders are

frequent and severe, that they are likely to multiply in

the years to come and that they complicate treatment

of many physical disorders, it gradually became evi-

dent that antidepressant medications could help a

significant proportion of people with depressive dis-

orders even when applied by general medical staff

in primary care and non-psychiatric health services.

It also became possible to speak publicly about de-

pression because society accepted that depression

was a disease that could be effectively treated by

medical means – medicinal drugs – like many other

diseases.

Since the introduction of imipramine we know that

antidepressant medications are not a miracle cure.

They do help approximately two thirds of the people

with depression if appropriately used (Klerman and

Cole, 1965) : although this is considerably better

than the response to placebo, which helped approxi-

mately one third of the people to whom it had been

given in clinical trials, it still leaves one third of the

patients with depression in whom the prescription

of an antidepressant medication will not improve

the condition. The addition of psychotherapy, better

social support and the use of other, additional medi-

cations will help some of those who did not respond

to the treatment with the first prescribed anti-

depressant, but some others will still remain unwell.

There is thus considerable room for further im-

provement of the effectiveness and safety of anti-

depressants and it is to be hoped that future research

will result in still better medications and other meth-

ods of treatment of depressive disorders. Meanwhile,

imperfect as they may be, the currently available

antidepressant medications are a powerful tool that

can be used in general and specialized mental health

services.

The lessened stigma of depression and the growing

conviction that antidepressant medications are effec-

tive emboldened patients to seek help from health

workers and motivated non-psychiatrists to deal with

depression, to prescribe antidepressants and in gen-

eral to see patients with depression as having a man-

ageable health problem. The number of patients and

doctors with this mindset grew over time, supported

by an increase in the array of available medications,

and the encouraging results of studies showing their

usefulness and ever milder side effects. The general

public and the media supported this notion as well. In

several countries, direct advertisements to consumers

1 Despite a greater number of depressive symptoms requiring

treatment in old age, the prevalence of major depressive disorder

has not been reported to correlate with age (Patten et al., 2001 ;

Steffens et al., 2000). One explanation may be the inappropriateness

of the diagnostic criteria for depression which are valid for

depressive disorders in adults but not for those in the elderly.


may have played a role (Berndt, 2005). The Prime

Minister of Norway took a few weeks off to treat his

depression and came back in good health. Famous

artists and other stars described their depression and

how they got better. Although this change of public

opinion – from seeing depressive disorders as an in-

tractable form of madness to being a physical illness

that could be treated by pills prescribed by the general

practitioner – was positive because it changed the

way patients and medical staff thought about de-

pression, it was also a step towards a different

interpretation of depression. Increasingly, reports

appeared claiming that depressive disorders are no

more than variations of mood that do not warrant

medical attention. Psychiatric epidemiologists pub-

lished studies showing that the lifetime prevalence of

depressive disorders was nearly 80%, a figure that

can easily be interpreted by the lay public as evidence

that depressive disorders are part of normal life.

This banalization of depressive disorders came about

partly spontaneously and partly owing to promotion

by various sects and anti-psychiatry movements.

Depressive disorders, it was proclaimed, were most

often not really diseases : rather, they were conditions

that everyone had. Medications that had previously

been hailed as miraculous cures were declared by

some as an expensive and unnecessary form of

placebo. Worse, they were reported as dangerous be-

cause they affected people’s personality and made

them dependent on drugs. According to these argu-

ments, it was only the coalition between doctors and

drug manufacturers that kept alive the myth of de-

pressive illness and its medical solution.

Studies showing that successful treatment of de-

pressive disorders not only helps people who suffer

from them but also benefits society and patients’ fam-

ilies were neither widely known nor sufficiently pub-

licized. What received much greater airing and

prominence was the high cost of many medications

and the large amounts of money made by producers

and distributors of medications. To some extent, the

idea that drugs used to treat mental disorders are ex-

pensive stems from the stigma that accompanies

mental illness and the disregard for people who have

these disorders. Even when psychiatric medications

are inexpensive – a month’s supply of a drug such

as chlorpromazine costs no more than US$1 –

governments do not buy them, and the general public

accepts that even a dollar a month is too much to

spend for a person whom most of the population

considers not worth it.

Developments in research and technology have in-

creased the number of active substances that could

be used to treat depression, and the knowledge

about their mechanisms of action continued to ad-

vance, which has enhanced possibilities of adjusting

the treatment with psychopharmacological medi-

cations to the clinical needs of individual patients (see

Table 1).

The results of studies carried out to assess the ef-

fectiveness of the new substances showed that newly

discovered medications are at least as good as their

predecessors and that they have some advantages

over other drugs.

Studies comparing medications have increased,

but they are frequently sponsored by drug companies,

and their results are not always in harmony.

Government-sponsored studies, which might help to

resolve some of the contradictory results, are still far

too few in numbers. There are also still far too few

investigations of the effects of new drugs for patients

in populations outside the major industrialized coun-

tries2.

Some studies did show differences in dosage and

effects of medications given to patients living in

countries with varying climate, nutrition and general

morbidity patterns, but definitive studies of the effect

of drugs on patients from different populations are

still lacking. The scarcity of studies on psychotropic

drugs in the third world is part of the larger problem

of the predominance of research in a few highly de-

veloped countries. One recent study showed that only

6% of the articles on mental health in the scientific

literature come from other than high-income coun-

tries. The US and UK alone contribute 50% of the ac-

cessible scientific literature on mental health matters

(Saxena et al., 2006).

In the light of these considerations, it is not

surprising that the CINP, aware of its obligation

to facilitate clinical interpretation of neuropsycho-

pharmacological findings (Ban, 2006a), felt that it

would be useful to carry out a detailed technical re-

view of antidepressant medications.

Antidepressants are now used to treat many con-

ditions, even if the justification for their use reflects

more of clinical experience and consensus instead

of evidence (see Table 3) – but it was decided that

this review would concentrate on the use of anti-

depressants for the treatment of depression as de-

fined in ICD-10 (World Health Organization, 1992)

2 More recently, studies sponsored by international pharmaceutical

companies have included patients from India and other countries in

the third world ; the results of these investigations usually do not

report results obtained in such countries separately and mix the data

from those countries with data obtained in other countries.


Table 1. Commonly used antidepressants3, including their primary mode of action and influence on other receptor systems

Pharmacological

group Generic name

Primary

pharmacodynamic

mode of action

Secondary

pharmacodynamic

actions

Additional

effects

SSRI Citalopram SRI (++)

SSRI Escitalopram4 SRI

SSRI Fluoxetine SRI (++) 5-HT2C

SSRI Fluvoxamine SRI (++)

SSRI Paroxetine SRI (+++) (M1)

SSRI Sertraline SRI (+++) DRI

SNRI Venlafaxine SRI/NRI (+/+)

SNRI Duloxetine SRI/NRI

SNRI Milnacipran SRI/NRI

NARI Reboxetine NRI (M1)

(NARI) Viloxazine (NRI)

NaSSA Mirtazapine a2 5-HT2,3 ; +5-HT1 H1, a1, a2

MT Agomelatine5 MT1/MT2 5-HT2C

RIMA Moclobemide MAI (M1)

MAOI Selegiline6 MBI MAI, APD

MAOI Phenelzine MAI

MAOI Isocarboxacid MAI/MBI

MAOI Tranylcypromine7 MAI/MBI APD

MAOI Pirasidol8 MAI/MBI

SMA Nefazodone9 SMA (+) 5-HT2A, SRI

SMA Trazodone SMA 5-HT2, SRI a1

DNRI Bupropion DNRI (+) NRI

DA Trimipramine DA 5-HT2 H1, M1, a1, a2

GM Tianeptine GM

S-TCA Clomipramine SRI NRI, D2 M1, a1

S/N-TCA Amitriptyline SRI/NRI (+/++) 5-HT2 H1, M1, a1, a2

S/N-TCA Amitriptylinoxide SRI/NRI H1, (M1), a1, a2

S/N-TCA Dibenzepine SRI/NRI

S/N-TCA Dosulepine/Dothiepin SRI/NRI (+/+) 5-HT2

S/N-TCA Doxepin SRI/NRI H1, M1, a1

S/N-TCA Imipramine SRI/NRI M1, a1

S/N-TCA Melitracen10 SRI/NRI M1

S/N-TCA Protriptyline SRI/NRI

N-TCA Desipramine NRI (+++) (M1)

N-TCA Lofepramine NRI (++) M1, a1

N-TCA Nortriptyline NRI SRI, 5-HT2 M1, a1

S-TetraCA Mianserin a2 NAR H1, a1

N-TetraCA Amoxapine NRI

N-TetraCA Maprotiline NRI H1, (M1), a1

For abbreviations see p. 9.

3 St. John’s wort is not included in the list of antidepressants because of

it has no proven efficacy in severe depression.4 In addition to its serotonin reuptake-inhibiting properties,

escitalopram also binds to the allosteric site on the serotonin

transporter. A new class of SSRIs has been proposed (allosteric

serotonin reuptake inhibitors, ASRIs).5 Not yet available ; currently under review by European authorities

(EMEA).6 In some countries selegiline has only been approved as a drug

against Parkinson’s disease, not as an antidepressant.

7 In some countries irreversible MAOIs are not longer available (e.g.

Czech republic, Spain and others).8 The use of pirasidol is limited to Russia and other eastern countries

of the same geographical region. In the Russian literature it can also be

found also under other names, such as pirlindol, pyrazidol, pirazidol

and pirazidolum (for review see Mosolov, 1998).9 Nefazodone has been withdrawn from the market in some

countries.10 Melitracen has activating properties in low dosages and is

predominantly used in Asian countries in a combined formulation

(Deanxit) with the antipsychotic drug flupentixol.


and DSM-IV (American Psychiatric Association,

1994).

Later, it became obvious that it would be necessary

to add chapters on the use of antidepressants for

anxiety and chronic pain because these conditions are

frequently associated with depression and possibly

rely on the same pathophysiological mechanisms and

pathways.

The review is based on published evidence ; how-

ever, it also incorporates advice and comments of

leading experts in the fields of psychiatry, pharma-

cology and public health. Additional sources of ex-

pertise consulted include regulatory agencies, patient

and family organizations, representatives of the phar-

maceutical industry and public health authorities. Our

hope was that combining a review of the literature

with the outcome of a wide-ranging discussion involv-

ing people whose experience usually is not published

(or is published in places that are difficult to access)

might produce a solid body of facts on which the CINP

could reach consensus and make its opinion widely

known. The particular aim of the consensus was to

provide evidence and other information that would

help to answer to at least the following questions :

$ Are antidepressant medications effective in allevi-

ating symptoms of depression and in preventing

relapses of depressive illness? (predominantly

chapters 9 and 7)$ Are the side effects of antidepressant drugs cur-

rently in use so severe that they outweigh the ben-

efits of these drugs? (chapters 7.3 and 9.1.1.3)$ Is the treatment of depressive disorders with anti-

depressant drugs cost-effective for individuals and

societies? (chapter 14)

$ What areas of scientific investigation related to anti-

depressant medications and their use deserve pri-

ority? (chapter 8)$ Are there depressive disorders that do not require

treatment with antidepressant drugs?11 (chapter 12)

This review presents evidence and experience that

should help to answer these questions and facilitate

the process of reaching a consensus that will guide

public health action and the education of health

workers, of the general public and of those who suffer

from depressive illnesses.

4. Method used to produce the review

4.1 Consensus process

The challenge for the CINP Task Force created in May

2005 was to review the evidence on the use, effective-

ness and safety of antidepressant medications and to

assemble experience that clinicians using them and

carers (e.g. family members) have accumulated. This

challenge was to be met by preparing a review of pub-

lished evidence and exposing it to a process of con-

sultation with experts in different parts of the world.

Thus, after an initial meeting with some members of

the Task Force, Dr T. C. Baghai and Dr H. Grunze,

with the assistance of Dr F. Padberg, prepared a re-

view of pharmacological and therapeutic evidence on

Table 1 abbreviations : (primary modes of action are explained in the text) : (+)=modest receptor binding affinity ; (++)=appreciable receptor binding affinity ; (+++)=strong receptor binding affinity ; +5-HT1=serotonin 1 receptor stimulation ;

5-HT2=serotonin 2 receptor antagonism; 5-HT2C= 5-HT2C receptor antagonist ; 5-HT3=serotonin 3 receptor antagonism;

a1=a1-receptor antagonism; a2=a2-receptor antagonism; all. 5-HTT=binding to the allosteric site of the serotonin transporter ;

APD=amphetamine prodrug; DA=dopamine (D2) receptor antagonist ; DNRI=dopamine and noradrenaline reuptake in-

hibitor ; DRI=dopamine reuptake inhibition ; GM=glutamatergic modulator ; H1=blockade of histamine 1 receptors ;

M1=blockade of cholinergic muscarinic receptors ; MAI=monoamine oxidase A inhibition ; MBI=monoamine oxidase B

inhibition ; MAOI=irreversible inhibitor of monoamine oxidase A and B; MAOBI=irreversible inhibitor of monoamine

oxidase B ; MT=melatonergic antidepressant ; MT1/MT2=melatonin 1 and melatonin 2 receptor agonist ; NAR=noradrenaline-

releasing properties ; NARI=selective noradrenaline (norepinephrine) reuptake inhibitor ; NaSSA=noradrenergic and selective

serotonergic antidepressant ; NRI=noradrenaline (norepinephrine) reuptake inhibition ; N-TCA=tricyclic antidepressant

with primary noradrenergic effects ; N-TetraCA=tetracyclic antidepressant with primary noradrenergic effects ;

RIMA=reversible inhibitor of monoamine oxidase A; SMA=serotonin-modulating antidepressant ; SNRI=selective serotonin

and noradrenaline reuptake inhibitor ; S/N-TCA=tricyclic antidepressant with similar serotonergic and noradrenergic effects ;

SRI=serotonin reuptake inhibition ; SRS=serotonin reuptake stimulation; SSRI=selective serotonin reuptake inhibitor ;

S-TCA=tricyclic antidepressant with primary serotonergic effects ; S-TetraCA=tetracyclic antidepressant with primary

serotonergic effects.

11 For example, the NICE (National Institute for Clinical Excellence,

UK) recommendations acknowledge a role for antidepressants

in primary care in moderate and severe, but not mild depression.

For these patients, NICE recommends observation or psychological

intervention as first-line treatment, and antidepressants only in the

case of refractoriness (National Institute for Health and Clinical

Excellence, 2004).


antidepressants. This initial review was supplemented

with a review of evidence on the economic aspects

of the treatment of depression prepared by Prof. Dr M.

Knapp and Dr B. Barrett. That version of the review

was presented to the CINP Task Force in January 2006

and revised in the light of comments received during

the meeting. Several chapters were added with the

involvement of experts in the relevant fields, such as

the chapter on psychopharmacotherapy of children

(first draft contributed by Dr K. D. Ghalib) and the

chapter on psychotherapy (drafted by Dr J. C.

Markowitz).

The main purpose of the technical review is to

reflect the actual scientific evidence on the use and

usefulness of antidepressants in the treatment of de-

pression. But it also deals with other major indications

for antidepressant medications (Table 3).

Table 2. Classification and criteria of major depressive disorder (DSM-IV; American Psychiatric Association, 1994) and

depressive episode (ICD-10 ; World Health Organization, 1992) (adapted from Bauer et al., 2002c)

DSM-IV ICD-10

Major depressive disorder

A. Single episode (296.2x)

B. Recurrent (296.3x)

A. Depressive episode (F32)

B. Recurrent depressive disorder (F33)

Severity :12

$ Mild (F–.0) : at least 2 main symptoms, plus at least 2

accessory symptoms; none of the symptoms intense$ Moderate (F–.1) : at least 2 main symptoms, plus at least

3 accessory symptoms ; some symptoms marked$ Severe (F–.2) : all 3 main symptoms, plus at least 4 accessory

symptoms ; some symptoms severe with intensity

Criteria major depressive episode (abridged) :

A. Over the last 2 weeks, 5 of the following features should

be present most of the day, or nearly every day (must

include 1 or 2) :

1. Depressed mood

2. Loss of interest or pleasure in almost all activities

3. Significant weight loss or gain (more than 5% change

in 1 month) or an increase or decrease in appetite

nearly every day

4. Insomnia or hypersomnia

5. Psychomotor agitation or retardation (observable by

others)

6. Fatigue or loss of energy

7. Feelings of worthlessness or excessive or inappropriate

guilt (not merely self-reproach about being sick)

8. Diminished ability to think or concentrate, or

indecisiveness (either by subjective account or as

observed by others)

9. Recurrent thoughts of death (not just fear of dying),

or recurrent suicidal ideation, or a suicide attempt or a

specific plan for committing suicide

Criteria of depressive episode (abridged) :

Minimum duration of episode : about 2 weeks

Main symptoms:

1. Depressed mood

2. Loss of interest and enjoyment

3. Reduced energy, increased fatigability

Accessory symptoms :

1. Reduced concentration and attention

2. Reduced self-esteem and self-confidence

3. Ideas of guilt and unworthiness

4. Agitation or retardation

5. Ideas or acts of self-harm or suicide

6. Sleep disturbances

7. Loss of appetite

B. The symptoms cause clinically significant distress or

impairment in social, occupational or other important areas

of functioning.

C. The symptoms are not due to a physical/organic factor or

illness

D. The symptoms are not better explained by bereavement

(although this can be complicated by major depression)

12 Severity of disease according ICD-10 does not necessarily include

ratings of disability and impairment.


The revised draft was sent to the group of advisors

listed on p. 199 (Annex 13: List of Advisors) and

further revised based on comments received. In April

2006, translation of the text into Chinese, French,

Russian and Spanish began so translations would be

ready for the next phase of the project.

That phase commenced with a series of regional

meetings that brought together 8–12 experts from the

country in which the meeting was held and 8–10 rep-

resentatives of other countries of the regionwho agreed

to critically review the document and to organize a

national meeting similar to the one they attended13.

By the time that this review went to press national

meetings were held in the following countries :

Argentina, Australia, Austria, Brazil, Chile, China,

Croatia, Czech Republic, Denmark, Dominican

Republic, Ecuador, France, Hong Kong, Japan,

Kazakhstan, Korea, Philippines, Serbia, Singapore,

Slovakia, Taiwan, Ukraine.

A list of countries represented at the regional

meetings held in St. Petersburg, Munich, Shanghai,

Caracas and Paris is given in Annex 10. Comments

and suggestions as well as references to local studies

published in English and other languages received

from the participants at these meetings served to re-

draft the review. The results of the examination of the

review at national level will be published locally and

may subsequently be brought together in a summary

paper. In July 2006 the review was examined by the

Executive Committee and Council of the CINP, which

recommended its publication and adopted the

Consensus Statement presented in chapter 15.

4.2 Data sources

The data considered in the development of this tech-

nical review have been extracted from different sour-

ces : the Medline database (up to October 2007), the

Cochrane Library, review articles from Medline-

indexed journals, meta-analyses14 (see Box 1), textbook

chapters known to the authors of the draft or brought

to their attention by members of the Task Force or the

Advisory group and material supplied by pharma-

ceutical companies. Several national and international

treatment guidelines were also examined, including

the American Psychiatric Association (APA) Practice

Guideline for the Treatment of Patients with Major De-

pressive Disorder (American Psychiatric Association,

2000), the Canadian Psychiatric Association and

Canadian Network for Mood and Anxiety Treatments

(CANMAT). Clinical guidelines for the treatment of

depressive disorders (Canadian Psychiatric Associ-

ation and Canadian Network for Mood and Anxiety

Treatments (CANMAT), 2001), the guidelines by the

German Psychiatric Society (Deutsche Gesellschaft fur

Psychiatrie, Psychotherapie und Nervenheilkunde,

DGPPN), Praxisleitlinien in Psychiatrie und Psycho-

therapie, Behandlungsleitlinie affektive Erkrankung

edited by van Calker and Berger (2000), and the World

Federation of Societies of Biological Psychiatry

(WFSBP) Guidelines for Biological Treatment of Uni-

polar Depressive Disorders, parts 1 and 2 (Bauer et al.,

2002c ; Bauer et al., 2002b) as well as the Textbook of

Mood Disorders (Stein et al., 2006).

The review is mostly, but not exclusively, based on

papers published between 1990 and 2007 – not least

also because of time constraints – because over the

past two decades the methodology of studies became

more uniform and comparable, and consistent and full

information became easier to retrieve since papers

from this period are usually available electronically.

Table 3. Indications other than depressive disorders

for antidepressant medication (based on clinical experience,

consensus and evidence)

Main categories

of diseases Specific condition

Anxiety disorders

(see chapter 19.9)

$ Generalized anxiety disorder$ Panic disorder$ Social phobia$ Post-traumatic stress disorder$ Obsessive-compulsive disorder

Pain conditions

(see chapter 5.2.1.3.5)

$ Chronic pain$ Somatoform disorders

Schizophrenic

spectrum disorders

$ Schizophrenia$ Schizoaffective disorders$ Postschizophrenic depression

Other indications $ Adjustment disorders$ Personality disorders$ Akathisia$ Eating disorders$ Impulse control disturbances$ Insomnia

13 Suggestions concerning the organization of national meetings are

given in Annex 10.

14 When using meta-analyses as the primary source of evidence, the

authors were aware of the methodological limitations of the

approach (Anderson, 2000b). Only when properly conducted can

meta-analyses bring out possible subgroup differences

(heterogeneity) and publication biases (funnel plot analysis and

others) (Sterne et al., 2000 ; Thompson, 1994). Meta-analyses

performed according to the Cochrane method usually have the

largest acceptance and best scientific ranking (see Box 1).


4.3 Additional sources of information

In addition to scientific experts, families and carers are

represented on the Task Force group by EUFAMI – the

European Federation of Association of Families of

People with Mental Illness15 (for more information on

EUFAMI, see chapter 19.12, Annex 12: Additional in-

formation on the European Federation of Associations

of Families of People with Mental Illness (EUFAMI)).

4.4 Limitations

As the previous section makes clear, this technical re-

view is based on publicly available materials obtained

via a Medline database search and other evidence that

was brought to the attention of the authors. For that

reason, the review may be subject to several biases.

For example, modern medicine requires decision

making on the basis of hard data, i.e. data that come

mainly from randomized controlled trials (RCTs). But

even these data are not flawless, and translating RCT

results to everyday clinical practice is sometimes

problematic. One major cause may be that the

population of patients included in RCTs differs sig-

nificantly from the ‘natural ’ population of the ‘real

world’. To avoid this bias, in recent years the US

National Institute of Mental Health (NIMH) designed

and independently sponsored a clinical trial known

as Sequenced Treatment Alternatives to Relieve

Depression (STAR*D) (Menza, 2006). Results from the

initial phase of this trial are touched on in this review.

Owing to the current technical and legislative cli-

mate16, patients who are included in randomized trials

(RCT), tend to be chronic, refractory and closely af-

filiated with doctors or with institutions and associ-

ations. This situation has a number of consequences,

including lower response to active drugs and higher

response to placebo. Moreover, a continuous increase

in placebo response and simultaneous drop in the ac-

tive compound response rate has been observed in

RCTs over the past few decades. For this reason, it is

now essentially impossible to interpret results of

studies that do not include a placebo group.

Box 1. Overview of the Cochrane method (example from Cipriani et al., 2005b)

Search strategy:

$ Relevant studies were located by searching the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled

Trials Register (CCDANCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), Medline (1966–2004) and

Embase (1974–2004).$ Non-English-language articles were included.

Selection criteria :

$ Only randomized controlled trials were included.$ For trials with a cross-over design, only results from the first randomization period were considered.

Data collection and analysis :

$ Data were independently extracted by two reviewers using a standard form.$ Responders to treatment were calculated on an intention-to-treat basis : dropouts were always included in this analysis.$ When data on dropouts were carried forward and included in the efficacy evaluation, they were analyzed according to the

primary studies ; when dropouts were excluded from any assessment in the primary studies, they were considered as

treatment failures.$ Scores from continuous outcomes were analyzed, including patients with a final assessment or with the last observation

carried forward.$ Tolerability data were analyzed by calculating the proportion of patients who failed to complete the study and who

experienced adverse reactions out of the total number of randomized patients.$ The primary analyses used a fixed-effects approach, and presented Peto odds ratio (PetoOR) and standardized mean

difference (SMD).

15 EUFAMI is a not-for-profit organization registered in Belgium that

currently represents 48 member associations from 1 non-European

and 26 European countries. It was founded in 1992 by members of a

several family and carer organizations. Family organization activities

include advocating for better services, equal and housing rights,

raising awareness at the national and local level, and countering

stigma.

16 A variety of attributes of clinically routine patients, such as

psychiatric comorbidity, concomitant somatic disease, concomitant

use of most psychopharmacologic and other medications, suicidality,

pregnancy and others represent exclusion criteria in RCTs and

induce the selection of a subgroup of patients. Also, in some

countries the fact that treatment in RCTs is sponsored causes the

predominant inclusion of specific social subgroups of patients

without health insurance.


Statistical significance and clinical effectiveness are

not synonymous (for a definition, see Box 6) and not

always closely correlated. The so-called efficacy gap

between outcomes in clinical trials and in primary care

may be influenced by patient compliance, family and

social supports, and negative media reporting on

antidepressants (Wade, 2006). Another source of con-

fusion is the use of refined statistical methods to

demonstrate the therapeutic efficacy and effectiveness

of antidepressants without a re-evaluation of the psy-

chiatric nosology employed and without additional

research in psychopathology. In addition it may be

relevant to the interpretation of study results that by

the 1990s single-center clinical investigations were re-

placed by multi-center centrally coordinated clinical

investigations in which individual contributions are

restricted to a small proportion of the total sample.

Moreover, education and research in pharmacother-

apy are controlled predominantly by the pharma-

ceutical industry (Ban, 2006b). In fact, most studies

utilized for this report are from recent years and may

shift the overall impression on the efficacy of anti-

depressants into the direction of limited efficacy, and

thus may impact treatment related considerations,

potentially underestimating the efficacy of anti-

depressants in a clinical cohort. It is therefore also

important to keep in mind that the outcome of indus-

try-sponsored phase III studies often cannot be taken

at face value. The overt and covert influence of the

vested interests of study sponsors on results (spon-

sorship bias) has recently received a fair amount of

attention (Healy, 2006 ; Heres et al., 2006 ; Lexchin et al.,

2003 ; Lexchin and Light, 2006 ; Montgomery et al.,

2004a; Perlis et al., 2005 ; Procyshyn et al., 2004).

On the other hand, failed trials are usually not pub-

lished or are published onlywith low priority and after

an extensive delay, as publication is usually not in the

interest of the sponsor and may interfere with mar-

keting strategies. For a complete assessment of the

utility of antidepressants it would be helpful to take all

those studies into account. But because it is not poss-

ible to report in full about unpublished studies, the

Task Force decided to base its work only on peer-

reviewed, published papers and information from

book chapters. Unpublished studies have not been con-

sidered in the main review, except within the chapter

on treatment of children and adolescents (chapter

10.2.1), which includes some unpublished data avail-

able on Internet sites of pharmaceutical companies.

Some, but not all companies have now committed

themselves to an open database policy of supplying

information regarding all controlled, company-

sponsored trials on their Internet site. However, using

this information from some companies but not from

others would also unfairly bias the results and views

expressed here. Hence, the Task Force’s decided to

base its report only on peer-reviewed, published

papers and information described in chapter 4.2 above.

Unpublished materials, papers not available using a

Medline database search and abstracts (posters and

lectures) were considered only if they were presented

at major conferences or explicitly supplied as ad-

ditional information by a company (e.g. on the com-

pany’s freely accessible Web page). Overall, those

materials had no major impact on the technical review.

The CINP Task Force is also well aware that most

evidence quoted in this technical review originated

from clinical studies carried out in Europe and North

America. Results may therefore not be representative

of populations living elsewhere and under different

cultural and climatic conditions. Biological differ-

ences, e.g. in metabolism, differences in food intake,

different patterns of physical morbidity as well as

cross-cultural differences in concepts of health and in

the expression of depressive episodes all lead to dif-

ferences in treatment outcome. The use of medication

may differ from culture to culture with consequences

for both compliance and treatment outcome. For ex-

ample, Sugahara reports an adherence rate of 66.8%

over 13 weeks of antidepressant treatment in a non-

psychiatric outpatient clinical setting in Japan

(Sugahara et al., 2005), whereas in Western European

countries and North America compliance is usually

worse (Brown et al., 2005 ; Demyttenaere, 1998).

Most RCTs include patients who have been diag-

nosed as suffering from major depression or depress-

ive disorders according to the Diagnostic and

Statistical Manual of Mental Disorders, 4th revision

(DSM-IV), or the International Statistical Classification

of Diseases and Related Health Problems, 10th re-

vision (ICD-10). By defining specific subgroups of

patients suffering from depressive disorders, both

operationalized diagnostic systems may influence

treatment outcome. In addition, as mentioned above,

a relatively high placebo response rate in patients

suffering from depressive disorders has an impact on

efficacy studies of substances with possible anti-

depressant effects by reducing the likelihood of sep-

arating them from placebo. Finally, because the vast

majority of RCTs deal with major depressive disorder,

it remains unclear whether one can extrapolate from

these studies to other (minor) forms of depression or

depression comorbid with other mental or somatic

illnesses.

Another important, yet often forgotten, method-

ological issue is that the fact that just because two


studies are significantly positive in favor of a specific

medication does not mean that both drugs are equal in

efficacy. Variations in sample sizes make it hard to

compare trials due to the related statistical power of

the study. When including a large number of subjects,

a drug-placebo difference in the Hamilton Rating Scale

for Depression (HAMD) of 2 may still be significant,

but not clinically meaningful. On the other hand, if the

power calculation was too optimistic and only a small

number of patients have been included, even a HAMD

difference of 6 may lack statistical significance. In the

case of superiority in comparison with placebo treat-

ment, both statistical significance and effect size are

very important factors influencing clinical effective-

ness. However, it would clearly be beyond the scope

of a review to detail the methodology of each trial

mentioned and the Task Force decided that it would

refer the reader to the original publications. Also, pla-

cebo response rates may differ substantially from

study to study due to different allowances of rescue

medication, settings, severity of illness and so on.

Thus, relevant findings may be obscured by high pla-

cebo responses and may also lead to the perception

that placebo could be an adequate antidepressant.

Again, it would be difficult within the scope of a re-

view to give more detailed information for every sin-

gle trial concerning all these potentially confounding

factors.

Nevertheless, the introduction of RCTs was a great

step forward in clincal psychopharmacology, simply

by the fact that they replaced testimonials (consensus

of experts), contaminated by many other factors, in

the demonstration of efficacy of antidepressants.

Therefore, proving efficacy in RCTs remains the key

issue for regulatory approval ; for instance, the

EuropeanMedicines Agency (EMEA) recommends for

the approval of an antidepressant medication both

multiple arm short-term studies, including at least

three dosages of the agent to be tested, an active com-

parator and placebo, and a randomized withdrawal

study, proving maintenance of effect, with an ob-

servational period of at least six months (Dokument

cpmp/ewp/ 518/97, Committee for Proprietary

Medicinal Products, 2002.). However, even these

sophisticated designs have their inherited short

comings, and some experts would give preference to

non-placebo controlled comparator trials proving

superiority of the new compound (Barbui et al, 2001).

Also between regulatory agencies there is no clear

consensus what kind of evidence has to be considered

sufficient to support an antidepressant claim, or, to

express it in the words of a title of this review, what

makes an antidepressant ‘useful’. EMEA, for example,

dedicates several chapters on specific recommend-

ations for safety and the use of an antidepressant in

geriatric patients, adolescents and special groups, e.g.

treatment-refractory patients.

Table 4 supplies a comparative overview about the

regulatory requirements in three selected regions.

The limitations noted in this chapter have to some

extent been corrected by the process of collaboration

described in chapter 4.1. No review can in itself be an

unbiased and conclusive piece of evidence, but can

only direct readers to the original publications.

Clearly, responsible treatment decisions should never

be based on reviews, no matter how comprehensive,

but on one’s own critical reading of the sources. The

Review should help readers in this respect and serve

as support to the development of treatment guidelines

at national level in which the knowledge of local con-

ditions and experience can help to produce useful in-

structions for the practicing health professionals.

5. Diagnosis and epidemiology

5.1 Diagnosis of depressive disorders

Despite decades of intensive biologically oriented

psychiatric research, the etiology of depressive dis-

orders is not yet fully understood. A multifactorial

genesis is supposed. Besides psychological and social

factors, biological variables, too, apparently play a

major role, and lead in aggregate to disturbed central

nervous system homeostasis. The so-called catechol-

amine- and serotonin-deficiency hypothesis (Burke

and Preskorn, 1995), which postulates a dearth of

monoamines (noradrenaline and serotonin) within

the synaptic cleft, is essential in understanding the

pathophysiology of depression.

Depressive syndromes responsible to specific anti-

depressant therapies are classified within diagnostic

entities using operationalized diagnostic systems such

as the Diagnostic and Statistical Manual of Mental

Disorders, 4th revision (DSM-IV) (American Psychi-

atric Association, 1994) and the International Classifi-

cation of Diseases, 10th revision (ICD-10) (World

Health Organization, 1992). Table 5 lists the variety of

symptoms that characterize depressive disorders.

To diagnose a major depressive disorder (MDD),

according to the DSM-IV five main criteria of de-

pression must be met, and according to ICD-10 a

minimum of two main symptoms and two accessory

symptoms must be present (see Table 2 adopted from

Bauer et al., 2002c).

Sometimes, owing to standardized diagnostic pro-

cedures, subsyndromal depression in elderly patients


does not fulfill the complete diagnostic criteria

according to DSM-IV or ICD-10 even when anti-

depressant therapies are clearly needed (see chapter

10.2.2). In addition, differences in the clinical picture of

depressive disorders influence both the choice and

outcome of specific antidepressant treatment. The

tendency of patients to stop eating and lose weight

may also alter the clinical presentation of depressive

disorders. These patients are more often referred to

general practitioners or specialists in internal medicine

than to psychiatrists.

The PRIME-MD Patient Health Questionnaire

(PHQ-9) (Nease and Maloin, 2003) and even simpler

screening questions (Arroll et al., 2005) have been

suggested as appropriate instruments for accurately

identifying depressed patients in primary care settings

because there is good evidence that screening helps

to identify persons in need of treatment (Berg, 2002).

Table 4. Requirements for licensure of a medication as an antidepressant in three exemplary regions

EU (EMEA) (The European

Agency for the Evaluation of

Medicinal Products, 2002)

US (FDA) (U.S. Food and Drug

Administration, 2006)

South Africa (MCC) (Medicines

Control Council, 2007)

A: Acute

treatment

EMEA gives specific

recommendations for an

antidepressant claim:

Superiority vs. placebo in a

three arm trial including both

placebo and an active control

to check internal validity,

recommended duration 6

weeks. At least three different

fixed doses of the test

substance should be used to

determine the lower end of

the effective dose range as

well as the optimal dose.

‘Reports of adequate and

well-controlled investigations

provide the primary basis for

determining whether there is

‘substantial evidence’ to support

the claims of effectiveness for new

drugs’

FDA demands no specific design for

antidepressants, but recent

licensures had the following

characteristics :

Superiority vs. placebo in two

pivotal studies (randomized,

double-blind, adequate number

of patients and statistical power).

Studies may include an active

treatment control or a

dose-comparison control

No specific recommendations

are supplied for a separate

prophylactic claim

MCC gives no specific

recommendations for an

antidepressant claim, but

the following general

recommendations :

‘Data presented in support of the

safety and efficacy of the

medicine should be derived from

clinical trials conducted in

compliance with internationally

accepted GCP guidelines. The

studies should be properly

designed and conducted, and

should be of acceptable statistical

power. ’B : Maintenance

of effect

(Relapse

prevention)

Randomized withdrawal study

after acute response on

test substance with

re-randomization either to

test substance or placebo,

recommended duration up to

6 months.

Note : For a claim for acute

treatment, it is mandatory to

fulfill both A and B

‘The trial design of the relevant

clinical studies should be such

that the safety and efficacy of the

medicine can be established in

comparison to either placebo

and/or a registered medicine in

the UK, USA, Sweden, Canada,

Australia and EU.’

Registration of an antidepressant

in selected other countries

appears to be highly supportive

for licensure :

‘The Council aligns itself with the

following regulatory authorities :

USA (FDA), UK (MHRA),

Sweden (MPA,) Australia (TGA),

Canada (Health Canada),

European Union (EMEA) and

Japan (MWH).’

No specific recommendations are

supplied for a separate prophylactic

claim

C: Prevention

of recurrence

(Prophylaxis)

Double-blind comparison

against placebo, minimum

duration 1 year.

EMEA=European Medicines Agency ; FDA=US Food and Drug Administration ; MCC=Medical Control Council of South

Africa.


The use of operationalized diagnostic systems such

as ICD-10 and DSM-IV may cause an inclusion of

larger populations in diagnostic categories in com-

parison to the former used categories based on psycho-

pathology and psychiatric nosology e.g. introduced by

Kurt Schneider or Emil Kraepelin. Distinguishing

vital depression, depressive psychopathy18 and reactive

depression according Schneider may influence also

therapeutic outcome during antidepressant therapies.

Nevertheless the diagnostic systems help to compare

similar populations suffering from depressive dis-

orders and to evaluate treatment effects worldwide.

In this chapter the effects of diagnostic categories

and subgroups on treatment outcome are described

not only on basis of scientific evidence, but also based

on a broad clinical consensus within the CINP anti-

depressant task force. The review of the subgroups of

depression is selective, based on the relevance of

clinical features to treatment choices.

5.2 Features of particular relevance to the

treatment of depressive disorders

The basis of the following chapter 5.2 are rarely RCTs

but predominantly a clinical consensus of the CINP

antidepressant task force predominantly based on

clinical experience, open studies, case series and case

reports. The information provided in this chapter

should serve as a contribution to the actual knowledge

base, not as a guideline for treatment. Table 6 sum-

marizes diagnostic indications including diagnostic

subgroups and psychiatric comorbidities for specific

classes of antidepressants.

5.2.1 Unipolar depression

A significant proportion of depressive disorders show

an episodic course. With the exception of the recurrent

brief depressive episodes singled out in the ICD, the

threshold for reaching a diagnosis is that symptoms be

present for at least 2 weeks. Shorter duration places

the episodes into a ‘subthreshold’ group. The differ-

ences between threshold and subthreshold depression

are discernible but not very helpful in clinical work

since it has been shown that subthreshold depression

(for which treatment may not be reimbursable in some

countries) causes disability and often requires treat-

ment. Especially in children and adolescents, as well

as in the elderly, depressive disorders comprise a

variety of inherently difficult diagnostic problems.

These difficulties may be further aggravated by the

presence of other conditions such as anxiety or per-

sonality disorders. The following sections describe

specific subtypes of depressive symptoms that may

influence antidepressant therapy. For other subtypes

of depression that respond similarly to treatment, no

differentiation appears to be warranted.

5.2.1.1 Severity of the disease

Depressive episodes can be classified as mild, moder-

ate or severe (ICD-10). Subsyndromal depression

may enhance the risk of developing a syndromal de-

pressive disorder according to ICD-10 and DSM-IV,

and treatment may be necessary. In addition to clinical

judgment, e.g. using ICD-10 diagnostic criteria or the

Clinical Global Impressions scale (CGI-S, Item I,

severity of disease) (National Institute of Mental

Health, 1976), severity groups can be distinguished

using instruments such as the Hamilton (Hamilton,

1960) or Montgomery–Asberg rating scales for de-

pression (Montgomery and Asberg, 1979).

This subdivision is of clinical importance because

there is some consensus in the literature that mild

depressive syndromes should be treated by

Table 5. Symptomatology of depressive disorders (American

Psychiatric Association, 1994 ; World Health Organization,

1992 ; World Health Organization, 2005b)

Category of

depressive symptoms Symptom list

Affective symptoms $ Depressed mood*$ Anhedonia*$ Anxiety17

Psychomotor

disturbances

$ Retardation$ Agitation$ Loss of energy and activity*

Disturbances of

cognition and

memory

$ Feelings of guilt$ Feelings of worthlessness$ Mood-congruent and

-incongruent delusions$ Concentration deficits$ Memory deficits

Psychovegetative

disturbances and

somatic complaints

$ Sleep disturbances (insomnia,

early morning awakening)$ Diurnal changes$ Loss of appetite and weight$ Sexual dysfunction$ Constipation$ Pain syndromes$ Hypertonia$ Tachycardia

* Core symptoms of depression.

17 Anxiety is not included in the diagnostic systems of ICD-10 and

DSM-IV, but there is a broad clinical consensus that anxiety

symptoms are accompanying depression frequently.18 ‘Psychopathy ’ here is used as a historical term, not as a diagnostic

category.


psychotherapy without additional biological therapies

such as pharmacotherapy or electroconvulsive ther-

apy (ECT). In moderate depression non-biological

treatments are also the first choice in some guidelines,

although, moderately depressed patients respond

equally well to antidepressant medication. Moreover,

Table 6.Diagnostic indications for specific classes of antidepressants according clinical experience, open studies, case series, case

reports and the consensus of the CINP Antidepressant Task Force

Diagnostic subgroups

or comorbidities Specific indications Specific features

Mild to moderate unipolar

depression

$ Usually treatment with established

antidepressants, but treatment with

St. John’s wort possible

$ Good tolerability of phytotherapeutics$ Only St. John’s wort showed sufficient

efficacy

Severe unipolar depression,

depression with melancholic

features

$ Dually acting antidepressants

(TCAs, SNRIs, NaSSA)$ ECT

$ Better efficacy in comparison to SSRIs

$ Better efficacy in comparison to

antidepressants

Depression with psychotic symptoms $ Usually combination therapy using

antidepressants and antipsychotics$ Lithium augmentation$ Highest effectiveness of ECT$ Some reports support the effectiveness

of a SSRI monotherapy

$ High rate of treatment refractoriness$ Augmentation strategies should be

considered at early stages to enhance

efficacy

Psychomotor agitation and

retardation/katatonic features

$ Combination of antidepressants with

benzodiazepines or sedating

antidepressants in case of agitation$ Nonsedating and activating

antidepressants such as SSRIs or NARIs

in case of psychomotor inhibition$ Good effectiveness of ECT

$ Acute sedating effects relieving rapidly

the patient’s restlessness are useful in

clinical routine$ Avoiding sedation in case of

psychomotor retardation is useful$ Katatonic features may predict rapid

ECT effects

Atypical features $ MAOIs and SSRIs as first line treatments $ Better clinical effectiveness in

comparison to other antidepressants

Seasonal features $ Bright light therapy as an early

augmentation strategy in case of at least

moderate depression$ Bright light therapy as a monotherapy

in case of mild depression possible

$ Suicidality may be enhanced during

bright light therapy

Depression with chronic pain $ Antidepressants with mixed

serotonergic and noradrenergic or

selective noradrenergic mode of action

efficacious (TCAs, SNRIs,NARI,NaSSA)

$ Possibly higher remission rates$ Better relieve of pain syndromes

Adjustment disorders $ Earlier use of psychosocial therapies in

combination with antidepressants

$ RCTs are rare, but clinical experience

suggests effectiveness of

antidepressants

Bipolar depression $ SSRIs or MAOIs as a first line

treatment recommended

$ Combination with mood stabilizers

recommended

$ Monotherapy with mood stabilizers

possible

$ TCAs and other dually acting

antidepressants such as SNRIs may

increase the switch risk

Dysthymia and double depression $ Early combination of antidepressants

with psychotherapy recommended

$ Combination may enhance effectiveness

especially in chronic depression

Recurrent brief depression $ No established treatment regimes

supported by RCTs

$ Higher risk for suicidal ideation


there is a distinct probability that patients with mild to

moderate depression may respond to phytother-

apeutics such as St. John’s wort (Kasper, 2001;

Laakmann et al., 1998) or benzodiazepines without

antidepressants (though this option is not rec-

ommended) (Laakmann et al., 1996). There is also

some evidence that very severe depressive syndromes

show a better response to ECT, tricyclic anti-

depressants (TCAs) and dual-action substances such

as venlafaxine, duloxetine and mirtazapine.

5.2.1.2 Depression with psychotic symptoms

Psychotic features of depression such as hallucinations

and delusions, e.g. delusional hypochondria, feelings

of guilt or nihilistic thoughts, are predominantly mood

congruent, but may also be non-congruent with de-

pressed mood. Depressive episodes with psychotic

symptoms are in most cases an indicator of the par-

ticular severity of the disease, including high risk

of suicide. This additional risk factor must be taken

into account in planning treatment. In patients suffer-

ing from psychotic symptoms, a combination of anti-

depressant therapy with antipsychotic medication is

usually recommended (Coryell, 1996). It has, however,

been reported that this combination confers no benefit

for some patient subgroups, e.g. elderly patients

(Mulsant et al., 2001). TCAs and selective serotonin

reuptake inhibitors (SSRIs) in combination with anti-

psychotics are recommended, and amoxapine has been

shown to exert somewhat lower but likewise signifi-

cant efficacy (Anton and Burch, 1990 ; Rothschild et al.,

1993). SSRI monotherapy reportedly is efficacious dur-

ing acute and maintenance treatment (Zanardi et al.,

1996 ; Zanardi et al., 1997). ECT has been recommended

as a possible first-line treatment because of its high

effectiveness during acute episodes (Coryell, 1998) and

more favorable long-term outcome (Birkenhager et al.,

2004) in this subgroup of patients, especially in com-

parison with pharmacotherapy (American Psychiatric

Association Committee on Electroconvulsive Therapy

et al., 2001). Finally, early consideration of lithium

augmentation is recommended in this patient group

especially in the case of antidepressant treatment fail-

ure (Bauer et al., 2003 ; Price et al., 1983).

5.2.1.3 Other clinical features with a possible impact on

antidepressant therapies

5.2.1.3.1 Severe psychomotor agitation and

retardation

Severe psychomotor retardation, stupor, immobility

or, in contrast, severe agitation (called catatonic

features by some authors) are also seen in depressed

patients (Fink, 1992 ; Starkstein et al., 1996 ; Taylor and

Fink, 2003). ECT has been reported to have an excel-

lent effect in these cases (Fink, 1990 ; Rohland et al.,

1993). Administration of benzodiazepines (lorazepam)

during acute-phase treatment can lead to immediate

relief of catatonic symptoms. For routine clinical cases,

sedating antidepressants or combinations of non-

sedating antidepressants with sedating benzodiaze-

pines are used in agitated patients, whereas activating

substances such as SSRIs or noradrenalin reuptake

inhibitors (NARIs) are used in patients with pre-

dominantly psychomotor inhibition.

5.2.1.3.2 Melancholic features

Melancholic forms of depression are characterized by

a higher age of occurrence, a loss of the ability to feel

pleasure, depressive delusions and a variety of often

severe somatic symptoms (Table 2 and Table 5), as

well as major psychomotor symptoms. The treatment

of depression with melancholic features is similar to

that recommended for severe depression. Patients

frequently respond to augmentative strategies, such as

addition of lithium and sleep deprivation.

5.2.1.3.3 Atypical features

There is no clear agreement about the features that

characterize atypical depression (Fountoulakis et al.,

1999). In French-speaking countries the term ‘atypical ’

is used for depressed patients with psychotic features.

According to DSM-IV, a diagnosis of atypical de-

pression requires meeting two of the following

criteria : increase in appetite and weight gain, hyper-

somnia, leaden paralysis and a long-standing pattern

of interpersonal rejection sensitivity. The Inventory

of Depressive Symptomatology – Clinician Rating

(IDS-C30) is also suitable for diagnosing atypical

depression, and includes earlier age at onset, greater

comorbidity with anxiety symptoms and greater

symptom severity compared with non-atypical de-

pression (Novick et al., 2005). Empirical data support

the hypothesis that monoamine oxidase inhibitors

(MAOIs) and SSRIs represent a first-line treatment

option that is superior to other pharmacological treat-

ment (Andrews and Nemeroff, 1994 ; Henkel et al.,

2006 ; Sogaard et al., 1999). Owing to the special pre-

cautions they require, in some countries irreversible

MAOIs are not recommended as a first-line treatment.

5.2.1.3.4 Seasonal features

Patients suffering from depression that recurs on

a regular, annual basis during fall or early winter


and spring often show subsequent symptoms of bi-

polar disorder (chapter 5.2.2.1). In addition, depressive

syndromes are frequently characterized by features

listed as atypical in DSM-IV (see chapter 5.2.1.3.3).

If depressive symptoms are of moderate severity,

seasonal forms of depression are treated like other re-

current episodes. Bright light therapy (phototherapy;

see also chapter 19.7) can be used as an early aug-

mentation strategy (chapter 12.3.8). Because of its

proven efficacy (Kasper et al., 1990 ; Rosenthal et al.,

1985), bright light therapy can even be used as mono-

therapy in the case of mild depression19 during a lim-

ited treatment trial. But the possibility of occurrence or

enhancement of suicidal ideation during photo-

therapy must be taken into account (Praschak-Rieder

et al., 1997).

5.2.1.3.5 Depressive syndromes in pain conditions

Depressive disorders and predominantly chronic pain

are frequent comorbid conditions. Approximately

70% of patients with major depression present with

physical complaints (Fava, 2002 ; Simon et al., 1999b).

Severe pain caused by somatic diseases comorbid with

depression makes the treatment of depression diffi-

cult. Somatoform disorders, fibromyalgia and similar

conditions characterized by pain are often ac-

companied by depressed mood. Effective treatment of

neuropathic pain requires the application of anti-

depressants with a mixed serotonergic and nor-

adrenergic mode of action, such as the TCA

amitriptyline (Saarto and Wiffen, 2005, 2007). Newer

antidepressants have been shown to be useful in

the treatment of pain conditions with and without

comorbid depression. Various pharmacodynamic

classes, such as SSRIs, NARIs, noradrenergic and selec-

tive serotonergic antidepressants (NaSSAs) (Mattia

et al., 2002) and selective serotonin and noradrenalin

reuptake inhibitors (SNRIs) (Barkin and Barkin, 2005 ;

Gendreau et al., 2005) have shown efficacy in anec-

dotal reports, only SNRI and TCA have proven effi-

cacy according a recent Cochrane review (Saarto and

Wiffen, 2007). It seems plausible that antidepressants

with both serotonergic and noradrenergic properties

could be particularly effective in treating pain and

painful physical symptoms. Higher remission rates in

these subgroups of depressed patients have recently

been discussed (Fava, 2003c). Antidepressants are now

seen by many as an essential supplement in a variety

of therapeutic regimes for pain control.

5.2.1.3.6 Depressive syndromes in adjustment

disorders

Because symptoms of adjustment disorders and de-

pressive disorders may be identical, and also because

depressive episodes often occur after exposure to

severe stress, there is no reason to offer patients

suffering from adjustment disorder therapeutic regi-

mes other than those that offered to patients with

depressive disorders. This is especially true during

the period of acute treatment. Although controlled

efficacy trials in adjustment disorders are rare, both

clinical experience and retrospective studies (Hameed

et al., 2005) suggest no difference between depression

and adjustment disorder in response rates to treat-

ment. The use of psychosocial therapies in adjustment

disorders may begin earlier and be more intense.

5.2.2 Other forms of depressive disorders

5.2.2.1 Bipolar depression

Diagnostic criteria for a depressive episode due to bi-

polar I disorder are the same as already described

for cases of unipolar depression (see chapter 5.1). In

addition, a diagnosis of bipolar disorder must be

based on at least one previous manic or mixed epi-

sode, including a period of abnormally and persist-

ently elevated, expansive or irritable mood lasting

at least 1 week (even shorter, if hospitalization is

necessary). During this time, grandiosity or inflated

self-esteem are normally present together with de-

creased need for sleep, hyperactivity, psychomotor

agitation, racing thoughts with flight of ideas, dis-

tractibility and a drive to keep talking that causes

marked impairment in social functioning. In the

case of a mixed episode, these symptoms occur

simultaneously with depressive symptoms for at

least 1 week. In the case of bipolar II disorder, the

patient’s history must include at least one episode of

hypomania (a period of manic symptoms of lesser

severity that lasts at least 2–4 days). However, shorter

hypomanic bleeps may also justify treating a patient

according to criteria for bipolar depression, not uni-

polar depression (Akiskal et al., 2000; Cassano et al.,

1988). Finally, continuity between bipolar II disorder

and unipolar severe (major) depression has been sug-

gested (Akiskal and Benazzi, 2006).

Because the symptoms of bipolar depression are

identical to those of unipolar depression, and because

at the time of the initial depressive episode it is not

19 There exists no clear cut definition for ‘mild depression’ in the

literature. In addition to the severity of disease mentioned in the

ICD-10 (World Health Organization, 1992) the subdivision of

depressive syndromes can be done with rating scale cut off values

using the CGI or HAMD scale (e.g. as done in Laakmann et al., 1996

and 1998).


possible to make a diagnosis of bipolar disorder, up to

50% of younger patients suffering from depression at

the first index episode later receive a diagnosis of a

bipolar disorder (Angst, 2006 ; Goldberg, 2003). These

rates are, however, controversial (Patten, 2006).

Although the evidence for the efficacy and effective-

ness of antidepressant treatment of bipolar depression

is less compelling than that for treatment of unipolar

depression, the same substances that lead to clinical

improvement in unipolar depression can be used in

bipolar depression. Because of a lower switch risk

from depression to hypomania or mania and given

their good efficacy, predominantly SSRIs or MAOIs

(Gijsman et al., 2004) and bupropion (Sachs et al., 1994)

in combination with mood stabilizers are considered

to be the treatment of choice (Grunze et al., 2002). In

addition monotherapies using mood stabilizers such

as lithium or lamotrigine or atypical antipsychotics

(e.g. quetiapine) are possible. Because there is no

uniform definition of ‘switch’, the switch rates in

scientific publications vary widely. Nevertheless, a

threefold higher switch rate during TCA therapy in

comparison with SSRI treatment has been reported

(Peet, 1994). It has thus been suggested that all anti-

depressants, but especially TCAs and dual-action

antidepressants such as SNRIs, be recommended20 in

combination with mood stabilizers to prevent an en-

hanced switch risk.

It should be mentioned that for bipolar depression

there is also reasonably good evidence for mono-

therapy with the mood stabilizers lithium and lamo-

trigine as well as with the atypical antipsychotics

olanzapine and quetiapine (Yatham, 2005). Moreover

the use of adjunctive antidepressant medication in was

not associated in with increased efficacy in compari-

son to treatment with mood stabilizers alone (Sachs

et al., 2007). However, to date there is no proof that

these treatment regimens work any better than anti-

depressants (Moller et al., 2006).

5.2.2.2 Dysthymia and depressive disorder in

combination with dysthymia21

Diagnostic criteria for dysthymia and depressive dis-

orders differ in the severity and duration of symp-

toms. Dysthymia constitutes a chronic depressive

syndrome of lower intensity of symptoms than severe

depression, although it produces very similar levels of

disabilities. Also, an additional and superimposing

major depressive episode can occur in patients already

suffering from dysthymia, diagnosed then as a ‘double

depression’ or ‘double major depressive disorder’.

When a dysthymic episode follows a depressive epi-

sode, the differential diagnosis of both disorders is

difficult because the symptoms of dysthymia are then

indistinguishable from the (reduced) symptoms of

depressive disorder with only partial remission, which

should be diagnosed in this case. Only after full re-

mission lasting at least 6 months can the subsequent

dysthymic symptoms are diagnosed as dysthymia.

Because both diagnostic entities respond to the

same antidepressant, identical acute treatment plans

can be prescribed for depressive disorders, dysthymia

and double depression. In addition, antipsychotic

treatment such as amisulpride22 (Rocca et al., 2002;

Zanardi and Smeraldi, 2005) may be of use. Due to the

chronic nature of dysthymic disorders, earlier im-

plementation of psychotherapy can help. Treatment

goals should be formulated somewhat more cau-

tiously because dysthymia appears to have less likeli-

hood of complete recovery (Judd et al., 1998a). The

combination of pharmacotherapy and an empirically

supported psychotherapy may be optimal for chroni-

cally depressed patients (Keller et al., 2000 ; Rush and

Thase, 1999 ; Markowitz, 1993).

5.2.2.3 Recurrent brief depression23

Recurrent brief depression (RBD) is characterized by

depressive episodes that occur at least once a month

and last only a few days (Pezawas et al., 2001). The

combination of depressive disorders and RBD exhibits

a relatively high prevalence. The substantially higher

risk for suicidal ideation in such cases presents a spe-

cial concern. Most trials investigating antidepressant

therapies were designed to judge therapeutic efficacy

in major depressive disorders. Different study designs

are needed to properly investigate the combination of

depressive disorders and RBD. The literature contains

a variety of negative results concerning RCTs of SSRIs

in the treatment and prophylaxis of RBD (e.g. Angst

and Dobler-Mikola, 1985 ; Montgomery et al., 1994),

20 In clinical practice this recommendation is followed more

frequently in the US than in European countries. The scientific basis

for this suggestion is still a matter of debate.21 From a scientific perspective, there is presently insufficient reason

to define ‘double depression’ as a specific subgroup of depressive

disorders.

22 Amisulpride is not available in the US, and for the time being, the

use of other antipsychotics for dysthymia is not recommended.23 According to DSM-IV, recurrent brief depression can only be

diagnosed as subthreshold major depressive disorder (MDD).

According to ICD-10, it is a diagnostic category of recurrent

depressive disorder (RBD). The combination of severe depressive

disorders and RBD is sometimes called combined depression (CD)

(Pezawas et al., 2001).


but methodological problems and highly selective

patient samples may account for the results (Pezawas

et al., 2001). There are as yet no efficacious treatment

algorithms for RBD (Pezawas et al., 2005).

5.2.3 Depressive disorders with comorbid psychiatric

disorders

Comorbidity of depressive disorders with other psy-

chiatric disorders is common (Pincus et al., 1999) and

significantly affects treatment outcomes. The greater

the number of concurrent comorbid conditions, the

greater the severity, morbidity and chronicity of de-

pressive disorders (Rush et al., 2005c). Treatment of

depression that occurs with other conditions thus calls

for special attention and reflection in treatment plans.

5.2.3.1 Other psychiatric disorders24

5.2.3.1.1 Anxiety disorders

A lifetime prevalence of more than 40% for the co-

morbid depression and anxiety disorders, such as

panic disorder, phobias and generalized anxiety dis-

order, has been reported in patients suffering from

depressive disorders (Hasin et al., 2005). Up to now,

however, it has not been sufficiently clear whether the

two diagnostic conditions are distinct or represent a

single mixed anxiety-depression syndrome (or a

‘spectrum disorder’). Patients with depressive dis-

orders and comorbid panic disorder show differences

in the clinical course and severity of disease compared

with patients suffering from depressive disorders

alone (Grunhaus et al., 1994).

Because comorbid conditions can diminish the

clinical effectiveness of antidepressant pharmaco-

therapy (Grunhaus et al., 1986), they should be

considered in treatment plans. Administering anti-

depressants with demonstrated efficacy for both

diagnostic entities (e.g. in the case of depressive and

anxiety disorders, SSRIs such as paroxetine

(Montgomery, 1992)), together with implementing

specific psychotherapeutic options for depression

and anxiety, seems to be a useful strategy (see also

chapters 13 and 19.9).

5.2.3.1.2 Substance abuse

Disorders related to the use of alcohol, nicotine and

other drugs often occur together with depression, and

in the US have a lifetime comorbidity of 40, 30 and

17%, respectively (Hasin et al., 2005). Depressed pa-

tients with comorbid substance abuse are more likely

to have an earlier age of onset of depression, greater

depressive symptomatology, greater functional im-

pairment and more previous suicide attempts than

patients with depression alone (Davis et al., 2006).

Because pharmacokinetic and -dynamic drug interac-

tions, as well as psychosocial consequences of drug

abuse, all influence response and recovery rates from

depressive disorders, a combined therapeutic ap-

proach should address both the depressive disorder

and the comorbid condition. This is especially true for

psychotherapeutic and psychosocial approaches, but

it holds as well for pharmacological treatment plans,

e.g. in choosing antidepressants of lower pharmaco-

logical interaction potential, as is the case for some

SSRIs, NARIs and dual-action antidepressants.

5.2.3.2 Personality disorders25

About one-third of depressed patients also have a

personality disorder. The most common forms are

obsessive-compulsive (16%), paranoid (10%) and

schizoid (7%) personality disorder (Hasin et al., 2005).

In such instances, the effects of biological anti-

depressant therapies are less impressive, and treat-

ment takes longer. Depression may be a positive

predictive factor in the treatment of persons who have

personality disorders (Shea et al., 1992). Early im-

plementation of psychotherapeutic approaches in

treatment may be helpful.

5.2.4 Depressive disorders with comorbid somatic

disorders26

5.2.4.1 Physical disorders27

Depressive syndromes are frequently present in

people with severe and chronic physical disorders.

Somatic disorders or their treatment may be directly

responsible for depressive symptoms (Patten and

Barbui, 2004). The choice of treatment will depend on

the severity of depression, comorbid somatic risks and

somatic treatment.

If an organic factor is the source of the depressive

syndromes (‘organic depression’), treating the organic

disease first must be considered when it can be done

directly (e.g. substitution of thyroid hormones in case

24 Axis I disorders according to DSM-IV.

25 Axis II disorders according to DSM-IV.26 The concept of comorbidity does not necessarily include known

causal interdependencies between somatic diseases and depression.

Nevertheless, in some cases of comorbidity these may be known,

and in others they may exist without precise knowledge. In addition,

different somatic and psychiatric phenotypes of the same disease

may exist.27 The treatment of depression during chronic pain conditions is

described in chapter 5.2.1.3.5.


of hypothyroidism) and when depression is of mild to

medium severity. When depression is severe or there

is risk of suicide, an additional symptomatic anti-

depressant treatment is obligatory. The same is true

if the organic factor cannot be treated owing to other

conditions (e.g. immune system suppressors in the

case of transplantation) or if recovery is unlikely

(e.g. stroke). Table 7 lists possible organic causes for

depressive syndromes.

5.2.4.1.1 Cardiovascular disorders

A variety of studies confirm the interdependency of

medical disorders and the risk for developing de-

pressive symptoms caused by comorbid depressive

disorders or adjustment disorder (Glassman et al.,

2003 ; Glassman, 2005 ; Glassman et al., 2006). An ex-

ceptionally high comorbidity of depressive symptoms

and cardiovascular disorders (CVDs) has been de-

scribed (Purebl et al., 2006), but the detection of de-

pression in patients suffering from CVD is relatively

low. Moreover, the comorbidity of depressive dis-

orders and CVD significantly influences the medical

outcome of coronary artery disease and myocardial

infarction (Frasure-Smith et al., 1993 ; Musselman et al.,

1998), especially when depressive symptoms are re-

fractory (Carney et al., 2004). Knowledge about dif-

ferential risk factors or predictors of adverse events in

patients suffering from myocardial infarction and de-

pression is still limited (Jaffe et al., 2006). Depression

enhances cardiovascular mortality independent of

other cardiovascular risk factors (Penninx et al., 2001)

and appears also to be an independent additional risk

Table 7. Examples of organic factors that may cause depressive disorders (see also Evans et al., 2005 ; Katona, 1997 ;

World Psychiatric Association, 2006)

Category of organic disease Organic illness

Neurological disorders $ Stroke$ Dementia$ Epilepsy$ Huntington’s chorea$ Hydrocephalus$ Central nervous system (CNS) infectious diseases$ CNS neoplasias$ Parkinson’s disease$ Narcolepsy$ Sleep apnea$ Trauma$ Wilson’s disease

Endocrine disorders $ Adrenal disorders (Cushing’s disease, Addison’s disease)$ Hyperaldosteronism$ Hyper- or hypoparathyroidism$ Hyper- or hypothyroidism$ Postpartum hormonal changes

Other medical disorders $ Neoplasias and paraneoplastic syndromes$ Cardiopulmonary diseases$ Autoimmune disorders (e.g. lupus erythematodes)$ Porphyria$ Uremia$ Avitaminoses (vitamins B12, C, folate, niacin or thiamine)

Pharmacogenic depression28

$ Analgesics (ibuprofen, indometacin, opiates, phenacetin)$ Antibiotics (streptomycin, sulfonamides, tetracyclines)$ Antihypertensives (reserpin, clonidine, digitalis)$ Chemotherapeutics (asparaginase, azathioprine, bleomycine, trimethoprim, vincristine)$ Hormones (high-estrogen oral contraceptives)$ Immune system therapy/suppression (corticosteroids, interferons, mycophenolate

mofetile, tacrolismus)

28 It is presently not clear whether depressive syndromes following

treatment with classical antipsychotics represent symptoms of the

disease or a side effect of treatment.


factor for cardiovascular disease (Wulsin and Singal,

2003). The most important influencing factor may

be the severity of the depressive syndrome (Penninx

et al., 2001) or the presence of a major depressive

disorder (Schulz et al., 2000). Less severe forms of

depression seem to be less deleterious. Another ap-

parently important influencing factor is activation

of central stress regulation systems, predominantly

hypothalamic-pituitary adrenal (HPA)-axis activation

present in the majority of depressed patients (Leder-

bogen et al., 1999).

There is consensus that it is important to treat

depression in this patient subgroup sufficiently,

although, both a significantly lowered risk of death

or recurrent myocardial infarction in patients taking

selective SSRIs (Taylor et al., 2005) and a failure to

prove lowered cardiac risk due to antidepressant

treatment (Berkman et al., 2003; Shimbo et al., 2005)

have been reported. Antidepressant pharmacotherapy

stipulates using drugs that have as low a drug-drug

interaction risk as possible and exert no negative in-

fluence on cardiac conductance, rhythm or output.

Most modern antidepressants fit this profile, including

SSRIs, NARIs and dual-action substances. In addition,

because depression may worsen coronary blood flow

(Lederbogen et al., 2001), it seems plausible to make

use of the diminishing effects of SSRIs on platelet ag-

gregation (Maurer-Spurej et al., 2004) to achieve fur-

ther benefit for patients suffering from depression and

cardiovascular disease.

5.2.4.1.2 Endocrinological disorders and diabetes

mellitus

Depression has been shown to be a risk factor for type

II diabetes mellitus (Eaton et al., 1996) ; a bidirectional

positive association has been assumed (Eaton, 2002 ;

Evans et al., 2005). Endocrinological disturbances

known to be present during depressive states, such

as hypercortisolism, may facilitate the development

of diabetes. A negative influence of depression on

therapeutic adherence and the risk of vascular com-

plications and disability have been described. The

effectiveness of antidepressant treatments in diabetic

patients has been shown, but the potential benefit

for blood glucose and HbA1c levels remains unclear

(Evans et al., 2005). Antidepressants and antipsycho-

tics with sedating properties due to antihistaminergic

effects also facilitate weight gain and the develop-

ment of metabolic syndromes, worsen diabetes melli-

tus or abett a switch from prediabetic syndrome

to frank diabetes (American Diabetes Association,

2005).

5.2.4.1.3 Renal disorders

Severe acute and chronic renal diseases can cause

depressive syndromes (Kimmel and Peterson, 2005)

within adjustment disorders. They also represent a

psychosocial burden capable of initiating episodes

of depressive disorders. Both cases call for an anti-

depressant treatment plan. In addition to psychother-

apeutic counseling, antidepressant pharmacotherapy

may be necessary. Renal failure can complicate anti-

depressant pharmacotherapy because diminished re-

nal clearance can provoke increased side effects

and toxic effects of antidepressants. Increased respon-

siveness to antidepressant drugs (Finkelstein et al.,

2002) along with greater unpredictability and inter-

patient variability (Dawling et al., 1982) have been

reported.

Dose adjustment is often necessary, e.g. half the

standard does at the outset of treatment. Anti-

depressants with a lower likelihood of interacting

with other drugs via the cytochrome P-450 system

(see chapter 9.1.1.1), such as the SSRIs sertraline or

citalopram, are suggested. Frequent evaluation of

side effects and blood level monitoring are useful tools

to prevent overdoses. If renal failure progresses to

end-stage renal disease and hemodialysis, hemo-

perfusion or hemofiltration are necessary, lower anti-

depressant plasma levels are possible, and dose

adjustment may be required considering blood levels,

efficacy and side effects.

5.2.4.1.4 Hepatic disorders

Patients suffering from chronic hepatitis may develop

enhanced risk for depression, especially in the case of

treatment with interferon (Asnis and De La Garza, II,

2006), and some may even require prophylactic anti-

depressant treatment (Schaefer et al., 2002; Schaefer et

al., 2003). Comorbidity of depression and hepatic dis-

eases demands specific precautions. Antidepressant

drugs are metabolized in the liver, and only a small

proportion of some substances (e.g. 2% of paroxetine)

can be secreted unchanged in the urine (Tossani et al.,

2005). Antidepressants rank 5th on the list of drugs

that cause liver injury (Andrade et al., 2005). The

hepatotoxic properties of antidepressants can lead to

transient increases in liver enzymes, but also to

fulminant liver failure. For that reason, in depression

accompanied by liver disease it is necessary to start

treatment using substances that have a lower prob-

ability of causing additional liver damage. TCAs,

MAOIs and nefazodone appear to have higher hepa-

totoxicity compared with newer agents such as SSRIs

(Lucena et al., 2003). But SSRIs and other modern


substances also require dose adaptation in patients

suffering from liver disease to prevent side effects

and intolerable toxicity which may occur because of

a lower clearance of antidepressants and metabolites,

and consequently prolonged elimination times

(Demolis et al., 1996 ; Joffe et al., 1998; Suri et al., 2005).

Milnacipran may be an exception : because it is meta-

bolized outside the liver, it appears possible to use

milnacipran in the case of liver impairment without

having to adapt the dose (Montgomery et al., 1996;

Puozzo et al., 1998).

5.2.4.2 Neurological disorders

Depression is a relatively common psychiatric co-

morbidity of most neurological disorders, with pre-

valence rates ranging between 20 and 50% among

patients with epilepsy, stroke, dementia, Parkinson’s

disease and multiple sclerosis (Kanner, 2005b). In

addition, a side effect of treatment of neurological

disorders (e.g. with corticosteroids) enhances risks

for depression. Antidepressant pharmacotherapy is

therefore mandatory in most cases of medium to

severe depression. Antidepressant pharmacotherapy

may however worsen the neurological condition of

patients. For example, in patients taking high doses of

antidepressants, the incidence of seizures rises mark-

edly. This is particularly important if TCAs, especially

maprotiline, are used.

5.2.4.2.1 Epilepsy

A bidirectional relationship between the incidence of

epilepsy and depression has been described (Kanner,

2005a). In addition, patients with treatment-resistant

epilepsy who have undergone temporal lobectomy

often experience post-surgical depression follow-

ing temporal lobectomies (Kanner, 2003), and anti-

depressant pharmacotherapy may be necessary.

Lifting of depression after resective surgical treatment

for epilepsy has also been reported (Spencer et al.,

2003).

Because lower therapeutic doses of antidepressants

may also trigger seizures in patients suffering from

epilepsy, cautious treatment using the lowest effi-

cacious doses is mandatory, especially with TCA

treatment, because TCAs may diminish the threshold

for seizures. But SSRIs, too, have the potential to pro-

long epileptic seizures, e.g. during ECT treatment)

(Curran, 1995), or to cause lower sodium levels, which

lower the seizure threshold. Fluoxetine and fluvox-

amine seem to exhibit the lowest risk for seizures

(Pisani et al., 1999). In addition, pharmacokinetic in-

teractions between antidepressants and antiepileptic

drugs are to be expected, especially with carbamaze-

pine.

5.2.4.2.2 Stroke and dementia

Patients suffering from severe depression who need

hospitalization are at an increased risk of developing

cerebrovascular disorders (Nilsson and Kessing,

2004). Patients hospitalized after stroke very often not

only suffer from neurological disturbances but also

show depressed mood, requiring treatment. A concept

of a vascular or ‘arteriosclerotic depression’ has been

proposed (Krishnan and McDonald, 1995). Symptoms

of depression in Alzheimer’s disease (AD) (Derouesne

and Lacomblez, 2004) and other forms of dementia are

often seen but are rarely distinguishable from apathy,

loss of drive and affective disturbances that are among

the symptoms of Alzheimer’s disease. Moreover,

depressive symptoms seem to be an independent

risk factor for later development of AD (Green et al.,

2003 ; Ownby et al., 2006). A history of depression is

associated with a more rapid cognitive decline in

patients with AD and pronounced neuropathological

changes in the hippocampus (Rapp et al., 2006). It has

been suggested that AD and depression are associated

with shared risk factors such as sex, age, vascular

function and apolipoprotein E4 (APOE4) (Gallarda,

1999).

This connection notwithstanding, meta-analyses

show no improvement in cognitive function or dis-

ability following treatment for post-stroke depression

(Anderson et al., 2004), although relief of depression

in itself may justify pharmacologic treatment (Hackett

et al., 2004). Moreover, good efficacy of the NaSSA

mirtazapine in preventing post-stroke depression

has been reported (Niedermaier et al., 2004 ; Ween,

2005). Also SSRI or NARI in the treatment of post-

stroke depression have shown to be superior to

placebo (Rickards, 2005), moreover SSRI or TCA

treatment during the first 6 months poststroke sig-

nificantly increased the survival of both depressed

and nondepressed patients (Jorge et al., 2003). The re-

covery after stroke appeared to be enhanced by the

use of antidepressant medication if treatment was

started within the first month after stroke (Narushima

et al., 2003b). In addition, on the long term, an im-

proved cognitive function after remission of post-

stroke depression is likely to remain stable if no

additional cerebrovascular events occur (Narushima

et al., 2003a) and also an improvement of executive

functioning following stroke seems to be enhanced

due to antidepressant treatment (Narushima et al.,

2007).


Treatment of depressionmust not be allowed to con-

tribute to a worsening of dementia, e.g. due to anti-

cholinergic side effects. For this reason SSRIs, NARIs,

SNRIs and NaSSAs would appear to compare favor-

ably with TCAs.

5.2.4.2.3 Parkinson’s disease

The risk for depressive disorders in patients suffering

from Parkinson’s disease (PD) (Hantz et al., 1994)

is controversial. A high prevalence of depression

in PD (20–40%) has been reported (Lieberman, 2006),

and even up to 50% (McDonald et al., 2003). In

addition, depression may precede the diagnosis of

PD (Schuurman et al., 2002). Although published

controlled studies are lacking it seems that anti-

depressant treatment is beneficial for patients and

improves the overall quality of life (Anon., 2002 ;

Weintraub et al., 2005). Both SSRIs and SNRIs are

generally well tolerated and efficacious (Lemke, 2002 ;

Menza et al., 2004). Selegiline can be integrated into

MAO-B inhibitor treatment plans for PD (Bodkin and

Amsterdam, 2002), even though its therapeutic effect

on depression may in some cases be only modest

(Amsterdam, 2003). The potential benefit of the anti-

cholinergic properties of TCAs in PD should be

considered. Given that concomitant heart disease,

prostatic enlargement and acute angle-closure glau-

coma are frequent comorbid conditions in elderly pa-

tients suffering from PD, TCAs should be used with

caution in this patient group (Cummings and

Masterman, 1999). A moderate association of SSRI use

and extrapyramidal motor side effects has been re-

ported in susceptible patients (Schillevoort et al.,

2002). These effects include acute dystonia, akathisia

and aggravation of parkinsonism (Anon., 2001). They

may be caused by an interaction between serotonergic

and dopaminergic pathways (Lambert et al., 1998).

5.2.4.2.4 Encephalitis disseminata/multiple

sclerosis

Even though patients suffering from multiple sclerosis

often show affective disturbance without depression,

such as pathological laughing and crying (Feinstein

et al., 1999), anxiety and euphoria (Diaz-Olavarrieta

et al., 1999), an association between multiple sclerosis

and depression has also been reported (Patten and

Metz, 1997). In these cases, antidepressant pharma-

cotherapy should be considered.

5.2.4.2.5 Migraine

Depression is one of the most frequent comorbid dis-

orders in chronic migraine (Mercante et al., 2005).

Comorbid migraine significantly influences the qual-

ity of life of depressed patients (Hung et al., 2006).

When migraine accompanies depressive disorder,

antidepressant pharmacotherapy not only ameliorates

depressive symptoms but can also prevent migraine

attacks. Both TCAs (amitriptyline) and SSRIs (fluoxe-

tine) have shown effectiveness in this indication, in

the usual antidepressant doses (Campo-Arias, 2004),

but exacerbation of migraine attacks during SSRI

treatment has also been described (Bickel et al., 2005).

Patients prescribed triptans for migraine who are also

taking SSRIs, MAOIs or lithium may be at enhanced

risk of developing serotinin syndrome. Because the

number of serotonin syndromes reported is low, and

their severity mild to moderate, combined use of trip-

tans and SSRIs or lithium appears to be only a relative

contraindication. But owing to the limited results

published to date, MAOIs should be strictly avoided

(Gardner and Lynd, 1998).

5.2.4.3 Infectious disorders

Infectious diseases are often accompanied by psychi-

atric syndromes such as depression. This may be true

not only during the acute state of the disease but also

after adequate treatment of the medical condition. For

example, mixed anxiety-depression syndrome has

been reported to follow medical recovery from falci-

parum malaria (Dugbartey et al., 1998). Also, patients

infected with hepatitis C are more likely to suffer

psychiatric comorbidities such as depressive disorders

(Butt et al., 2006). In addition, specific somatic thera-

pies such as interferones or antibiotics may increase

the risk of developing severe depressive symptoms.

Infectious diseases affecting the nervous system, such

as Lyme disease (Fallon and Nields, 1994) or neuro-

syphilis (neuro-lues) (Pavlovic and Milovic, 1999),

have been associated with psychiatric disorders, in-

cluding major depression.

A particular interdependency has been described

between infection with the human immunodeficiency

virus (HIV), acquired immunodeficiency syndrome

(AIDS) and depressive disorders : depression is be-

lieved to be associated with HIV risk behaviors

(Hutton et al., 2004), and HIV infection is associated

with depression and suicidal behavior (Jin et al., 2006;

Porche and Willis, 2006). For further details see (Maj

et al., 1993).

Both the infection and the depressive syndrome

should be adequately treated, considing all options,

including antidepressant pharmacotherapy. Possible

interactions between antidepressants and medical

treatments such as antibiotics must also be taken into

account.


5.2.4.4 Neoplasias and paraneoplastic syndromes

Stressful life events including severe physical illness

including neoplasias have been linked to depressive

symptoms and to major depressive disorder (Monroe

and Simons, 1991). Depression occurs at an increased

rate in patients suffering from cancer (Rodin et al.,

2007). Recently in cancer patients rates of 19% for

depressive symptoms and 8% for major depressive

disorder have been reported (Wedding et al., 2007).

Moreover most chemotherapeutics used in the

pharmacological teatment of cancer (see Table 10) may

cause a pharmacogenic depression.

Oncologists play a key role in screening for psychi-

atric disorders including anxiety and depression in

patients with cancer (Miovic and Block, 2007). The

treatment should include the available pharmaco-

and psychotherapeutic approaches and improves

quality of life substancially (Miovic and Block, 2007).

Of course potential interactions of antidepressant

medications with somatic disturbances due to cancer,

e.g. renal (see chapter 5.2.4.1.3) or liver (see chapter

5.2.4.1.4) failure and pharmacological interactions

with chemotherapeutics (see chapter 9.1.1.1) have to

be taken into account and substances with low inter-

action potential e.g. citalopram, sertraline or venla-

faxine may be advantageous. In addition mianserin

has shown good efficacy in a RCT (van Heeringen and

Zivkov, 1996).

5.3 Epidemiology of depressive disorders

Depressive disorders are very common. They are

among the main causes of disability due to disease,

and the World Health Organization (WHO) estimates

that they will be the second most important cause of

disability by the year 2020 (World Health Organiz-

ation, 2002). Chronic depressive episodes are common

and are associated with greater illness burden and

socioeconomic disadvantage (Gilmer et al., 2005).

Throughout Europe, 23% of years of healthy life is lost

due to brain disorders ; they cause approximately one-

third of all burden of disease (Olesen and Leonardi,

2003). Among these disorders, depression plays a

predominant role. In Europe depression is the major

cause of disability, with a prevalence of around 5%

per year (Paykel et al., 2005), a still present widespread

underrecognition and undertreatment of depressive

disorders has been reported recently (Lecrubier, 2007).

Epidemiological studies of depression show con-

siderable variation across and within countries (see

Figure 1), to a large extent on account of imperfect as-

sessment instruments. One recent estimate put preva-

lence at 16% (Ebmeier et al., 2006). In a study carried

out by the International Consortium of Psychiatric

Epidemiology (ICPE), 37000 adults in 10 countries (in

the Americas, Europe and Asia) were interviewed

with the WMH-CIDI (World Health Organization

Composite International Diagnostic Interview; Kessler

et al., 2003 ; Robins et al., 1988 ; Wittchen, 1994). The

lifetime prevalence of depression varied widely from

3% in Japan to 16.9% in the US, with most countries in

the range between 8% and 12% (Andrade et al., 2003).

Across the Asia-Pacific region, lifetime rates ranged

from 1.1 to 19.9% (Chiu, 2004). In an extended WHO

household survey with the WMH-CIDI of more

than 60000 adults in 14 countries (Americas, Europe,

Middle East, Africa and Asia), the 12-month preva-

lence of mood disorders ranged from 0.8% (Nigeria)

to 9.6% (US) (Demyttenaere et al., 2004). A South

American study that focused not on the diagnosis of

depression but on depressive symptoms found

prevalence rates up to 72.6% (Rodriguez and Puerta,

1997). The prevalence of depression in Venezuela is

reported to vary between different parts of the coun-

try. Only 1 out of 10 depressed patients receives care

and treatment. Similar numbers hold true for Mexico.

With a lifetime prevalence of 9.1% for affective dis-

orders, there is a wide variance between urban and

rural areas. However, use of services for any psychi-

atric disorder is low: 11.7% for those with one psy-

chiatric diagnosis and 19.4% for those with two

diagnoses (Medina-Mora et al., 2003).

These results and the ICPE study demonstrate the

potential impact of psychosocial and cultural factors

on the manifestation and diagnosis of depression as

well as the methodological difficulties of studies of

depression. The European Study of the Epidemiology

of Mental Disorders (ESEMeD), which used methods

similar to those of the WHO study, found a 12-month

prevalence rate of 4.2% for mood disorders across six

European nations, comparable to the results of the

WHO study (Alonso et al., 2004) and to earlier WHO

estimates of the prevalence of depression (Sartorius et

al., 1993 ; Sartorius, 1993). Other publications describ-

ing the prevalence of depression in northern Africa are

currently in preparation.

The low rates in Nigeria, however, might be

explained by the fact that most diagnostic criteria for

depression and the scales used in developed countries

may be not appropriate for assessing functional im-

pairment in rural African communities, and that many

features of depression, e.g. fatigue, could be mis-

interpreted as signs of HIV infection. Another possible

explanation may be that depression occurs at a later

age in Africa (Gureje et al., 2007). The Nigerian survey

sample had a mean age of onset of about 30 years, but


the median age of onset of major depressive disorder

in the sample was about 45 years. In other words, most

of the respondents had lived through the mean age of

onset. Another survey among the elderly in Nigeria

confirms a much later age of onset (compared with

what is commonly reported in the literature) and

yields a much higher prevalence of depression.

Correcting for these confounders by using appropriate

scales and symptom criteria, Bolton et al. found the

point prevalence as high as 21% for depression in

Uganda (Bolton et al., 2004).

The fact that older prevalence studies reported

lower prevalence rates in comparison to newer studies

has been reported early : The lowest figures in studies

performed between 1961 and 1978 are at least 9 times

greater than the highest figures in surveys between

1931 and 1961 (Hoenig, 1980). Because the second

period correspondents with the introduction of anti-

depressants, it could be argued that the presence of

effective treatments may enhance the awareness

for now better treatable diseases. But in addition the

postulated increasing prevalence or changing diag-

nostic systems including a higher sensitivity for de-

pressive disorders may serve as an explanation.

The average age of onset is reported to be between

20 and 30 years (Ebmeier et al., 2006). Marked gender

differences have been reported ; women are affected

twice as often as men (Kessler, 2003). In addition,

women are twice as likely as men to report a positive

family history of mood disorder, which is associated

with a younger age of onset of depression (Nierenberg

et al., 2007). In addition not only the prevalence but

also the consequences of depressive disorders, such as

impairment and suicidality, are affected by age and

gender of patients (see also chapter 10). The mean

duration of depressive episodes was 16 weeks. About

90% of patients are suffering from at least moderate up

to very severe forms of depression, causing severe im-

pairment in their daily activities (Kessler et al., 2003).

The particular health importance of depression is

further heightened by the prediction that the preva-

lence of depressive disorder will increase in the years

to come (Sartorius, 2001). The rationale for this pre-

diction includes demographic factors (e.g. increased

life expectancy at all ages), better chances of survival

of people with chronic diseases often comorbid with

depression, iatrogenic effects (e.g. because the wide-

spread use of drugs is likely to increase rates of de-

pression), passive risks inherent in social changes

(such as diminishing family care and increased num-

bers of people living alone) and rising levels of stress

observable in many countries. While depressive dis-

orders in most, but not all studies appear to be within

the same range worldwide (2–7%), estimates of rates

of suicide attempts and completed suicides vary

greatly among countries. The recent increases in sui-

cide rates in eastern European countries are a par-

ticularly good example of the impact of changes in

society on rates of suicide (Sartorius, 1995).

6. Standards of care

According to WHO, fewer than 25% (in some coun-

tries less than 10%) of depressed patients receive ad-

equate care :

Barriers to effective care include the lack of resources, lack of

trained providers, and the social stigma associated with

mental disorders, including depression.

Primary care-based quality improvement programs for

depression have been shown to improve the

$ quality of care$ satisfaction with care$ health outcomes$ functioning$ economic productivity$ and household wealth at a reasonable cost.

(World Health Organization, 2005b).

To achieve these goals, as put forward by WHO,

education of the population and those who deliver

health care is crucial to increase the number of patients

being diagnosed correctly and early. When a diagnosis

0

5

10

15

20

25

30

Prevalence (%)

Ankara, Turkey

Athens, Greece

Bangalore, India

Berlin, Germany

Groningen, Netherlands

Ibadan, Nigeria

Mainz, Germany

Manchester, UK

Nagasaki, Japan

Paris, France

Rio de Janeiro, Brazil

Santiago, Chile

Seattle, USA

Shanghai, China

Verona, Italy

Figure 1. Differential prevalence of depression in primary

health care in different WHO centers (Goldberg and

Lecrubier, 1995 ; Ustun and Sartorius, 1995).


of depression has been established, patients and

caregivers should gain unrestricted access to mental

health and complementary services. Even in highly

industrialized countries, there is a large gap between

the relatively high prevalence of depressive disorders

and the less frequent use and late onset of the use of

antidepressant treatments (Henkel and Moller, 2005).

In the case of treatment-resistant depressive disorders,

further enhancement of therapeutic approaches should

be provided as well (see also chapter 9.1.12) to attain

the ultimate treatment goal of full remission.

Unfortunately, these standards are realized for only

a minority of patients. On a global scale, the primary

diagnosis is more often made and treatment supplied

by other resources, e.g. traditional healers.

6.1 Diagnosis

In comparing recommendations and clinical practice

in different countries, there seems to be no general

consensus on who should establish the diagnosis of

depression. Whereas most European guidelines, in-

cluding the World Federation of Societies of Biological

Psychiatry (WFSBP) guidelines (Bauer et al., 2002c),

explicitly or implicitly refer to a trained psychiatrist

for establishing a diagnosis of depression, several re-

view papers by US experts acknowledge a role for

primary care physicians in establishing diagnosis and

initiating initial treatment. In the US, a majority of

patients suffering from depressive disorders are

diagnosed and treated by general practitioners or

well-trained clinical psychologists. The screening in-

struments for GPs therefore should incluce a screening

for the main core symptoms of depression (see chapter

5.1). Other countries take a different approach, e.g.

China, where most depressed patients are treated

by psychiatrists and in some extend by neurologists

and internal specialists, or some South-East Asian,

e.g. Philippines, and South American countries, e.g.

Bolivia, where traditional healers play a prominent

role (Seguin, 1986). Their contribution to the manage-

ment of depression should not be underestimated,

as non-specific aspects, including beliefs and trust,

are important variables for any treatment success

(Alarcon et al., 1999 ; Shepherd and Sartorius, 1989).

Nevertheless, psychiatric consultation is rec-

ommended when a patient has not shown marked

improvement within 8 weeks of initial treatment or

when the primary care physician is concerned about

the complexity of the case (Wittchen andPittrow, 2002),

and also when collaboration between psychiatrists

and clinical psychologists is needed. In some countries

guidelines recommend also shorter intervals, e.g.

6 weeks in China. Aside from considerations of

cost-effectiveness, the main argument is that the

primary care physician is generally in a better position

to diagnose and treat depression if he or she is re-

sponsible for the overall medical care of the patient,

which may include other ongoing medical diseases

and the potential for drug-drug interactions. In ad-

dition, patients tend to see the primary care physician

first because somatic complaints are part of the de-

pressive syndrome. The important role of primary

care physicians is also shown in a German survey

(Wittchen and Pittrow, 2002), which found that 10.9%

of unselected patients visiting their primary care

doctor suffer from depression. However, only 55% of

them were recognized by their doctors as having de-

pression, despite the fact that 72% of the primary care

physicians participating considered their competence

in diagnosing depression to be good.

To study the degree to which primary care physi-

cians recognize depression as a mental health prob-

lem, Dutch researchers looked at accuracy of diagnosis

and treatment in accordance with clinical guidelines

for depression. The researchers found that non-

recognition, misdiagnosis and inadequate treatment

were not limited to patients with relatively mild and

brief depression but were also prominent in patients

with persistent depressionwho consulted their general

practitioner 8.2 times on average during the year their

depression persisted (Van Os et al., 2006). Standard-

ized training programs are obviously needed and can

be helpful in improving management of depression by

primary care physicians (Van Os et al., 1999).

Thus, arguments in favor of early consultation

with a psychiatrist include the complexity of a dif-

ferentiated diagnosis and treatment of depressive

disorders, including all the considerations mentioned

above and – of utmost importance – expertise in as-

sessing the risk of suicide and, in rare cases, homicide.

If health resources are limited, e.g. in developing

countries where both psychiatrists and clinical psy-

chologists are often in very short supply, patients

should have access to personnel with sufficient

knowledge and experience to diagnose depression,

e.g. general practitioners or at least trained nurses. If

resources allow, identification of the core symptoms of

depression should be considered against a checklist,

such as the Diagnostic and Statistical Manual of

Mental Disorders, 4th revision (DSM-IV) (American

Psychiatric Association, 1994), or the International

Statistical Classification of Diseases and Related

Health Problems, 10th revision (ICD-10) (World

Health Organization, 1992), to improve confidence in

and reliability of diagnosis of depression. Structured

interviews, such as the Structured Clinical Interview


for DSM-IV (SCID), may be helpful tools, especially

if in doubt. Due to the time-consuming nature of

the SCID in primary care settings, the shorter Mini

International Neuropsychiatric Interview (MINI) can

help to generate reliable DSM-IV and ICD-10 diag-

noses. Note, however, that though such instruments

may be very sensitive, their validity could be low. In

non-specialist settings, the value of routine adminis-

tration of simple questionnaires to detect and measure

depression remains unclear. A review by Gilbody et al.

found it unreliable in the majority of studies (Gilbody

et al., 2003b). In contrast, the US Preventive Services

Task Force (US Preventive Services Task Force, 2002)

and the Canadian Task Force on Preventive Health

Care (MacMillan et al., 2005) report on good evidence

that screening instruments improve accurate identifi-

cation of depression in adults in primary care settings,

although evidence for children and adolescents is in-

sufficient. Of the multitude of screening instruments

available, the PRIME-MD Patient Health Question-

naire (PHQ-9) is considered the best available screen-

ing tool for depression in primary care (Nease and

Maloin, 2003).

Comorbidity, especially with anxiety disorders

or substance abuse, may often mask the underlying

depressive illness. On the other hand, after establish-

ing the diagnosis of depression, patients should rou-

tinely be interviewed for other major psychiatric

disorders, as their presence will impact the choice of

treatment. Organic conditions such as neurological

illnesses, e.g. multiple sclerosis or any other lesions

involving subcortical or cortical areas and other limbic

circuits, should always be excluded.

However, when discussing the potential under-

diagnosis of depression, someone should also be

aware of the caveat of overdiagnosing. As demon-

strated by Beck (Beck, 1967) in a sample of 486 pro-

bands, ranging from non depressed controls to

severely depressed patients, there is still a fair amount

of clinical features of depression even in normal con-

trols (see Table 8). With increasing public and

specialist awareness of depression, strict diagnostic

criteria should be followed, the diagnosis should

not be based of one of few features, and the diagnosis

should be regularly rechecked to avoid overdiagnosis

and at least unnecessary, if not harmful, treatment.

Once a diagnosis of major (unipolar) depression has

been established, keeping all potential caveats in

mind, the level of symptom severity, functional im-

pairment and impact on quality of life should be de-

termined. If possible, this should be done not only on

the basis of patients’ reports but also on the basis of the

history supplied by relatives and objective data, e.g.

recent periods on sick leave. To characterize the de-

pressive syndrome as well as to choose the appropri-

ate treatment and treatment setting, any psychotic

symptoms and – most important – suicidal thoughts

or plans must be assessed at the first visit. Especially

suicidality, the outstanding threat of depressive dis-

orders, determines the further treatment plan, since in

some instances it may be necessary to hospitalize a

patient against his or her will. Given that more than

10% of depressed patients commit suicide (Angst

et al., 2005 ; for patients who received no inpatient

psychiatric treatment, lower rates have been reported

(Simon and Von Korff, 1998)), acute suicidality con-

stitutes a medical emergency that calls for immediate

and consequent action. In addition it is essential to

optimize the awareness of suicidal ideations and

attempts. Predictors of elevated suicide risk include

greater severity of depression, suicidal ideation,

hopelessness, unemployment, comorbid psychotic

disorder, substance abuse, personality disorder, a

family history of mental disorders, history of

attempted suicide, male gender, or being widowed

or divorced (Brown et al., 2000; Moscicki, 1999). Thus,

it is crucial to be aware of the patients’ history

and evaluate signs of suicidality, e.g. hopelessness

(Goldston et al., 2006 ; Sinclair et al., 2005), on a regular

basis.

Table 8. Frequency of Clinical features of patients varying in

depth of depression, based on a sample of n=486 probands

(adapted from Beck, 1967)

Clinical feature

Depth of depression

None

(%)

Mild

(%)

Moderate

(%)

Severe

(%)

Sad facies 18 72 94 98

Stooped posture 6 32 70 87

Crying in interview 3 11 29 28

Speech : slow, etc. 25 53 72 75

Low mood 16 72 94 94

Diurnal variation of mood 6 13 37 37

Suicidal wishes 13 47 73 94

Indecisiveness 18 42 68 83

Hopelessness 14 58 85 86

Feeling inadequate 25 56 75 90

Conscious guilt 27 46 64 60

Loss of interest 14 56 83 92

Loss of motivation 23 54 88 88

Fatigability 39 62 89 84

Sleep disturbance 31 55 73 88

Loss of appetite 17 33 61 88

Constipation 19 26 38 52


To obtain a full clinical picture prior to treatment,

patients and, if available, relatives should be

interviewed about previous illness and treatment

history, and other concurrent psychiatric and somatic

disorders, including non-psychiatric medication.

Because psychosocial stress factors may both contrib-

ute to the onset of a depressive episode and interfere

with treatment success, recent life events should be

documented and may lead to early psychotherapeutic

intervention in addition to medication.

Especially for patients who do not respond to

treatment, diagnosis should be rechecked regularly for

correctness. Treatment success could, for example, be

confounded by ongoing substance abuse or underly-

ing personality disorder. In addition, because in most

cases bipolar disorder first manifests with a depressive

episode, patients and relatives should be questioned

for emerging (hypo)manic symptoms both at the

initial taking of the patient’s history and also during

treatment. Emergence of (hypo)manic symptoms

usually leads to changes in treatment plans, e.g.

discontinuing antidepressants and switching to mood

stabilizers.

6.2 Access to mental health services

The following principles of access to services are

adapted from the British Association for Psy-

chopharmacology (BAP) guidelines for treating bi-

polar disorder (Goodwin, 2003) but also apply to

unipolar depression (see Box 2).

Whether diagnosis and treatment initiation should

be done by a primary care physician, a health pro-

fessional or a trained psychiatrist has been discussed

above. While WHO has recommended general prac-

titioners and World Psychiatric Association (WPA)

psychiatrists as primary care suppliers, CINP cur-

rently has no position of its own. With respect to

easy access to a trained psychiatrist, including the

possibility of direct hospital admission, health and

insurance policies in different countries may not yet

reflect this standard; elsewhere, a lack of resources

makes it difficult. Nevertheless, considering the

consequences of inadequate diagnosis and treatment

(including treatment settings) for prolonged illness,

chronicity and finally potential suicide, measures

must be taken to ensure these standards worldwide.

6.3 Enhanced care

Guidelines (e.g. APA (American Psychiatric Asso-

ciation, 2000), WFSBP (Bauer et al., 2002c ; Bauer et al.,

2002b)) embody a uniform consensus that, indepen-

dent of the choice of the specific medical treatment

intervention, general components of psychiatric man-

agement and psychotherapeutic support should be

initiated and continued throughout the entire treat-

ment (Bauer et al., 2002c). As a first step, a therapeutic

alliance must be established. This includes the psy-

chiatrist or physician taking full responsibility for

diagnosis, physical examination, other investigations

and explanation of the medical plan of management

to the patient and his relatives. The therapist should

take his time to listen to the patient’s complaints and

always communicate clearly, understandably and

honestly what he thinks. He should determine to-

gether with the patient a treatment plan and the ap-

propriate treatment setting, and, for outpatients,

ensure regular visits. During acute phase treatment,

weekly or biweekly visits are recommended (Bauer

et al., 2002c) ; during the continuation phase and after

syndromal recovery, a frequency of one visit per

month appears to be adequate (Bauer et al., 2002c). In

the case of concurrent psychotherapy supplied by a

psychotherapist, frequent communication between the

physician and therapist about the patient’s status

should be ensured. In addition, a good communication

between the treating psychiatrist and the GP about the

patients general health status and the recommended

laboratory controls during antidepressant treatment is

essential.

Box 2. Principles of access to services (adapted from the BAP guidelines)

$ Assessment should be offered by a trained psychiatrist29

with an understanding of both the medical and psychological treatments available for management of depressive dis-

orders.$ Patients should have access to early intervention, which must include the option of hospital admission.$ Appropriate use of legal powers of detention is mandatory for the successful management of risks in some patients with

acute depression and suicidality.$ Consistent outpatient follow-up is necessary, and many individual patients may require more complex interventions in

community settings.

29 Because there are too few trained psychiatrists worldwide, clinical

psychologists and well-trained nurses may also help to provide

sufficient care for depressed patients.


Box 3 presents an example for enhanced care

adapted from Goodwin et al. (Goodwin, 2003).

Other aspects of enhanced care, e.g. therapeutic

drug monitoring, will be addressed more specifically

in the next chapter (see also chapter 9.1.1.1.3).

In primary care settings, integrated quality im-

provement strategies involving combinations of

clinician and patient education, nurse case manage-

ment, enhanced support from specialist psychiatric

services and monitoring of drug concordance have

been shown to be clinically and cost-effective in the

short term, but this effect disappears in longer-term

follow-up. However, simple and relatively cheap

telephone support, counselling and medication moni-

toring delivered by counsellors or nurse practitioners

are clinically effective and likely to be cost effective

(Gilbody et al., 2003a; Gilbody et al., 2003b).

7. Goals of treatment : response, remission,

recovery

Traditionally, treatment is divided into acute, con-

tinuation and maintenance (prophylactic) phases

(Kupfer, 2005) (see Figure 2).

Clinical trials focus on symptomatic relief measured

by specific scales, e.g. the HAMD score (Hamilton,

1967), and define response and remission in relation to

these scores (usually 50% reduction of the baseline

score as ‘response’ and a specific cut-off as ‘re-

mission’, see Box 4). It should be kept in mind that

remission as defined in clinical trials does not necess-

arily correspond to remission in clinical terms.

Clearly, clinical management of depression goes far

beyond these criteria, which are meant to establish

evidence for efficacy of treatment. Although remission

is recognized as the optimal outcome of treatment for

depression, remission lacks a universally accepted

definition (Israel, 2006).

$ Goals of clinical management can be divided into

acute, intermediate and long-term goals. The ulti-

mate goal of acute treatment is to achieve remission,

in other words not only being asymptomatic (in the

sense of not meeting the criteria for diagnosis of the

disorder and having no or only minimal residual

symptoms) but also showing improvement in

psychosocial and occupational functioning. The in-

termediate goal is further stabilization and prevent-

ing relapse, eliminating subsyndromal symptoms

and restoring the prior level of functioning. The

long-term goal is full recovery (Rush et al., 2006a) to

prevent further episodes, maintain functioning

and ensure a satisfactory quality of life (AHCPR

(Agency for Health Care Policy and Research), 1999 ;

Box 3. Principles of enhanced care (adapted and modified according to Goodwin, 2003)

$ Educate yourself and then the patient and his relatives about the disorder.$ Ensure that you are always up to date regarding the latest developments in diagnosis and treatment through continuing

medical education.$ Try to base the treatment decision on evidence and not on beliefs.$ Use the evidence also to address the acute treatment modalities of the illness, the risk of relapse and the benefit of

psychotherapeutic engagement to the patient.$ Educate the patient and his relatives about the treatment for the illness to enhance adherence.$ In addition, inform the patient and his relatives about possible side effects of medication and potential symptoms that may

question the original diagnosis, e.g. emergence of (hypo)manic symptoms.$ Inform the patient and his relatives that enhanced drive before the onset of antidepressant action in the initial anti-

depressant treatment phase could lead to increased risk of suicide.$ Make the patient aware of stressors, the impact of sleep disturbance, the importance of regular patterns of activity and

early signs of relapse.$ Educate the patient about the poor outcome associated with alcohol and substance abuse and, if required, give appropriate

advice and offer treatment.$ Evaluate and manage functional impairment and supply the patient and his family with a realistic view about his capacity

to work and function within the family. Identify potential sources of psychosocial support in the community and help the

patient to contact them.

Acute treatment Continuation and maintenancetreatment

Response Remission Relapse Free interval Recurrence

Spontaneous course

Healthy

Depressed

Figure 2. Long-term treatment of depression (modified from

Kupfer, 1991).


American Psychiatric Association, 2000 ; Bauer et al.,

2002c).$ From the patient’s perspective, the most important

criteria for remission are the presence of features of

positive mental health such as optimism and self-

confidence, self-satisfaction and a return to one’s

usual, normal self and level of functioning

(Zimmerman et al., 2006). Therefore, while the

patient is still depressed, the therapist should facili-

tate the maintenance of social activities and prevent

stigmatization. This includes the use of psycho-

therapeutic and sociotherapeutic approaches.$ Depressive disorders are frequently associated with

significant impairments in social functioning due to

a long persistence of residual symptoms after re-

mission of depressive symptoms (Fava et al., 2007;

Hirschfeld et al., 2000). To regain social and occu-

pational functioning therefore is one of the major

treatment goals.$ Depression is associated with marked suffering,

morbidity, and a high risk of recurrence and/or

chronicity. Treating patients with depression to a

state of remission is associated with a significantly

improved long-term outcome, including reduced

risk of relapse (Ramana et al., 1995 ; Rush et al.,

2006b) and improved functioning. Thus, remission

(which can be defined as the nearly complete ab-

sence of depressive symptoms) should be the goal of

the acute phase of pharmacotherapy (Thase and

Ninan, 2002).$ However, an important goal in all phases of the ill-

ness is to prevent suicide as the most deleterious,

and unfortunately still frequent outcome of de-

pression (Angst et al., 2005), as well as to prevent

death from somatic disorders associated with de-

pression, e.g. cardiovascular disease (Angst et al.,

2002a).

Optimal clinical effectiveness of the treatment should

also include optimized safety and tolerability. Asses-

sing and documenting the achievement of these treat-

ment goals on a regular basis is of utmost importance

because it guides further treatment decisions.

7.1 Acute treatment

Initiation of antidepressant treatment should be a first

step of an overall treatment plan. If antidepressant

treatment with medication is the choice, it may be

combined with varying degrees of psychosocial inter-

vention ranging from basic psychoeducation to formal

augmentation with an empirically supported psycho-

therapy, if necessary in combination with psychosocial

support. The decision which medication to choose

depends on several factors (see Box 5).

Depending on the setting (inpatient or outpatient),

the medical constitution of the patient and previous

experience, the rate of titration may vary considerably.

The usual recommendation for outpatients is to start

with the lowest effective dose to ensure good toler-

ability. If no side effects occur or if side effects fade

within a few days, further stepwise dosage increases

up to the usual standard dose (see Table 11) can be

made until relief of symptoms is observed.

Especially when specialist care is not available, e.g.

in a general hospital, and ease of use, high tolerability

and low drug-drug interaction potential are of im-

portance, the recommended first choice of anti-

depressant is a selective serotonin reuptake inhibitor

(SSRI) or other, newer antidepressant with a favorable

side effect profile (Voellinger et al., 2003). Regardless

of the drug chosen, during antidepressant pharma-

cotherapy one must reckon with a delay of several

weeks until sufficient antidepressant effects can be

seen. Up to now no definite response prediction using

Box 4. Definition of response and remission (Thase, 2003)

$ The traditional definition of response to antidepressant therapy includes a 50% improvement in symptoms30.$ Remission is defined as the absence of depressive symptoms and a full return to premorbid levels of functioning. In most

randomized controlled studies, an absolute rating scale threshold is defined as remission (e.g. HAMD score f7).$ Full Recovery is defined as the full regain of social and occupational functioning without residual symptoms of depression.

Box 5. Choice of a specific drug

The availability of different antidepressants may vary from country to country (see chapter 14). Among the antidepressants

available, proven efficacy must be the first consideration. In the next step, the choice of a specific drug should take into

account not only the subtype of depression but also previous experience with antidepressants, especially potential

tolerability problems in conjunction with contraindications due to medical comorbidity, and finally the preference of the

patient after explaining potential advantages and disadvantages of candidate medications.

30 Response and remission are usually measured using instruments

such as the Montgomery–Asberg Depression Rating Scale (MADRS)

or the HAMD rating scale. In comparing RCTs, it is important to be

aware of the time interval after which response or remission was

achieved.


biological variables can be used during an anti-

depressant pharmacotherapy. Nevertheless behav-

ioral changes such as an early improvement in motor

retardation or a reduction of anxiety have been

reported to be dependent of the clinical profile of the

class of the prescribed antidepressant and may be

clinically usefull to predict the later treatment re-

sponse (Katz, 2004). This has also been true in the case

of a comparison of the effects of TCA and psy-

chotherapy – whereas Amitriptyline had early effects

on vegetative symptoms of depression psychotherapy

showed more delayed effects on mood, suicidal idea-

tion, work, and interests (DiMascio et al., 1979). In

addition also an overall early onset of improvement

has been shown to be highly predictive of later out-

come (Stassen et al., 1996, 1997 ; Stassen and Angst,

1998). An absence of any change (improvement<20%)

during the first two weeks of treatment is highly pre-

dictive of clinical non-response during the following

weeks of treatment (Stassen et al., 1996 ; Stassen and

Angst, 1998). Therefore the prior postulated lag of

clinical response to antidepressants has been ques-

tioned during the last years due to the fact that an

effective antidepressant treatment initiates clinical

changes even during the first week of antidepressant

treatment (Stassen et al., 1999 ; Taylor et al., 2006).

If a treatment is not the first medication trial and

a patient has previously been on fluoxetine or

irreversible monoamine oxidase inhibitors (MAOIs), a

washout period of at least 2 weeks (up to 5 weeks in

the case of a switch from fluoxetine to irreversible

MAOIs) must be observed, especially when treatment

with a serotonergic acting drug is planned. Otherwise,

serotonin syndrome – a potential lethal complica-

tion – may, rarely, occur (Boyer and Shannon, 2005 ;

Haddad, 2001). Serotonin syndrome is not specific

only to SSRIs but may also occur with other sero-

tonergic acting substances, e.g. venlafaxine in com-

bination withMAOIs (Phillips and Ringo, 1995). When

switching to reversible MAOIs, e.g. moclobemide, a

few (2–3) days of pausing medication is sufficient

(Dingemanse et al., 1995 ; Dingemanse et al., 1998). For

details of MAOI tolerability, see also chapter 9.1.3.2.

On the other hand, sudden discontinuation of anti-

depressant treatment usually cannot be advised, but

the possibility of immediate switching has been pro-

posed (Wohlreich et al., 2005b; Wohlreich et al.,

2005a). When switching from one medication to an-

other, overlapping tapering is recommended unless a

specific medication, e.g. an irreversible MAOI, re-

quires a washout phase (Larsen, 1988).

Sudden cessation of treatment can lead to discon-

tinuation symptoms (see chapter 9.1.1.3.2), which have

been described for numerous classes of antidepressant

drugs (particularly common with MAOIs, venlafaxine

and SSRIs, especially paroxetine, and less common

with fluoxetine and escitalopram) (Baboolal, 2004 ;

Haddad, 1998; Rosenbaum et al., 1998 ; Schatzberg

et al., 2006). The reported frequency of antidepressant

discontinuation syndromes varies widely from

10–60% depending on the class of medication and

study methodology, with an estimated average of 20%

(Warner et al, 2006). A survey of the French pharma-

covigilance database revealed that SSRIs are clearly

associated with a higher risk of discontinuation syn-

drome than other antidepressants (OR 5.05, 95% CI

3.81–6.68) and in particular venlafaxine and paro-

xetine (OR 12.16, 95% CI 6.17–23.35 and OR 8.47, 95%

CI 5.63–12.65, respectively) (Trenque et al., 2002).

Discontinuation syndrome may also affect newborns

of mothers who are taking SSRIs. A database analysis

revealed a total of 93 suspected cases of SSRI-induced

neonatal discontinuation syndrome. These were re-

garded as sufficient to suggest a possible causal re-

lation. Sixty-four of the cases were associated with

paroxetine, 14 with fluoxetine, 9 with sertraline and 7

with citalopram (Sanz et al., 2005a). It is also worth

noting that the novel pharmacological compound

agomelatine has not been on the market sufficiently

long enough for a final judgement regarding discon-

tinuation symptoms, but the substance was not

associated with discontinuation symptoms in one,

specially designed, randomized, double blind, pla-

cebo-controlled, discontinuation study (Montgomery

et al., 2004c). Antidepressant discontinuation syn-

drome presents as a flu-like syndrome and is to some

degree similar to the well-known activation syndrome

that can occur when starting a serotonergic drug.

Symptoms of discontinuation syndrome include agi-

tation, sleep disturbances, sweating, gastrointestinal

discomfort and headache, and may take up to 2 weeks

to subside. Symptoms may put the patient at risk for

an early relapse (Fava, 2003a; Harvey et al., 2003) and

may stress the therapeutic alliance (Garner et al.,

1993). Abruptly stopping TCA treatment may put

susceptible patients at risk for cholinergic syndrome,

especially older patients or patients with pre-existing

neurological conditions (Garner et al., 1993). Where

there is doubt whether the symptomatology is related

to drug discontinuation, reintroducing the previous

medication with consequent cessation of symptoms

may clarify the issue.

Expectations regarding the potential efficacy of a

given treatment differ according to expert reviews and

guidelines. For acute treatment, recommendations

vary regarding how long the drug of first choice


should be tested and when to alter treatment de-

pending on time and degree of improvement. All

available antidepressants are estimated to produce

treatment responses of 50–75% in moderately to sev-

erely depressed patients, which means that despite

sufficient dosage, 25–50% of patients do not respond

sufficiently to the initial treatment selection. However,

of those responding, the estimated likelihood that

they would have also responded to placebo is 25% to

50%. This has also been outlined by Davis et al.’s

meta-analysis, in which, response rates with active

drugs, ranged from 45% to 79%, and, with placebo,

from 23% to 48%. (Davis et al., 1993). Higher levels

of pain and somatization predict a longer time to re-

mission. Higher levels of pain correlates with severity

of depression as shown in a Swedish population

study (Andersson et al, 1993). Pain especially may

be a marker for depression that is more difficult

to treat as demonstrated by a secondary analysis of

an imipramine/interpersonal psychotherapy combi-

nation study (Karp et al., 2005). The investigators

of this study concluded that patients with recurrent

depression should thus be screened for painful

physical symptoms. They also suggest these symp-

toms may require a more aggressive treatment or the

use of dual-mechanism antidepressants, although the

usefulness of this approach still needs to be proven.

The decision regarding whether a response is suf-

ficient can be guided by administration of established

rating scales. As outlined by Rush and Kupfer (Bauer

et al., 2002c ; Kupfer and Rush, 1983), non-response

would be defined as a f25% decrease in baseline

symptom severity, partial response as a 26–49% de-

crease and response as a o50% decrease. According

to World Federation of Societies of Biological

Psychiatry (WFSBP) guidelines, an acute-phase medi-

cation trial should last at least 6 weeks, and 8–10

weeks to define the full extent of symptom reduction

(Bauer et al., 2002c). This contrasts with a re-

commendation from a round-table consensus pub-

lished by Hirschfield et al. calling for a switch of

antidepressant in the case of non-response after 4

weeks of treatment. Patients remaining as partial re-

sponders after 6–8 weeks should receive a dose esca-

lation, followed by augmentation or switching

strategies (Hirschfeld et al., 2002 ; Quitkin et al., 2005).

These recommendations are based, among others,

on the findings of Nierenberg et al. (2000) showing

that in patients who had not received at least 30% re-

duction of symptom severity by 4 weeks on fluoxetine,

the likelihood of a response at 8 weeks was only about

12–27%. Similarly, Stassen and Angst (1998) reported

that in a controlled study comparing moclobemide

and fluoxetine, onset of improvement occurred in

more than 70% of patients within the first 3 weeks.

There was no evidence for pronounced improvement

rates thereafter. Also, during mirtazapine and paro-

xetine treatment early improvement was a highly sen-

sitive predictor of later stable response or remission

(Szegedi et al., 2003). By the same token, evidence

suggests that older patients especially may take longer

to show a full response to antidepressant medication

(up to 12 weeks) (Furukawa et al., 2000). To bridge the

time until onset of symptomatic improvement and for

acute relief of symptoms, e.g. agitation and sleep dis-

turbance, short-term addition of benzodiazepines may

be considered, as they have been shown to accelerate

response (Furukawa et al., 2000 ; Furukawa et al.,

2001a; Furukawa et al., 2001b; Smith et al., 2002). Bear

in mind, however, that depressed patients treated in

mental health settings often receive long-term treat-

ment with benzodiazepines, which is inconsistent

with guideline recommendations (Clark et al., 2004;

Valenstein et al., 2004). Additional augmentation

therapies such as sleep deprivation and light therapy

may also be considered.

To establish true refractoriness in the case of non-

response or suspected insufficient dosage, if available,

therapeutic drug monitoring (TDM) may be helpful

(see also chapter 9.1.1.1.3). TDM is based on the hypo-

thesis that a well-defined relationship exists between

drug plasma concentration and its clinical effects

(therapeutic effects, adverse effects and toxicity). This

hypothesis is generally well accepted for lithium and

for the TCAs nortriptyline, amitriptyline, desipramine

and imipramine (Baumann et al., 2005). But results are

inconsistent for other tricyclics, SSRIs and several

more recently introduced antidepressants, with the

exception of venlafaxine (Corruble and Guelfi, 2000).

Due to the economic aspects of TDM (measuring

plasma levels for a single psychoactive drug, including

its metabolites, costs between E20 and E80) (Baumann

et al., 2005), TDM should be reserved for cases where a

relationship can be demonstrated between serum

concentration effectiveness and side effects and in

conjunction with a clinical question, e.g. insufficient

treatment response, side effects due to overdosing and

so on. Moreover, serum level measurements should

only be performed under steady-state conditions (at

least five half-lives, in most drugs 1 week after a dos-

age increase or decrease) and when the concentration

of a drug is at a minimum (trough level). Several

factors may interfere with antidepressant serum con-

centration, including absorption and excretion of the

drug, bioavailability and binding to plasma proteins.

These factors determine the plasma half-life of the


drug, e.g. a short (about 2–10 hours) plasma half-life

for venlafaxine, trazodone, tranylcypromine and

moclobemide, or a very extensive plasma half-life,

e.g. 3–15 days, for fluoxetine and its metabolite nor-

fluoxetine.

Several potential pharmacokinetic interactions be-

tween antidepressants and other medications are due

to common metabolism by cytochrome P-450 (CYP)

enzyme isoforms and/or enzyme inhibition (see also

chapter 9.1.1.1.2, Table 12). Genetically determined

polymorphisms of CYP2D6 and CYP2D19 are of high

clinical relevance for antidepressants that are sub-

strates of these enzymes, including tricyclic anti-

depressants (TCAs), some SSRIs, venlafaxine and

mirtazapine. Roughly 5–8% of Caucasians are con-

sidered to be poor metabolizers (PM) and 1–7% are

ultrarapid metabolizers (UM) (Baumann et al., 2005) ;

the first leads to increased serum levels and the latter

to insufficient buildup of serum concentrations. In

Asian populations, the PM type may be less prevalent

(about 1% among Thai, Chinese and Japanese popu-

lations, and up to 4.8% among Indians (Kitada, 2003)).

But other enzymes may show variabilities that require

further investigation in populations other than

Caucasians (Morrison and Levy, 2004).

Concomitant medication processed by the same

enzymes influences the metabolic rate of other sub-

stances. For example, some SSRIs that inhibit CYP2D6,

especially fluoxetine and paroxetine, but also bupro-

pion, may result in clinically significant inhibition

with a consequent increase in serum levels of other

substrates, e.g. antiarrhythmics, b-receptor antago-

nists such as propanolol and metoprolol, and opioids,

e.g. codeine. Other antidepressants, including imipra-

mine, nefazodone, venlafaxine and reboxetine31, are

metabolized by the CYP3A4 pathway; some anti-

depressants, e.g. norfluoxetine, the metabolite of

fluoxetine and fluvoxamine, also show potent inhi-

bition of this enzyme (Baumann et al., 2005). Thus,

TDM may also be an important tool in monitoring in-

teractions when augmentation or combination treat-

ments are considered (Baumann et al., 2005).

When the chosen antidepressant treatment is effec-

tive and symptomatic remission has been achieved,

the usual recommendation is to continue the anti-

depressant in unchanged dose unless side effects re-

quire tapering down. It is also recommended to

continue the full dose of acute treatment during the

maintenance phase. Frank et al. and Franchini et al.

demonstrated that patients on maintenance therapy

who received only half the acute phase dose of

imipramine or paroxetine, respectively, rather than

the full dose showed a significantly higher rate of

recurrence (Franchini et al., 1998 ; Frank et al., 1990).

Thus, the frequent clinical practice of reducing dosage

for maintenance treatment lacks an evidential base

and may increase the patient’s risk of relapse. The

situation may be different when full response during

acute treatment has already been achieved with low-

dose antidepressants ; in this case, it may be reasonable

to continue treatment in the lower-dose range

(Furukawa et al., 2003).

7.2 Continuation and maintenance treatment

Following initial remission from acute depression,

continuation treatment should ensure stabilization,

prevent early relapses, improve further functionality

and foster reintegration. It is generally recommended

to continue with the effective antidepressant mono-

therapy or combination treatment for at least another

3–6 months (Hirschfeld, 2000, see also Table 9), but

patients with a history of long previous episodes may

be candidates for longer continuation phase treatments

(Ramana et al., 1995). Although relapse or recurrence

may be prevented with long-term pharmacotherapy,

this approach is only suited to patients at high risk of

relapse or recurrence (Nierenberg et al., 2003). In a

prospective 15-month follow-up study in depressed

patients strong predictors of subsequent early relapses

were residual symptoms. Relapses occurred in 76%

(13/17) of patients with residual symptoms and 25%

(10/40) of patients without (Ramana et al., 1995). It is

thus strongly recommended to continue treatment

until all symptoms have totally subsided (Prien, 1990).

However, for patients whose history includes a

previous, untreated episode, the individual duration

of continuation treatment can be determined by asking

about the time elapsed until spontaneous recovery

occurred. For example, if a previous untreated episode

lasted 9 months, continuation treatment of this epi-

sode should now last at least for the same time period.

In general, treatment durations of between 6 months

and 2 years have been recommended (Burrows, 1992 ;

Burrows et al., 1993).

If a decision for long-term maintenance treatment

(prophylaxis against new depressive episodes) has

been made, the transition from continuation to

prophylaxis is not clear-cut. However, if there is no

indication for prophylaxis or if the patient refuses to

continue on medication, slow tapering off at the end of

continuation is strongly advised. It has been suggested

that the tapering phase should last at least 4–6 months

(Bauer et al., 2002c).

31 As of this writing, reboxetine is marketed in Europe but not in the

US.


Maintenance treatment is most commonly appro-

priate for patients with recurring episodes, especially

when more than one episode prior to the present one

has occurred during the last 5 years or when remission

has been difficult to achieve. Other factors that influ-

ence the decision in favor of maintenance treatment

include the number as well as the severity of previous

episodes, the duration of previous symptom-free in-

tervals, and comorbidity with other psychiatric or

medical illnesses as well as the presence of suicidal

ideation. Combining an antidepressant with lithium

may not only improve relapse prevention (Sackeim

et al., 2001a) but also be more protective against

suicide (Muller-Oerlinghausen et al., 2006). Once a

patient has stabilized on the combination, it is unwise

to withdraw lithium for at least a year (Bauer et al.,

2000 ; Bschor et al., 2002). However, there are no con-

trolled studies for assessing the optimal length of

maintenance treatment in general or how to identify

clear predictors for choosing an individual time span.

In patients with more than two or three relapses, year-

long or sometimes lifelong prophylactic treatment has

been recommended, e.g. the WFSBP Guidelines rec-

ommend maintenance treatment of 5–10 years in

recurrent patients not at special risk. They consider

lifelong maintenance in patients at greater risk, e.g.

with more severe episodes, and especially when two

or three attempts to withdraw medication have been

followed by another episodewithin a year (Bauer et al.,

2003).

Risk factors for recurring depression have also been

summarized by Nierenberg et al. (Nierenberg et al.,

2003) based on evidence from several studies (Doogan

and Caillard, 1992 ; Judd et al., 1998b ; Keller, 1999;

Keller and Boland, 1998 ; Kupfer et al., 1992;

Montgomery et al., 1988 ; Nelson, 2006 ; Ramana et al.,

1995 ; Rush et al., 2006b) (Table 10).

Analysing recent randomized, controlled mainten-

ance studies, Fakra et al found that treatment prevents

roughly 50% of the recurrences that occur under

placebo, regardless of the duration of the study or

the pharmacological nature of the antidepressant drug

(Fakra et al, 2006). Of special interest for daily prac-

tice, dealing with refractory patients, are the recent

Table 9. Selected guidelines for duration of antidepressant treatment following acute treatment response (adapted from

Geddes et al., 2003 and extended)

Recommended duration

of continuation after

medical management of

the acute episode (months)

Number of episodes that would indicate

that longer ‘maintenance’ treatment

is appropriate

UK Defeat Depression Consensus

Statement (Paykel and Priest, 1992)

4–6 o2

US Agency for Health Care Policy and

Research (Agency for Health Care Policy

and Research, 1993)

4–9 o2

British Association for Psychopharmacology

(Anderson et al., 2000)

6 o3 in the past 5 years (or o6 in total)

American Psychiatric Association

(American Psychiatric Association, 2000)

4–5 not specified

Korean Guidelines (Lee et al., 2006) 6–12 2 years up to indefinitely for patients with :

– o3 episodes

– 2 episodes + family + family history of

mood disorder

– comorbid dysthymia

– a history of recurrence within 1 year

after discontinuing medications

– a severe depressive episode

– a history of poor acute treatment response

Brazilian Guidelines (Fleck et al., 2003) 6 o3 in past 5 years (or o5 in total)

Australian and New Zealand Guidelines

(Ellis, 2004)

12 in recurrent depression:up to 3 years


findings of the STAR*D (Sequenced Treatment

Alternatives to Relieve Depression) study. With two or

more acute treatment trials needed to achieve re-

mission, the probability of a relapse increases : 33.5%

after the first treatment step, 47.4% after the second,

42.9% after the third and 50% after the fourth (Rush

et al., 2006b).

On the other hand, chances of relapse decrease and

prognosis improves depending on the time elapsed

since discontinuing medication. The risk of a de-

pressive relapse is 60% on placebo (compared with

29% on antidepressants) after 1 year. For the second

and third year, the risk to relapse on both anti-

depressants and placebo is reduced by 50% compared

with the first year (29% for placebo) and may continue

to decline (Geddes et al., 2003). Thus, decisions re-

garding long-term treatment must be made on an

individual basis, taking into account the patient’s

past experience with longer medication-free intervals,

if any.

In selected patients, long-term treatment may be not

favorable. A literature review by Fava (Fava, 2003a)

raised the question whether at least a substantial sub-

group of depressed patients may not benefit from

maintenance medication and may experience a

worsening of the long-term course of the illness.

According to Fava, the mechanism of this paradoxical

effect may include growing tolerance to anti-

depressants, onset of resistance upon each challenge

with the same antidepressant and withdrawal symp-

toms on sudden discontinuation of antidepressants,

leading to destabilization. Fava speculates that con-

tinued drug treatment may initiate biological pro-

cesses that counteract the initial acute effects of a drug

and may result in loss of clinical effectiveness. When

drugs are withdrawn abruptly, these processes may

operate unopposed at least for some time and increase

vulnerability to relapse.Whereas amultitude of clinical

studies (e.g., Frank et al, 1990, Robinson et al, 1991,

Terra and Montgomery, 1998), including a meta-

analysis of long-term treatment (Geddes et al., 2003),

clearly support the efficacy of antidepressant main-

tenance in clinical trial subjects, the role of long-term

antidepressant continuation in less severely depressed

patients still requires further clarification.

7.3 Managing side effects

This section focuses on general management of side

effects. Medication-specific side effects are detailed in

the specific sections on patients (see chapters 9.1.2 up

to 9.1.11).

Patients’ complaints about side effects of medica-

tions should always been taken seriously to forestall

non-adherence and uncontrolled discontinuation.

But patients do not always report side effects spon-

taneously, so active probing is recommended.

Therapists must be familiar with drug side-effect pro-

files.

7.3.1 Frequency of the occurrence of side effects

Minor side effects are common and are associated with

most medication trials. They differ depending on the

class of drug, e.g., SSRIs may produce more agitation,

anxiety, diarrhea, insomnia, nausea and vomiting,

whereas TCAs produce more dry mouth, dizziness

and constipation. A meta-analysis of Trindade reports

on an equal number of side effects in controlled

studies comparing SSRIs and TCAs, though different

in their nature (Trindade et al., 1998). However,

more recent metaanalyses express a tendency for a

better overall tolerability of newer antidepressants

when compared with older one’s (Anderson, 2000 ;

Anderson, 1998 ; Peretti et al., 2000 ; Wilson and

Mottram, 2004), also reflected by a slightly higher ad-

herence to SSRIs in controlled studies (Anderson,

2000 ; Anderson, 1998 ; Peretti et al., 2000; Wilson and

Mottram, 2004). The patient interview must clarify

whether somatic symptoms are true side effects or part

of the depressive syndrome. For patients taking SSRIs,

symptoms may also be due to an activation syndrome

including restlessness and agitation or to unreported

discontinuation (Fava, 2006).

7.3.2 Consequences for treatment

If side effects are tolerable and the patient is respond-

ing either completely or at least partially and is willing

to continue with a drug despite side effects, careful

tapering of the medication is a reasonable first step. If

side effects are already occurring at unusually low

Table 10. Risk factors that influence the probability of

recurrence of a depressive episode (modified from

Nierenberg et al., 2003)

Risk factors for depressive recurrence

Residual symptoms

More than three prior depressive episodes

Chronic depression (episode o2 years)

Family history of mood disorders

Comorbidities (e.g. anxiety disorder, substance abuse)

Late onset (age >60 years)

Two or more acute medication trials to achieve remission


doses, TDM and potential identification of a poor

metabolizer status may be helpful (Baumann et al.,

2005). If, after tapering medication, side effects do not

subside or efficacy is lost, switching drugs with slow

tapering off, stopping and then titration of a new

antidepressant is advised. In general, SSRIs and mixed

serotonergic/noradrenergic antidepressants have a

more favorable side-effect profile than older TCAs or

irreversible MAOIs (Preskorn, 1995, Kahn and

Halbreich, 2005). But newer antidepressants may also

not be as well tolerated as generally assumed, and

an activation syndrome, observed especially with

SSRIs, may have implications for their use, e.g. in

adolescents (see chapter 10.2.1.5). The frequency of

these side effects may be underestimated because

clinical trials often only disclose spontaneously re-

ported side effects, and in natural settings they

may be much more common. In the context of man-

aging side effects, psycho-education of the patient

plays an essential role. Experience of side effects is

less frightening if the patient is aware about their

possibility, especially when they may subside after

some days, e.g. increased sleepiness. Informed pa-

tients may be more likely to tolerate a drug and to stay

on it.

When side effects are severe, stopping an anti-

depressant and restarting with another is advised,

provided the patient is willing.

8 Mechanisms of action and future directions in

the development of antidepressants

8.1 The development of antidepressants based on

the monoamine hypothesis of depression

Following the accidental discovery of monoamine

oxidase inhibitors (MAOIs) and tricyclic anti-

depressants (TCAs) some 50 years ago (Slattery et al.,

2004), the use of opium and some former alternatives

(e.g. dinitrile succinate, hematoporphyrin, reserpine)

in the treatment of depression was fortunately

promptly abandoned (Ban, 2001). Further information

on the development of psychopharmacology can be

seen in a CINP monograph (Ban et al, 1998). The

pharmaceutical industry has developed numerous

antidepressants that had similar therapeutic and

adverse side effects. In the process, the mechanisms

underlying the actions of effective drugs have been

defined. These relate to blocking the re-uptake of

transmitters, reducing their enzymatic break down or

acting pre-synaptically to prolong their release. The

observation that imipramine reduced the transport of

tritiated noradrenaline and serotonin into rat brain

slices in vitro, whereas iproniazid, the first clinically

effective MAOI, inhibited the intraneuronal metab-

olism of these biogenic amines, gave support to the

emerging monoamine hypothesis of depression (Ban,

2001). However, despite the refinement of the phar-

macology of antidepressants, which led to the syn-

thesis of drugs that were highly selective in blocking

either the reuptake of noradrenaline (noradrenaline

reuptake inhibitors, NRIs, as exemplified by maproti-

line and reboxetine) or serotonin (selective serotonin

reuptake inhibitors, SSRIs, as exemplified by fluox-

etine) (Brunello et al., 2002 ; Nutt, 2002), it soon became

apparent that not all antidepressants blocked the

monoamine transporters. Indeed, mianserin, a tetra-

cyclic compound, was the first effective antidepressant

to act on neither monoamine transporters nor on

monoamine oxidase (Tatsumi et al., 1997). Later it was

found that mianserin had a unique mode of action in

that it increased the release of noradrenaline by

blocking the presynaptic, inhibitory, a2-adrenoceptors.

As these receptors, on stimulation by intersynaptic

noradrenaline, normally reduce the influx of calcium

ions and thereby reduce the calcium-dependent re-

lease of noradrenaline, drugs that specifically block

the presynaptic a2-adrenoceptors would be expected

to increase the intraneuronal concentration of calcium

and thereby increase noradrenaline release. This is

how mianserin was thought to act. More recently

mirtazapine, a structural relative of mianserin, has

been developed, which combines enhanced release of

noradrenaline with increased release of serotonin,

leading to enhanced activation of postsynaptic 5-HT1A

receptors and an antagonism of 5-HT2 and 5-HT3 re-

ceptors (Haddjeri et al., 1998). Thus, a slight modifi-

cation of the tetracyclic structure of mianserin has

led to the development of a dual-action antidepressant

that lacks the gastrointestinal and neurological

side effects of the SSRIs, adverse effects that are the

result of activation of serotonin receptors (5-HT2C,

5-HT3) in the gastrointestinal tract and on blood vessel

walls. Also pharmacotherapies for depression with

dopaminergic activity predominantly developed as

antipsychotic agents have shown efficacy in the treat-

ment of depression (Amore and Jori, 2001 ; Papakostas,

2006).

Moreover the positive influence of antidepressants

on monoamine neurotransmitter systems is not

limited to the treatment of depressive disorders.

Therapeutic effects are also observed in the treatment

of anxiety disorders such as panic disorder or gen-

eralized anxiety disorders (Kahn et al, 1979) leading to

the hypothesis that influence on specific neuro-

transmitters may influence the regulation of behavior


and moods such as impulsive aggression (Linnoila

et al., 1983) independently of disease categories (for

review see Morilak and Frazer, 2005).

It is interesting to note that following 2 decades

of emphasizing the specificity of action of anti-

depressants on noradrenaline, serotonin or even

dopamine (e.g. bupropion), there is now a renewed

interest in antidepressants with dual action, in other

words, tricyclic-like antidepressants that lack cardio-

toxicity and other adverse side effects.

Venlafaxine and to a far lesser extent duloxetine are

examples of monoamine reuptake inhibitors that, at

normal therapeutic doses, show a greater potency

in inhibiting serotonin rather than noradrenaline re-

uptake, whereas milnacipran is more selective in in-

hibiting noradrenaline reuptake at normal doses.

These dual-action antidepressants (Briley, 1998) en-

hance both noradrenaline and serotonin. While venla-

faxine exerts its dual action at higher therapeutic

doses, both duloxetine and mirtazapine do so across

the therapeutic dose range (Briley, 1998).

Recent developments also show important differ-

ences between different subtypes of SSRIs. For ex-

ample, escitalopram, which binds to both the primary

binding site and to the allosteric site on the serotonin

transporter, seems to be different from other SSRIs

(Chen et al., 2005 ; Sanchez et al., 2004 ; Thase, 2006).

Despite the plethora of different types of anti-

depressants that have been marketed over the past 30

years (Table 11) (for review see Richelson, 2001), the

main advance has been made not in terms of efficacy

but safety. Modern antidepressants are no more effec-

tive than the first tricyclics, such as imipramine or

amitriptyline.

While it is generally assumed that all effective anti-

depressants enhance monoaminergic function in some

way, their common mode of action remains an en-

igma. It has long been realized that there is a disparity

between the qualitative and quantitative effects of

these drugs on monoamine transport and the onset

of their therapeutic action (Nestler, 1998). In addition

to the delay in onset of therapeutic action, acute

depletion of tryptophan from the diet, an event that

significantly decreases the concentration of brain

serotonin, results in either no effect or a mild

dysphoria in healthy volunteers and does not affect

the mood state of untreated depressed patients

(Delgado, 2004; Nestler, 1998). Nevertheless, trypto-

phan depletion is able to acutely reverse therapeutic

action in long-term SSRI treatment and to cause acute

relapse in recovered unmedicated patients who have

responded to SSRIs (Bell et al., 2001 ; Delgado et al.,

1999 ; Smith et al., 1997). These effects show that in

vulnerable individuals, acute lowering of 5HT func-

tion can contribute to depressive states.

The discovery that chronic antidepressant treat-

ment produces adaptive changes in postsynaptic b-

adrenoceptors that approximately correlated with the

onset of the antidepressant effect (Sulser et al., 1978)

stimulated new ideas regarding the mode of action

of antidepressants by directing research away from

presynaptic to postsynaptic events. It soon became

apparent that the changes in postsynaptic monoamine

receptors were coupled to changes in intracellular

signal transduction molecules. This stimulated re-

search into the effects of chronic antidepressants on

neuropeptides, neurotrophic factors and intracellular

signaling molecules (Manji et al., 2001 ; Wong and

Licinio, 2004). A variety of recent studies support the

hypothesis that possibly a decreased expression of

brain-derived neurotrophic factor (BDNF) contributes

to the development of depressive disorders and that

upregulation of BDNF plays a role in the action of anti-

depressant treatments (Duman and Monteggia, 2006).

Thus, the monoamine hypothesis of depression,

and the explanation of how antidepressants work,

has gradually evolved into a molecular hypothesis.

This hypothesis is based on the view that adverse en-

vironmental factors, such as stress, acting on a genetic

vulnerability, cause maladaptive changes in a range

of neurotransmitters among which the monoamines

are presumed to play a significant role. Effective

antidepressant treatments normalize the disturbed

neurotransmitter networks that are assumed to be

responsible for the clinical features of depression

(Castren, 2005). Themonoamine hypothesis has stimu-

lated the search for genes that are altered in de-

pression or by chronic application of antidepressants

in the hope that the molecules encoded by these

genes could provide targets for novel types of anti-

depressants (Knuuttila et al., 2004 ; Wong and Licinio,

2004).

In spite of the rapidly increasing knowledge

about antidepressants up to now there is no es-

tablished relationship between the pharmacological

profile of antidepressants and their therapeutic ef-

fects.

8.2 Developments leading to new understanding

of the mechanism of action of antidepressants

Despite the advances that have been made in the

treatment of depression over the past 50 years, a

number of major problems remain. These include a

lack of response or only a partial response to treatment

by a substantial proportion of patients. In addition, the


diagnosis of depression, and the different types of de-

pression, is dependent on the symptoms; these are

frequently complicated by comorbidity with other

psychiatric disorders. Clearly, the development of

specific diagnostic tests for depression would be a

major advantage, but to date, no such tests have been

reliably devised. It would also be a help if there were

reliable animal models of depression, but again, those

that are available have been of limited value for de-

tecting novel compounds or in elucidating the mech-

anisms whereby antidepressants work. Most animal

models of depression rely on stress-induced abnor-

malities in behavior and in the subsequent changes in

neuroendocrine and neurotransmitter (mainly mono-

amine) function.

In the past, animal models of depression have

largely been based on acute observations of the effects

of drugs that either reduce the functional activity of

brain monoamines that are assumed to be responsible

for the symptoms of depression (for example, reser-

pine) or that reverse the behaviors that simulate some

of the symptoms of depression (for example, learned

helplessness induced by unavoidable foot-shock).

While such models have been useful in the develop-

ment of new antidepressants that largely resemble

those already available, they have been less successful

in identifying novel agents. This situation has stimu-

lated research into models (in rats) that not only exhi-

bit behavioural changes that may be relevant to

depression (anhedonia, decreased libido, changes in

locomotor activity and in the sleep profile, cognitive

and memory deficits) but also in neurotransmitter

function (particularly in the monoamines), in the

hypothalamic-pituitary-adrenal (HPA) axis and in the

immune axis. A relevant animal model should fulfil at

least 3 criteria, namely predictive validity (an ability to

detect all treatments that are therapeutically effective),

face validity (an ability to produce behavioral changes

that are similar to those seen in depressed patients)

and construct validity (by exhibiting psychobiological

changes that may underlie depression). While several

rodent models of depression fulfil the first two criteria,

it is more difficult to validate the third criterion until

the precise causes of depression are known. Never-

theless, the olfactory bulbectomised rat model and the

gestational stress models probably fulfil these criteria

better than others.

The olfactory bulbectomised rat (OBX) model is

now widely accepted as a model that bears similarities

to the agitated form of depression (Harkin et al., 2006;

Jesberger and Richardson, 1988 ; Leonard and Song,

2002 ; Willner, 1990). Thus surgical removal of the

olfactory bulbs results in changes in the behavioural,

endocrine, immune and neurotransmitter systems that

are largely reversed by chronic, but not acute, anti-

depressant treatment, including electroconvulsive

seizures (ECS) (Leonard and Song, 2002 ; Zhou et al.,

1998).

Dysfunction of the brain serotonergic system has

been shown to relate to the mood changes in depres-

sion and bipolar disorder (Spoont, 1992) and there is

evidence that the changes in serotonin are widespread

and linked to the depression-like behaviour in the

OBX model (Hasegawa et al., 2005 ; Watanabe et al.,

2006). The OBX model has been shown to be particu-

larly suitable for studying the complex relationships

between the brain, behaviour, the neuroendocrine and

immune systems, in addition to detecting poutative

antidepressants that do not act primarily on brain

monoamine systems (Breivik et al., 2006).

The gestational stress (GS) model is based on the

observation that pre-natal stress, in both animals and

humans, as associated with an increased risk of de-

pression in later life (Huizink et al., 2004). Such

changes are associated with an increased incidence

of depression and anxiety particularly in female off-

spring (Weinstock, 2007).

When pregnant rats undergo daily restraint stress

for one week during the mid-gestational period, the

offspring show increased immobility in a stressful en-

vironment (such as the open field apparatus) and in

the forced swim test, a test that simulates learned

helplessness and depressed mood. This suggests that

rats stress in utero display depressive-like behaviours

post partum, changes that are reduced by chronic

antidepressant treatment.

Despite the limitations of these rodent models of

depression, they have been beneficial in providing

possible links between the main symptoms of de-

pression and changes in monoamines, endocrine and

immune systems (Leonard and Song, 1999). As these

models, like depressed patients, only respond effec-

tively to chronically administered antidepressants,

they also give some insight into the possible mechan-

isms of action of these drugs.

Recent reports describe alterations in the expression

of numerous genes, notably those coding for neuro-

trophic factors such as BDNF and nerve growth factor

(NGF) (Alfonso et al., 2006) as well as structural

modifications in the areas of the brain related to mood

disorders in such animal models submitted to those

paradigms. This has led to depression research being

focused on the hippocampus, amygdala, cortex and

related neuronal circuits (LeDoux, 2000). The import-

ance of these regions in the pathophysiology of

depression has gained support from brain-imaging


studies, which have identified many cortical and sub-

cortical structures that are altered in depressed pa-

tients. These observations are complemented by those

from post-mortem studies : in the same regions,

alterations of both neuron and glial cell density and

size appear to be affected, suggesting functional im-

pairment of these regions associated with depressive

disorders (for review see Gould and Manji, 2004).

Effective antidepressant treatments have also ident-

ified the importance of these brain regions (Tamminga

et al., 2002).

Clearly, the application of neuroscience to under-

standing brain function and psychopathology has re-

sulted in novel insights into the psychobiology and

biological subtypes of depression (Hasler et al., 2004),

and possibly how antidepressants work. This raises

the question, ‘Is mood chemistry?’, the subject of

an important review by Castren (Castren, 2005). This

new concept suggests that depression results from a

malfunction of neuronal networks and that anti-

depressants work by improving information proces-

sing in the affected networks. At the basis of such

disordered networks lies a failure of neuroplasticity.

Thus, some antidepressants seem to increase the de-

velopment of new neurons in the hippocampus

(Malberg et al., 2000). This increase in neurogenesis in

the hippocampus associated with long-term anti-

depressant treatment correlates with behavioral

changes caused by chronic antidepressant treatments

in animal models of depression (Santarelli et al., 2003).

Note that numerous alterations other than a decrease

in the rate of neurogenesis or in neuronal turnover in

the hippocampus have been reported in depression,

such as modifications in neuronal architecture. Very

few publications have reported the effect of anti-

depressants on them.

Such observations are particularly pertinent to

the mode of action of antidepressants, as for the first

time, a cellular explanation has been proposed that

identifies a possible reason for the delay in onset of

response to treatment independent of the nature of

that treatment. This hypothesis has led to the further

observation that elimination of neurons through

apoptotic cell death increases simultaneously with in-

creased neurogenesis, events that are linked to

antidepressant-induced increases in neurotrophic fac-

tors such as BDNF. It may be hypothesized that, in

the hippocampus, antidepressants increase neuronal

turnover rather than neurogenesis per se (Sairanen

et al., 2005).

What are the implications of such findings for the

development of future antidepressants? Clearly, the

conventional approach whereby specific monoamine

neurotransmitters are targeted must be reconsidered.

It can be argued that such an approach has failed to

bring about any major benefits to the depressed pa-

tient in terms of therapeutic efficacy. Further targets,

while they may include monoamine receptors such as

the 5-HT2A, 5-HT2C, 5-HT6 and 5-HT7 (Pauwels, 2000),

have certainly produced some potentially interesting

possibilities in rodent models of depression, but so

far they have not yet been validated clinically. There

is evidence that 5-HT1A and 5-HT1B/D antagonists

augment the antidepressant response, but the clinical

evidence that such drugs are effective antidepressants

when administered alone is equivocal (Bosker et al.,

2004). Similarly, the a2-adrenoceptor has been targeted

following the discovery that the tetracyclic anti-

depressants mianserin and mirtazapine act as anta-

gonists at the pre-synaptic a2-adrenoceptor (Blier,

2001) and block certain 5HT2 receptors. Therefore,

both drugs influence noradrenergic and serotonergic

neurotransmission.

Recently, it was shown that a peptide that is a

member32 of the S100 protein family interacts with

the 5-HT1B receptor ; there is experimental evidence

that the function of this receptor depends on ex-

pression of the p11 peptide (Sanacora et al., 2000). The

concentration of the p11 peptide was shown to be low

in post-mortem brains from depressed patients. In

knockout mice lacking the p11 peptide, depressive-

like behavior was noted, whereas overexpression of

p11 increases 5-HT1B receptor function in cells and

recapitulates behaviors seen after antidepressant

treatment. Chronic antidepressant treatments, includ-

ing electroconvulsive therapy (ECT), increased p11

expression and counteracted the depression-like

phenotype (Svenningsson et al., 2006). These results

serve to emphasize the potential importance of the

5-HT1B receptor in animal models for depression

and suggest that the 5-HT1D receptor, the analogous

serotonin receptor in humans, may play a role in

antidepressant therapies.

Non-monoamine approaches have included anta-

gonists of tachykinin receptors. The endogenous ago-

nists include the peptide substance P, which is

physiologically involved with pain perception, but

experimental studies have demonstrated that NK1

receptors may function to modulate serotonergic

transmission (Santarelli et al., 2001). Antagonists of

these receptors would therefore be expected to exert

the opposite effect upon serotonergic transmission and

32 S100 is a protein characterized by two calcium binding sites. There

are at least 21 different types of S100 proteins in the so-called S100

protein family.


enhance function (Culman et al., 1997). While con-

siderable excitement was generated regarding the

antidepressant potential of the first NK1 antagonist to

be developed some years ago (Schwarz and Ackenheil,

2002), further clinical studies have proved disap-

pointing. Nevertheless, with three known types of NK

receptors, the search continues for antagonists with

potential therapeutic properties (Kramer et al., 1998).

Among the amino acid neurotransmitters, atten-

tion has been directed to the N-methyl-D-aspartate

(NMDA) receptor complex. Experimental findings

have shown that most classes of antidepressants de-

crease the affinity of the glycine site on the NMDA

receptor complex (Grundemar and Hakanson, 1994)

following chronic antidepressant treatment. This

modulation of the NMDA receptor complex may

prove to be a novel approach to drug development, as

the NMDA antagonist ketamine has been shown to

cause a rapid but transient improvement in mood in

depressed patients (Paul et al., 1994). At the cellular

level, NMDA antagonists block the atrophy of hippo-

campal CA3 pyramidal neurons and the inhibition

of neurogenesis caused by stress (Berman et al.,

2000a). Another possible approach to modulating

the glycine site on the NMDA receptor involves

s(sigma)-receptor antagonists. Igmesine was the first

s1-receptor antagonist shown to have antidepressant

activity (Manji and Lenox, 1999 ; Roman et al., 1990),

but it could not subsequently be confirmed in rando-

mized controlled trials (RCTs) (Volz and Stoll, 2004).

Therefore, and due to marketing reasons, it has not

been developed further (Volz and Stoll, 2004). An ex-

ploratory RCT using the antibiotic drug d-cycloserine

(DCS), which acts as a partial agonist at the NMDAR-

GLY site, showed a reduction in depressive symptoms

but no statistically significant advantage in compari-

son to placebo adjuvant treatment (Heresco-Levy et al.,

2006). The antidepressant tianeptine has been demon-

strated to counteract the stress-induced increase in

the NMDA/AMPA (a-amino-3-hydroxy-5-methylisox-

azole-4-propionic acid) ratio (Kole et al., 2002).

Recently the idea that influence on the regulation of

glutamatergic neurotransmission may contribute to

the development of new substances with anti-

depressants (Krystal, 2007 ; Witkin et al., 2007) has

been supported by the publication of case reports

(Goforth and Holsinger, 2007; Liebrenz et al., 2007)

and one RCT (Zarate et al., 2006) showing a rapid

antidepressant efficacy of ketamine treatment.

Of the other amino acid receptors that are possible

targets, the observation that the concentration of

c-amino butyric acid (GABA) is decreased in the

brains of depressed patients (Sanacora et al., 2000)

suggests that GABA receptor agonists, particularly

those targeting the G protein-coupled GABA-B recep-

tor that are prominently located in limbic regions of

the brain, may be of interest. For a detailed review of

new hypotheses on antidepressant modes of action,

see (Slattery et al., 2004).

A novel antidepressant, agomelatine, was recently

developed. It acts as an agonist at melatonergic re-

ceptors MT1 and MT2 and as an antagonist at 5-HT2C

receptors (Audinot et al., 2003 ; Descamps-Francois

et al., 2003 ; Millan et al., 2003 ; Millan et al., 2005;

Pevet, 2002 ; Yous et al., 1992). Melatonin is secreted by

the pineal gland and, via the suprachiasmatic nucleus

in the hypothalamus, acts as the endogenous circadian

rhythm oscillator. Circadian rhythms are known

to be altered in depression (Darcourt et al., 1992).

Consequently, it has been hypothesized that a drug

acting as an agonist at melatonin receptors and as

an antagonist at 5-HT2C receptors (which have been

implicated as being oversensitive in anxiety and de-

pression) could facilitate resynchronization in circa-

dian rhythms (Krauchi et al., 1997 ; Leproult et al.,

2005) and have useful antidepressant properties

(Kennedy and Emsley, 2006; Loo et al., 2002).

The close interrelationship between the endocrine

and immune systems has stimulated research into the

role of pro-inflammatory cytokines into the etiology of

depression. Thus, the observation that inflammatory

mediators, such as the pro-inflammatory cytokines

interleukin (IL)-1 and IL-6, tumor necrosis factor-a, c-

interferon and prostaglandin E2, are elevated in the

blood of depressed patients has led to the macrophage

hypothesis of depression (Smith, 1991). In addition,

the treatment of non-depressed persons suffering from

hepatitis with a-interferon often results in severe de-

pression (Wichers and Maes, 2002). Furthermore,

many of the symptoms that occur in depression

(e.g. altered sleep profile, mood, memory, appetite,

libido, cognitive function, endocrine function) may

also be caused by pro-inflammatory cytokines that are

increased in the blood and cerebrospinal fluid (CSF)

of depressed patients (Dantzer, 2004). Conversely,

chronic treatment with antidepressants attenuates the

release of pro-inflammatory cytokines from activated

macrophages both in the blood (Xia et al., 1996) and

in the brain (Obuchowicz et al., 2006). These findings

suggest that antagonists of pro-inflammatory cyto-

kines, and possibly cyclo-oxygenase (COX)-2 in-

hibitors that reduce the synthesis of prostaglandin E2

in the brain, could act as novel antidepressants

(Leonard, 2001). There is some clinical evidence that

COX inhibitors have antidepressant-like activity

(Collantes-Estevez and Fernandez-Perez, 2003).


Epidemiological studies show that there is a corre-

lation between chronic depression and the likelihood

of dementia in later life (Geerlings et al., 2000 ; Visser

et al., 2000). Inflammatory changes in the brain are

pathological features of both dementia and depression

(Steffens et al., 1997). It would appear that an increase

in inflammation-induced apoptosis, together with a

reduction in the synthesis of neurotrophic factors

caused by a chronic increase in brain glucocorticoid

concentrations (Leonard and Myint, 2006b, Sapolsky,

2000), may play a major role in the pathology of these

disorders. In addition, a reduction in the neuro-

protective components of the tryptophan-kynurenine

pathway in the brain (such as kynurenic acid) further

contribute to the neurodegenerative changes seen in

chronic depression (Leonard and Myint, 2006a). Such

changes have been postulated to cause neuronal

damage and thereby predispose the depressed patient

to dementia (Leonard and Myint, 2006b). How do

antidepressants counteract the neurodegenerative

changes that underlie chronic depression? There is

now experimental evidence that antidepressants in-

crease the development of new neurons in the hippo-

campus (Malberg et al., 2000), an effect that may

account for delay in the therapeutic response. New

neuronal networks are thus established in response

to chronic antidepressant treatment (Sairanen et al.,

2005). In support of this view, antidepressants are

known to enhance axonal and dendritic sprouting

(Vaidya et al., 1999). Thus, in chronic depression,

glucocorticoids and inflammatory mediators are re-

sponsible for increasing neuronal apoptosis and pre-

venting repair of damaged neuronal networks.

Effective antidepressant treatment appears, at least

partly, to reverse such changes.

Whereas neurotransmitter receptors would appear

to be the most accessible targets for the development

of new antidepressants, there is now considerable

research interest in intracellular signal transduction

mechanisms. These are targets for neurosteroids,

neurotrophic factors and enzymes that are linked,

directly and indirectly, to postsynaptic receptors that

reflect the action of both neurotransmitters and other

physiologically active molecules such as the cytokines.

To date, only one drug has been developed that

appears to act by inhibiting a component of the post-

receptor signaling system, rolipram, a phosphodi-

esterase inhibitor that is presumed to act by inhibiting

breakdown of the second messengers cyclic adenosine

and guanosine monophosphates. As a consequence,

the postsynaptic response to receptor stimulation

is increased. Nonetheless, compared with TCAs, roli-

pram has shown inferior therapeutic efficacy in

RCTs (Hebenstreit et al., 1989 ; Scott et al., 1991). In

the future, it seems likely that other postsynaptic tar-

gets will be investigated, including mitogen-activated

protein (MAP) kinase agonists that indirectly increase

the synthesis of BDNF, a key neurotrophic factor

for repairing damaged neurons (Altar, 1999). Other

possible targets include protein kinase C (PKC), an

enzyme involved in regulating neuronal excitability,

neurotransmitter release and long-term synaptic

events (Manji and Lenox, 1999). Finally, in view of the

importance of mechanisms that reduce apoptosis, and

thereby assist in neurogenesis, antidepressants may be

developed that act as promoters of anti-apoptotic

proteins such as Bcl-2. This protein attenuates apop-

tosis by sequestering the pro-apoptotic caspase en-

zymes (Altar, 1999).

Dysregulation of the hypothalamic–pituitary–

adrenocortical (HPA) system is well known and one

of the major neuroendocrine abnormalities in major

depressive disorder. This dysregulation includes

elevated levels of corticotropin-releasing hormone

(CRH) (Nemeroff et al., 1984), corticotropin (ACTH)

and cortisol (Linkowski et al., 1987) during depressive

episodes, which normalize after clinical remission.

Nevertheless, newer, more recent contributions to our

knowledge about depression have also been made.

Higher HPA activity during the first weeks of anti-

depressant pharmacotherapy seems to be associated

with lower rates of early treatment response (Hatzinger

et al., 2002). Furthermore, and significantly, persisting

cortisol hypersecretion indicates lower remission rates

(Ising et al., 2006) and a higher risk for recurrence of

depression, even when a reduction of depressive

symptoms or even clinical remission has been

achieved (Zobel et al., 1999). Moreover, during the

long-term course of depression, increasing HPA sys-

tem deterioration is highly correlated not only with

severity of disease, indicated by higher psychometric

depression scores, but also with the number of pre-

vious episodes (Hatzinger et al., 2002). However, both

molecular investigations and animal studies show that

classical antidepressants, e.g. TCAs, modulate regu-

lation of the HPA system by enhancing expression of

glucocorticoid receptors, thereby improving the feed-

back mechanism of the HPA system (Barden et al.,

1995 ; Holsboer and Barden, 1996). Thus, regulation of

the HPA system appears to play a major role in the

pathophysiology of depressive episodes. As such,

it opens a variety of new pharmacotherapeutic ap-

proaches to depression that differ fundamentally from

antidepressants available up to now.

The HPA and immune axis has become an import-

ant target for antidepressant development due to


the key role of stress in initiating depression. In the

development of novel drugs that target the HPA axis,

one approach involves antagonists of the CRF

(=CRH)-1 receptors. Clinical studies have shown that

the concentration of CRF is increased in the cerebro-

spinal fluid (CSF) of both suicide victims and in de-

pressed patients (Nemeroff, 1996). However, despite

initial promising clinical experience, so far CRF

antagonists have shown no efficacy in treating de-

pression in RCTs. More success has been reported

in developing glucocorticoid type-2 receptor anta-

gonists. This approach was based on the observation

that hypersecretion of cortisol is a frequent occurrence

in patients with chronic depression in which melan-

cholic features are prominent. Preliminary clinical

evidence suggests that novel glucocorticoid receptor

antagonists may be beneficial in such subgroups

of depressed patients (Gallagher and Young, In

Press).

In conclusion, there are many possibilities for the

future development of antidepressants. Microarray

technology should enable candidate genes to be

identified and targeted, and undoubtedly such meth-

ods will play an increasingly important role in drug

discovery in years to come. However, it seems that the

more conventional approach involving the identifi-

cation of malfunctioning neurotransmitters and their

signaling systems, and correcting their defects with

novel molecules, offers the greater chance of success in

the near term.

8.3 The role of pharmacogenetics in understanding

how antidepressants work

Pharmacogenetics, a term proposed by Vogel in

1959, is the study of genetically based, inter-individual

variability in response to drugs and their side effects.

It is now realized that polymorphisms of the cyto-

chrome P-450 microsomal oxidase system in the liver

are responsible for many of the genetic differences that

affect drug responsiveness and metabolism.

An important area that is related to pharmaco-

genetics is pharmacogenomics. Whereas pharmaco-

genetics is concerned with the individual patient and

how differences in metabolism and drug response are

a reflection of genetic makeup, pharmacogenomics

involves the structure of the genome and how targeting

compounds to it may lead to novel drugs that can be

used to treat specific psychiatric disorders.

Classical genetics of human disease concentrate on

monogenic disorders in which a single mutation or

gene is the cause of the disorder. However, complex

medical disorders such as diabetes, coronary artery

disease and hypertension, and psychiatric illness are

polygenic and therefore influenced by multiple factors

linked to the genetic substrate and the environment.

Recent research has tended to focus on genes that

encode neurotransmitter receptors together with en-

zymes involved in monoaminergic transmission. So

far, the results of studies have been equivocal in their

findings, with multiple claims for gene associations

that could not be replicated. The limitations of the

studies include small sample sizes coupled with the

small magnitude of the genetic effect. Nevertheless,

meta-analyses have identified several genetic variants

of candidate genes. In bipolar disorder, for example,

a variant of the MAO-A gene has been identified

(Furlong et al., 1999), although other investigators

have been unable to confirm this finding (Schulze et al.,

2000).

There have been several studies of the promoter

polymorphism of the serotonin transporter gene. The

type of polymorphism is functionally important, as

there appears to be an association between depression

and anxiety and the short allele (Lesch et al., 1996). In

addition, the short allele of this functional poly-

morphism in the promoter region of the serotonin

transporter gene was found to enhance the influence

of stressful life events on depression (Caspi et al.,

2003). However, once again, not all investigators have

been able to replicate this finding (Serretti et al., 1999).

Polymorphisms of other receptors and enzymes of the

biogenic amines have also been investigated. These

include the tyrosine and tryptophan hydroxylase

genes, the catechol-O-methyl transferase gene, as well

as genes for the serotonin and dopamine receptors

(Kato, 2001). To date these studies have yielded in-

conclusive or negative results.

In addition, functional polymorphisms in the

angiotensin converting enzyme (ACE) gene seem

to influence the risk for developing depressive dis-

orders (Arinami et al., 1996 ; Baghai et al., 2006a),

HPA axis activity (Baghai et al., 2002) and the clinical

effectiveness of antidepressant therapies (Baghai et al.,

2001 ; Bondy et al., 2005). Also, the glucocorticoid

receptor-regulating co-chaperone FKBP5 has been

shown to influence both the susceptibility to de-

pression and response to antidepressant treatment

(Binder et al., 2004).

The conventional view that unipolar depression is

under the control of the same genes irrespective of the

age of onset of the disorder has been challenged by

studies of late-onset depression (Hickie et al., 2001)

Thus, Hickie et al. (2001) have shown that late-onset

depression is associated with a mutation in the meth-

ylene tetrahydrofolate reductase gene, which controls


an important cofactor in monoamine biosynthesis ; this

mutation was not found in patients whose depression

occurred at an earlier stage. It appears that this same

mutation predisposes patients to cerebrovascular

disease and is associated with increased plasma

homocysteine and folate deficiencies, which fre-

quently occur in late-onset depression. Such observa-

tions serve to emphasize the difficulties that exist in

attempting to identify specific genetic factors that may

predispose to depression. Moreover, operationalized

diagnostic systems such as ICD-10 and DSM-IV, actu-

ally in use, promote only relatively fuzzy distinctions

between subgroups of depressed patients who suffer

from potentially biologically different diagnostic

entities. This confusion may contribute to reported

difficulties in association studies. In future, better diag-

nostic systems or investigation of endophenotypes

may help to define genetically different subgroups of

depressive disorders.

Only a few small studies have been published in

which pharmacogenetics has been used to predict

therapeutic response in individual patients. These

studies have investigated genetic variations in the

serotonin receptors (Lesch and Gutknecht, 2004),

serotonin transporter and their promoter regions,

and their associations with poor response to treatment

with SSRI antidepressants (Joyce et al., 2003 ; Zanardi

et al., 2001). Again, other investigators have been

unable to replicate the observations that these

parameters are associated with poor antidepressant

response (Kim et al., 2000). For a more extensive

update on recent findings, we refer to published re-

views on pharmacogenetics and pharmacogenomics

(Holsboer, 2001 ; Kirchheiner et al., 2004 ; Malhotra

et al., 2004; Mancama and Kerwin, 2003 ; Serretti et al.,

2005).

The current lack of knowledge of susceptibility

genes for depression seems unlikely to discourage

further research aimed at identifying the genetic basis

of mood disorders by the application of DNA

genotyping and genome-wide case-control studies

(Risch, 2000).

9 Pharmacological treatment options

9.1 The use of medication in the acute treatment of

depressive disorders

9.1.1 Introduction

This section provides general information regarding

benefits and risks during the pharmacotherapy of

depression, followed by further discussion regarding

mechanism of action and specific drugs. General

considerations during antidepressant acute and

maintenance therapies are described in chapter 7. The

treatment of depressive disorders consists of com-

plex multimodal therapy that is determined by the

current state of the illness. The main modalities are

pharmacotherapy, psychotherapy and sociotherapy33.

Although they are often used in combination, here

we will predominantly describe pharmacotherapeutic

options. Pharmacotherapy is not always mandatory

for less severe forms of depression, but severe de-

pression usually requires medication or electro-

convulsive therapy (ECT). In addition, a variety of

other biological interventions, such as sleep depri-

vation and bright light therapy, may be helpful in

certain patient subgroups. The discovery of tricyclic

antidepressants (TCAs) was a milestone in the treat-

ment of depression, and the TCA amitriptyline has

consistently been included in the World Health

Organization’s (WHO’s) list of essential drugs (World

Health Organization, 2005a), updated biennially,

although information about antidepressants has re-

mained unchanged over the last few years. In de-

veloping countries or in other countries in which

TCAs are preferred antidepressants it may also be

reasonable to consider drugs with proven efficacy that

are better tolerated than amitriptyline such as SSRIs

but that are sometimes not prescribed because of their

cost. However, despite the undoubted effectiveness

of TCAs, it soon became apparent that the anti-

cholinergic and antihistaminergic side effects of

TCAs such as Imipramine or Amitriptyline can cause

problems. New antidepressants, both TCAs such as

desipramine and newer classes such as SSRIs, NARIs

or SNRIs were developed with a more selective mode

of action. The results were lower rates of of anti-

cholinergic and antihistaminergic side effects in most

of the published studies. But interestingly also anti-

depressant effects of selectively anticholinergic acting

substances have been reported (Furey and Drevets,

2006).

For historical reasons, currently available anti-

depressants are usually classified according to their

chemical structure and mode of action. This classifi-

cation seems sensible, e.g. to separate TCAs and

tetracyclic antidepressants from modern substances

to describe safety and tolerability properties and to

follow widespread habits and to follow a scientific and

historical classification. Nevertheless it may be useful

to use a different ordering scheme in evolving treat-

ment plans and algorithms. Classification according to

33 Sociotherapy designates non-medical, social and work-related

components of the care process.


the predominant mode of action, which is already ap-

plied to modern antidepressant substances, is more

logical and practical. We thus suggest describing dif-

ferent classes of modern antidepressants according

their main mode of action, and recommend subdivid-

ing the older tri- and tetracyclic substances according

their predominant influence on serotonergic and nor-

adrenergic neurotransmission. In this review, we

present the classes of antidepressants in their ap-

proximate chronological order.

Currently, tri- and tetracyclic antidepressants with

predominant serotonergic (S-TCA), noradrenergic

(N-TCA) or mixed serotonergic/noradrenergic (S/N-

TCA) action are available. To simplify things for more

practicable treatment plans, tri- and tetracyclic anti-

depressants are summarized within the TCA group34.

Additional agents on the market include selective

and reversible inhibitors of monoamine oxidase A

(RIMA); an irreversible MAO-B inhibitor (MAOBI) ;

non-selective and irreversible inhibitors of MAO-A

and -B (MAOIs) ; selective serotonin reuptake in-

hibitors (SSRIs) ; selective noradrenaline reuptake in-

hibitors (NARIs) ; antidepressants with a dual mode of

action, such as selective serotonin and noradrenaline

reuptake inhibitors (SNRIs) ; and noradrenergic and

specific serotonergic antidepressants (NaSSAs) acting

via blockade of a2- and 5-HT2 receptors and enhanced

release of noradrenaline and serotonin (Blakely, 2001;

Frazer, 2001 ; Haddjeri et al., 1998 ; Kent, 2000 ; Pacher

et al., 2001 ; Stahl, 1998b). In addition, a dopamine

and noradrenaline reuptake inhibitor (DNRI) and

serotonin modulating antidepressants (SMAs) are

available. The most recently developed mechanism

of action is agonism at melatonergic MT1 and MT2

receptors and selective antagonism at serotonergic

5-HT2C receptors, represented by the antidepressant

agomelatine (Audinot et al., 2003), which is currently

under review by authorities in Europe. Other

developments include the use of single enantiomers

instead of racemic compounds35.

A consistent trend towards increased use of generic

antidepressants over the last few years has been re-

ported (Bruck et al., 1992)36. In addition, it remains

unclear whether pharmacogenetic differences in popu-

lations of different countries play a major role in

clinical trials investigating efficacy and tolerability.

Moreover, outsourcing of clinical trials may cause

difficulties in interpreting study results ; caution is re-

commended, especially in cases where study results

from different countries are pooled. In particular, there

is concern that the practice by pharmaceutical com-

panies of comparing the results of multicenter studies

carried out in many different countries could raise

doubts about the findings.

A summary of commonly used antidepressants, in-

cluding their primary mode of action and influence on

other receptor systems, is shown in Table 1. According

the review from Sanchez et al. (1999) semiquantitative

information about receptor affinities concerning the

main pharmacodynamic mode of action of the anti-

depressants and their major metabolites has been in-

cluded (Sanchez and Hyttel, 1999). Similar

information about receptor affinities concerning sec-

ondary and additional pharmacodynamic profiles

may not be helpful in clinical routine due to a huge

interindividual variation in the sensitivity of de-

pressed patients. Therefore this detailed information

has been omitted. Possible adverse events can be de-

duced from chapter 7.3 and Table 16, the magnitude of

adverse events due to secondary pharmacodynamic

actions has to be evaluated in each individual patient

and may vary during the treatment course.

Box 6. Definitions efficacy/clinical effectiveness/efficiency

Efficacy is the power of a substance to produce the effects that it is supposed to produce (e.g. antidepressant effects).

Clinical effectiveness is the ability to successfully achieve clinical remission.

Efficiency describes the relationship between effectiveness and the spent resources and costs.

34 For educational purposes it could be justified to use only a

pharmacodynamic classification model of antidepressants. Due to

historical reasons and after a consensus process in addition the

classification according the chemical structure was retained.35 Antidepressants such as fluoxetine, trimipramine, mirtazapine,

mianserin, venlafaxine and reboxetine are generally marketed as

racemic compounds. Both the pharmacological and pharmacokinetic

profiles of these substances may differ between the enantiomers, e.g.

of citalopram (Baumann et al., 2002 ; Baumann and Eap, 2001) or

fluoxetine. In the case of the latter, a different pharmacological

profile of the two enantiomers may cause differences in cardiac

tolerability (Magyar et al., 2003).

36 Original brand-name antidepressants and generic substances are

assumed to exert similar efficacy and tolerability, but we do not

know whether that is true for each country. Direct comparisons

between brand-name formulations and generics and between

different generic substances have not yet been published.


Despite the development of a variety of new anti-

depressants with different pharmacodynamic profiles,

to date the hope of better efficacy and clinical

effectiveness (see Box 6) over older antidepressants

has not been fulfilled.

In contrast to efficiency, the focus of effectiveness is

achievement as such, not the resources spent, so any-

thing that is effective is not necessarily efficient, but

anything that is efficient also has to be effective. In

psychiatry, the distinction between efficacy (ideal use)

and clinical effectiveness (typical use) is often drawn.

Whereas efficacy may be shown in clinical trials,

clinical effectiveness has to be demonstrated in clinical

practice.

Some reports of better efficacy for some recently

developed antidepressants require further confir-

mation. Up to now there is no consensus that any

of the recently developed antidepressants showed

superiority in head-to-head comparisons with older

antidepressants such as TCA or irreversible MAOI’s

concerning their clinical effectiveness. But even in

the case of a proven efficacy of antidepressants the

clinical effectiveness may be diminished due high

discontinuation rates. These seem to be influenced

by noncompliance due to side effect profiles of anti-

depressants (Hotopf et al., 1997). In addition, it is

necessary to evaluate the clinical relevance of small

mean differences in depression rating scales between

active substances or antidepressant and placebo treat-

ment, even in the case of statistical significance.

Moreover, the results of failed trials, e.g. due to high

placebo response rates, and the probable huge amount

of still unpublished data from clinical trials, should be

evaluated before recommendations for specific sub-

stances can be made (see chapter 4.4).

The usual recommended daily dosages for starting

and maintaining antidepressant treatments are pre-

sented in Table 11.

A further problem is the lack of information about

both efficacy and tolerability of antidepressants for

large portions of the world population. Predominantly

genetic, but also cultural differences, may contribute to

a differential responsiveness of ethnic groups during

antidepressant treatment. In interpreting the existing

literature it is particularly important to consider the

lack of information about the treatment effects of most

and especially newer antidepressants, e.g. in the black

African population.

Nevertheless, the main advantages of newer anti-

depressants are the overall better tolerability and

safety in comparison with older substances. Although

newer antidepressants are better tolerated and cause

fewer and less serious side effects, their specific

Table 11. Commonly used antidepressants, including dosage

recommendations37

Generic name

Dose recommended by the producer

Startingdose (mg)

Dosage range(mg/day)

Agomelatine 25 25–50Amitriptyline 25–75 150–300Amitriptylinoxide 30–60 180–300Amoxapine 50 100–400Bupropion 100 200–300Citalopram 20 20–60Clomipramine 25–50 100–250Desipramine 25–75 100–300Dibenzepine 120–180 240–720Dosulepine/Dothiepin 75 75–150Doxepin 25–75 150–300Duloxetine 40/6038 60–120Escitalopram 5–10 10–20Fluoxetine 20 20–80Fluvoxamine 50–100 100–300Imipramine 25–75 150–300Isocarboxacid 20 20–60Lofepramine 70 140–210Maprotiline 25–75 150–225Melitracen 20 20–30Mianserin 30 60–120Milnacipran 50 100–200Mirtazapine 15 30–45Moclobemide 150–300 300–600Nefazodone 100 300–600Nortriptyline 25–50 75–300Paroxetine 20 20–60Phenelzine 15 30–90Protriptyline 10 20–60Reboxetine 4 8–12Selegiline oral : 30 oral : 30–60

transdermal : 6 transdermal : 6–12Sertraline 50 50–200Tianeptine 37.5 37.5Tranylcypromine 10 20–40Trazodone 50–100 200–600Trimipramine 25–50 150–400Venlafaxine 75 75–375Viloxazine 100 200–500

37 Different dosages are used on different continents and in different

countries (Patten et al., 2005 ; Sartorius, 1986). For some populations,

e.g. Japanese patients, the dose recommendations presented above

are usually too high. In addition, marketing aspects may influence

dosage recommendations owing to calculation of the lowest possible

daily treatment costs. Indication-adjusted dose recommendations

may also be important. Finally, indications for antidepressants vary

from one country to another.38 Recommended starting dose in the US is 40 mg ; in Europe it is

60 mg.


side-effect profile still must be taken into account

during treatment. In addition, the latency of several

weeks until the onset of sufficient therapeutic effects

remains a serious and clinically relevant problem. This

principle holds true for each antidepressant and each

class of antidepressant mechanisms. There are some

reports of a faster onset of response for newer dual-

acting compounds, e.g. mirtazapine (Benkert et al.,

2000 ; Benkert et al., 2006 ; Leinonen et al., 1999;

Montgomery, 1999) and venlafaxine (Benkert et al.,

1996 ; Montgomery, 1999) in comparison to other anti-

depressants e.g. SSRIs or TCAs, but the clinical rel-

evance of these findings remains controversial (Blier,

2003 ; Nierenberg, 2001). In addition early drug-

specific behavioral changes which may be predictive

for the clinical response (Katz et al., 2004) are not re-

corded sufficiently in all RCTs. Moreover, demo-

graphic factors and treatment settings appear to

influence antidepressant choice more than clinical fac-

tors and evidence (Sim et al., 2006). The only methods

of achieving more rapid acting, but unfortunately in

most cases not sustained, antidepressant effects are

wakefulness therapy (Wu and Bunney, 1990) (see

chapter 12.3.6) and in some patients, in a more potent

and enduring way, ECT (ECT review group, 2003;

Gangadhar et al., 1982) (see chapter 12.3.1).

A further general problem in the pharmacotherapy

of depression is the possible non-response to initial

antidepressant treatment (Charney et al., 2002;

Nierenberg and Amsterdam, 1990; Sackeim, 2001).

The problem of inconsistencies in defining treatment

resistant/refractory depression (see the definition in

Box 8) has been described in a recent review (Berlim

and Turecki, 2007).

About 50% of depressed patients do not respond

adequately to a first course of an adequate anti-

depressant treatment (about 30% do not show satis-

factory improvement, and about 20% drop out due

to problems of tolerance). Adequacy of treatment

includes treatment with proven efficacy during a time

interval of at least 4–6 weeks in a sufficient therapeutic

dose range, including reliable patient adherence to

therapy (Fava, 2003a; Kupfer and Charney, 2003;

Sackeim, 2001). Half of these patients fail to respond to

a second antidepressant treatment trial. If several

antidepressant treatment trials have been ineffi-

cacious, even lower response rates after switching to

another drug may be observed (Fava et al., 2006).

Some authors include the use of augmentation strat-

egies in the definition of treatment resistance or non-

response to antidepressant treatment. In addition

to obvious biological hypotheses for therapy resist-

ance, such as occult medical conditions causing

depression, substance abuse interfering with anti-

depressant treatments or abnormal metabolism (Rush

et al., 2003b), psychosocial factors, too, may be re-

sponsible for failed treatment trials (Grote and Frank,

2003). As described further below, even given the dif-

ficulty in predicting the most effective solution for any

one patient, the range of appropriate pharmacological

treatment strategies includes adjustment of dosage,

switch to an antidepressant of another class, switch

to an antidepressant of the same class, combination

therapies with more than one antidepressant, and

pharmacological and non-pharmacological augmen-

tation strategies. Strategies such as lithium augmen-

tation (Bauer et al., 2003 ; Zullino and Baumann, 2001)

or augmentation using thyroid hormones (Bauer et al.,

1998) and other available methods are described in

chapter 9.1.12. In addition, the concomitant use of

benzodiazepines, e.g. lorazepam for the treatment of

agitation in depressive disorder or alprazolam for the

treatment of anxiety in depression (Moller, 2002), can

be a clinically useful addendum. Prescription of

anxiolytics as a monotherapy is barely effective in

severe depression (Laakmann et al., 1996). Never-

theless, in the case of persistent non-responsiveness,

the UK ECT review group and other authors consider

the use of ECT in comparison with all of these strat-

egies as clinically more effective and still the method

of choice for treatment-resistant depression (Davidson

et al., 1978 ; ECT review group, 2003 ; Folkerts et al.,

1997 ; Kroessler, 1985) even if not all of these patients

respond well to ECT.

Box 7. Definition of pharmacotherapy-resistant depression (modified according to Berlim and Turecki, 2007 ; Burrows et al.,

1994 ; Fava, 2003b; Fava and Davidson, 1996 ; Helmchen, 1974 ; Leonard, 1988 ; Nierenberg and Amsterdam, 1990 ; Rush et al.,

2003b; Sackeim, 2001 ; Souery et al., 1999 ; Thase et al., 1997)

Therapy resistance or non-response to treatment in depression are terms used to describe the lack of reaction to appropriate

treatment.

The definition of appropriate treatment varies among experts. While some consider that appropriate treatmentmust include

two courses of pharmacotherapy with antidepressants of different groups in sufficient doses and duration (Burrows et al.,

1994), others believe that, in addition, pharmacotherapeutic augmentation therapy and treatment with cognitive-behavioral

therapy and interpersonal psychotherapymust precede the decision that the condition is therapy resistant (Thase et al., 1997).


Non-response to pharmacotherapy (see Box 7) used

as primary treatment implies that sufficient treatment

attempts have been made with efficacious psy-

chotherapies such as cognitive-behavioral therapy

(CBT) or interpersonal psychotherapy (IPT) (Thase

et al., 1997). The following chapters introduce the

intravenous use of antidepressants, pharmacogenetics

and therapeutic drug monitoring, and general side

effects, then describe all presently available anti-

depressants according their mode of action, clinical

effectiveness and main side-effect and risk profile.

9.1.1.1 Metabolism, pharmacokinetics, pharmacogenetics,

therapeutic drug monitoring and interactions of

antidepressants

9.1.1.1.1 Introduction

The pharmacological effect of an antidepressant de-

pends on its presence in the target organ, i.e. the brain.

Metabolites may contribute to its overall activity

(Hendset et al., 2006 ; Rudorfer and Potter, 1997).

Therefore, the consequences of its absorption, distri-

bution, metabolism and elimination (ADME), which

are the fundamental parameters defining its pharma-

cokinetics, must be considered at a level of importance

similar to that of its pharmacodynamics at receptor

and transporter sites. Cytochrome P-450 and con-

jugating enzymes are the main enzyme systems in-

volved in the metabolism of antidepressants. The

study of their individual roles helps to understand

pharmacokinetic interactions and their clinical conse-

quences, even though, especially in the case of TCAs,

a clear correlation between clinical response and

plasma levels of antidepressants cannot be drawn

(Burrows et al., 1972 ; Burrows et al., 1977). Many

isozymes of cytochrome P-450 and glucuronidating

enzymes present a genetic polymorphism, which re-

sult in important interindividual differences in drug

metabolism in patients. Thus it may be assumed that

drug plasma concentrations, rather than dose, reflect

concentration in the brain, and this assumption has

prompted numerous studies on the relationship of

drug plasma concentrations and clinical effects and

the introduction of therapeutic drug monitoring

(TDM).

9.1.1.1.2 Metabolism and pharmacogenetics of

antidepressants

Most antidepressants are metabolized by a phase I

reaction implicating one or several isozymes of cyto-

chrome P-450 to more polar metabolites. Then, via a

phase II reaction, they undergo conjugation (Table 12)

(Liston et al., 2001). Drugs such as tertiary amine TCAs

and SSRIs such as fluoxetine, citalopram and escitalo-

pram, but also venlafaxine are converted to active

metabolites that may also be eliminated by phase I and

phase II enzymes.

As both environmental and genetic factors deter-

mine the fate of the drug in the organism, pharmaco-

genetic tests represent a useful tool for diagnosing the

metabolic status of the patient. The first case report

on the clinical consequences of impaired hydroxyla-

tion of nortriptyline, due to a genetically determined

poor metabolizer status (CYP2D6) and high plasma

concentrations of this antidepressant in a depressed

patient (Bertilsson et al., 1981), prompted rapid de-

velopment of research in the field of pharmacogenetics

of psychotropic drugs. Most forms of cyctochrome

P-450 implicated in the metabolism of antidepressants

present a genetic polymorphism (CYP1A2, CYP2C9,

CYP2C19, CYP2D6, CYP3A5 and CYP2B6), or their

activity varies highly among individuals (CYP3A4)

for as yet unknown reasons. The genetic polymor-

phism of CYP2D6 is the most relevant for the metab-

olism of psychotropic drugs (Table 12). Generally,

gene deletion or a defective gene leads to poor

metabolizer (PM) status, and gene duplication or

multiplication results in ultrarapid drug metabolism

(ultrarapid metabolizer, UM). These patients differ

from extensive (EM) or intermediate (IM) metab-

olizers, who are carriers of two or one active genes,

respectively. The proportion of PMs, EMs, IMs and

UMs differs among different ethnic groups. From a

clinical point of view, PMs have a higher risk of

experiencing adverse effects as a consequence of

impaired drug metabolism, whereas UMs are at risk of

non-response to a treatment due to the fact that even at

high doses, steady-state drug concentrations may not

reach therapeutic levels. This situation is illustrated

by case studies of UMs who responded to tricyclic

drugs only after very high drug doses (Bertilsson

et al., 1985) or after comedication with a cytochrome

P-450 inhibitor (Baumann et al., 1998 ; Conus et al.,

1996).

Genotyping and phenotyping represent certain

‘trait markers’ and ‘state markers’, respectively

(Steimer et al., 2001). Phenotyping is available for most

of the above-mentioned CYP isozymes. It is generally

carried out by administering one or several (‘cocktail ’)

test probes to patients and subsequently collecting

blood or urine, followed by analyzing the parent

compound and the metabolite formed by the particu-

lar enzyme (Clement Jerdi et al., 2005). Clearly, the

result of phenotyping is influenced by comedication,


Table 12. Antidepressants as substrates of cytochrome P-450 (CYP)

Class of

antidepressants Drug

Active (and clinically

non-relevant) metabolites

Drug (and/or metabolite)

substrate of

CYP2D6 CYP2C19

Other forms

of CYP

Tricyclic and structurally related antidepressants

Amitriptyline + (+) + CYP3A4,

nortriptyline + CYP1A2,

(10-OH-amitriptyline) + CYP2C9

(10-OH-nortriptyline)

Amitriptyline N-oxide (+) (+) (CYP3A4,

CYP1A2,

CYP2C9)

amitriptyline and others

(cf. amitriptyline)

Clomipramine + (+) + CYP1A2,

CYP3A4,

CYP2C19

desmethylclomipramine + (+)

(2- and 8-OH-clomipramine)

Desipramine +

Dothiepine

(2-OH-desipramine)

·

Doxepin (a) + + CYP2C9,

CYP1A2desmethyldoxepin (a)

Imipramine + (+) + CYP1A2,

CYP3A4desipramine +(2-OH-imipramine)

(2-OH-desipramine)

Lofepramine (+)

desipramine +(2-OH-desipramine)

Maprotiline + CYP1A2

(N-desmethylmaprotiline)

(3-OH and 2-OH-maprotiline)

Mianserin (b) + + CYP3A4,

CYP2B6,

CY1A2

N-desmethylmianserin

+(mianserin N-oxide)

(8-OH-mianserin)

Milnacipran ·

Mirtazapine (b) + · CYP1A2,

CYP3A4N-desmethlymirtazapine +(8-OH-mirtazapine)

Nortriptyline

(10-OH-nortriptyline)

+Trimipramine (b) + (+) + CYP3A4

desmethyltrimipramine +(OH-metabolite)


Table 12. (cont.)

Class of

antidepressants Drug

Active (and clinically

non-relevant) metabolites

Drug (and/or metabolite)

substrate of

CYP2D6 CYP2C19

Other forms

of CYP

SSRIs

Citalopram (b) + (+) + CYP3A4

desmethylcitalopram +(didesmethylcitalopram)

(citalopram propionic acid derivative)

Escitalopram + (+) CYP3A4

S-desmethylcitalopram +(S-didesmethylcitalopram)

(S-citalopram propionic acid derivative)

Fluoxetine (b) + (+) + CYP2C9,

CYP3A4norfluoxetine +

Fluvoxamine + - CYP1A2

Paroxetine +Sertraline x + CYP3A4,

x2C9, x2B6norsertraline

Other antidepressants

Bupropion x CYP2B6

Dibenzepine ·

Duloxetine + CYP1A2

(desmethylduloxetine)

Milnacipran x x xNefazodone x (+) CYP3A4

3-OH-nefazodone

m-CPP +Reboxetine (b) x CYP3A4

Trazodone + (+) CYP3A4,

CYP1A2

m-CPP

Venlafaxine (b) + + CYP2C9,

CYP3A4O-desmethylvenlafaxine

(N-desmethylvenlafaxine)

(N,O-didesmethylvenlafaxine)

Viloxazine ·

St. John’s wort ·

MAOIs

Moclobemide x +Tranylcypromine ·

* From Baumann (in preparation), (cf. also Wilkinson, 2005).

·No studies available.

(a) A mixture of geometric isomers : the isomers differ in their pharmacological and pharmacokinetic profile.

(b) Chiral drugs : the isomers (of the drug and of their chiral metabolites) may differ in their pharmacological and pharmaco-

kinetic profile.


which inhibits the test enzyme. Guidelines are avail-

able for the optimal use of pharmacogenetic tests

(De Leon et al., 2006).

Because their clinical relevance has not yet been

demonstrated in studies with psychiatric patients, we

will mention only briefly that transport proteins such

as P-glycoprotein may regulate the transport of many

drugs, including antidepressants, from the intestine

into the blood and through the blood-brain barrier

(Fromm, 2000; Kim, 2006; Lin, 2003 ; Marzolini et al.,

2004). Some but not all antidepressants are substrates

of this transport protein, which displays a genetic poly-

morphism (Uhr et al., 2000 ; Uhr and Grauer, 2003).

9.1.1.1.3 TDM of antidepressants

TDM of antidepressant drugs is widely practiced

to optimize the pharmacotherapy of depression

(Baumann et al., 2004 ; Brøsen, 1996; Burke and

Preskorn, 1999 ; Mitchell, 2000 ; Mitchell, 2004).

Table 13 lists indications for TDM of antidepressants

and other psychotropic drugs. Bear in mind that, un-

fortunately, poor compliance is observed not only in

patients treated with antidepressants (Meijer et al.,

2001). Treating physicians also induce underuse or

inappropriate use of TDM for antidepressants (Mann

et al., 2006b). Only for some antidepressant drugs,

such as TCAs (and lithium), in contrast to former

publications (Burrows et al., 1972 ; Burrows et al.,

1977) now there is reasonably good evidence for a re-

lationship between drug plasma concentration and

clinical effectiveness (Baumann et al., 2004). Table 14

represents the result of a consensus among experts

with regard to recommended plasma concentration

ranges (‘ therapeutic windows’) for antidepressants.

The concomitant analysis of the active metabolite

is mandatory for some drugs, as indicated in Table 14.

This consensus guideline includes a comprehensive

list with drugs with a recommended TDM level

for each one, as well as numerous recommendations

for treating physicians and laboratories about how

to use TDM optimally. It also contains tables sum-

marizing the literature data on drug plasma con-

centrations measured at fixed doses and they may

inform about the reliability of the drug plasma con-

centration measured in a patient treated with a par-

ticular dose.

9.1.1.1.4 Pharmacogenetics and TDM

It is now generally acknowledged that pharmacoge-

netic tests represent a useful tool in finding an optimal

drug dose (Bertilsson et al., 2002 ; Ensom et al., 2001;

Ingelman-Sundberg et al., 1999; Steimer et al., 2001),

but clearly tests should be combined with TDM

(Baumann et al., 2004 ; Kirchheiner et al., 2001;

Kirchheiner et al., 2004). Pharmacogenetic tests are

also recommended in elderly patients as part of an

approach aimed at avoiding adverse effects (Egger

et al., 2005). The main advantage of these tests is to

explain unexpected plasma concentrations of drugs

and their metabolites.

A few pharmacoepidemiological studies confirm

that, indeed, the CYP2D6 genotype determines the

plasma concentration of some antidepressants

(Grasmader et al., 2004 ; Mulder et al., 2006), and one

Table 13. Indications for TDM of antidepressants (according to Baumann et al., 2004)

Suspected non-compliance

Drugs for which TDM is mandatory for safety reasons (e.g. lithium)

Lack of clinical response, or insufficient response even if doses considered adequate

Adverse effects despite the use of generally recommended doses

Risk for drug interactions in comedicated patients

Situations involving problems of pharmacovigilance

Relapse prevention in long-term treatment, prophylactic treatment

Recurrence despite good compliance and adequate doses

Presence of a genetic particularity concerning drug metabolism (genetic deficiency, gene multiplication)

Special populations

$ Children and adolescents

$ Elderly patients (o65 years)

$ Patients with somatic comorbidities (hepatic or renal insufficiency, cardiovascular disease)

Forensic psychiatry

Problems occurring after switching from an original preparation to a generic form (and vice versa)


may conclude that CYP2D6 genotyping before starting

pharmacotherapy could help to prevent increased

drug plasma concentrations and concentration-

dependent adverse effects. There is some preliminary

support for the hypothesis that pharmacogenetic tests

may also be advantageous from an economic point of

view, as they may help to avoid adverse effects and

rehospitalization, and reduce the duration of hospi-

talization (Chen et al., 1996). A recent analysis of the

literature demonstrates the advantage of including

TDM and pharmacogenetic tests in pharmaco-

vigilance programs (Jaquenoud Sirot et al., 2006)

(cf. also Phillips et al., 2001). However, despite a

25-year history of pharmacogenetics in psychiatry,

these tests are still rarely routinely used, as shown in

a recent study carried out in New Zealand and

Australia (Gardiner and Begg, 2005), in spite of some

recommendations to introduce pharmacogenetic test-

ing into clinical practice (De Leon, 2006 ; De Leon et al.,

2006a; De Leon et al., 2006b; Gardiner and Begg, 2006 ;

Zourkova and Hadasova, 2003).

9.1.1.1.5 Pharmakokinetic interactions

Many patients are comedicated with other psycho-

tropic and/or somatic drugs as a consequence of co-

morbidities or non-response to monotherapy. Patients

suffering from recurrent depression are submitted to

long-term treatment. This increases the lifetime risk of

comorbidities, which necessitate simultaneous treat-

ment with several drugs. Adverse effects are then to be

expected as a consequence of pharmacodynamic in-

teractions between drugs or when a pharmacokinetic

interaction results in an increase in drug plasma con-

centrations, which may reach toxic levels.

Several drugs (fluoxetine, paroxetine, fluvoxamine,

trimipramine etc.) and metabolites (norfluoxetine)

are known to be clinically relevant inhibitors of

some forms of cytochrome P-450 (Table 12). As a

consequence, pharmacokinetic interactions between

antidepressants and other drugs (including anti-

depressants) may have important clinical conse-

quences, as they may act as substrates and/or

inhibitors of cytochrome P-450 (Table 12). Classical

examples are the interaction between fluvoxamine

(Bertschy et al., 1991) or fluoxetine (Aranow et al.,

1989) and tricyclic drugs.

Table 15 lists some of the most potent inhibitors and

inducers of the cytochrome P-450 isoforms CYP1A2,

CYP2C9, CYP2C19, CYP2D6 and CYP3A4/5

(Armstrong and Cozza, 2000 ; Baxter, 2006 ; Bonnabry

et al., 2001 ; Cozza and Armstrong, 2005 ; Jaquenoud

Sirot et al., 2006 ; Wilkinson, 2005) (cf. also http://

medicine.iupui.edu/flockhart/table.htm (14-8-2006),

www.pharmacoclin.ch (14-8-2006)). It is striking to

observe that authors differ in their appreciation of

the inhibiting and inducing properties of some

compounds (cf. also Armstrong and Cozza, 2000).

Regrettably, some therapists tend to avoid ‘risky’ co-

medications, which per se could be extremely useful

for the patient. TDM should be recommended to allow

concomitant treatments that, a priori, seem to present

a risk but that could be highly beneficial for some

patients.

9.1.1.2 Galenic forms of antidepressants

9.1.1.2.1 Oral antidepressants

Antidepressant medication used for oral application

is delivered as immediate release (IR) and extended

release (ER, XR) formulations. In addition quick

dissolving tablets are available from some manu-

facturers possibly enhancing the convenience by the

Table 14. TDM of antidepressants : recommended plasma

concentration ranges (‘ therapeutic windows’)

(Baumann et al., 2004)

Drug and active metabolite

Antidepressants

Recommended

therapeutic range

(consensus)

Amitriptyline plus nortriptyline 80–200 ng/ml

Citalopram 30–130 ng/ml

Clomipramine plus norclomipramine 175–450 ng/ml

Desipramine 100–300 ng/ml

Doxepin plus nordoxepin 50–150 ng/ml

Escitalopram 15–80 ng/ml

Fluoxetine plus norfluoxetine 120–300 ng/ml

Fluvoxamine 150–300 ng/ml

Imipramine plus desipramine 175–300 ng/ml

Maprotiline 125–200 ng/ml

Mianserin 15–70 ng/ml

Mirtazapine 40–80 ng/ml

Moclobemide 300–1000 ng/ml

Nortriptyline 70–170 ng/ml

Paroxetine 70–120 ng/ml

Reboxetine 10–100 ng/ml

Sertraline 10–50 ng/ml

Tranylcypromine f50 ng/ml

Trazodone 650–1500 ng/ml

Trimipramine 150–350 ng/ml

Venlafaxine plus

O-desmethylvenlafaxine

195–400 ng/ml

Viloxazine 20–500 ng/ml


patients (Behnke et al., 2003). While there is common

consensus that no differences concerning the clinical

effectiveness can be observed, tolerability advantagtes

of ER formulations in comparison to IR formulations

have been reported e.g. in case of the SNRI venlafaxine

(DeVane, 2003 ; Entsuah and Chitra, 1997 ; Norman

and Olver, 2004 ; Olver et al., 2004).

9.1.1.2.2 Transdermal antidepressants

To date only one antidepressant, the MAOBI selegiline

is available in some countries as a transdermal patch

(see chapter 9.1.2). The patients’ acceptance seems to

be good and it has been described that the transdermal

system possibly may excert a better efficacy in com-

parison to orally administered selegiline (Morgan,

2007).

9.1.1.2.3 Intravenous antidepressants

Parenteral administration of antidepressants during

the first 2 weeks of an acute depressive episode is

common practice in several countries, particularly

in continental Europe. However, the advantages of

parenteral over oral administration of antidepressants,

if any, have not been clearly demonstrated, neither

from a pharmacological nor from a clinical viewpoint.

It is reasonable to suggest that intravenous (i.v.)

administration avoids intermediate stages and thus

may result in higher plasma levels of TCAs. Unfortu-

nately, most of the relevant literature is published

in languages other than English, and access to it is

limited. There has been, however, published, that

intravenous administration of Clomipramine and

Maprotiline may have a faster onset of action in com-

parison with oral therapy (Gastpar et al., 1986).

The drugs that are currently available for i.v. ad-

ministration are clomipramine, doxepine, maprotiline,

citalopram and mirtazapine. Note that clomipramine

is not approved by the FDA for treatment of de-

pression but only for obsessive-compulsive disorder

(OCD). In continental Europe, however, i.v. clomi-

pramine infusions are common practice, although

research that supports the treatment is lacking.

Eight studies have been published on the treatment

of refractory depression (Bogdanowicz et al., 1991;

Ceskova et al., 1983; Fountoulakis et al., 2004 ; Laux

and Reimer, 1979 ; Nahunek et al., 1983 ; Ravizza, 1979;

Sallee et al., 1997 ; Zapletalek et al., 1982), only three

on the treatment of OCD (Fallon et al., 1998; Koran

et al., 1998 ; Mundo et al., 1999), whereas another

three studies use i.v. clomipramine as a challenge

test (Golden et al., 1990 ; Kupfer et al., 1991 ; Sallee

et al., 1998). Open studies are confirming a fast onset

of treatment response with parenteral clomipramine

and desipramine in drug resistant depression

within one week (Ceskova et al., 1983 ; Nahunek et al.,

1983).

Table 15. Typical inhibitors and inducers of cytochrome

P-450

Antidepressants and

other CYP-450 substrates

CYP inducing (+) and

inhibiting (x) properties

Broccoli (Brassica oleracea) CYP1A2+Caffeine CYP1A2xCarbamazepine CYP2C9+, CYP3A+Cimetidine CYP1A2x, CYP2D6x,

CYP2D6xCiprofloxacin CYP1A2xClarithromycin CYP3AxDexamethasone CYP2C9xDihydralazine CYP1A2xDiltiazem CYP3AxEfavirenz CYP3A+Erythromycine CYP3AxFluoxetine CYP2C19x, CYP2D6xFluvoxamine CYP1A2x, CYP2C9x,

CYP2C19xGrapefruit juice (Citrus paradisi) CYP3AxHaloperidol CYP2D6xIndinavir CYP3AxIntraconazole CYP3AxKetoconazole CYP3AxLevomepromazine CYP2D6xMDMA (‘ecstasy’) CYP2D6xMexiletine CYP3AxMifepristone CYP3AxNefazodone CYP3AxNevirapine CYP3A+Norfloxazine CYP1A2xOmeprazole CYP1A2+Paroxetine CYP2D6xPhenobarbital CYP2C9+, CYP3A+Phenytoin CYP2C9+, CYP3A+Primidone CYP2C9+Rifampicin CYP1A2+, CYP2C9+,

CYP3A+Ritonavir CYP1A2+, CYP3AxRofecoxib CYP1A2xSaquinavir CYP3AxSt. John’s wort

(Hypericum perforatum)

CYP2C9+, CYP3A+

Tobacco smoking (Nicotiana) CYP1A2+Valproic acid CYP3Ax, CYP2C9xVerapamil CYP3Ax


The usual practice of infusions suggests starting

with ½ ampoule (amp) of clomipramine (1 ml,

12.5 mg) and adding 1 amp (2 ml, 25 mg) every day

to reach a maximum of 5–6 amp (125–150 mg).

Anecdotal data report higher doses up to 8–9 amp per

day (200–225 mg), but this is considered to be a highly

aggressive strategy not supported by the literature.

Close monitoring of cardiac function and blood pre-

ssure is essential because of side effects. Maprotiline is

also available in i.v. form (Drago et al., 1983 ; Kissling

et al., 1985; Zapletalek et al., 1982), but data regarding

its efficacy are few. Intravenous citalopram was re-

cently introduced (Kasper and Muller-Spahn, 2002).

In one double-blind study i.v. citalopram showed

superior response rates over oral (p.o.) citalopram

(79 vs. 63%) in severely depressed patients at 8 weeks

(Guelfi et al., 2000 ; review: Moukaddam and

Hirschfeld, 2004). It has also been shown to be effective

in the treatment of OCD in an open trial (Pallanti et al.,

2002). Even more recently, i.v. mirtazapine was in-

troduced and was reported to be effective in the

treatment for depressed patients in open naturalistic

studies (Konstantinidis et al., 2002 ; Muhlbacher et al.,

2006).

Overall, the practice of i.v. administration has not

been adequately shown to be superior to oral admin-

istration in the majority of depressive patients, but it

may be recommended for treatment of refractory

cases. In these refractory cases, it seems that at least

some of these patients benefit from the bypassing of

the gastrointestinal tract and achieve better and faster

drug levels.

9.1.1.3 Summary of side effects39

Antidepressant drugs can produce common side

effects according their receptor profiles. In addition,

possible discontinuation symptoms and the potential

for allergic reactions and blood dyscrasias must be

taken into consideration.

The use of TCAs appeared to be problematic in

some cases due to their inherent side-effect profile.

Anticholinergic and antihistaminergic side effects are

of particular concern, and possible cardiovascular

complications, especially in case of overdose, have

consequently limited their use (Burrows et al., 1976 ;

Burrows et al., 1981 ; Vohra et al., 1975; Vohra and

Burrows, 1974). New antidepressants have a more

selective mode of action and are therefore more fre-

quently used as a first-line therapy due to their favor-

able tolerability profile (Burrows and Norman, 1997).

Despite their fewer anticholinergic effects, however,

it is important to pay attention to the specific side-

effect profiles of the newer substances. In particular,

the activating properties of NARIs can cause tremor

and restlessness together with sleep disturbances.

SSRIs raise serotonin levels at multiple sites and at

multiple receptors throughout the brain (Stahl,

1998a), and can lead to nausea, headache, agitation

and a general ‘activation syndrome’, sexual dysfunc-

tion and sometimes sleeplessness. Substances with

additional antihistaminergic properties, such as

mianserin, mirtazapine and doxepin, may induce

drowsiness, especially during the beginning of the

treatment. Later, increased appetite and weight gain

often emerges as a problem that markedly influences

compliance (Kent, 2000). Especially during the first

days of use of antihistaminergic antidepressants,

patients must be informed about possible effects on

their driving performance (see chapter 9.1.1.3.4). But

untreated depression, too, usually worsens patients’

driving due to prolonged reaction times and concen-

tration deficits. After the first week of treatment

(Ramaekers, 2003) and during long-term treatment

driving ability generally normalizes. This normal-

ization may depend on the applied daily dosage. In

addition, differences in driving performance based

on treatment with sedating or non-sedating anti-

depressants have been reported (Ridout et al., 2003 ;

Wingen et al., 2005).

Table 16 presents specific side-effect profiles based

on the effect of antidepressants on receptors and neu-

rotransmitters. Using this table in combination with

Table 1, one can deduce the specific side-effect profile

to be expected for a specific antidepressant.

9.1.1.3.1 Blood dyscrasias and disturbance of

erythro- and leucopoiesis during the use of

antidepressants

Neutropenia and thrombocytopenia40 have been

observed during treatment with mood stabilizers

like carbamazepine (Sheehan and Shelley, 1990),

lamotrigine (LeDrew et al., 2005 ; Ural et al., 2005)

and valproate (Vesta and Medina, 2003). During39 The subdivision in different classes of antidepressants including

additional effects on specific receptors can be seen in Table 1.

Together with Table 16 an individual side effect profile of each

single antidepressant can be deduced. In addition to that profile also

the used dose and the individual sensitivity of a patient influences

the probability and magnitude of side effects.

40 Also, antipsychotics such as clozapine or olanzapine (Duggal et al.,

2004), used in augmentation therapies (see chapter 9.1.12), may

cause leukopenia culminating in agranulocytosis.


antidepressant monotherapy using a variety of sub-

stances, including TCA (Gibson, 1974 ; Gravenor et al.,

1986) and tetracyclic substances such as mianserin

(Thomas and Read, 1990), neutropenia has been

reported. Divergent reports about newer antidepres-

sants such as SSRIs (Ozcanli et al., 2005; Trescoli-

Serrano and Smith, 1996), venlafaxine (Anghelescu

et al., 2002 ; Lucht et al., 2000) and mirtazapine (Anon.,

2004 ; Ozcanli et al., 2005) have been published. They

have also been reported to have negative effects on

leucopoiesis, but due to rare reports and frequent

combination therapies the causal interdependencies

are not clear. As a therapeutic or even prophylactic

option additional lithium therapy should be owing

to its potential not only to augment antidepressant

therapies (Bauer et al., 2003) but also to stimulate

leucopoiesis (Hager et al., 2002).

Table 16. Modes of action and receptor profiles, and direct and indirect effects of antidepressants possibly associated

with clinically relevant and compliance-influencing side effects

Influenced receptors

or neurotransmitters Mode of action Typical side effects (receptor)41

M1 receptor Antimuscarinic/anticholinergic $ Dry mouth$ Accommodation disturbances$ Constipation$ Miction disturbances$ Worsening of angle-closure glaucoma$ Hyperhidrosis$ Cognitive disturbances$ Delirium$ Cardiac arrhythmias

H1 receptor Antihistaminergic $ Sedation$ Drowsiness$ Daytime tiredness$ Increased appetite$ Weight gain$ Metabolic syndrome

a1/2-receptor Antiadrenergic $ Hypotension

NA transporter Noradrenalin reuptake inhibition/

noradrenergic effects

$ Tremor$ Dry mouth$ Tachycardia$ Restlessness$ Sleep disturbances$ Hypertonia

5-HT transporter blockade/5-HT

receptor agonism

Serotonin-reuptake inhibition/

serotonergic effects

$ Headache (5-HT1D)

Restlessness, agitation, akathisia (5-HT2)$ Anxiety, panic (5-HT2)$ Decreased appetite (5-HT2)$ Weight reduction (5-HT2)$ Sleep disturbances (5-HT2)$ Sexual dysfunction (5-HT2)$ Nausea (5HT3)$ Diarrhea (5-HT4)

Serotonin syndrome (all 5-HT receptors ;

predominantly in combination)$ Lack of emotion$ SIADH42

$ Enhanced bleeding risk43

41 The sorting order represents grading from common and less

serious to more serious but predominantly rare side effects.42 Syndrome of inappropriate secretion of antidiuretic hormone,

possibly resulting in hyponatremia and generalized epileptic

convulsions43 Due to decreased platelet concentration or diminished platelet

aggregation.


9.1.1.3.2 Dependence potential of antidepressants44

and demarcation from a discontinuation syndrome

Haddad identified 21 English-language case reports of

antidepressant addiction (Diagnostic and Statistical

Manual of Mental Disorders, 4th revision (DSM-IV)

‘substance dependence’ criteria) published since 1963

(Haddad, 1999). Sixteen of these reports involved

tranylcypromine or amineptine, which have atypical

dopaminergic and stimulant properties, but have been

withdrawn from the market in most countries. Subject

characteristics included male sex (14/21), personality

problems (10/21) and prior substance misuse (14/21).

Signs of addiction such as increasing tolerance and

compulsive use are not a feature of antidepressants45.

Accordingly, addiction in the currently accepted sense

of the term is not clinically associated with anti-

depressant drugs. Only bupropion, used as an anti-

depressant and for smoking cessation, has been

controversial. But the compound has been shown not

to be amphetamine-like, and its potential for human

abuse is very unlikely (Griffith et al., 1983 ; Miller and

Griffith, 1983). DSM-IV, whatever its limitations, does

seem accurately to capture the real hazards of addic-

tion, and on that basis, antidepressants are not, as a

class, substances of misuse and hence should not be

described as addictive.

Still, the addictive potential of antidepressants is a

popular, widely held belief. It is promoted by reports

in which individuals claim to have had severe with-

drawal symptoms and to have extreme difficulties in

stopping taking antidepressants. Moreover, authors

such as Charles Medawar nourish the belief by paint-

ing it as part of a broader conspiracy (Medawar and

Hardon, 2004) : ‘Both literally and metaphorically, all

the drugs in this story cause some degree of depen-

dence. People get hooked not only on the drugs, but

also on the idea of drugs as solutions for mental dis-

tress. Subtle interplays of power and dependence

nurture this process of medicalisation, as if through a

‘Conspiracy of Goodwill’. ’ On this basis, addiction

becomes equated with the side effects of drugs, and

even ideas about drugs. When it is reasonable to use

the emotive term ‘addictive’ and when it is not ap-

pears to be a matter of debate.

It would, however, be surprising if, on discontinu-

ation, psychotropic drugs did not produce some

withdrawal effects. Clearly they are often taken for

relatively long periods of time, and receptors adapt

in significant ways to their presence. Once the drug

is removed, these changes will be expressed as im-

balances in neurotransmitter function and subjective

adverse effects. Typically, these effects may include

agitation, sleep disturbances, sweating, gastrointesti-

nal discomfort and headache, and may take up to

2 weeks to subside. In addition several reports about

a ‘flu-like syndrome’ after sudden cessation of anti-

depressants such as SSRIs, MAOIs, or SMAs have

been published (Belloeuf et al., 2000 ; Curtin et al.,

2002 ; Lejoyeux et al., 1992 ; Rajagopalan and Little,

1999 ; Schatzberg et al., 1997). In a prospective survey

of 97 patients stopping an SSRI treatment (Bogetto et

al., 2002), the onset of symptoms occurred within 2

days on average. Discernible effects were more likely

with high doses and prolonged treatment. With less

than 5 weeks’ exposure, withdrawal effects are very

unusual and would be unexpected. When a discon-

tinuation syndrome occurs, it is particularly dramatic

in newborns whose mothers were treated with sero-

tonergic drugs until delivery (Isbister et al., 2001 ;

Misri and Kostaras, 2002 ; Nijhuis et al., 2001 ; Wen

et al., 2006).

Differences in the rates of discontinuation syn-

drome have been reported after patients stabilized on

fluoxetine, sertraline or paroxetine had their mainten-

ance therapy interrupted with double-blind substi-

tution for 5–8 days. The incidence of discontinuation

syndrome was lower in fluoxetine than in sertraline

or paroxetine groups (14, 60 and 66%, respectively)

in accordance with the half-life of the substance

(Rosenbaum et al., 1998). The symptom categories

seen with SSRIs and venlafaxine are disequilibrium

(giddiness or even vertigo), sensory abnormalities

(e.g. headache, ‘pins-and-needles’ sensation), gastro-

intestinal upset (e.g. nausea), general somatic distress

(e.g. lethargy), sleep disturbance and affective symp-

toms (Fava et al., 1997 ; Haddad, 1998 ; Schatzberg et al.,

2006). In a database analysis, a total of 93 suspected

cases of SSRI-induced neonatal withdrawal syndrome

were reported and were regarded as sufficient infor-

mation to confirm a possible causal relation. Sixty-four

of the cases were associated with paroxetine, 14 with

fluoxetine, 9 with sertraline and 7 with citalopram

(Sanz et al., 2005b). A survey of the French pharma-

covigilance database revealed that SSRIs are clearly

associated with a higher risk of withdrawal syndrome

(OR 5.05, 95% CI 3.81–6.68) and in particular with

the SNRI venlafaxine and the SSRI paroxetine

44 The definition of ‘dependence potential ’ varies among different

systems of classification. DSM-IV defines ‘substance dependence’ in

relation to a mixed picture of tolerance, withdrawal effects and

compulsive drug-taking behavior, usually accompanied by a craving

for the positive effects of the drug.45 In addition, antidepressants have no market value for drug

abusers, an authentic measure of abuse potential.


(OR 12.16, 95% CI 6.17–23.35 and OR 8.47, 95% CI

5.63–12.65, respectively) (Trenque et al., 2002). It

should, of course, be a critical part of the information

given to patients that such effects can arise. They can

usually be abolished by restarting the withdrawn drug

and avoided by substituting fluoxetine to cover with-

drawal, since it has a prolonged half-life.

In the war of words and their meanings that domi-

nate this debate, the potential of causing ‘withdrawal’

seems to be used synonymously with dependence and

addiction by some authors and the expression ‘dis-

continuation symptoms’ sometimes appears to be

preferred by those who feel the effects are too mild to

be regarded as evidence of a serious problem. The

frequency and severity of withdrawal symptoms is a

key issue. Withdrawal symptoms following long-term

use of antidepressants are related not to the disease

but to drug tapering or stoppage. They must be

distinguished from a recurrence of the actual de-

pressive episode and from a rebound with symptoms

of an even higher intensity (Bauer et al., 2002b).

Unfortunately, measurement of withdrawal effects is

imprecise and is confounded by expectations under

ordinary clinical conditions. The more sensitive the

measure, the more likely it is that withdrawal effects

will be detected. It would, however, be extremely

misleading to imply that these effects generally con-

stitute a serious barrier to discontinuation in the

majority of patients (Bogetto et al., 2002). When

clinician and patient ratings are compared under

double-blind conditions, there is also a high level of

agreement (Rosenbaum et al., 1998). This finding is

important because the claim is sometimes made that

companies and clinicians are in a conspiracy to deny

how severe these symptoms are.

Just as it would be surprising not to have some

withdrawal effects, odd physical effects as a result of

individual differences on discontinuing a drug are also

to be expected. About 50 comments on paroxetine

withdrawal, from discussion boards posted between

January 1999 and May 2002, were provided to the

‘Seroxat users’ website (http://www.seroxatuser-

group.org.uk). There is in fact a reasonable concor-

dance with the symptoms described in the literature,

although the effects are often described as very severe

and unexpected. Discontinuation symptoms and

treatment interruption-emergent events were more

frequent after paroxetine compared with fluoxetine

treatment due to the different half-lives of the com-

pounds (Judge et al., 2002). In addition, similar to the

misuse of nonpsychotropic medications, excessive

use of antidepressants has also been reported, and

the addiction potential of antidepressants has been

discussed (Dean, 2002 ; Haddad, 1999). Withdrawal

symptoms have even (though rarely) been described

following discontinuation of herbal antidepressants

such as St. John’s wort (Beckman et al., 2000).

The apparent absence of appropriate notification

that such effects can occur runs consistently through

the messages. There is also a pervasive hostility to the

doctors (usually general practitioners, it would ap-

pear) who prescribe the drug. It is a real challenge to

know how to evaluate this evidence in a quantitative

sense as well as qualitatively, in relation to the motiv-

ation and needs of people who use Internet discussion

boards. There is clearly a remarkable opportunity to

harness patient experience through the Internet, but a

qualitative free-for-all could well be self-perpetuating

and ultimately uninformative because it is very likely

to suffer from a variety of confounding biases. There is

also the complication that there appears to be a pros-

pect of secondary gain from suing multinational drug

companies who own patents on individual drugs. This

issue is related to a much broader challenge, which is

to improve current methods of post-marketing sur-

veillance.

Finally, aside from the issues of addiction, but im-

portant from the point of view of management, it is

certainly possible that on discontinuation patients

may relapse with the original anxiety or depressive

symptoms that promoted the use of antidepressants

(Geddes et al., 2003). To prevent discontinuation

symptoms a slow tapering of antidepressant medi-

cation in case of a planned discontinuation has been

recommended (Rosenbaum and Zajecka, 1997;

Shelton, 2001 ; Warner et al., 2006). Clearly, when this

occurs, a clinical decision must be made whether to

continue with the medication and accept the benefit of

symptom control or discontinue mediciation and see

the return of symptoms. There is no convincing evi-

dence that the use of antidepressants makes returning

anxiety or low-grade depressive symptoms worse, but

obviously the costs and benefits of long-term use of

any medication must be weighed on an individual

basis.

In conclusion, the consensus view among experts is

that antidepressant drugs are not addictive (Nutt,

2003) in the normally understood sense of the word

and as regularly applied, e.g. to opiates. However, as

with all medicines, their benefit comes at the potential

cost of adverse effects. These adverse effects are

somatic symptoms on withdrawal. Extending pre-

scription for minor symptoms or syndromes runs the

risk of the harm being perceived as greater than the

benefit. There are undoubtedly some problems with

the use and, particularly, the discontinuation of


antidepressants that merit clinical care, clear labeling

and information for patients. But there seems little

reason why, with that precaution, they should not be

used safely. This is the usual experience of psy-

chiatrists working in secondary care.

9.1.1.3.3 Use of antidepressants during pregnancy,

post-partum depression and breast feeding

The pregnancy and post-partum periods are con-

sidered to be relatively high risk times for developing

depressive symptoms as well as depressive episodes

in women (see also chapter 10.1) (for review see Cohen

et al., 2004 ; Nonacs and Cohen, 2003). Both acute

and prophylactic treatment of depressive disorders

during pregnancy may pose a difficult-to-solve thera-

peutic problem and require individual risk-benefit

analysis. Untreated depression is associated with im-

paired feto-placental function, premature delivery,

miscarriage, low fetal growth and perinatal unwanted

effects, whereas use of antidepressant drugs during

pregnancy might entail risk of teratogenesis, neonatal

toxicity, discontinuation symptoms and neuropsycho-

logical-behavioral impairment (Bellantuono et al.,

2006). In addition, during antidepressant pharmaco-

therapy after birth, each available antidepressant

is excreted in the milk (approximately 1% of plasma

levels can be seen) and may influence infants during

breast feeding (for review see Burt et al., 2001 ; Dodd

et al., 2000 ; Suri et al., 1998). Therefore, the risk of

untreated depressive disorders causing maternal

stress that also influences the fetus and birth out-

comes, as well as enhanced risk for suicide, must be

evaluated together with a possible increased risk for

fetal malformation, growth impairment, fetal and

neonatal toxicity, and behavioral teratogenicity caused

by antidepressant treatment (Wisner et al., 2000).

These benefits and risks of antidepressant phar-

macotherapy must also be assessed and compared

with other non-pharmacologic treatment alternatives,

e.g. ECT (chapter 12.2), which can safely be adminis-

tered during pregnancy and breast feeding (Rabheru,

2001 ; Walker and Swartz, 1994). Sleep deprivation

(chapter 12.3.7) (Parry et al., 2000) and bright light

therapy (chapter 12.3.8) (Oren et al., 2002) should be

considered. Because RCTs during pregnancy are not

ethically acceptable and no controlled studies of the

use of antidepressants during pregnancy have been

published, all knowledge on the subject is anecdotal.

Single case reports, case series and epidemiological

data must be analyzed carefully, including patients’

individual histories. In addition to concerns about

malformations and neonatal complications, the risk of

influence on behavioral development, e.g. abnormal

emotional behavior in offspring, cannot to date be

excluded. Accordingly, recent studies in new born

mice have shown an effect of serotonin and SSRI

(Fluoxetine) treatment on behavioral phenotypes,

leading to the hypothesis that these effects may indi-

cate a critical role of serotonin in the maturation of

brain systems that modulate emotional function

(Ansorge et al., 2004).

Enhanced risk of intrauterine death or congenital

malformation has generally not been reported in con-

junction with TCAs and fluoxetine or other SSRIs

(Wisner et al., 1999). Nevertheless, more neonatal

complications were seen. Children of mothers treated

with fluoxetine during the first trimester of pregnancy

showed lower maternal weight gain during pregnancy

Box 8. Discontinuation symptoms and relapse after stopping antidepressant treatments : conclusion

Antidepressant medications do not produce dependence that corresponds to criteria of the ICD-10 and the DSM-IV

classifications.

They have no dependence potential in laboratory animal trials, and their use does not satisfy other criteria for the diagnosis

of substance dependence46, such as increasing tolerance and craving.

If applied in therapeutic doses, sudden interruption of intake will cause discontinuation symptoms, as reported for several

antidepressants, such as escitalopram (Baldwin et al., 2005), paroxetine and sertraline (Rosenbaum et al., 1998) or venlafaxine

(Fava et al., 1997). This fact and several case reports of dependence on fluoxetine (Menecier et al., 1997), tianeptine (Guillem

and Lepine, 2003 ; Leterme et al., 2003 ; Saatcioglu et al., 2006 ; Vandel et al., 1999) and tranylcypromine47 (Ben-Arie and

George, 1979 ; Briggs et al., 1990 ; Westermeyer, 1989) led to the erroneous belief that antidepressant medications produce

dependence, which resulted in the reluctance of doctors and patients to use these medications where indicated.

46 Definitions of dependence and addiction are still controversial

(O’Brien et al., 2006). ‘Physical dependence’ is characterized by

symptoms of withdrawal after discontinuation of a substance ;

‘addiction’ is most commonly is defined as the compulsive need and

repeated use of a substance despite clear evidence of morbidity

secondary to such use leading to tolerance and craving beyond

voluntary control.47 The dependence potential of tranylcypromine is related to the fact

that one of its metabolites is an amphetamine (Briggs et al., 1990).

Some countries in Europe have discontinued its use, partly because

of that and partly because of other adverse effects.


(which is also associated with untreated depression)

together with decreased birth weight of neonates and

a higher rate of premature birth (Chambers et al.,

1996). Moreover, infants of mothers treated with

fluoxetine during breast feeding showed reduced

growth (Chambers et al., 1999). The overall develop-

ment of children of mothers receiving TCAs or SSRIs

during pregnancy did not differ from that of controls

(Wisner et al., 1999). A meta-analysis reported that use

of newer antidepressants such as SSRIs, SNRIs,

NARIs, NaSSAs and DNRIs is not associated with an

increased risk of major malformations above the

baseline of 1–3% in the population (Einarson and

Einarson, 2005). Nevertheless, a recently published

case-control study that has been somewhat contested

by experts (Blier, 2006) reported an association be-

tween the maternal use of SSRIs in late pregnancy and

persistent pulmonary hypertension in newborns as a

probable cause of substantially enhanced infant mor-

tality (Chambers et al., 2006). In addition, a warning

has been published not to use paroxetine within the

first trimester of pregnancy owing to a twofold

increase in the rate of cardiovascular malformation

(GSK Clinical Trial Register ; http://ctr.gsk.co.uk/

Summary/paroxetine/epip083.pdf). Recently pub-

lished reports confirm the potentially increased risk of

congenital malformation following paroxetine treat-

ment (Cuzzell, 2006), therefore its use during preg-

nancy should be avoided. Also, the manufacturer of

bupropion has established a ‘Pregnancy Registry

program’ primarily to collect safety data regarding the

use of this substance during pregnancy (White and

Andrews, 1999). Newer compounds whose terato-

genic risks are unknown or incomplete should not be

used as first-line agents in the pharmacological treat-

ment of depression during pregnancy and breast-

feeding (Gentile, 2005). Even agents considered so far

to be safe for mother and child during breast feeding,

such as mirtazapine (Aichhorn et al., 2004) and es-

citalopram (Rampono et al., 2000), should be evalu-

ated carefully as they have not been available for

sufficiently long time for a final risk evaluation. The

Health Reserarch Group therefore even suggests to wait

at least seven years from the start of the marketing of a

new drug until reliable statements about the safety of

this drug can be published, because the numbers of

probands and patients receiving new drugs in RCTs

may be to small to detect even life threatening rare

adverse events (Wolfe et al., 2005). Although pub-

lished studies show that plasma levels in babies are

often below detectable levels (Blier, 2006), data from

large prospective studies are lacking. Finally, the

specific safety profiles of maintenance and contin-

uation therapies during pregnancy and the post-

partum period must also be considered (Ernst and

Goldberg, 2002).

9.1.1.3.4 Antidepressants and fitness to drive

Most patients treated with antidepressants are not

hospitalized, but continue to live in their community.

It is therefore important to know whether anti-

depressants influence activities such as car driving,

which requires intact psychomotor functioning. Some

antidepressants produce side effects that include diz-

ziness, sedation, blurred vision, sleepiness, and diffi-

culty concentrating on tasks and making decisions.

Some of these symptoms must be assumed to be

similar to those observed in untreated depressed

patients, and therefore the driving capacity of each

patient must be examined individually, independently

of his or her treatment (Laux, 2002).

One of the main tests used in this context is the

same as that introduced for testing driving behavior

in subjects who have ingested alcohol : the standard

deviation of lateral position (SDLP) is an index of

road-tracking precision or ‘weaving’, as described in

detail by Van Laar et al. (1992). This test is carried out

in real conditions, where the subjects are driving a test

car (on-the-road driving test), but other methods have

also been used, where car driving is only simulated

(Brunnauer et al., 2006 ; Laux, 2002). This means that

comparisons between different studies are sometimes

difficult. The literature is surprisingly thin with regard

to studies regarding the influence of antidepressants

on driving behavior, and most of them were carried

out with healthy volunteers treated with a single dose

of an antidepressant drug (Table 17).

In healthy subjects, tricyclic drugs such as im-

ipramine (van Laar et al., 1995) or amitriptyline

(Louwerens et al., 1984) and others generally impair

driving behavior after acute medication, but some

tolerance my develop after prolonged administration

(Table 17). According to Laux et al., most tricyclic

drugs (amitriptyline, clomipramine, doxepin, imipra-

mine, nortriptyline, opipramol and trimipramine) and

the tetracyclic antidepressants maprotiline and mian-

serin clearly decrease driving capacity, especially

during the first 10–14 days following initiation of

treatment (Laux, 2001). A retrospective cohort study

showed that elderly patients treated with TCAs rep-

resent a higher risk group for traffic accidents in com-

parison to a group of control subjects (Ramaekers,

2003 ; Ray et al., 1992). Tricyclic drugs are increasingly

used in low doses for the treatment of neuropathic

pain (Sindrup et al., 2005). In a small group of patients


suffering from this disease, a first dose of 25 mg

amitriptyline significantly impaired driving perform-

ance, in comparison to placebo. After a 2-week treat-

ment with 25 mg/day amitriptyline, tolerance had

developed as the differences between placebo vs

verum were not any more significant (the drug was

always administered in the evening, about 13h before

the test).

These effects of the TCA appear to be related to their

pharmacological properties as a1-, muscarinic and/or

H1 antagonists. As expected, due to their pharmaco-

logical profile, the H1 antagonists mianserin (15 mg/

day) and mirtazapine (30 mg/day) impaired slightly

driving performance on day 2 in healthy volunteers

(Ramaekers et al., 1998) (Table 17). However, tolerance

apparently developed as on day 8, the effect was gone

for mirtazapine, and strongly decreased for mianserin.

Dose was then increased to 30 mg/day and 60 mg/

day, respectively : on day 16 of treatment, there was

some impairment of the driving performance with

both antidepressants. This indicates that tolerance was

not complete. In a similar study carried out by the

same research group with healthy volunteers treated

for one week with 30 mg/day mirtazapine confirmed

that this drug impairs car driving performance on day

2, but not later on (Wingen et al., 2005). As concluded

also from other studies, mirtazapine should be ad-

ministered in the evening and the physician should

inform the mirtazapine treated patient that car driving

represents some risks, especially at the beginning of

the treatment. A naturalistic clinical study with de-

pressive patients treated chronically with mirtazapine

nevertheless demonstrated that this drug did less im-

pair driving performance than TCAs, SSRIs and ven-

lafaxine (Brunnauer et al., 2006), but it also confirms

that depressive illness per se represents a risk factor.

In contrast, escitalopram (Wingen et al., 2005),

fluoxetine (Ramaekers et al., 1995), paroxetine (Robbe

and O’Hanlon, 1995), sertraline (Warrington, 1991)

and moclobemide (Ramaekers et al., 1992), which are

mostly devoid of the properties mentioned above for

TCA (a1-, muscarinic and/or H1 antagonists), do not

Table 17. Fitness to drive during application of antidepressants in healthy volunteers

Antidepressant Study details Outcome Reference

Amitriptyline Healthy volunteers, 75 mg SDLP elevation, adaptation after

1 week

Louwerens et al., 1984

Dothiepin Healthy volunteers, 75–150 mg SDLP not different from placebo Ramaekers et al., 1995

Doxepin Healthy volunteers, 75 mg SDLP elevation, adaptation

after 1 week

Schoenmakers et al., 1989

Escitalopram Healthy volunteers, 10–20 mg Driving and psychomotor

performance not affected

Wingen et al., 2005

Fluoxetine Healthy volunteers, 20 mg Reduced attention, driving

performance not affected

Ramaekers et al., 1995

Imipramine Healthy volunteers, 50 mg SDLP elevation, adaptation after

1 week

van Laar et al., 1995

Mianserin Healthy volunteers, 30–60 mg Impaired driving performance,

adaptation after 1 week

Louwerens et al., 1984 ;


Mirtazapine Healthy volunteers, 15–30 mg SDLP elevation, impaired driving

performance, adaptation after

1 week

Ramaekers et al., 1995 ;

Ramaekers et al., 1998 ;

Wingen et al., 2005

Moclobemide Healthy volunteers, 200 mg Driving performance not different

from placebo


Nefazodone Healthy volunteers, 200 or 400 mg Highway driving performance not

impaired, slight impairment of

lateral position control after

400 mg per day

van Laar et al., 1995

Paroxetine Healthy volunteers, 20–40 mg Impaired psychomotor performance,

road tracking not affected

Robbe and O’Hanlon, 1995

Sertraline Healthy volunteers, 100–200 mg Simulated car driving not affected Warrington, 1991

Venlafaxine Healthy volunteers, 37.5–75 mg No effect on SDLP or psychomotor

performance

O’Hanlon et al., 1998

SDLP, Standard deviation of lateral position.


significantly influence driving behavior (Table 17).

However, the information that sertraline does not im-

pair simulated car driving in healthy volunteers is

only mentioned in an abstract of a review paper

(Warrington, 1991), but no comprehensive exper-

imental report is available (Table 17). With regard to

escitalopram, an already mentioned study (Wingen

et al., 2005) (Table 17) shows that a one week treatment

with 20 mg/day escitalopram did not result in an

impairment of the driving capability of the healthy

subjects, whether after acute nor after a 1-week treat-

ment. This is in line with the low affinity of escitalo-

pram for histamine receptors.

Conflicting results were obtained for venlafaxine.

While it is considered relatively safe by some authors

when tested in healthy volunteers (Ramaekers, 2003;

O’Hanlon et al., 1998) (Table 17), others observed

that depressive patients treated with venlafaxine per-

formed less well than those treated with mirtazapine,

but no data are available about the doses used

(Brunnauer et al., 2006).

It has to be considered that patients may have

comedications such as benzodiazepines, either pre-

scribed or as a self-medication. They certainly impair

driving ability much more that antidepressants

(Bramness et al., 2003 ; Van Laar and Volkerts, 1998,

Van Laar et al., 1992). This effect can be even more

pronounced in situations where such a drug is a sub-

strate of CYP3A4 (e.g. alprazolam) or CYP2C19

(e.g. diazepam) and where it is administered to sub-

jects comedicated with other drugs (see also chapter

9.1.1.1.5) which per se do not impair driving behavior

but which are known inhibitors of one of these en-

zymes (e.g. fluoxetine, moclobemide) (Ramaekers,

2003).

The effect of an antidepressant can be be directly

compared with that of alcohol, at a particular blood

alcohol concentration (BAC: 0.5, 0.8, …, mg/ml)

(Ramaekers, 2003). It is clinically important that some

tricyclic drugs (and benzodiazepines) enhance the

impairing effect of alcohol on skills related to driving

behavior (Landauer et al., 1969), while generally SSRIs

do not modify these alcohol effects (Baxter, 2006).

In conclusion, depressed patients must be informed

that, owing to their illness, driving performance may

definitely decrease, and that the risk of traffic accidents

is increased by alcohol or benzodiazepine consump-

tion. Moreover, the decision to medicate with an anti-

depressant must be made based on the patient’s

situation with regard to his daily occupations, includ-

ing car driving. However, it must be considered that,

as shown by a recent study, patients often ignore

warning labels on packages indicating that these

drugs may impair driving capability (Veldhuijzen

et al., 2006).

9.1.2 Monoamine oxidase inhibitors48

9.1.2.1 Efficacy

A comparable efficacy profile for all available irrevers-

ible MAOIs similar to that of TCAs has been reported,

but this is true only for outpatients (Thase et al., 1995),

even if they have been TCA treatment failures. For

inpatients, TCAs have been reported to be more ef-

fective than phenelzine and isocarboxazid (for review

see : Thase et al., 1995). In other studies a similar effi-

cacy of phenelzine in comparison to the TCAs imi-

pramine in inpatients (Davidson et al, 1981),

nortriptyline (Georgotas et al., 1986) and amitriptyline

in outpatients (Ravaris et al., 1980) has been reported.

Responsivity to MAOI treatment is highest in patients

suffering from depression with anergic or atypical

features49 (Henkel et al., 2006 ; Himmelhoch et al.,

1991 ; Thase et al., 1992 ; Thase et al., 1995), but anergic

features were predominantly investigated in bipolar

depression. Despite this efficacy profile, there is a

broad consensus that irreversible MAOIs are con-

sidered predominantly as a second-line treatment

strategy because of their potential to cause serious

adverse events (see below, chapter 9.1.2.2) (Bauer et al.,

2002c). Especially with depression resistant to TCAs,

MAOI monotherapy or the combination of MAOIs

and TCAs or mood stabilizers has been suggested

based on promising results of case reports and retro-

spective data analyses (Amsterdam and Shults, 2005;

Feighner et al., 1985 ; Schmauss et al., 1988).

Tranylcypromine treatment has shown no significant

advantage in terms of remission rates compared with

venlafaxine and mirtazapine combination therapy

in outpatients with treatment-resistant depression

(McGrath et al., 2006). Due to the lower side-effect

burden of the SNRI/NaSSA combination compared

with irreversible MAOIs, combination therapy may

also be suitable for patients suffering from highly

treatment resistant depression (McGrath et al.,

2006), but comparative RCTs up to now are missing.

48 The following sections describe the efficacy and safety profile of

all available antidepressants. Substances are classed in groups

according to their main mode of action. Because frequency of

prescription varies among different countries, the group order

corresponds to a more neutral and approximately historical

chronology.49 See chapter 5.2.1.3.3 for a detailed description of the concept of

atypical depression. In France the term ‘atypical depression’ is

synonymous to depression with psychotic symptoms (see chapter

5.2.1.2).


Dose-escalating strategies with MAOI therapy have

also been suggested, but very few clinical data indicate

that ultra-high-dose treatment with tranylcypromine

is effective in refractory depression (Adli et al., 2005).

As described in chapter 5.2.4.2.3, the preferential

MAO-B inhibitor selegiline, which is mainly used in

combination therapy for Parkinson’s disease, may also

exert significant antidepressant effects (Amsterdam,

2003; Bodkin and Amsterdam, 2002). This is especially

true at higher doses (>10 mg/day), which possibly

also inhibit MAO-A activity (Mann et al., 1989).

Selegiline transdermal system has shown superiority

in comparison to placebo in several short-term (Feiger

et al., 2006) and long-term RCTs (Amsterdam

and Bodkin, 2006). In addition it has been described

that the transdermal system possibly may excert a

better efficacy in comparison to orally administered

selegiline (Morgan, 2007). To date only a selegiline

transdermal system has been approved as an anti-

depressant by the US Food and Drug Administration

(FDA). The approval process in Europe is still on-

going. Actual data have been summarized in a re-

cently published review (Frampton and Plosker,

2007). The reversible inhibitors of monoamine oxidase

A (RIMAs) are considered to be as effective as TCAs

and SSRIs, but somewhat less effective than irrevers-

ible MAOIs (Lotufo-Neto et al., 1999 ; Sogaard et al.,

1999). It has been reported that there is evidence from

meta-analyses that higher doses of moclobemide may

sometimes enhance efficacy in treating depressive

disorders (Lotufo-Neto et al., 1999).

9.1.2.2 Safety and tolerability

Interactions of predominantly irreversible MAOIs

with sympathomimetic medication or tyramine-

containing food carry a risk of hypertensive crisis of

potentially fatal outcome (Amsterdam and Shults,

2005 ; Brown and Bryant, 1988). For this reason, there is

broad clinical consensus that MAOIs are considered

only as second-line antidepressants. Moreover, they

entail dietary restrictions that prevent ingestion of

tyramine-rich food (see Box 9).

MAOI ultra-high-dose therapy can cause delirium.

In addition, following discontinuation of irreversible

MAOI therapy, withdrawal phenomena such as agi-

tation, anxiety, sleeplessness or drowsiness and even

hallucinations and delirium have been described

(Dilsaver, 1988). For more information concerning a

possible dependence potential of MAOIs, see chapter

9.1.1.3.2 and Box 8. The risk of serotonin syndrome

due to the concomitant use or accidental combination

of other serotonin-enhancing antidepressants, such

as SSRIs, S-TCAs, SNRIs or SMAs, must be taken into

account. Depending on the half-life of the substances

used, a drug-free time interval of at least 2 weeks

in the case of serotonergic medication before or after

irreversible MAOIs is necessary to minimize the risk

of severe adverse events. Prescribing MAOIs follow-

ing fluoxetine requires lengthening the time interval

to 5–6 weeks. In the case of serotonergic substances fol-

lowing the RIMA moclobemide, the time interval can

be shortened to 3 days. Restricted intake of tyramine-

rich foods is not necessary when using RIMAs; how-

ever, in dose ranges above 900 mg/day, e.g. for

moclobemide50, the risk of interactions with tyramine

might again become clinically relevant (Bonnet,

2003). Moreover, RIMAs interact with concomitantly

used serotonin-enhancing drugs (Livingston and

Livingston, 1996), and have the potential to cause

severe serotonin syndrome (Dardennes et al., 1998 ;

Guma et al., 1999 ; Roxanas and Machado, 1998).

Prescribing the selegiline transdermal patch in higher

dose ranges (9 or 12 mg/day) requires dietary mod-

ifications. Moclobemide may be suitable, particularly

in the treatment of bipolar depression, due to a low

switch risk (Silverstone, 2001).

Box 9. List of tyramine-rich foods and beverages (excerpt)

High-protein food that has undergone protein breakdown by aging, air drying, fermentation, pickling, smoking or bacterial

contamination.

Patients should not eat dried meats, dry sausages, hard salamis, pickled herring, any spoiled or improperly stored meat,

pods of broad beans (fava bean), liver, yeast extract, sauerkraut, pepperoni, soybean products (including soy sauce and tofu)

or aged cheeses.

In addition beverages, such as tap beers and beers that have not been pasteurized, (red) wine and excessive use of caffeine

or chocolate should be avoided.

Patients must beware of all supplements containing tyramine.

50 During the licencing process, from a clinical point of view, overly

low doses have been recommended possibly due to marketing or

pricing strategies. In the UK, in comparison with other countries, a

200% dose has been proposed. The same recommendation was

made in Germany several months after introduction of the drug onto

the market.


9.1.3 Non-selective monoamine reuptake

inhibitors/tricyclic antidepressants

Ever since the introduction of the first antidepressant,

imipramine, and for a long time, tricyclics were the

primary pharmacotherapeutic option in the treatment

of depression. The TCA amitriptyline is even men-

tioned in the World Health Organization’s (WHO’s)

list of essential drugs (World Health Organization,

2005a). Nevertheless, in recent years tri- and tetra-

cyclic antidepressants have lost their status as first-

line treatment for depression in several developed

countries due in part to their particular side-effect

profile and the introduction of newer antidepressants

in these countries.

Even absent sufficient scientific justification for this

approach, from a clinical point of view in preparing

antidepressant treatment plans it may be useful to

subdivide TCAs not only according their sedating and

activating properties but also according to their influ-

ence on serotonergic, noradrenergic and dopamin-

ergic neurotransmission.

In the event of treatment failure and pharma-

cotherapy resistance, switching from serotonergic to

noradrenergic or mixed action TCAs seems to be

plausible. But unfortunately, controlled studies sup-

porting this method are still are lacking.

9.1.3.1 Efficacy51

As described previously, TCA treatment is effective

in depressive disorders, independent of subtype or

severity of depression. Controlled studies comparing

TCAs with other classes of antidepressants are pro-

vided within chapters 9.1.2 to 9.1.10. Especially in

severely depressed, hospitalized patients mixed S/N-

TCAs compare favorably with SSRIs (Anderson, 1998;

Anderson, 2000a; Danish University Antidepressant

Group, 1986 ; Danish University Antidepressant

Group, 1990) and the RIMA moclobemide (Danish

University Antidepressant Group, 1993), whereas

SSRIs and MAOIs appear to be superior in depressive

disorders with anergic or atypical features (see chap-

ters 9.1.2.1 and 9.1.5.1). The influence of gender and

depression subtype on antidepressant response is

unclear, but higher age does seem to predict a better

response to TCAs (Parker, 2002 ; Parker et al., 2003).

From a clinical point of view, but again without suf-

ficient support in the literature (Sartorius, 1974), TCAs

with lesser sedating effects, such as clomipramine or

desipramine, appear superior in retarded and anergic

depression. TCAs with inherently stronger anti-

histaminergic effects, such as doxepin, amitriptyline

and dosulepine, have advantages in agitated patients

with significant sleep disturbances.


The main concerns in using TCAs as a first-line treat-

ment are anticholinergic and antihistaminergic side

effects possibly influencing substantially tolerability

and therapy adherence. Sedating properties may help

in the treatment of depression-related sleep disturb-

ance, but daytime drowsiness and sedation often lead

to discontinuation of treatment. In the long term, in-

creased appetite, resulting weight gain and in some

cases even risk of enhancing the high rate of metabolic

syndromes in depression also play a crucial role.

Treatment safety can be increased by using modern

antidepressants with greater specificity and a toler-

ability profile that includes a lower risk of cardio-

vascular and neurological side effects.

Suicidal behavior may be a further reason to be

cautious in prescribing TCAs as first-line treatment.52

Whereas SSRIs, NaSSAs and SNRIs are associated

with fewer completed suicide attempts in cases of

drug overdose, a positive association between TCAs

and fatal suicide attempts has been reported (Frey

et al., 2002 ; Gibbons et al., 2005; Jonsson et al., 2004).

One reason may be that despite the efficacy of TCAs

in treating depression, they have greater toxicity

compared with the newer antidepressants. This is es-

pecially true in case of overdose due to the electro-

cardiographically measured QTc time prolongation

and enhanced cardiotoxicity caused by some, but not

all TCAs.

9.1.4 Other modes of action not directly involving

monoamines : the modified TCA tianeptine

Despite its modified tricyclic structure, initial studies

showed that tianeptine did not share pharmacological

properties with TCAs, MAOIs or SSRIs (Wilde and

Benfield, 1995). Although acute in vitro and in vivo

studies suggest that tianeptine enhances [3H]5-HT re-

uptake into rat cortical and hippocampal synapto-

somes (Fattaccini et al., 1990 ; Mennini et al., 1987),

more recent studies assessing the release of serotonin

51 TCAs are available in both oral and i.v. forms. There is no

scientific evidence for a differential efficacy profile between them.

See chapter 9.1.1.2.3 for a more detailed description of i.v.

administration of antidepressants.

52 In chapter 11 (Suicidality and antidepressants : depression and

suicide) the discussion about the postulated potential of SSRIs to

induce suicidal ideations or suicide attempts has been evaluated in

detail.


by microdialysis following chronic (14-day) adminis-

tration clearly demonstrate that there is no significant

change in serotonin release (Malagie et al., 2000).

Previous studies had shown that, following chronic

administration, tianeptine induces adaptive changes

in cortical, but not hippocampal serotonin transporters

(Pineyro et al., 1995a; Pineyro et al., 1995b).

Experimental studies now indicate that tianeptine

has neuroprotective effects that contribute to its anti-

depressant properties (Defrance et al., 1988 ; McEwen

and Olie, 2005). In this respect it resembles other

classes of antidepressants (see chapter 8 for details).

Thus, changes in neurogenesis and neuroplasticity

of the hippocampus, cortex and amygdala may play

a prominent role in the efficacy of tianeptine. In

addition, tianeptine has been shown to change the

neuronal architecture of the hippocampus and amyg-

dala, and the rate of apoptosis in the hippocampus

and temporal cortex, and to restore hippocampal vol-

ume following exposure to chronic stress (McEwen

and Olie, 2005). Such effects have been explained in

terms of modulation of glutamatergic transmission

(see also chapter 8.2) (Kole et al., 2002 ; Reagan et al.,

2004). In other words, experimental evidence suggests

that changes in glutamatergic function reflect adaptive

changes to stress of the glutamate transporter that are

located on glial cells ; any change in serotonergic

function following tianeptine is therefore likely to be

indirect.

9.1.4.1 Efficacy

The efficacy of tianeptine in most published studies

was comparable to SSRIs (Kasper and Olie, 2002) ; only

one RCT showed an advantage of fluoxetine in elderly

patients (Guelfi et al., 1999). Comparison with other

antidepressants such as amitriptyline (Guelfi et al.,

1989 ; Invernizzi et al., 1994) and mianserin (Brion

et al., 1996) also turned up no significant differences

in efficacy.


Tianeptine does not appear to be associated with

severe anticholinergic or cardiovascular side effects

(Loo and Deniker, 1988). Specific advantages in the

case of comorbidities such as cardiovascular disorders

(Pogosova et al., 2004) and Parkinson’s (Levin, 2006)

disease have been described. The overall tolerability

profile compared with SSRIs has been shown to be

favorable, especially in the case of paroxetine (Kasper

and Olie, 2002; Lepine et al., 2001). Nor have any de-

tectably significant differences (in comparison with

fluoxetine) been reported (Loo et al., 2001).

9.1.5 Selective serotonin reuptake inhibitors

9.1.5.1 Efficacy

Today, in many countries, SSRIs are the anti-

depressant substances prescribed most frequently as

a first-line treatment (Ostacher et al., 2005). Good

efficacy has been described for each of the currently

available substances, regardless of the etiology or

severity of depression. Although several reports sug-

gest that some drugs may be superior to SSRIs

(venlafaxine (Cipriani et al., 2005b; Cipriani et al.,

2006 ; Smith et al., 2002 ; Thase et al., 2001), milnacipran

(Puech et al., 1997), mirtazapine (Thase et al., 2006a)),

it is difficult to interpret what these results mean

clinically. For example, escitalopram has been shown

to have comparable efficacy to venlafaxine (Kennedy

et al., 2006). Escitalopram also demonstrates a statisti-

cally significant, but clinically speaking minimal

superiority over the other SSRI, citalopram (Bech

et al., 2004 ; Lepola et al., 2004 ; Moore et al., 2005).

Consequently, use of escitalopram has been rec-

ommended (Montgomery, 2006), especially in severe

depression (Llorca et al., 2005). Another RCT reports

the superiority of escitalopram over both citalopram

and paroxetine (Boulenger et al., 2006). Prior meta-

analyses showed neither significant nor clinically rel-

evant differences in efficacy (Edwards and Anderson,

1999). But a recently published pooled analysis of

all available study data to date found significant

advantages of escitalopram in comparison with sev-

eral SSRIs, e.g. citalopram, fluoxetine and sertraline,

and in comparison with the SNRI venlafaxine (Kasper

et al., 2006). Nevertheless, more RCTs are needed to

evaluate the clinical relevance of these findings,

draw final conclusions and make specific rec-

ommendations.

Despite of the fact that SSRIs have shown no overall

relevant inferiority compared with TCAs in a variety

of randomized controlled trials (Moller et al., 1998)

and meta-analyses (Geddes et al., 2000), there is some

evidence of better efficacy and clinical effectiveness

of TCAs in the subgroup of inpatients compared with

outpatients (Anderson, 1998 ; Anderson, 2000a). This is

especially true in comparing the TCA amitriptyline

with SSRIs, taking into account that in most cases in-

patients show a higher severity of the disease and a

higher proportion of patients suffer from melancholic

features of depression.

SSRIs and irreversible MAOIs also show an overall

similar efficacy in the treatment of depression.

Indeed, except among outpatients suffering from de-

pression with atypical features (chapter 5.2.1.3.3),

MAOIs give better results (Thase et al., 1995). In


addition, MAOIs show advantages during ultra-high-

dose treatment in patients suffering from treatment-

resistant depression, whereas increasing the SSRI

doses has no substantial beneficial effect (Adli et al.,

2005).

Despite their similarities, various SSRIs do have

specific differences (Table 18).

9.1.5.2 Safety and tolerability53

Different SSRIs show different safety profiles.

Nevertheless, the safety and tolerability profile of

SSRIs as a pharmacological group of compounds

compares very favorably with TCAs (Mace and

Taylor, 2000). Specifically, anticholinergic side effects

especially are more common during TCA therapy.

Therefore, lesser cardiovascular toxicity together with

a lower risk for constipation and reduction of urinary

flow can be expected. Also, anticholinergic side effects

on the visual system, such as enhanced risk for

worsening of angle-closure glaucoma and accommo-

dation disturbances, are rare with SSRIs54. Only

paroxetine shows greater anticholinergic side effects

and more adverse events, e.g. compared with the

more selective escitalopram (Boulenger et al., 2006).

The result is a lower discontinuation rate (Peretti

et al., 2000) during SSRI treatment. In addition, SSRIs

have proven safer than TCAs in cases of overdose

(Barbey and Roose, 1998 ; Cheeta et al., 2004 ; Mason

et al., 2000), which is beneficial during antidepressant

treatment, especially in suicidal patients. In addition,

a simplified dose regimen compared with TCA

therapy diminishes the danger of antidepressant

therapies being below therapeutic dose ranges.

These factors all contribute to an efficacious and cost-

effective first-line therapy in depression vis-a-vis

TCAs despite higher prescription costs (Goldstein and

Goodnick, 1998).

Nevertheless, clinicians need to be aware of the

particular side-effect profile of SSRIs (Ferguson, 2001;

Lader, 1996). The most frequent side effects following

short-term treatment are gastrointestinal disturbances

such as nausea, diarrhea and emesis. Also common

are restlessness and agitation, sleep disturbances,

dizziness and headache. During long-term SSRI

Table 18. Clinical highlights and differences among SSRIs based predominantly on clinical experience and consensus

(modified according to Stahl, 1997 ; Stahl, 2006)

Generic name Specific clinical features of SSRIs

Citalopram (Bezchlibnyk-Butler et al., 2000) One of the most selective SSRIs

Possibly lower incidence of sexual dysfunction

Possibly better tolerability in the elderly

Low interaction potential

Escitalopram (Baldwin, 2002) One of the most selective and best-tolerated SSRIs

Possibly rapid onset of action and high effect size during antidepressant

treatment ; good effect in anxious depression and comorbid anxiety disorders

Fluoxetine (Calil, 2001) Good effect in atypical depression

Good effect in patients with fatigue and low energy

Long half-life, weekly administration possible

Fluvoxamine (Ware, 1997) Good effect in anxious depression and comorbid anxiety disorders ; potential

advantages in psychotic depression

Possibly lower incidence of sexual dysfunction

Discontinuation effects after rapid tapering

Paroxetine (Green, 2003) Good effect in anxious depression and comorbid anxiety disorders

Mild anticholinergic action

Discontinuation effects more likely than for other SSRIs

Sertraline (Khouzam et al., 2003) Good effect in atypical depression ; least selective over dopamine

Low interaction potential

More gastrointestinal side effects, but best documented cardiovascular safety

53 All possible interactions of antidepressants with other

pharmacotherapeutics are beyond of scope of this review ; the

interactions described represent a selection and are not exhaustive.

54 In cases of acute angle-closure (closed-angle, narrow-angle)

glaucoma, paroxetine is contraindicated due to greater

anticholinergic side effects compared with other SSRIs (Bennett and

Wyllie, 1999).


treatment sexual dysfunction, including loss of libido,

anorgasmia and disturbances of erectile or ejaculatory

function in men, are significant limitations of SSRI

therapy. Some studies show these aspects to be less

prominent with fluvoxamine therapy than with other

SSRIs (Waldinger et al., 1998). Delayed ejaculation

appears to occur more with paroxetine (Montejo-

Gonzalez et al., 1997). Disorientation, restlessness and

myoclonus together with hyperreflexia, tremor and

pain syndromes together with unstable vital signs

represent the potentially fatal serotonin syndrome

(Boyer and Shannon, 2005). It may occur pre-

dominantly as an interaction of combining SSRIs

with MAOIs or other serotonergic substances (e.g.

S-TCAs or triptans used during acute therapy of

migraine attacks), even during time intervals before

and after treatment in dependency of the half-life of

the substances, but also during SSRI monotherapy.

In most cases, therefore, a washout period of 2 weeks

(fluoxetine ; 6 weeks before MAOI therapy) is rec-

ommended, and combining SSRIs and MAOIs is

contraindicated. But there are published reports of

good tolerability of combined therapy with SSRIs and

triptans, possibly due to the fact that some triptans

do not cross the blood-brain barrier after oral admin-

istration (Blier and Bergeron, 1995 ; Goldberg et al.,

1999).

Rare side effects are weight gain, anticholinergic

effects and extrapyramidal motor side effects (EPMSs).

Caution must be exercised in prescribing SSRIs

for patients suffering from Parkinson’s disease

(Lemke, 2002), but there is no good evidence that

SSRIs are associated with a worsening of motor fea-

tures in Parkinson’s (Burn, 2002; Lemke et al., 2004). A

very rare adverse event during SSRI therapy of

younger patients, though not uncommon in the

elderly, is inappropriate secretion of antidiuretic

hormone (ADH) with possible electrolyte imbalance

and hyponatremia leading to increased risk of seizures

(Arinzon et al., 2002 ; Degner et al., 2004 ; Finfgeld,

2003). In addition, combined use of SSRIs and sub-

stances that increase the risk of bleeding events is

discouraged owing to blockade of serotonin reuptake

in platelets and subsequent platelet dysfunction

(Serebruany, 2006). Risk of gastrointestinal hemor-

rhage in particular may be enhanced if nonsteroidal

antiphlogistics or aspirin are combined with SSRIs

(Weinrieb et al., 2005). Discontinuation symptoms

can occur after SSRI treatment (Haddad, 2001) but

seem to be rare events following treatment with

fluoxetine, due to its long half-life, and some other

SSRIs, e.g. sertraline (Sir et al., 2005) and escitalopram

(Baldwin et al., 2005) (see also chapter 9.1.1.3.2).

9.1.6 Selective serotonin and noradrenaline reuptake

inhibitors

9.1.6.1 Efficacy

SNRIs represent a group of newer antidepressants that

act dually on serotonin and norepinephrine reuptake.

Today, three substances of this group are available :

venlafaxine, milnacipran and duloxetine. Compared

with venlafaxine, duloxetine more potently blocks

serotonin and noradrenaline transporters in vitro and

in vivo (Bymaster et al., 2001). This is especially true

for the noradrenaline reuptake-inhibiting effect after

application of lower doses. Judging the comparative

efficacy and clinical effectiveness is difficult because

overall, newer antidepressants probably do not differ

substantially with respect to these parameters for

treatment of major depressive disorder (Hansen et al.,

2005). Moreover, the available three SNRIs have been

suggested to have similar efficacy (Stahl et al., 2005).

Response rates during venlafaxine and duloxetine

treatment were comparable, but patients treated with

venlafaxine show a favorable trend in reaching re-

mission (Vis et al., 2005). In comparison with the SSRIs

sertraline (Sir et al., 2005) and escitalopram (Bielski

et al., 2004 ; Montgomery et al., 2004b), venlafaxine

demonstrated comparable efficacy effects in treatment

of depressive disorders and quality of life. Venlafaxine

has also proved to significantly reduce depressive

symptoms comparedwithfluoxetine (Clerc et al., 1994).

Several meta-analyses have also suggested superior

efficacy of venlafaxine over SSRIs (Cipriani et al.,

2005b; Cipriani et al., 2006 ; Smith et al., 2002), but

because most of the studies investigated the efficacy of

fluoxetine and paroxetine in comparison with SNRIs,

the results must be evaluated carefully before con-

clusions about the efficacy of SSRIs as a pharmaco-

logical class can be drawn. The described superiority

is reported to be enhanced when not only treatment

response but also remission is used as an efficacy

criterion (Stahl et al., 2005 ; Thase et al., 2001), but to

date no sufficient evidence for a faster response of

SNRIs in comparison to SSRIs has been published.

In addition, better efficacy and tolerability of escitalo-

pram over venlafaxine have been reported in the con-

text of remission rates (Montgomery and Andersen,

2006), whereas a meta-analysis found no significant

differences (Kennedy et al., 2006) (for review see

Friedli et al., 2000 ; Miller et al., 2003 ; Scott and

Freeman, 1992; Thase, 2004). Meta-analyses have

shown milnacipran to have an antidepressant efficacy

similar to that of imipramine and significantly

superior to that of SSRIs (Puech et al., 1997). Direct

comparisons between duloxetine and paroxetine in


RCTs showed, controversially, both superiority of

the SNRIs (Goldstein et al., 2004) and no significant

differences (Detke et al., 2004). Studies show dulox-

etine to have effectiveness similar to escitalopram

(Hirschfeld and Vornik, 2004).

In contrast, direct comparisons between SNRIs

(venlafaxine and milnacipran) and TCAs turned up

no significant or clinically relevant differences in effi-

cacy (Samuelian and Hackett, 1998 ; Van Ameringen55

et al., 2002). Direct comparison of venlafaxine and

mirtazapine showed only trends in favor of mirtaza-

pine but no significant differences (Guelfi et al., 2001).

Besides its efficacy in treating depression, dulox-

etine has also been reported to significantly reduce

painful physical symptoms (Detke et al., 2002).


SNRI treatment has a favorable tolerability profile

compared with TCAs; most adverse events occur ear-

ly in treatment and tend to decrease or disappear with

continued treatment (Stahl et al., 2005). Venlafaxine is

similar to sertraline in terms of treatment efficacy and

quality of life, but sertraline showed a more favorable

tolerability profile with respect to discontinuation

symptoms and the risk of elevated blood pressure (Sir

et al., 2005). This risk seems to be less prominent in

newer SNRIs such as duloxetine and milnacipran

(Stahl et al., 2005). Nevertheless, duloxetine tends to

have more adverse events than paroxetine (Detke

et al., 2004 ; Goldstein et al., 2004). An extended release

(ER) formulation of venlafaxine has tolerability ad-

vantages over the immediate release (IR) formulation

(Norman and Olver, 2004 ; Olver et al., 2004) (see

chapter 9.1.1.2). Hypertension may occur more fre-

quently with high doses of venlafaxine than with low

doses (Thase et al., 2006b). Discontinuation of the SSRI

escitalopram results in a lower rate of reported dis-

continuation symptoms (Baldwin et al., 2005). In most

studies SNRIs proved more efficacious than SSRIs and

had better tolerability than TCAs, which at least in the

case of milnacipran probably has a positive impact on

the cost-effectiveness of treatment (Dardennes et al.,

1999) (for more details on the cost-effectiveness of

SNRIs see chapter 14.4.2). The fatal toxicity index

for venlafaxine in cases of overdose seems to be

in between that of SSRIs and TCAs (Koski et al., 2005),

leading to the recommendation that venlafaxine

be reserved as a second-line treatment after SSRIs

(Medicines and Healthcare products Regulatory

Agency, 2006 ; National Institute for Health and

Clinical Excellence, 2004).

9.1.7 Selective noradrenaline reuptake inhibitors

9.1.7.1 Efficacy

Controlled data directly comparing the single avail-

able NARI reboxetine56 with other antidepressants are

rare. One study looking at reboxetine and sertraline

found no difference in response after 5 weeks of

treatment, whereas reboxetine was found to be ad-

vantageous for remission between weeks 2 and 4, and

at week 5 (Eker et al., 2005). Reboxetine was found to

be similar to fluoxetine in efficacy for depressive dis-

orders, and more effective in a subgroup of severely

depressed patients (Massana et al., 1999). Among

patients suffering from post-stroke depression, rebox-

etine was less efficacious in anxious depressed pa-

tients than citalopram, but more efficacious in

retarded depressed patients (Rampello et al., 2004). In

addition, reboxetine is reported to be at least as effec-

tive as other classes of antidepressants, including

TCAs, and again in a subgroup of patients, in

depressed patients with melancholic features, TCA

was found to have advantages over reboxetine

(Montgomery, 1998).


In all published studies, reboxetine showed a good

safety and tolerability profile (Burrows et al., 1998).

Reboxetine is safer and more tolerable than TCAs.

NARI use was not associated with an increased risk of

seizures, orthostatic hypotension or cardiovascular

side effects. In addition, sexual dysfunction appears to

be less common with reboxetine than with the SSRI

fluoxetine (Clayton et al., 2003). Reboxetine has a dif-

ferent side effect profile than SSRIs, with advantages

in terms of agitation, nervousness, anxiety and gas-

trointestinal events (Montgomery, 1998). Patients

treated with reboxetine sometimes experience agi-

tation and sleep disturbances ; they may also be troub-

led by hyperhidrosis. Despite the low anticholinergic

activity of reboxetine, its a-receptor agonistic effects

may affect micturation. In that event concomitant

treatment with tamsulosin, an a1A-adrenoceptor an-

tagonist, may prevent such patients from discontinu-

ing reboxetine. Increased heart rate and blood

pressure have also been reported. Weight loss occurs

only rarely.

55 The Medline database contains the wrong spelling ‘Van

Amerongen’.

56 Reboxetine is available in Europe and Australia, but as mentioned

above, to date it has not been marketed in the US.


9.1.8 a-Receptor-blocking tetracyclic antidepressants

9.1.8.1 Efficacy

To date the structurally similar tetracyclic antidepress-

ants mianserin and mirtazapine represent the group

of a2-receptor-blocking antidepressants. Mianserin

was developed before mirtazapine and shows a higher

affinity for the a1-adrenoceptor and more influence

on noradrenaline (NA) reuptake (Kelder et al., 1997).

Mianserin exerts only weak NA reuptake-inhibiting

effects. Mirtazapine is characterized as its own class of

antidepressant with noradrenergic and specific sero-

tonergic properties (NaSSA). The a2-antagonistic effect

of mirtazapine results in serotonergic activation,

whereas the a1-antagonistic effect of mianserin coun-

teracts the a2-antagonistic effect.

Both mianserin (Moller et al., 1995) and mirtazapine

(Benkert et al., 2002) are described as being at least

as effective as TCAs and have some advantages

over other newer antidepressants (Szegedi and

Schwertfeger, 2005). In addition to its antidepressant

effects, mirtazapine significantly improves sleep

parameters associated with insomnia (Thase, 1999a).

Mirtazapine also shows much more rapid onset of ac-

tion than SSRIs (Benkert et al., 2000 ; Benkert et al.,

2002 ; Blier, 2001 ; Blier, 2003 ; Quitkin et al., 2001 ; Tran

et al., 2003). But owing to the retrospective character of

some of these studies, further clarification is required

of the hypothesis that these effects are caused not only

by the sedating properties of mirtazapine but also its

specific effects on other symptoms of depression. An

RCT in elderly patients showed mirtazapine to have

an earlier onset of action compared with the SSRI

paroxetine (Schatzberg et al., 2002). It is better at re-

ducing depressive symptoms than fluoxetine

(Wheatley et al., 1998). Compared with other recently

developed antidepressants, such as dual-action SNRIs

and selective NARIs, mirtazapine shows no convinc-

ing differences in terms of overall efficacy or speed of

onset (Moller, 2000 ; Olver et al., 2001). Nevertheless,

from a clinical point of view, a significant advantage

(and simultaneously a disadvantage, as described in

chapter 9.1.8.2) of NaSSAs is their pharmacodynamic

profile, including antihistaminergic properties, which

are useful in treating depression-related sleep dis-

turbances without the use of additional hypnotic sub-

stances. Mirtazapine is also available in the galenic

form of fast dissolving tablets (see chapter 9.1.1.2).


NaSSAs have a substantially better side-effect profile

than a variety of TCAs (Blier, 2003 ; Montgomery,

1995 ; Tran et al., 2003). The safety of NaSSAs is similar

to that of SSRIs (Olver et al., 2001), but typical sero-

tonergic side effects such as sexual dysfunction and

gastrointestinal complaints are less frequently present

in mirtazapine-treated patients (Montgomery, 1995).

The most frequently reported adverse events during

mirtazapine therapy are antihistaminergic effects,

such as initial somnolence and dizziness, together

with increased appetite and cumulative weight gain

over the long term (Tran et al., 2003). The weight gain

often reduces patients’ compliance and may some-

times even facilitate development of a metabolic syn-

drome. Serious and potentially fatal side effects are

rare, but clinicians need to be aware of the potential

of both antidepressants to cause or enhance severe

neutropenia (Ozcanli et al., 2005). In addition, mian-

serin is reported to carry a risk for agranulocytosis

(Farmer, 1990 ; Girard, 1990 ; Launay et al., 2000). This

is especially true in patients with an enhanced sus-

ceptibility for these side effects (see chapter 9.1.1.3.4)

and in combination therapies (Imbarlina et al., 2004).

9.1.9 Serotonin modulating antidepressants

9.1.9.1 Efficacy

Nefazodone and its structural analog trazodone block

5-HT2 receptors, but only weakly inhibit the reuptake

of serotonin and noradrenaline (Blier et al., 2006). One

of the active metabolites of serotonin modulating anti-

depressants (SMAs) has 5-HT1 agonistic properties.

The drugs are reported to work as well as the TCA

imipramine and other older antidepressants (Cyr and

Brown, 1996; Ellingrod and Perry, 1995). Nefazodone

and trazodone are also as effective as the SSRIs fluox-

etine, sertraline and paroxetine (Avila et al., 2003 ;

Sussman et al., 2001). Trazodone is reported to be as

effective as the SNRI venlafaxine in ameliorating de-

pressive symptoms, and better at relieving sleep dis-

turbances. It is less good, however, at improving

cognitive disturbances and retardation (Cunningham

et al., 1994). The NaSSA mirtazapine shows significant

clinical advantages compared with trazodone in terms

of overall efficacy (van Moffaert et al., 1995). The se-

dating properties of nefazodone and trazodone make

them particularly suitable for agitated patients and

patients suffering from insomnia (Boerner and Moller,

1999 ; Thase, 1999a).


SMAs have a safety margin similar to TCAs, but

a more favorable tolerability profile (Lader, 1996),

with lower anticholinergic and antihistaminic activity

(Taylor et al., 1995). The specificity of action of SMAs


on neurotransmitter systems is believed to be the rea-

son for the enhanced safety and tolerability of the drugs

(Nemeroff, 1994). The side-effect profile of SMAs is

also different from that of SSRIs ; the most commonly

reported side effects are sedation, dry mouth, nausea,

somnolence and dizziness (Cunningham et al., 1994;

Cyr and Brown, 1996). Trazodone may enhance the

risk of priapism. Patients taking SMAs report fewer

complaints of nervousness, insomnia and sexual dys-

function compared with SSRIs (Preskorn, 1995).

Nevertheless, several case reports show that the po-

tential of nefazodone to cause severe hepatotoxicity

and even fulminant hepatic failure (Conway et al.,

2004 ; Schirren and Baretton, 2000 ; Tzimas et al., 2003)

makes reliable clinical monitoring crucial (Lucena

et al., 2003). The original producer has withdrawn

nefazodone from the market, but in some countries,

including the US, generic versions of the drug are

available. Trazodone is still available in eastern coun-

tries, such as China and Hong Kong, Indonesia, Japan,

Korea and Thailand.

9.1.10 Dopamine and noradrenaline reuptake inhibitors57

9.1.10.1 Efficacy

The mechanism of action of DNRIs is still not com-

pletely clear or understood. The FDA classifies DNRIs

as B-category antidepressants. In a variety of countries

bupropion is approved only for smoking cessation,

but not as an antidepressant. Nevertheless, it is used

off-label for combination therapies, especially in the

case of treatment-resistant depression.

Bupropion shows significant antidepressant efficacy

at least equal to the SSRIs sertraline (Coleman et al.,

1999 ; Croft et al., 1999 ; Kavoussi et al., 1997), fluox-

etine (Coleman et al., 2001 ; Feighner et al., 1991;

Workman and Short, 1993) and paroxetine (Weihs

et al., 2000). The same is true of comparison with the

TCA doxepin (Feighner et al., 1986), but the improve-

ment in sleep parameters was more pronounced in the

doxepin group. Likewise, no difference in efficacy is

evident between bupropion and the TCAs amitripty-

line (Remick et al., 1982) and imipramine (Workman

and Short, 1993). The same comparative study re-

vealed no differences in efficacy between bupropion

and the SNRI venlafaxine and the SMA trazodone

(Workman and Short, 1993). Despite a few contradic-

tory results, its good efficacy combined with a lower

switch risk than SNRIs argues for recommending

bupropion especially in the treatment of bipolar de-

pression (Post et al., 2006 ; Thase, 2005).


Compared with patients treated with the SSRI sertra-

line, patients treated with bupropion show a lower

rate of serotonergic side effects, such as sexual dys-

function, gastrointestinal complaints, insomnia and

agitation (Coleman et al., 1999 ; Croft et al., 1999;

Kavoussi et al., 1997). Particularly in male patients,

sexual dysfunction may be prominent and can be re-

duced by using an ER formulation of bupropion.

In addition, side effects are reportedly fewer with

bupropion than with fluoxetine (Coleman et al., 2001).

Patients given doxepin had predominantly more

anticholinergic and antihistaminergic side effects than

those given TCAs (Feighner et al., 1986). Bupropion

has also been classified as a B-group antidepressant for

use during pregnancy. Although the risk for general-

ized seizures is considered to be a rare consequence of

bupropion treatment (Montgomery, 2005), it must be

taken into account in treatment plans using bupropion

(Ross and Williams, 2005). This risk may be further

enhanced under conditions that increase the chance of

seizures, such as alcohol withdrawal, anorexia and

bulimia (Horne et al., 1988). Indeed, in cases of acci-

dental or intentional overdose, generalized seizures

seem to be a relatively frequent complication (Pesola

and Avasarala, 2002 ; Shepherd et al., 2004).

9.1.11 Herbal preparations used in the treatment of

depression

Although herbal treatments make up a reasonable

share of antidepressant prescriptions in some coun-

tries, e.g. Germany, whether they should be classified

as antidepressants is a matter of ongoing controversy

(Bauer et al., 2002c). The main reason is that RCTs

have not shown these medications to be useful in cases

of severe depression. An additional reason is the un-

certainty regarding their precise pharmacological

mechanism of action. Nevertheless, a variety of herbal

substances with possible antidepressant effects have

been investigated in less-sophisticated studies and

less severely depressed patients. For most of these

substances, e.g. Kava-Kava extract, no antidepressant

effects could be demonstrated. For others, RCTs have

shown antidepressant effects (Akhondzadeh et al.,

2005), but to date, no placebo-controlled replication

studies have been published.

57 The mechanism of action of bupropion is still unclear. It may be

related to inhibition of presynaptic dopamine and noradrenaline

(norepinephrine) reuptake transporters (Foley et al., 2006), but

positron emission tomography (PET) studies in humans show no

effects on dopamine or noradrenaline transporters at therapeutic

doses (Kugaya et al., 2003 ; Learned-Coughlin et al., 2003 ; Meyer

et al., 2002).


9.1.11.1 St. John’s wort

9.1.11.1.1 Efficacy

The most studied of the herbal substances is St. John’s

wort (Hypericum perforatum). It is worth noting that

many different preparations of St. John’s wort are

available over-the-counter, and these differ in the

number, concentration and balance of active and in-

active, helpful and potentially harmful constituents.

Both serotonergic mechanisms and MAO inhibition

have been proposed as antidepressant modes of action

(Deltito and Beyer, 1998). In addition, mechanisms

similar to those of SSRIs, but to a lesser extent, have

been reported (Kasper and Schulz, 1999). Despite

some controversy in findings (Shelton et al., 2001a),

studies conclude that Hypericum is suitable for treat-

ment of mild to moderate depressive syndromes (Kalb

et al., 2001 ; Kasper, 2001 ; Lecrubier et al., 2002 ;

Uebelhack et al., 2004 ; Wong et al., 1998) if prep-

arations provide sufficient concentrations of hypericin.

In some countries, it has already been approved for

that indication. In randomized controlled studies,

Hypericum was therapeutically equivalent to the SSRIs

fluoxetine (Behnke et al., 2002 ; Schrader, 2000), par-

oxetine (Szegedi et al., 2005) and sertraline (Brenner

et al., 2000 ; Gastpar et al., 2005). Indirect comparisons

with fluoxetine show no relevant differences in effi-

cacy (Volz and Laux, 2000). Even advantages of

Hypericum over fluoxetine have been demonstrated

(Fava et al., 2005a), but neither active compound ex-

hibited statistically significant superiorityoverplacebo.

Nevertheless, remission rates were higher in SSRI-

treated patients (Bjerkenstedt et al., 2005). Therapeutic

equivalence to imipramine and superiority over pla-

cebo have been shown in the treatment of mild to

moderate depression (Philipp et al., 1999 ;Woelk, 2000).

Recent meta-analyses show inconsistent results (Linde

et al., 2005). Hypericum reportedly shows effectiveness

similar to low-dose TCA (Kim et al., 1999) or SSRI

therapy (Kasper and Dienel, 2002), but problems of

design in some studies prohibit definite conclusions.

9.1.11.1.2 Safety and tolerability

Comparative studies show significantly better toler-

ability of Hypericum compared with SSRIs and TCAs

(Bjerkenstedt et al., 2005 ; Szegedi et al., 2005 ; Woelk,

2000). In particular, Hypericum was devoid of anti-

cholinergic side effects, sedation, gastrointestinal

disturbances and sexual dysfunction (Trautmann-

Sponsel and Dienel, 2004). The substance is considered

to be safer than TCAs with regard to cardiac function

(Czekalla et al., 1997). Nevertheless, risks to be aware

of include photosensitization (Kasper, 2001 ; Kasper

and Schulz, 1999). Because Hypericum involves sero-

tonergic mechanisms and monoamine oxidase inhi-

bition, concurrent use of SSRIs and MAOIs should be

avoided (Deltito and Beyer, 1998). Treatment with

Hypericum, which induces both CYP3A4 and the drug

transporter protein P-glycoprotein, can result in phar-

macokinetic interactions with serious clinical conse-

quences, such as loss of activity of comedication

(Henderson et al., 2002; Hennessy et al., 2002 ;

Izzo and Ernst, 2001). This outcome has been demon-

strated for digoxin (Johne et al., 1999) and cyclosporine

(Ruschitzka et al., 2000) owing to induction of hepatic

metabolizing enzymes, and for contraceptives, es-

pecially in case of low-dose oral contraception

(Murphy et al., 2005). To date no results have been

published concerning discontinuation symptoms fol-

lowing tapering of Hypericum.

9.1.11.2 Kampo

Kampo (a traditional Japanese herbal medicine) for-

mulas are widely used along with modern medicines

as adjunctive strategies in Japan (Kanba et al., 1998 ;

Kanba et al., 1999). A kampo formula is made from

two or more herbs that have various pharmacological

activities. Kampo prescriptions should not only be

selected according to traditional theory but also be

prescribed based on symptoms. The Japanese Ministry

of Health, Labor and Welfare has approved more than

100 kampo prescriptions for use in clinical practice.

Some open studies have shown the efficacy of

kampo formulas for patients with neurosis and mild

major depression. Also, Yamada and Kanba have re-

ported six outpatients with premenstrual dysphoric

disorder (PMDD) who were treated successfully with

Kamishoyosan (Yamada and Kanba, 2002). For major

depression, schizophrenia and other mental disorders,

kampo formulas are used with psychotropics, such

as antidepressants and antipsychotics. For example,

partial remitted major depressive disorder was treated

successfully with Rokumigan or Hachimijiogan

(Yamada et al., 2005). These substances are also used

for the treatment of adverse events induced by psy-

chotropics. Twenty outpatients with SSRI-induced

nausea and dyspepsia were successfully treated with

Goreisan (Yamada et al., 2003b).

9.1.11.3 Morinda officinalis, Jieyu and Banxia Houpu

decoction (Chinese traditional herbal medicine)

Morinda officinalis (Cui et al., 1995) and a decoction/

brew of Banxia Houpu (Luo et al., 2000) are herbal

medicines that have been used since ancient times


in traditional Chinese medicine to treat depression-

associated symptoms. Jieyu pill and decoction have

been investigated in patients suffering from depress-

ive symptoms and showed antidepressant properties

in randomized, but not placebo-controlled studies

(Feng et al., 2004 ; Shen et al., 2004). To date, putative

antidepressant effects and possible mechanisms of ac-

tion ofMorinda officinalis and Banxia Houpu have been

investigated in animal models of depression (Li et al.,

2001 ; Zhang et al., 2002). In addition, phase III clinical

trials are ongoing. It is thus premature draw final

conclusions about the possible antidepressant efficacy

and effectiveness of these compounds.

9.1.12 Strategies in the event of non-response

to antidepressant treatments : combination and

augmentation

9.1.12.1 The concept of non-response to antidepressant

treatment

Patients who do not respond to at least two anti-

depressant monotherapies (in some wider definitions

even one) are usually referred to as treatment resist-

ant. However, reasons for this ‘treatment resistance’

or ‘non-response to antidepressant treatment’ (see

also Box 7, definition of pharmacotherapy-resistant

depression) may vary and often do not reflect true

resistance to treatment. The definition by Ananth

(Ananth, 1998) as a ‘failure to respond adequately to

two successive courses of monotherapy with pharma-

cologically different antidepressants given in adequate

dose for sufficient length of time’ includes a number of

prerequisites : correct diagnosis, adequate treatment in

terms of dosage, duration and compliance, and un-

successful previous therapy.

Before switching antidepressants, sufficient lengthof

treatment (see chapter 9.1) and the adequacy of dosage

should be considered. If in doubt, TDM (see chapter

9.1.1.1.3) may be helpful to ensure adequate blood

levels of medication (Corruble and Guelfi, 2000).

Switching strategies after unsuccessful antidepressant

trials often results in low remission rates (Fava et al.,

2006). Adli et al. (Adli et al., 2005) conducted a sys-

tematic review of whether dose escalation leads to

additional benefit following failure of a medium dose.

They concluded that ‘available data suggest differen-

tial efficacy of various pharmacological classes at more

than medium dosage. Direct evidence shows no in-

crease of efficacy with high-dose selective serotonin

reuptake inhibitor (SSRI) treatment ; however, indirect

evidence suggests enhanced therapeutic efficacy with

high-dose tricyclic antidepressants. Few clinical data

show ultra-high-dose treatment with the irreversible

MAOI tranylcypromine to be effective for refractory

depression. Data concerning other selective com-

pounds are insufficient to allow any definitive con-

clusion on the benefit of high-dose treatment. ’

Recently published reviews summarize the actual

knowledge about switching strategies (Ruhe et al.,

2006b) and dose escalating strategies (Ruhe et al.,

2006a) which are especially recommended in case of

partial response.

Factors in addition to pharmacological treatment

resistance that may lead to less favorable outcomes

include psychiatric comorbidity, e.g. alcohol and sub-

stance abuse, personality disorders and anxiety and

panic disorder (Adli et al., 2005). Sharan and Saxena

(Sharan and Saxena, 1998) have identified several

other factors predictive for poor response, including a

family history of affective disorders, severity of de-

pression, suicide attempts, number of previous epi-

sodes, long duration of depression prior to treatment,

negative life events and poor social support. Aware-

ness of these factors and adequate action, e.g. addition

of psychotherapy with negative life events, are an a

priori requisite for making pharmacological changes.

In addition it is essential to be aware of all factors in-

fluencing the patients’ compliance (Demyttenaere

et al., 2001a; Demyttenaere et al., 2001b). Treatment-

resistant depression may also influence vulnerability

to other mental disorders. For example, the incidence

of dementia is significantly increased in older patients

with insufficiently treated depression (Shim and Yang,

2006). In support of these results, magnetic resonance

imaging (MRI) findings showing decreased hippo-

campal volumes in treatment-refractory depressed

patients, and enhanced neuronal plasticity and cellu-

lar resilience may indicate a new direction for

developing novel, improved therapeutics for difficult-

to-treat depression (Manji et al., 2003).

Figure 3 summarizes a stepwise approach for

managing non-response to an initital antidepressant.

9.1.12.2 General introduction to combination and

augmentation

When a previousmonotherapy has not been efficacious

at all, even after a trial with maximum dosage, swit-

ching medication is usually recommended (Kennedy

et al., 2001). A recently published analysis of the

National Institute of Mental Health Sequenced Treat-

ment Alternatives to Relieve Depression (STAR*D)

trial pointed out that approximately 25% of patients

non-responsive to citalopram benefit from switching

either to sertraline, bupropion or venlafaxine (Rush

et al., 2006c).


However, when response is partial, it may be un-

wise to discontinue premedication and risk worsening

of symptoms. Thus, combination with another anti-

depressant or augmentation should be considered.

Sufficient evidence now exists that combining anti-

depressants or augmentation strategies could be more

effective thanmonotherapy in some patients (Kennedy

et al., 2001). Combination treatment is defined as

addition of another medication without expecting po-

tentiation of efficacy of the previous drug (see Box 10).

Benefits as well as side effects are additive. Usually, a

medication with an alternative and different pharma-

cology or a drug with a dual mechanism of action is

chosen for combination treatment (see also chapter

9.1.12.2.1). In contrast, augmentation means adding

another agent that by itself may be not specifically

helpful as a primary treatment of depression but that

may enhance responsiveness to a given antidepressant

(see Box). Examples for these strategies, ordinarily

used in antidepressant non- or only partially respon-

sive patients, include lithium, thyroid hormones, pin-

dolol and buspirone, and more recently, also some

atypical antipsychotics. Table 19 summarizes common

augmentation strategies.

9.1.12.2.1 Combination treatment

9.1.12.2.1.1 Combination of different antidepressants

9.1.12.2.1.1.1 Efficacy

Although we lack scientific evidence to define specific

and effective next-step treatment options for treat-

ment-resistant depressive disorders (Rush et al., 2004),

combination of antidepressants is a very common

strategy in such cases (de la Gandara et al., 2005a;

Schatzberg, 2004). Generally, antidepressants with

different pharmacological profiles are combined. In a

recent literature search, Dodd et al. (Dodd et al., 2005)

identified only 8 randomized trials between 1978 and

2004 that studied combinations of antidepressants, 5 of

them including fluoxetine. In addition, 16 open-label

trials were identified, most of them using again at least

one SSRI. Combining antidepressants with predomi-

nant serotonergic and noradrenergic properties, e.g.

prescribing SSRIs and SNRIs, is also one of the most

frequent clinical therapeutic options (de la Gandara

et al., 2005a). SSRIs and NaSSAs are also frequently

used in combination. A combination of the SSRI

fluoxetine and the tetracyclic a2-blocker mianserin

showed superior efficacy over placebo in several

studies (Dam et al., 1998 ; Ferreri et al., 2001).

Especially in the case of prior treatment resistance,

combining two dual-action substances, such as mirta-

zapine and venlafaxine, can be of clinical use, but

more controlled studies confirming the superior

effectiveness of these combinations are required

(de la Gandara et al., 2005b ; Rojo et al., 2005). Further

reasons for combining different antidepressants

are specific side-effect profiles, e.g. using anti-

histaminergic properties of one antidepressant for

early amelioration of sleep disturbances or improve-

ment of appetite, especially in geriatric depression.

9.1.12.2.1.1.2 Safety and tolerability

Combining two or even more antidepressants can en-

hance tolerability (King et al., 1994), owing to clinical

effectiveness of lower doses : sexual dysfunction

due to SSRI treatment may be reduced using lower

dosages within combination strategies. For example,

bupropion showed a reduced rate of sexual dysfunc-

tion compared with some SSRIs (Coleman et al., 1999 ;

Coleman et al., 2001 ; Croft et al., 1999). At the same

time, a variety of possible pharmacokinetic inter-

actions (Baumann, 1996) enhances risk for severe ad-

verse events, e.g. increased TCA toxicity due to

cytochrome P-450 inhibition by fluoxetine or fluvox-

amine (for more details see chapter 9.1.1.1). The fact

that TDM of these compounds is not widely practiced

Inadequate response to firstantidepressant

Reevaluate diagnosisExclude comorbid medical or

psychiatric disorderReview dose

Increase dose of firstantidepressant

Continue increased dose for4 weeks

Reevaluate dose and continueoptimized regimen for further

2 weeks

Combine with antidepressantfrom a different

pharmacological class oraugment with a non-

antidepressant (e.g. lithium)

Switch to an antidepressantfrom a different

pharmacologic class or dualaction agent

Dis

ease

app

aren

tly r

esis

tant

to o

ptim

al/s

uffic

ient

dos

e*

Partialresponse

Still partialresponse

nonresponse

No furtherimprovement

Figure 3. A stepwise approach to managing patients with

inadequate response to antidepressant therapy (adopted

from Hirschfeld et al., 2002). * TDM should be implemented

in routine care (Mann et al., 2006b). It is especially

recommended in case of treatment failures.


makes this risk more likely. Further increased risk is

associated with additional somatic diseases that re-

quire additional pharmacologic treatment.

9.1.12.2.1.2 Combination of ECT and antidepressants

9.1.12.2.1.2.1 Efficacy

A further option in enhancing the effectiveness of

antidepressant treatments may be concomitant use of

ECT in combination with antidepressants. Such a step

may be necessary due to possible non-responsiveness

to ECT in 15–25% of depressed patients (Husain et al.,

2004). However, study results regarding a putative

benefit of combining ECT with TCAs (Lauritzen et al.,

1996 ; Nelson and Benjamin, 1989) and the lack of

benefit of other concomitant medication, like SSRIs,

are still controversial (Lauritzen et al., 1996). In

particular, investigations of the efficacy of modern

antidepressants in combination with ECT, e.g. the

dual-action substances mirtazapine and venlafaxine,

are rare (Baghai et al., 2006b; Farah, 1997).

Owing to the severity of depressive syndromes

in patients following medication treatment failure,

the clinical recommendation is to combine ECT with

antidepressants at moderate doses over the entire

course of treatment. When that is not possible, anti-

depressants should be used at least during the last

2 weeks of ECT treatment to prevent exacerbation of

depression following ECT during the usual latency

until antidepressant response is achieved following

initiating pharmacotherapy or to use continuation

ECT (see chapter 12.2.3).

9.1.12.2.1.2.2 Safety and tolerability

Combining ECT with TCAs and SSRIs has been

described as a safe procedure (Lauritzen et al., 1996;

Nelson and Benjamin, 1989). Moreover, safety data on

such combinations are available : in a recent study

venlafaxine at dosages lower than 300 mg/day was

shown to be safe in combination with ECT. In high-

dose treatments above 300 mg/day, side effects of a

cardiovascular nature, such as transient asystolia and

bradycardia, were more frequent when ECT was

combined with propofol anesthesia (Gonzalez-Pinto

et al., 2002). Combination of ECT and MAOIs should

be treated with particular caution. In fact, it should

be avoided, if possible, owing to enhanced risk for

sometimes lethal complications, especially shortly

after starting pharmacological treatment (Naguib and

Koorn, 2002). At the very least a 2-week washout per-

iod should be observed. The combination of ECT with

lithium increases the risks associated with anesthesia

(Hill et al., 1976; Hill et al., 1977 ; Reimherr et al., 1977),

the risk of prolonged seizures (Sartorius et al., 2005)

and the risk of cognitive disturbances. But it re-

presents only a relative contraindication due to reports

of safe use of this combination and the specific risk of

discontinuing lithium treatment.

9.1.12.2.2 Augmentation treatment

Augmentation strategies have some advantages over

switching antidepressants. They eliminate the period

of transmission from one antidepressant to another

and build on the partial response. Consequently, if

they work, they can be rapidly effective ; they may,

however, also raise tolerability and safety issues.

As combination treatment has been dealt with exten-

sively in the previous chapter (see chapter 9.1.12.2.1),

we will now concentrate only on the different aug-

mentation strategies tested in unipolar depression.

9.1.12.2.3 Lithium

Of all the strategies listed in Table 19, lithium aug-

mentation is the best described (Bauer et al., 2003;

Bschor and Bauer, 2006 ; Zullino and Baumann, 2001).

A multitude of open and 12 randomized placebo-

controlled trials, including a meta-analysis (Bauer

et al., 2003), support the efficacy of lithium augmen-

tation in the acute treatment of treatment-resistant

unipolar depression. Lithium has been found to aug-

ment the therapeutic effects of a broad spectrum of

antidepressants, including TCAs (Bauer et al., 2003;

Bauer and Dopfmer, 1999) and SSRIs (Joffe et al., 1993 ;

Katona et al., 1995). The meta-analysis by Bauer and

Dopfmer (Bauer and Dopfmer, 1999) also demon-

strated that lithium augmentation is superior to pla-

cebo augmentation, with a response rate of about

40–50% at week 3 or 4 across studies, but only 20%

of patients respond as early as week 1. To allow full

assessment of patient response, lithium augmentation

should be administered for at least 4 weeks, ensuring

Box 10. Definition of combination and augmentation treatment

$ Combination treatment : combination of two or more treatments, each of which represents an antidepressant alone.$ Augmentation treatment : efficiency amplification of an antidepressant treatment with a substance that alone does not exert

sufficient antidepressant activity to be used as a monotherapy.


serum levels of 0.6–0.8 mmol/l (Bauer et al., 2002c).

Once stabilized on the combination, it is unwise to

withdraw lithium for at least a year (Bauer et al., 2000).

However, the utility of lithium augmentation may be

limited by side effects, e.g. polyuria, muscular weak-

ness and tremor. Especially in older patients lithium

toxicity may occur even within therapeutic plasma

levels and might present itself with a clinical picture

that is not always easy to differentiate from an increase

in severity of depression. Electroencephalogram (EEG)

may be a helpful monitoring tool for differential diag-

nosis in this clinical situation (Gallinat et al., 2000).

Whether the potential neurotoxicity of lithium plays

a major role in clinical practice or even has a distinct

neuroprotective effect cannot yet be concluded.

Patients on lithium therapy should be closely moni-

tored and regularly assessed for the presence of side

effects from the central nervous system (CNS) even

when their serum lithium levels are within therapeutic

levels. Research may be needed to develop better ways

to monitor lithium, possibly by substituting plasma

levels with other, more reliable indices. A candidate

index could be red blood cell lithium levels. This issue

has been discussed in an extensive review recently

(Fountoulakis et al., 2006). It is also unclear whether

lithium augmentation has the same efficacy across age

groups. Some publications point to a low response rate

and a high rate of severe side effects in the elderly.

9.1.12.2.4 Thyroid hormones

At least 13 prospective trials (9 open and 4 controlled

double-blind studies) support the usefulness of triio-

dothyronine (T3), with most studies employing

25–35.5 mg/day (Bauer et al., 2002c). Women es-

pecially seem to respond favorably to thyroid hormone

Table 19. Biological treatment strategies for partial and non-responding patients with major depressive disorders.

Modified from WFSBP Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1 (Bauer et al., 2002c)

Treatment strategy Mechanisms/drug classification

Pharmacological augmentation

Lithium Mood stabilizer

Lamotrigine, valproate, carbamazepine Anticonvulsants/mood stabilizer

Amisulpride, aripiprazole, olanzapine,

quetiapine, risperidone, ziprasidone

Antipsychotic agents, 5-HT2 antagonism

Pindolol 5-HT1A autoreceptor antagonist, b-receptor blocker 5-HT1A

Buspirone and D2-receptor agonist

Stimulants Dopamine and noradrenaline release and reuptake inhibition

Pergolide Dopamine (D1/D2) agonist

Bromocriptine Dopamine (D2) agonist

Pramipexole Dopamine (D2/D3) agonist

Reserpine Reuptake inhibition of biogenic amines

Hormone augmentation

Triiodothyronine (T3) Thyroid hormone

L-Thyroxine (T4) Thyroid hormone

Estrogen (only women) Ovarian steroid hormone

Dehydroepiandrosterone (DHEA) Adrenal androgen hormone

Miscellaneous

Ketokonazole, metyrapone Peripheral cortisol suppression

L-Tryptophan, 5-hydroxytryptophan Essential amino acid, 5-H’I’ precursor

V-3 fatty acids Food supplement

Folic acid (only women) Vitamin

Non-pharmacological

Electroconvulsive therapy Electric stimulation to elicit an epileptiform seizure in brain

[Repetitive transcranial magnetic stimulation] Non-invasive stimulation of the cerebral cortex

[Vagus nerve stimulation] Autonomic signals to limbic and cortical function

Phototherapy (bright light therapy) Chronotherapeutics

Wakefulness therapy (sleep deprivation) Chronotherapeutics

Physical exercise Supportive procedure


augmentation (Altshuler et al., 2001). A three-arm,

double-blind controlled study showed equal efficacy

of augmentation with T3 and lithium, and superiority

to placebo (Joffe et al., 1993). A recently published

STAR*D report confirmed the similar efficacy of T3 and

lithium with lower rates of adverse events and slightly

(but nonsignificant) higher remission rates in the T3

group (Nierenberg et al., 2006a). However, as not all

controlled double-blind studies showed significant

results in favor of T3, a subsequent meta-analysis

found inconsistent results favoring T3 augmentation

(Aronson et al., 1996). Recently, augmentation with

L-thyroxine (T4) has been postulated as an alternative

to T3, and open studies and functional neuroimaging

support the efficacy of this approach (Bauer et al.,

2002a; Bauer et al., 2005). Double-blind controlled

studies are still missing, however. When adding T4,

evidence so far suggests that supraphysiological do-

sages should be used; comparison of only 150mg/day

of T4 with 37.5 mg/day of T3 showed significantly

lower response rates for T4 (24 vs. 53%) (Joffe and

Singer, 1990). In some studies, dosage up to 500 mg/

day of T4 have been used with good efficacy and sat-

isfactory tolerability (Bauer et al., 1998). However,

the use of T4 in treatment-resistant unipolar de-

pression is still experimental, and for now evidence is

on the side of T3.

9.1.12.2.5 Anticonvulsants

Surprisingly little has been published regarding a po-

tential augmentative effect of anticonvulsants in uni-

polar depression. Open studies of valproate (Davis

et al., 1996 ; Svestka et al., 1990) and carbamazepine

(Post et al., 1986) suggest antidepressant properties

(Normann et al., 2002 ; Post et al., 1986). However,

verification by double-blind studies is still missing,

and in addition, studies of augmentation with carb-

amazepine show that it induces metabolism of venla-

faxine and citalopram, and that it may be necessary to

increase the dose of the antidepressant (Ciusani et al.,

2004 ; Steinacher et al., 2002).

In a double-blind add-on study to paroxetine in

non-treatment-resistant patients, lamotrigine showed

a faster onset of response but no significant differ-

ence in the outcome after 10 weeks (Normann et al.,

2002).

As far as treatment-resistant depression is con-

cerned, however, there is some evidence from open

studies for the augmentative efficacy of carbamazepine

(Cullen et al., 1991 ; Rybakowski et al., 1999; Varney

et al., 1993). The augmentative efficacy of lamotrigine

has been reported both in open and retrospective

studies (Barbee and Jamhour, 2002), as well as in one

small double-blind study (Barbosa et al., 2003). Most of

these studies (Barbosa et al., 2003 ; Blier and Ward,

2003), however, were conducted in mixed samples of

unipolar and bipolar II patients. Absent a separate

analysis, it is impossible to draw any clear conclusions

as far as unipolar treatment-resistant depression is

concerned. In summary, the evidence for the useful-

ness of augmentation with anticonvulsants remains

weak.

9.1.12.2.6 Pindolol

A potential role of 5-HT1A agonists in treating de-

pression and anxiety has been a major focus of re-

search in the past decade (Blier and Ward, 2003).

Pindolol is a b-adrenoreceptor antagonist. It also

blocks 5-HT1A and 5-HT1B/1D receptors, and therefore

should prevent the negative feedback effect of in-

creased somatodendritic serotonin (Dawson and

Nguyen, 2000). As a consequence, this action may ac-

celerate the onset of antidepressant action (Artigas

et al., 2001 ; Artigas et al., 2006).

A meta-analysis by Ballesteros and Callado

(Ballesteros and Callado, 2004) of nine randomized

controlled studies on the augmentative effects of

pindolol for SSRIs showed increased response with

pindolol after 2 weeks. After 6 weeks no difference in

outcome was observed. Despite positive open studies,

three out of four controlled trials have failed to show

advantage over placebo in treatment-refractory

patients (Moreno et al., 1997 ; Perez et al., 1999 ; Segrave

and Nathan, 2005). Only one small study applying

once-daily high-dose pindolol (7.5 mg) demonstrated

a significant advantage (Sokolski et al., 2004). In their

review on pindolol augmentation, Segrave andNathan

(Segrave and Nathan, 2005) speculate that the 2.5-mg

twice daily (t.i.d.) dose of pindolol that has been used

in all but one of these investigations may be sub-

optimal for achieving reliable and significant occu-

pancy of 5-HT1A autoreceptors, as shown by positron

emission tomography (PET) data (Rabiner et al., 2001)

and may explain the contradictory nature of the re-

sults of investigations of pindolol augmentation.

9.1.12.2.7 Buspirone

Buspirone is a partial 5-HT1A agonist that is believed

to activate postsynaptic 5-HT1A receptors and thus

may enhance the action of SSRIs. In addition, it

has been reported that it exerts affinity to D4 and to a

lesser extent to D1 and D2 receptors with a1- and a2-

antagonistic activity (Millan et al., 2000). A major

metabolite of buspirone enhances norepinephrine


release. Therefore, buspirone may also exert a dual

mechanism of action. However, in two double-blind

placebo-controlled studies, buspirone augmentation

both to fluoxetine and citalopram failed to demon-

strate significant benefit over placebo (Appelberg et al.,

2001 ; Landen et al., 1998) The study by Appelberg,

however, suggests at least a potential benefit in

more severe depression in a post hoc subanalysis

(Appelberg et al., 2001). Recently, the STAR*D study

investigated the efficacy of buspirone versus bupro-

pion augmentation in SSRI non-responders. In most

outcomes, the rate of improvement was similar for

both strategies, but buspirone was associated with

more tolerability problems (Trivedi et al., 2006a).

Clearly, further controlled studies are required to

clarify the role of 5-HT1A agonist in augmenting anti-

depressants.

9.1.12.2.8 Tandospirone

Similar to buspirone, tandospirone is a 5-HT1A recep-

tor agonist used in treating anxiety disorders. In

a Japanese study, the efficacy of augmentation of

clomipramine by tandospirone in 36 untreated out-

patients with major depressive disorder was evalu-

ated and compared with clomipramine monotherapy

and clomipramine plus diazepam. Outcome after

6 weeks, measured with the HAMD (17 items, HAMD-

17) and the Hamilton Anxiety Rating Scale (14 items;

HAMA-14) showed no statistically significant differ-

ence. However, at 2 weeks, the percentage improve-

ment of the HAMD-17 score in the tandospirone plus

clomipramine group tended to be higher, though

not statistically significant, than in the other groups

(Yamada et al., 2003a). More studies are required to

ascertain whether augmentation of antidepressants

by tandospirone for a few weeks might enhance the

onset of antidepressant response.

9.1.12.2.9 Second-generation antipsychotics

First-generation medium-potency antipsychotics, such

as sulpiride, have been shown to accelerate and im-

prove antidepressant (SSRI) treatment (Uchida et al.,

2005). More recently, the use of atypical antipsychot-

ics (see Table 19) to augment antidepressants in

non-psychotic depressive disorder has also been ad-

vocated. In addition, antidepressant effects of mono-

therapy with some of those substances have been

published both for bipolar (Post and Calabrese, 2004)

and unipolar depression (Amore and Jori, 2001).

Zhang et al. demonstrated that in the rat prefrontal

cortex the combination of olanzapine and fluoxetine

produced robust, sustained increases in extracellular

levels of dopamine and norepinephrine up to

361¡28% and 272¡16% of the baseline, respectively,

which were significantly greater than either drug

alone (Zhang et al., 2000). Thus, the combination

of olanzapine and fluoxetine has been tested in sev-

eral controlled studies both in unipolar and, more

extensively, bipolar depression. A small placebo-

controlled study of olanzapine added on to fluoxetine

supports this strategy (Shelton et al., 2001b). In a

second study the olanzapine/fluoxetine combination

was superior to olanzapine alone in the treatment

of depression with psychotic features (Rothschild

et al., 2004). Moreover, a larger double-blind study

that compared monotherapy with fluoxetine, nor-

triptyline and olanzapine against olanzapine/fluox-

etine combination in patients with treatment-resistant

depression also significantly favored the anti-

depressant/antipsychotic combination (Shelton et al.,

2005).

A large open study showed acute responsiveness

of previously SSRI (citalopram) treatment-resistant

patients to augmentation with low doses (0.25–2 mg/

day, depending on age) of risperidone (Nemeroff et al.,

2004). After a 6-week augmentation phase, 68.1%

of the patients with treatment-resistant depression

receiving add-on risperidone were classified as re-

sponders. However, significant superiority against

citalopram monotherapy was not maintained in

the subsequent double-blind continuation phase.

Recently, another placebo-controlled study on risper-

idone augmentation that included 97 patients whomet

criteria for unipolar non-psychotic major depression

and failed to respond, or only partially responded,

to at least a 5-week trial of an adequate dose of

antidepressant monotherapy. Primary outcome (re-

mission status) was determined by a Montgomery–

Asberg Depression Rating Scale (MADRS) rating f10

to denote remission. At the end of 4 weeks of treat-

ment 51.6% of the risperidone augmentation group

remitted compared with 24.2% of the placebo aug-

mentation group (p=0.011) (Nemeroff et al., 2004).

Augmentation with risperidone has also been com-

pared with addition of bupropion as a second anti-

depressant to SSRIs in a small, double-blind study.

Although there was no significant difference in any

outcome score at the end of the study (week 6), ris-

peridone produced a more robust effect as early as

week 1 (Papakostas et al., 2004).

A non-inferiority trial comparing amisulpride

with paroxetine treatment of major depression found

no statistically significant differences between the

treatment groups (Cassano and Jori, 2002). Open

and retrospective data also support the augmentative


efficacy of quetiapine, ziprasidone (Papakostas et al.,

2004) and aripiprazole (Barbee et al., 2004 ; Papakostas

et al., 2005 ; Papakostas, 2005 ; Simon and Nemeroff,

2005), although controlled studies have yet to be pub-

lished.

In conclusion, although it is possible to describe

the augmentative effects of several atypical anti-

psychotics, controlled evidence is still sparse, com-

parator studies to established strategies such as

lithium augmentation are lacking and we still need

more clinical experience of the utility of this approach

in treatment-resistant depression.

9.1.12.2.10 V-3 polyunsaturated fatty acids

Following publication of a potential epidemiological

link between low fish intake and depression (Hibbeln,

1998), low V-3 fatty acid levels in depression and in

women during the perinatal period have been found

(Rees et al., 2005). In four of seven double-blind ran-

domized controlled trials, significant improvement of

depressive symptoms was seen after regular ingestion

of eicosapentaenoic acid, an V-3 fatty acid, as an ad-

junct to antidepressant treatment compared with pla-

cebo (Nemets et al., 2002 ; Peet and Horrobin, 2002)

(for detailed information see the reviews of Sontrop

and Campbell, 2006, and Parker et al., 2006). Relatively

high doses between 0.5 and 2.8 g/day have been used

to achieve antidepressant effects (Freeman et al., 2006;

Peet and Horrobin, 2002).

Owing also to publication of negative results

(Silvers et al., 2005), to date it remains unclear whether

this therapeutic option has clear antidepressant effects.

Furthermore, we do not know whether it could be ef-

fective independent of other antidepressant treat-

ments or efficacious only in patients with abnormally

low V-3 fatty acid levels.

To date the safety and tolerability profile of V-3

fatty acid therapies seems to be excellent. Good toler-

ability has been reported even in post-partum de-

pression (Freeman et al., 2006). Diarrhea is a very

common side effect without markedly enhanced dan-

ger ; it can, however, influence blinding procedures in

double-blind studies. A somatic benefit for depressed

patients, who often are at enhanced cardiovascular

risk, has been proposed and needs to be further in-

vestigated (Frasure-Smith et al., 2004).

9.1.12.2.11 Other augmentation strategies

L-Tryptophan and 5-hydroxytryptophan used as

serotonin precursors have been studied in depressive

disorders with equivocal results. Some smaller studies

employing L-tryptophan showed potentiation of

MAOIs and augmentation of serotonergic anti-

depressants in treatment-resistant depression (for an

overview see Nelson, 2000) and in seasonal depression

refractory to light treatment (Lam et al., 1997).

However, unambiguous controlled studies are still

lacking.

Since an open pilot trial by Wharton with methyl-

phenidate in treatment-resistant depression (Wharton

et al., 1971), the use of stimulants has been docu-

mented in case series and one larger retrospective

chart review suggesting efficacy in treatment-

refractory depression (Stotz et al., 1999). Yet the only

randomized controlled study carried out so far of

methylphenidate in treatment-resistant depression

(Zhang et al., 2000) could not find a significant ad-

vantage over placebo.

More recently, modafinil has been tested in an open

pilot study as an add-on to antidepressants and

showed a 43% response rate (Rasmussen et al., 2005).

In a placebo-controlled study, however, it showed

significant improvement in SSRI partial responders for

fatigue and sleepiness, but only a trend to better out-

comes in depression rating scales (Fava et al., 2005b).

Clearly, more randomized, confirmative studies are

needed.

Dopamine agonists such as pramipexole also dem-

onstrated antidepressant activity in clinical trials

(Corrigan et al., 2000 ; Goldberg et al., 2004).

Besides countering agitation and sleep disturb-

ances, benzodiazepines may also have other augmen-

tative effects on antidepressant treatment (Furukawa

et al., 2000 ; Furukawa et al., 2001b). But their long-

term use is clearly discouraged due to their inherent

risk of addiction.

In some instances, e.g. perimenopausal depression,

augmentation with estrogen has been recommended

based on small pilot studies (Morgan et al., 2005;

Rasgon et al., 2002 ; Schneider et al., 1997; Schneider

et al., 2001). By the same token, estrogen carries health

risks such as increased risk of endometrial and breast

cancer, and thrombosis. A recent randomized double-

blind pilot study tested antidepressant augmentation

with the selective estrogen receptor modulator ralo-

xifene, showing good tolerability of raloxifene and a

non-significant trend to higher remission rates after

8 weeks (Grigoriadis et al., 2005). Clearly, more con-

trolled studies with adequate sample sizes are re-

quired. Also, in women only, the substitution of folic

acid (folate) improved the antidepressant action of

fluoxetine (Coppen and Bailey, 2000). In addition,

augmentation strategies using testosterone or dehy-

droepiandrosterone (DHEA) have been reported

(Fava, 2001).


9.1.12.2.12 Summary

Except for lithium and T3, there is still a lack of good

methodological studies supporting other pharmaco-

logical augmentation strategies. This area has begun to

receive more scientific attention, and ongoing studies

like STAR*D (Fava et al., 2003; Nierenberg et al.,

2006a; Trivedi et al., 2004), the Texas Medication

Algorithm Project (Rush et al., 2003a; Trivedi et al.,

2004) and the Berliner Algorithmus Projekt (Adli et al.,

2002 ; Adli et al., 2003) will supply further evidence for

augmentation strategies and develop evidence-based

algorithms for treatment-refractory patients. Other

national medication algorithms for the treatment of

depressive disorders have also recently come into

existence, e.g. in Korea (Lee et al., 2006) and in

Australia (Ellis, 2004). Using treatment algorithms

predominantly progressing from simpler to more

complex strategies may help to improve response

rates up to 90% (Thase and Rush, 1997).

9.1.13 New developments and novel pharmacological

treatment approaches

The therapeutic latency, the non-response rate of ap-

proximately 30% and the side effects of all anti-

depressants available so far are important reasons to

continuee the search for further treatment options for

depressive disorders. Priorities of interest include de-

veloping new drugs with fewer side effects and poss-

ibly faster response due to the possibility of using

higher-dose regimes (Norman and Leonard, 1994).

The following sections describe some pharmacological

principles that are currently not being used clinically

and that may disclose novel approaches in the treat-

ment of depression (Baghai et al., 2006c; Rupprecht

et al., 2004).

9.1.13.1 Influence on melatonergic neurotransmission

Melatonin secretion underpins precise circadian

rhythms (Lesieur et al., 1998). It is regulated via the

cyclic AMP (cAMP) signal transduction cascade

(Foulkes et al., 1997). A variety of animal studies and

clinical trials in depressed patients suggest that ago-

melatine, a synthetic melatonergic MT1 and MT2 re-

ceptor agonist (Audinot et al., 2003 ; Yous et al., 1992)

with 5-HT2C receptor antagonist (Millan et al., 2003)

properties within the CNS, has antidepressant effects

(Tuma et al., 2002). The antidepressant properties of

agomelatine and its good tolerability profile have been

demonstrated in several clinical trials (Kennedy and

Emsley, 2006 ; Loo et al., 2002 ; Montgomery et al.,

2004c ; Olie and Kasper, 2007) that compared it with

established antidepressants such as paroxetine and

venlafaxine, and with placebo. In particular, sleep-

related complaints improved without sedation during

the daytime. In a further randomized double-blind,

multicenter study, the absence of discontinuation

symptoms in sustained remitted patients was shown

following agomelatine therapy (Montgomery et al.,

2004c). Agomelatine thus represents a promising

novel strategy in the treatment of depression.

9.1.13.2 Serotonergic antidepressants

A promising strategy that was not developed further

was gepirone, an azapirone similar to buspirone that

acts as a partial agonist at 5-HT1A receptors (Silva

and Brandao, 2000 ; Van Reeth et al., 1999). In animal

studies gepirone shows anxiolytic and antidepressant

properties (Silva and Brandao, 2000 ; Van Reeth et al.,

1999). Thus far, three placebo controlled double-blind

studies in depressed patients have been published. In

all trials gepirone proved superior to placebo in the

treatment of depression ; it also showed good toler-

ability (Feiger, 1996 ; Feiger et al., 2003 ; Wilcox et al.,

1996).

Although these data support possible anti-

depressant properties of gepirone, the manufacturer

has halted its development. Development of other

serotonergic substances as antidepressants, such as

ipsapirone, flesinoxan and tandospirone, has also been

stopped. Only tandospirone has been marketed, in

Japan, as an anxiolytic drug.

9.1.13.3 Tachykinin receptor antagonists

The peptide family of tachykinins (Stout et al., 2001),

in particular substance P (SP), have drawn attention to

new developments within antidepressant pharmaco-

therapy (Kramer et al., 1998; Stout et al., 2001). The

tachykinin NK1 receptor is the receptor for SP, which

is co-localized with monoamines in several regions

of the CNS (Stout et al., 2001). Furthermore, intra-

cerebroventricular administration of SP causes in-

creased concentrations of catecholamine, and it has

been shown that NK1-receptor knockout mice exhibit

reduced anxiety and stress-related behavior (Stout

et al., 2001). Stimulation of enhanced hippocampal

neurogenesis, too, an effect also observed after appli-

cation of established antidepressants, has been re-

ported (Kramer et al., 1998 ; Stout et al., 2001). Despite

the fact that several synthetic NK1-receptor antag-

onists are available (Stout et al., 2001), only the results

of clinical trials with two substances have been pub-

lished. In a double-blind study, an NK1 antagonist

was compared with SSRI treatment and showed


superiority over placebo (Kramer et al., 1998). The

scores of both Hamilton depression and anxiety rating

scales were significantly reduced. A further study

demonstrated no superiority of MK 869 over placebo.

A subsequent substance was examined, and a signifi-

cant, but relatively small superiority in reducing

HAMD scores compared with placebo was found

(Kramer, 2002). A recent study confirmed the anti-

depressant properties of yet another NK1 antagonist

(Kramer et al., 2004), but this first promising anti-

depressant approach was not confirmed by clinical

data in further studies. These uncertainties necessitate

replicating the findings. Nevertheless, NK1 antagon-

ism appears to be a promising new antidepressant

treatment principle with an excellent tolerability pro-

file. To date, the first NK1 antagonist has been ap-

proved by the authorities not as an antidepressant,

but as an antiemetic.

9.1.13.4 Treatment strategies influencing the

hypothalamic pituitary adrenal system

9.1.13.4.1 Corticotropin-releasing hormone

receptor antagonists

Up to now, one corticotropin-releasing hormone

(CRH1) receptor antagonist (R121919) has been in-

vestigated. In an open trial examining the safety and

tolerability, not efficacy, of this compound in 20 de-

pressed patients, a distinct reduction in HAMD and

HAMA scores was evident within 4 weeks of treat-

ment (Zobel et al., 2000). The activity of the hypotha-

lamic pituitary adrenal (HPA) system was not altered

following administration of the CRH1 receptor antag-

onist. This indicates that the compound selectively

blocked CRH1 receptors, while the HPA system is also

under control of CRH2 receptors. Tapering off of the

study medication resulted in a certain deterioration

of the depressive syndrome. The compound was

withdrawn from further development owing to the

finding of increased liver enzymes in routine labo-

ratory screening.

Due to the lack of placebo-controlled double-blind

studies, further clinical trials using other CRH1 re-

ceptor antagonists are required to clarify the possible

antidepressant potential of these substances.

9.1.13.4.2 Steroid synthesis inhibitors

Inhibitors of steroid synthesis such as the fungicide

ketoconazole and metyrapone have been reported to

exert antidepressive effects. Case series and open trials

reported antidepressant effects of ketoconazole

(Anand et al., 1995 ; Ghadirian et al., 1995 ; Murphy,

1991 ; Sovner and Fogelman, 2002 ; Thakore and Dinan,

1995 ; Wolkowitz et al., 1993). In a placebo-controlled

study, hints of the putative antidepressant efficacy of

ketoconazole were found only in hypercortisolemic,

but not in normocortisolemic, patients (Wolkowitz

et al., 1999a). Another placebo-controlled double-blind

study in treatment-resistant depression has shown

insufficient antidepressant efficacy (Malison et al.,

1999). Similar antidepressant effects have also been

shown for metyrapone in case reports and open trials

(Ghadirian et al., 1995 ; Murphy et al., 1991 ; Murphy,

1991 ; Raven et al., 1996), as well as in placebo-

controlled double-blind studies. A study of eight pa-

tients found a reduction in the score of the MADRS of

more than 50% within 2 weeks of treatment (O’Dwyer

et al., 1995). A comparison of metyrapone with placebo

in addition to serotonergic antidepressant therapy

resulted in significant acceleration of antidepressant

effects (Jahn et al., 2004). Definite proof of the anti-

depressant properties of ketoconazole and metyr-

apone, however, is still lacking.

A further limitation of therapy using steroid syn-

thesis inhibitors is the risk of developing adrenal

gland insufficiency, and substitution of hydrocorti-

sone may be required during treatment (O’Dwyer

et al., 1995). Nevertheless, at least in hypercortisolemic

and severely depressed patients, this experimental

therapeutic approach can be considered in the case of

severe treatment resistance.

9.1.13.4.3 Neuroactive steroids

Neuroactive steroids modulate neurotransmitter

receptors (Rupprecht and Holsboer, 1999) and show

antidepressant and anxiolytic properties in animal

studies (Bitran et al., 1991 ; Khisti et al., 2000). Anti-

depressants, in particular SSRIs, enhance the con-

centration of endogenous 3a-reduced neuroactive

steroids within different areas of the brain (Rupprecht

and Holsboer, 1999). These mechanisms may play a

role in antidepressant treatment. However, synthetic

analogs of 3a-reduced neuroactive steroids for the

therapy of psychiatric disorders in humans are not yet

available.

DHEA is a neuroactive steroid that displays both

antagonistic properties at c-amino butyric acid

(GABAA) receptors and antiglucocorticoid effects

(Rupprecht, 1997 ; Rupprecht and Holsboer, 1999;

Wolkowitz et al., 1999b). One open study (Wolkowitz

et al., 1997) suggested possible antidepressant effects

of DHEA. An early placebo-controlled double-blind

study performed using an add-on treatment of DHEA

in depressed patients showed a significant reduction


in HAMD scores (Wolkowitz et al., 1999b). Yet DHEA

concentrations were found to be enhanced in de-

pressed patients compared with healthy volunteers

(Heuser et al., 1998), which seems to contradict the

indication of DHEA as treatment option in depressive

disorders.

9.1.13.4.4 Glucocorticoid receptor antagonists

Synthetic glucocorticoid receptor antagonists block the

effects of cortisol at glucocorticoid receptors. In initial

casuistic studies the glucocorticoid-/progesterone-

receptor antagonist mifepristone, used in some coun-

tries to terminate first-trimester pregnancy, improved

depressive symptoms in antidepressant treatment-

resistant depression (Murphy et al., 1993). An open-

label study in patients with psychotic depression

showed a reduction in the Brief Psychiatric Rating

Scale (BPRS) scores in the majority of the patients

(Belanoff et al., 2002), but reported no statistically

significant differences. Symptom amelioration could

be seen after 7 days in high-dose treatment groups.

A placebo-controlled case series in five patients

suffering from psychotic depression showed a re-

duction in HAMD score up to 26% (Belanoff et al.,

2001), but again, only a non-significant trend to a dif-

ference between verum and placebo could be seen. A

recent study demonstrated a statistically significant

influence of mifepristone on psychotic symptoms

measured using the BPRS, but no significant differ-

ences in other depression rating scales (DeBattista

et al., 2006).

Because of the antagonistic effects of mifepristone

at progesterone receptors, the use of this substance

as an antidepressant seems to be limited. Further in-

vestigations using the selective glucocorticoid receptor

antagonist Org 34517 have been carried out. Initial

clinical experience supports the possible antidepress-

ant efficacy of glucocorticoid receptor antagonists.

Nevertheless, the results of placebo-controlled double-

blind studies of sufficient power and over a suffi-

ciently long treatment period are needed before the

antidepressant potential of these substances can be

reliably assessed.

9.2 Continuation and maintenance therapy with

antidepressants, mood stabilizers and other

medication

The need for continuation treatment has also been

clearly demonstrated by placebo-controlled studies.

Relapse rates ranged from 31 to 80% for remitted

patients who were switched to placebo compared

with 0–31% of those who received active tricyclic

medication (Prien, 1990 ; Prien and Kupfer, 1986).

Studies with SSRI continuation, amineptine, nefazo-

done and reboxetine have reported similar results.

Tables 20 and 21, modified from Fakra et al (2006)

depicts continuation and maintenance studies

from 1988 to 2006, when most controlled mainten-

ance studies with new antidressants had been con-

ducted.

As a rule of thumb, continuation of antidepressant

treatment prevented roughly 50% of the recurrences

that occured under placebo, regardless of the duration

of the study or the pharmacological nature of the

antidepressant drug. Similarly, a systematic review

by Hirschfeld (Hirschfeld, 2001) found that approxi-

mately one-third to one-half of patients successfully

stabilized in acute-phase treatment will relapse if

medication is not sustained throughout the continu-

ation period, and only 10–15% will relapse if medi-

cation is continued. Therefore, it is recommended to

continue the successful initial antidepressant or com-

bination treatment at the same dose during the con-

tinuation phase (Thase, 1999b). For patients who remit

on antidepressant together with lithium as augmen-

tative treatment, combined treatment during continu-

ation has been suggested to be more efficacious than

antidepressants alone (Bauer et al., 2000 ; Bschor et al.,

2002).

Although usually cited as compelling evidence for

prophylactic treatment, the meta-analysis of Geddes

et al. (2003) has a stronger focus on continuation

treatment and prevention of early relapse. Of the 31

randomized trials included in this meta-analysis, most

trials went on for 12 months and were conducted in

acute responders to antidepressant treatment. Thus,

they are truly continuation treatment studies.

However, a few studies lasting up to 3 years also

support the persistence of effectiveness.

Although not true for the majority of patients,

some studies have suggested that continuous anti-

depressant treatment destabilizes patients (see

Hirschfeld, 2000). However, at the end of his review

Fava concluded that ‘at present we have no sound

data that antidepressant drugs may worsen the course

of depression and, if they do, whether the phenomena

is generalized or very limited.’ Thus, unless the indi-

vidual history of a patient shows evidence of negative

effects from long-term antidepressant treatment, con-

tinuation therapy should be offered to every patient

following recovery from a depressed episode. The

situation may be different for other subtypes of de-

pression, e.g. bipolar depression with a rapid-cycling

course ; these special conditions are, however, beyond

the scope of this review.


The ultimate goal with any psychiatric disorder is to

prevent recurrence of acute symptomatology and im-

prove functionality and quality of life in patients.

Clearly, this goal is no different with unipolar de-

pression. The prophylactic effect of continuing anti-

depressant medication has been demonstrated in a

multitude of studies (Geddes et al., 2003 ; Hirschfeld,

2000) (see Figure 4).

As already detailed in chapter 7 on the goals of

treatment, long-term prophylactic treatment following

continuation treatment is recommended in patients

with a history of recurring episodes. Besides prevent-

ing relapses, antidepressants may add value by virtue

of their neuroprotective properties (Sheline et al.,

2003). Taken together, approximately 60% of patients

at risk will experience a recurrent episode of

Table 20. Maintenance treatment using one antidepressant in comparison to placebo

Study

Number

of subjects

Length of treatment phase

Drug

Recurrence rate

Acute Contin Mainten Drug Placebo

Montogomery

(1988)

456 initial 6 weeks 18 weeks 1 year Fluoxetine 26% 57%

220 maint

182 complete

Frank (1990) 128 maint Until

remission

17 weeks 3 years Imipramine 40% 81%

106 complete

Robinson (1991) 88 initial Until

remission

16 weeks 2 years Phenelzine 29% 81%

47 maint

35 complete

Kupfer (1992) 20 maint Imipramine

19 complete (3–)5 years 18% 67%

Terra (1998) 436 initial 6 weeks 18 weeks 1 year Fluvoxamine 12.7% 35.1%

204 maint

Rouillon (2000) 500 initial Until

remission

4 months 1 year Milnacipram 16.3% 23.6%

214 maint

166 complete

Gilaberte (2001) 253 initial 8 weeks 24 weeks 48 weeks Fluoxetine 20% 40%

145 maint

121 complete

Hochstrasser

(2001)

427 initial 6–9 weeks 16 weeks 48 weeks Citalopram 22% 76%

269 maint Until

remission

(max

77 weeks)264 complete

Lepine (2004) 371 initial 4–6 months 18 months Sertraline 16.9% 33.3%

288 maint Followed by a 2 months

placebo period165 complete

Montgomery

(1988)

172/141–135 8 weeks 1 year Paroxetine 16% 43%

Versiani (1999) 283 initial 6 weeks 23+23 weeks Reboxetine 21.8% 56%

143 maint

Reynolds (1999) 41 complete Until

remission

16 weeks 3 years Nortriptyline 29%

(80–120 ng/l)

40%

(40–60 ng/l)

Klysner (2002) 230 initial 8 weeks 16 weeks >48 weeks Citalopram 32% 67%

121 maint

121 complete

Wilson (2003) 318 initial 8 weeks 16–20 weeks 100 weeks Sertraline 44.6% 54.4%

113 maint

76 complete

Reynolds (2006) 195 initial Until

remission

16 weeks 2 year Paroxetine 36.5% 64.2%

116 maint +/x psycho-

therapy


depression within 1 year if untreated, whereas

those who continue treatment will have a recurrence

rate of between 10 and 30% (Hirschfeld, 2001). If

in doubt about the indication for maintenance treat-

ment, an early decision in favor of long-term main-

tenance may improve long-term outcome: Solomon

(Solomon et al., 2000) showed that the risk of a new

episode increases by 16% with each successive re-

currence. If a patient has had a history of at least two

(Paykel and Priest, 1992) or three episodes (Prien et al.,

1984), prophylactic treatment is recommended.

Guidelines agree that maintenance dosages should be

similar to acute and continuation treatment unless

tolerability problems force reduction of the medi-

cation.

Of the 31 studies included in the meta-analysis

by Geddes et al. (2003), 5 studies had a duration of

3 years and 6 a duration of 2 years. However, most

of these studies included only a small number of

patients and thus do not encourage firm conclusions

by themselves. Among the randomized controlled

studies, the study by Prien et al. (Prien et al.,

1984) comparing imipramine and lithium alone

or in combination against placebo supplied good

evidence for the prophylactic efficacy of both the

antidepressant and lithium. The efficacy of imipra-

mine is also supported by a 36-month study of Frank

et al. (Frank et al., 1990). Similar evidence for con-

tinuing prophylactic efficacy has been supplied for

nortriptyline (Reynolds et al., 1999), sertraline (Keller

et al., 1998) and citalopram (Klysner et al., 2002), as

well as for the MAOI phenelzine (Robinson et al.,

1991).

9.2.1.1 Alternatives to long-term antidepressant

treatment

9.2.1.1.1 Lithium

If patients do not respond to prophylactic anti-

depressant treatment or do not tolerate side effects,

the first alternative is long-term lithium mainten-

ance therapy. Although it may be even more ef-

ficacious in bipolar disorder, and although some

negative results in unipolar disorder have been pub-

lished (Burgess et al., 2001a; Burgess et al., 2001b), the

efficacy of lithium in preventing relapses in unipolar

recurrent depression is well established (Coppen,

2000 ; Dunner, 1998; Paykel, 2001 ; Schou, 1995). These

findings are also supported by two meta-analyses

showing that lithium is more effective than placebo

in preventing recurrence of unipolar depression

(Angst et al., 2002a; Souza and Goodwin, 1991). InTab

le21

.Maintenan

cetreatm

ent–studiescomparingtw

oan

tidep

ressan

ts

Study

Number

ofsu

bjects

Len

gth

oftreatm

entphase

Drug

Relap

se/

recu

rren

cerate

Conclusion

Acu

teContin

Mainten

Drug

Placebo

Claghorn

(199

3)71

7initial

6weeks

1year

Paroxetine

15%

Parox.an

dIm

ip.>

placebo50

%more

dropouts

withIm

ip./Parox.dueto

sideeff

ect

219conti

Double-blindphase

Imipramine

4%

placebo

25%

Franch

ini(1997)

77initial

4months

24months

Fluvoxam

ine

18.7%

Nosignificantdifferen

cebetweentw

otreatm

ents

64conti

Sertraline

21.9%

Montgomery(199

8)58

0initial

6weeks

20weeks

Upto

2years

Mirtazapine

4.1%

Advan

tageofmirtazapineover

amitriptylinean

dplacebofortimeto

relapse

inthesu

rvival

analysis,an

dag

ainst

placeboforthenumber

of

relapses

217conti

Ran

domizationduringalltreatm

entphases

Amitriptyline

placebo

23%

Bump(200

1)11

6initial

12weeks

12weeks

18months

Nortriptyline

10%

Open

study,comparab

leeffi

cacy,butnortriptyline

producedfewer

residual

dep

ressivesymptoms

andside-eff

ects

59conti

(elderly

patients)

Ran

domizationduringalltreatm

entphases

placebo

16%


addition to preventing new episodes, lithium nor-

malizes the increased mortality rates for cerebro-

vascular and cardiovascular disorders in affectively

ill patients (Angst et al., 2002a) and reduces the risk

of suicide (Angst et al., 2002a; Goodwin et al., 2003;

Souza and Goodwin, 1991). For a recent up-to-date

review see also Muller-Oerlinghausen et al. (Muller-

Oerlinghausen et al., 2006). In addition, potential

neuroprotective effects, including preventive effects

against Alzheimer’s dementia, can be of interest

when prescribing long-term lithium prophylaxis.

The usually recommended serum lithium levels

for prophylaxis in unipolar recurrent depression

are 0.5–0.8 mmol/l, but individual variations may

occur. The use of extended-release forms of lithium

has been strongly encouraged, as these enable once-

daily dosing and are associated with fewer side effects,

both favoring enhanced treatment adherence of

patients.

9.2.1.1.2 Anticonvulsants in the prophylaxis of

unipolar depression

Carbamazepine has been studied in two small double-

blind comparator trials with lithium in recurrent

major depression (Angst et al., 2002a; Rush, 1999).

Both studies suggested equal efficacy for lithium and

carbamazepine. However, for prophylactic treatment,

the propensity of carbamazepine not only to induce

its own hepatic metabolism but also to accelerate

metabolization of drugs using CYP3A4 must be

kept in mind. Some antidepressants, e.g. venlafaxine,

mirtazapine, nefazodone, reboxetine and imipramine,

are substrates of CYP3A4 and thus may not achieve

sufficient plasma levels when used in combination

with carbamazepine. CYP1A2 and CYP2C9, which

contribute to carbamazepine metabolism, may also

be inhibited by fluvoxamine. Given its potential

interactions and lack of scientific evidence from

placebo-controlled studies, carbamazepine can only

be recommended as a subordinated choice when other

strategies have failed.

For other anticonvulsants only anecdotal reports

and small case series, no controlled studies, have

been published for prophylaxis in unipolar de-

pression.

9.2.1.2 General principles of long-term prophylactic

treatment

As a general recommendation, prophylactic treat-

ment of unipolar depression is not only restricted to

pharmacotherapy. Maintaining a good doctor-patient

relationship, monitoring adherence and psychoedu-

cation are important as well. Whereas approximately

40–70% of patients adhere to their antidepressant

drug regimen during the acute phase of therapy, only

15–50% still comply with therapy during the continu-

ation phase (Melfi et al., 1998). Automated systems

have been tested in primary care setting, alerting the

Numberof trials

NARI

MAOI

Tricyclic

SSRI

Other

Total

99% or 95% confidence intervals

Heterogeneity between five categories: χ24=18.6; p=0.001

0 0.5Antidepressant better

Treatment effect 2p<0.00001

Antidepressant worse1.0 1.5 2.0

32

2

4

15

10

1

–245.7

–15.7

–70.7

–94.9

–6.9

(205.4) 70% (4)

–57.5 (60.7)

(6.0)

(50.5)

(80.7)

(7.5)

465/2527(18%)

169/912(19%)13/61(21%)

113/449(25%)

(15%)14/71(20%)

1031/2505 2p<0.00001(41%)

313/889(35%)57/66(86%)

248/432(57%)

(37%)156/1034

28/72(39%)

Events/patients

385/1046

Allocatedantidepressant

Placeboadjusted

Antidepressant events Odds ratio

Antidepressant : PlaceboReduction

(S.E.)Logrank

O–E(Varianceof O–E)

(95% Cl)

Figure 4. Cochrane meta-analysis of the efficacy of antidepressants in preventing recurrence of unipolar depression: risk

of relapse, odds ratios by drug type (from Geddes et al., 2003). NARI, Noradrenaline (norepinephrine) reuptake inhibitor ;

MAOI, monoamine oxidase inhibitor ; SSRI, selective serotonin reuptake inhibitor.


physician if a refill has been missed for a specified

time. However, this approach did not improve com-

pliance (Bambauer et al, 2006) and cannot substitute

for a good doctor–patient relationhip.

As preparation for long-term prophylactic treat-

ment, patients and their relatives should be informed

especially about topics such as expected course of ill-

ness, treatment options, medication efficacy and side

effects, use of a daily self-reporting instrument for

mood to detect early warning signs of relapse or re-

currence, long-term perspectives and, if applicable,

projected end of treatment. Patients should also be

trained to distinguish between spontaneous, short-

lasting mood fluctuations (bleeps) and true emergence

of a new episode, which should be treated as soon

as possible (Rush, 1999). In addition, psychotherapy,

especially interpersonal therapy and cognitive behav-

ioral therapy, should be included in the overall treat-

ment portfolio (Baghai et al., 2006c). However, a

detailed description of the proven efficacy of psycho-

therapy in addition to medication is beyond the scope

of this review.

10 Specific age- and gender-related conditions

10.1 Gender-related differences58

Gender differences in unipolar depression are a

consistent finding in several longitudinal and

cross-sectional studies (for review see Kahn and

Halbreich, 2005; Kuehner, 2003). Lifetime prevalence

shows an unadjusted mean female/male ratio of 2.1,

whereas the point prevalence gender ratio is 1.7

(Kuehner, 2003). This estimate of differences in life-

time depression rates is calculated from large popu-

lation-based studies comprising up to almost 45000

subjects and, for point and period prevalence rates,

even up to 78000 subjects (DEPRES study (De-

pression Research in European Society) (Angst et al.,

2002b).

Several differences in comorbidity, symptoma-

tology and coping style between genders have been

described. Starting with comorbidities, frequent dis-

orders comorbid with depression in females include

anxiety (Breslau et al., 1995), somatoform disorders

and eating disorders, especially bulimia (Marcus et al.,

2005), whereas men are more likely to suffer from

comorbid alcohol and drug abuse (Marcus et al., 2005).

This gender difference may also be reflected in ways

of coping with depression. For example, Angst et al.

found that depressedmen were more likely to increase

consumption of alcohol, whereas women tried to cope

through emotional release and religion (Angst et al.,

2002b).

As far as other features of depression are concerned,

recently published results of the STAR*D (Sequenced

Treatment Alternatives to Relieve Depression) study

(Marcus et al., 2005) also show a significantly earlier

onset of the first major depressive episode in women,

and longer current major episodes for women com-

pared with men. In addition, depression in women

may also affect their offspring : children of mothers

suffering from depression are at high risk for disrup-

tive behavior and anxiety disorders as demonstrated

in a large sample of the STAR*D trial (Pilowsky et al.,

2006).

Some features of depression appear to be more

prevalent among men than among women, e.g. a

tendency to overreact and to attack in anger (Winkler

et al., 2005a). Criterial major depressive episodes ac-

cording to DSM-IV (American Psychiatric Association,

1994), however, are more prevalent in female than in

male depressed patients (Angst et al., 2002b). In the

large European DEPRES I and II study, women were

significantly more likely to have five or more criterial

symptoms of depression than men (female/male ratio

1.96).

Interestingly, differences in symptomatology are

already apparent in adolescent depression. Bennett

et al. (2005) interviewed 383 depressed adolescents

with the Childhood Version of the Schedule for

Affective Disorders and Schizophrenia (K-SADS-IIIR,

-IV; Bennett et al., 2005) and the Beck Depression

Inventory (BDI ; Bennett et al., 2005). In this sample,

with a mean age of 15.8 years, he found that depressed

girls were more likely to exhibit guilt, body image

dissatisfaction, self-blame, self-disappointment, feel-

ings of failure, concentration problems, difficulty

working, problems of sadness and depressed mood,

fatigue and health worries than depressed boys. In

contrast, depressed boys had higher clinician ratings

for anhedonia, depressed morning mood and morning

fatigue (Bennett et al., 2005).

Explanations for these gender differences are

manifold, and several factors may contribute to

them. According to Kuehner (2003), these factors in-

clude genetics, sex hormones, differing endocrine

stress reactivity, a higher incidence of thyroid axis

abnormalities, prior anxiety disorders, personality

traits, neuropsychological factors, gender role and

psychosocial factors, and life events, e.g. childhood

58 Gender-related differences of antidepressant pharmacotherapies

during pregnancy or post-partum and breast-feeding periods are

described more in detail in chapter 9.1.1.3.3.


sexual abuse. So far, there are no consistent findings

for gender differences in heritability (Kendler, 1998).

Only when broadening the criteria for depressive

disorders does heritability of those disorders appear

to be greater in women than in men (Kendler, 1998).

In elderly patients, a higher heritability for depressive

symptoms may be associated with female gender

(Jansson et al., 2004). In addition, gender-specific

effects of genetic polymorphisms, e.g. within the

angiotensin I converting enzyme (ACE) gene, may

play a role in varying responsiveness and speed of

onset of antidepressant action. In women, D/D and I/

D alleles have been associated with a faster onset of

different antidepressant therapies (Baghai et al., 2003;

Baghai et al., 2004). Overall, however, more research

is needed to reach firmer conclusions concerning a

gender-specific genetic preposition for depression and

response to treatment.

Sex hormones may play an important modulatory

role in the manifestation and course of depression,

and also for treatment response. There exist specific

vulnerabilities and complex interactions between

brain mechanisms and gonadal hormones (Halbreich

and Kahn, 2006). For instance, depressive symptoma-

tology in vulnerable women seems to increase

when their physiological estradiol levels decrease,

e.g. perimenstrually, in the post-partum period or

during perimenopause. Just as menopause seems

to negatively affect SSRI treatment response of de-

pressed women, antidepressant treatment seems to

be influenced by estradiol levels (Pinto-Meza et al.,

2006). At the same time, several studies have shown

estrogen treatment to be effective in post-partum as

well as perimenopausal depression (for review see

Kahn and Halbreich, 2005 ; Riecher-Rossler et al., In

Press). Estrogens may enhance serotonergic activity

and, if combined, may induce a better responsiveness

to SSRIs (Stahl, 2001) (for review see Kahn and

Halbreich, 2005). Estradiol may be involved in de-

sensitization at the 5-HT1A receptor (Bouali et al.,

2003 ; Carrasco et al., 2004). Other neuroendocrine

axes, such as the hypothalamic–pituitary–adrenal

(HPA) (Kornstein et al., 2002) and thyroid axes

(Kornstein et al., 2002), may also exhibit subtle differ-

ences between genders, thereby affecting vulnerability

to depression.

In general, treatment should not differ between de-

pressed men and women, but specific precautions

must be taken into account (see also chapter 9.1.1.3.3).

Clinically, gender differences in treatment response

have been demonstrated in several studies (Frank

et al., 1988; Kornstein et al., 2002 ; Yonkers and

Brawman-Mintzer, 2002), but could not be confirmed

by other studies (Scheibe et al., 2003 ; Thiels et al., 2005)

or a combined analysis of several studies (Hildebrandt

et al., 2003). When interpreting data, especially from

randomized controlled studies, a major methodo-

logical pitfall is the underinclusion of women in the

older studies (Yonkers and Brawman-Mintzer, 2002).

This makes potential findings of gender-specific

efficacy of tricyclics especially difficult to interpret.

The situation is slightly different with SSRIs, where

reported gender differences are based on more recent

studies with equal gender distribution.

In a review of 30 randomized placebo-controlled

trials of tricyclics conducted to obtain market author-

ization between 1979 and 1991, Wohlfarth et al. (2004)

could not identify a gender difference in the efficacy of

tricyclics. This finding contrasts with a meta-analysis

of Hamilton et al. (1995) of all published trials with

imipramine, which showed significantly different re-

sponse rates of 62% for men and only 51% for women.

On the other hand, several studies describe a signifi-

cantly higher response rate for women to SSRI treat-

ment compared with men, e.g. (Baca et al., 2004).

A better efficacy of SSRIs was also demonstrated by an

analysis of 15 randomized placebo-controlled studies

conducted at the Northwest Clinical Research Center

in Bellevue, Washington, between 1996 and 2003

(Khan et al., 2005). The researchers found that women

had a significantly greater response than men to SSRIs,

but not to SNRI antidepressants. The authors assume

that this different responsiveness may be due to subtle

differences in the serotonergic system between men

and women (Bano et al., 2004 ; Bell et al., 2001;

Nishizawa et al., 1997).

For other classes of medications, gender-specific

differences are less clear. For example, better response

rates to monoamine oxidase inhibitors (MAOIs) in

women have been described in studies that include a

substantial number of depressed patients with so-

called atypical features (Davidson and Pelton, 1986)

(see also chapter 5.2.1.3.3). However, atypical de-

pression characterized by dysphoria and pronounced

anxiety is a more likely finding in women than

men, andMAOIs had previously demonstrated a good

efficacy in this condition (Henkel et al., 2006). Thus,

the finding of higher responsiveness to MAOIs

for women may simply be due to the interaction of

depression subtype and gender. This is a good ex-

ample of the careful consideration of potential covari-

ables that is essential in identifying true gender

differences.

In summary, prevalence, symptomatology, treat-

ment response and consequences of depression are

not identical in men andwomen, and a gender-specific


psychiatric approach that takes into account gender-

specific risk and influencing factors (see also chapter

9.1.1.3.3) – including gender roles – is warranted

(Riecher-Rossler, 2000).

10.2 Age-related differences

10.2.1 Using antidepressant medications to treat

depression in child and adolescent populations

10.2.1.1 Introduction

Identifying and treating depressive disorders in child

and adolescent populations is often more complicated

than in adult populations for two main reasons. First,

the clinical features of depressive disorders in young

patients may differ substantially from those of adult

patients. Instead of manifesting neurovegetative or

straightforward depressive symptoms, depressed

children may exhibit behavioral problems that cause

difficulties in psychosocial functioning at home or at

school. Identifying these behaviors related to and

underlying depression requires not only evaluating

the patient but also talking to parents and teachers

as informants. The second difficulty stems from

the variety of treatment options based on relatively

little evidence of efficacy and safety in children and

adolescents. In addition, questions have been raised

recently regarding the possibility of increased suicidal

behavior in depressed youth treated with anti-

depressant medications (Leslie et al., 2005). All of these

issues must be considered before deciding whether

and how to treat young people with depression.

Comprehensive guidelines about identifying and

treating this age group have been published elsewhere

(Birmaher et al., 1998 ; Park and Goodyer, 2000).

Likewise, because comprehensive reviews of evi-

dence-based psychotherapies for depressed youth are

available (Compton et al., 2004 ; Curry, 2001), this

chapter instead will discuss the safety and efficacy of

antidepressants. First, wewill review randomized con-

trolled trials (RCTs) of antidepressants in depressed

children and adolescents. Next, we will discuss regu-

latory actions taken by drug safety agencies in the

US and UK. Finally, we will offer recommendations

regarding pharmacologic treatment of depressed chil-

dren and adolescents.

While empirical studies of antidepressant medi-

cations have been conducted in depressed child and

adolescent populations since the 1960s, the first well-

designed, double-blind, placebo-controlled studies –

most involving tricyclic antidepressants (TCAs) – did

not take place until the mid- and late 1980s

(Ambrosini, 2000). Since then, several RCTs, primarily

of newer antidepressants, such as selective serotonin

reuptake inhibitors (SSRIs), have been conducted in

child and adolescent populations. No RCTs of mono-

amine oxidase inhibitors have been conducted in de-

pressed child or adolescent populations. The only RCT

showing positive effects in childhood depression

shows therapeutic benefits of V-3 fatty acids in a 16-

week-long clinical trial (Nemets et al., 2006).

In a recently published meta-analysis the effective-

ness of antidepressants in comparison to placebo in

the treatment of pediatric major depressive disorder

has been confirmed (Bridge et al., 2007). It has been

stated that the benefits of antidepressants appear to be

much greater than risks from suicidal ideation/suicide

attempts. Similar conclusions were drawn due to in-

creasing suicide rates both in the US (14%) and the

Netherlands (49%) after decreasing SSRI prescriptions

(x22%) between the years 2003 and 2005 following

warnings of U.S. and European regulatory agencies

about a possible suicide risk with antidepressant use

in pediatric patients (Gibbons et al., 2007).

A Cochrane meta-analysis of TCAs, as well as all

known published RCTs of SSRIs and atypical anti-

depressants, will be described below. Whenever ap-

plicable, a distinction will be made between a given

drug’s attributes in child (age 12 and under) and ado-

lescent (age 13 and older) populations59.

10.2.1.1.1 Tricyclic antidepressants

Given the ample evidence for efficacy in adult popu-

lations, multiple clinical trials of TCAs – including

studies of amitriptyline, imipramine, nortriptyline and

desipramine in the serotonergic system – have been

conducted. A Cochrane review of 13 of these RCTs

involving over 500 young people was completed by

Hazell and colleagues (Hazell et al., 2002). Across

child and adolescent populations, the effect size (ES)

identified by this meta-analysis was statistically sig-

nificant, but small (ES x0.31, 95% CI x0.62 to x0.01 ;

negative ES indicates a reduction in depressive

symptoms). However, when subgroup analyses were

conducted, no significant benefit was seen with chil-

dren (ES 0.15, 95% CI x0.34 to 0.64), but a larger ad-

vantage was seen with adolescents (ESx0.47, 95% CI:

x0.92 to x0.02). This differential treatment response

is consistent with the superior efficacy of TCAs

in adult populations, and may be explained by

59 Age limits in the definitions of children and adolescents are

varying between different countries (e.g. in Germany the legal age

limit is 14 years). In the cited studies predominantly an age limit of

12 years has been used.


maturation of neurological pathways or other de-

velopmental differences between children, ado-

lescents and adults (Bostic et al., 2005). Importantly,

compared with placebo controls, in pediatric popu-

lations TCAs were associated with more vertigo,

orthostatic hypotension and dry mouth (Hazell et al.,

2002).

10.2.1.1.2 SSRIs and newer antidepressants

Given the lack of convincing evidence of effectiveness

and the narrow therapeutic window of TCAs, more

recent childhood depression trials have focused on

SSRIs and other newer antidepressants. However,

whereas 18 placebo-controlled RCTs of newer anti-

depressants have been conducted, only 12 have been

published (Table 22). This section describes published

SSRI trials with regard both to efficacy and to safety. In

addition, data regarding unpublished trials were ob-

tained from the report completed by the UK’s

Committee on Safety of Medicine (CSM) of the

Medicines and Healthcare products Regulatory

Agency (Commitee on Safety of Medicines, 2004), and

a recent review of antidepressants in depression

among youth (Cheung et al., 2005).

10.2.1.1.2.1 Fluoxetine

The first report about a case series of six patients,

aged 10–17 years, showing self-injurious ideation or

behavior during fluoxetine treatment of obsessive-

compulsive disorder was published by (King et al.,

1991).

Between 1990 and 2004, four trials of fluoxetine as a

treatment for child and adolescent major depressive

disorder were conducted, three of which were posi-

tive.

The negative study of fluoxetine, which was small

and possibly underpowered, involved 40 adolescents

from inpatient and outpatient settings. After 8 weeks

on 20–60 mg of fluoxetine, authors did not identify

significant differences for any of the outcome

measures used; subjects responded equally well to

fluoxetine or placebo. Other than weight loss, no drug-

associated adverse events were reported (Simeon

et al., 1990).

The first positive fluoxetine study, published in

1997 by Emslie et al., compared a 20 mg fixed dose of

fluoxetine to placebo in a group of 96 children and

adolescents aged 7–17 (Emslie et al., 1997). Subjects

were treated for 8 weeks at a single site. At the trial’s

end, compared with placebo, subjects assigned

to fluoxetine scored significantly better on both pro-

spectively identified primary outcome measures : the

Clinical Global Impressions-Improvement Score

(CGI-I) and the Children’s Depression Rating Scale-

Revised (CDRS-R). Significantly more youth given

fluoxetine ‘responded’ (i.e. received ratings of 1, ‘very

much improved’, or 2, ‘much improved’, on the CGI-

I). While endpoint mean CDRS-R scores were signifi-

cantly better for fluoxetine-treated youth than for

those who received placebo, the differences in terms of

‘remission’ (a dichotomous measure, prospectively

defined as a score of<29 on the CDRS, and potentially

less sensitive to change) did not reach significance.

Response rates did not differ for children 12 and under

compared with adolescents 13 and over. In compari-

sons with placebo, adverse events were not signifi-

cantly increased in the fluoxetine-treated group.

In 2002, Emslie et al. published an 8-week multisite

follow-up study of 219 subjects between the ages of 8

and 18 (Emslie et al., 2002). In this trial, the CDRS-R

was again used as a primary outcome measure. While

the mean 22-point drop in CDRS-R scores in the

fluoxetine group was significantly different from the

14.9-point decrease noted in the placebo group, it did

not achieve primary outcome ‘response’ criteria pro-

spectively defined as a o30% decrease in scores.

However, in post hoc analyses the authors demon-

strated that primary outcome would have been

achieved had response been defined at o20, 40, 60 or

70% decrease in CDRS scores, or if their calculation

correctly reflected the fact that the CDRS-R scale has

a minimum value of 17 instead of 0 (Cheung et al.,

2005). While no information was provided regarding

suicidality, patients receiving fluoxetine reported

fewer adverse events than did those receiving

placebo. Based on these results, fluoxetine received

US Food and Drug Administration (FDA) approval

to treat depressive disorders in children and ado-

lescents.

In the double-blind relapse-prevention phase of the

above-mentioned study, Emslie and colleagues con-

tinued to follow 40 subjects who remitted on fluox-

etine ; 20 of these fluoxetine responders were assigned

to continue fixed-dose fluoxetine, whereas 20 others

were switched directly from fluoxetine to placebo.

Over the subsequent 32 weeks, when compared with

those switched to placebo, fewer subjects who re-

mained on fluoxetine relapsed (60 vs. 34%, respect-

ively). Additionally, time to relapse was longer for

those who remained on fluoxetine compared with

those who were switched to placebo (181 days vs. 71

days, p=0.046). There were no statistically significant

differences in adverse events (Emslie et al., 2004).

Fluoxetine, alone and in combination with cogni-

tive-behavioral therapy (CBT), was compared with


Table 22. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents

Agent Author

Study characteristics Results

SponsorN Age

Dose

(mg)

Length

(weeks)

Sites

(n) Primary outcome

Active

treatment Placebo p value

Sig. ?

(Y/N)

Fluoxetine Simeon et al., 1990 40 13–18 20–60 8 1 none assigned n.a. n.a. n.a. N n.a.

Emslie et al., 1997 96 7–17 20 8 1 CGI-I (1 or 2) 56% 33% 0.02 Y NIMH

CDRS-R mean scores 38.4 47.1 <0.008 Y

Emslie et al., 2002 219 8–18 20 8 15 CDRS-R (›>/=30%) 41% 20% 0.09 N* Lily

March et al., 2004 439 12–17 10–40 12 13 CGI-I (1 or 2) FLX+CBT: 71.0% 34.8% 0.001 Y NIH

FLX: 60.6% 34.8% 0.001 Y

CDRS-R (cts) FLX+CBT: 33.79 41.77 0.001 Y

FLX: 36.30 41.77 0.34 N

Paroxetine Keller et al., 2001 180** 12–18 20–40 8 10 HAMD (f8 or ›o50%) 66.5% 55.2% 0.11 N GSK

HAMD (cfb) 18.98p8.24 19.79p9.88 0.13 N

Berard et al., 2006 286 13–18 20–40 12 33 MADRS (›>/=50%) 60.5% 58.2% 0.702 N

K-SADS-L (cfb) 9.3 9.8 0.616 N GSK

Emslie et al., 2006 206 7–17 10–50 8 40 CDRS-R (cfb) n.a. n.a. 0.684 N GSK

Sertraline Wagner et al., 2003 376 6–17 50–200 10 53 CDRS-R (mean reduction) x22.84 x20.19 0.007 Y Pfizer

Citalopram Wagner et al., 2004 174 7–17 20–40 8 21 CDRS-R (cfb) 36% 24% <0.5 Y Forrest

von Knorring et al., 2006 244 13–18 12 Kiddie-SADS-P, MADRS 59% 61% N

Escitalopram Wagner et al., 2006 264 6–17 10–20 8 25 CDRS-R (cfb) x21.9 x20.2 0.310 N

Venlafaxine Mandoki et al., 1997 40 8–17 37.5–75 6 1 n.a. n.a. n.a. n.a. N n.a.

* Authors note that results would have reached significance if response was defined as decrease in CDRS of o20, 40, 50 or 60%.

** Trial included 275 subjects, but 95 were randomized to imipramine and are not considered in the above analysis.

cfb=change from baseline ; cts=change in total score (adjusted mean) ; n.a.=not available ; GSK=GlaxoSmithKline.

CIN

PAntidepressan

tTask

Force

2007S89

placebo in the Treatment for Adolescents with

Depression Study (TADS). The first phase of this

National Institute of Mental Health) (NIMH)-

sponsored multisite RCT followed 439 adolescents

(aged 12–17) with moderate to severe depression for

12 weeks. The fluoxetine plus CBT condition was

superior to placebo on both primary outcome

measures : CDRS-R total score and CGI-I score of 1

or 2. Fluoxetine alone was statistically superior to

placebo on the CGI-I variable, but not the CDRS-R.

Compared with placebo, there was a statistically

significant increased risk of harm-related events – a

category that included suicidal and non-suicidal be-

havior such as self-cutting – in the groups treated with

fluoxetine (OR 2.19; 95% CI 1.03–4.62) ; however, there

was no statistically significant increased risk of

suicide-related events in the fluoxetine group.

Whereas suicidal thinking decreased in all treatment

groups, fluoxetine plus CBT was associated with the

greatest reduction (March et al., 2004). Combination

treatment with CBT and fluoxetine showed the

greatest benefit-to-risk ratio for adolescents with

moderate to severe depression, and was superior to

monotherapy. Moreover, fluoxetine alone was more

effective in treatment of depressed adolescents than

CBT alone, whereas CBT alone did not differentiate

from placebo (March et al., 2004 ; Pathak et al., 2005;

TADS study group, 2003 ; TADS study group, 2005).

Note that the placebo response rate was relatively low

in the TADS study (35%) in comparison with other

studies in children and adolescents, possibly due to

specific inclusion criteria.

10.2.1.1.2.2 Paroxetine

Keller et al. treated 180 adolescents (aged 12–18) with

either paroxetine or placebo in a multi-site, 8-week

RCT. The HAMD-17 was the primary outcome

measure ; both response (end of trial score of f8 or a

>50% reduction) and change from baseline were as-

sessed. Whereas youth treated with paroxetine im-

proved on primary outcome measures relative to

placebo, these improvements were not statistically

significant in the case of imipramine (Keller et al.,

2001). Adverse events were reported more often by

patients receiving paroxetine (11 patients) versus

placebo (2 patients). Additionally, paroxetine-treated

patients had an increased risk of suicidal ideation

compared with placebo-treated patients (5.4 vs. 0%

respectively).

Two additional paroxetine studies, both conducted

several years ago and previously unpublished, have

recently been published (Berard et al., 2006 ; Emslie

et al., 2006). Neither study demonstrated efficacy of

paroxetine compared with placebo on primary out-

come measures. In the first study (Berard et al., 2006),

which focused on adolescents aged 13–18, more treat-

ment-discontinuing adverse events and suicide-

related behavior were reported in the paroxetine

group compared with placebo (11.8 vs. 7.1% and 4.4

vs. 2.1% respectively ; these differences were not stat-

istically significant). In the second study (Emslie et al.,

2006), which evaluated paroxetine in 206 children

aged 7–17, serious adverse events were more com-

monly reported by children treated with paroxetine

(6 subjects) versus placebo (1 subject). Additionally,

treatment discontinuation due to an adverse event

occurred more commonly with paroxetine (8.9%)

compared with placebo (2%).

10.2.1.1.2.3 Sertraline

In 2003, Wagner et al. published the combined results

of two separate 10-week trials involving 376 child and

adolescent subjects (aged 6–17) with depressive dis-

orders (Wagner et al., 2003). These studies were con-

ducted at 53 sites in five countries, and the combined

analysis was planned a priori. Although the individ-

ual trials did not reach statistical significance on the

primary outcome measure (mean reduction in CDRS-

R), when combined they demonstrated a small but

statistically significant effect. Of note, at the study’s

endpoint, the mean difference in CDRS-R score was

significant for adolescents (sertraline : x28.95 ; pla-

cebo: x24.11 ; p=0.01) but only borderline significant

for children (sertraline : x31.44 ; placebo: x27.56 ;

p=0.5). Compared with placebo, three times as many

sertraline-treated subjects discontinued treatment as a

result of suffering adverse events.

10.2.1.1.2.4 Citalopram

Wagner et al. also published results from an 8-week

trial of citalopram in 174 children and adolescents

(aged 7–17) with depressive disorders (Wagner et al.,

2004). Compared with placebo, response criteria

(CDRS-R f28) were achieved by significantly more

citalopram-treated depressed youth. Citalopram and

placebo were discontinued due to adverse events at a

similar rate (5.6 and 5.9%, respectively). No differ-

ences between children and adolescent populations

were reported.

According to the CSM report, a large unpublished

trial of citalopram in depressed teenagers (aged 13–18)

did not demonstrate an antidepressant effect over

placebo. Additionally, compared with placebo, greater

percentages of citalopram-treated youth reported


self-harm or suicidal thoughts, made serious suicide

attempts or required hospitalization.

In contrast, von Knorring et al. reported a response

rate of about 60% for both citalopram and placebo in

244 adolescents (aged 13–18 years), but a better out-

come in the citalopram group when the study results

were controlled for the application of psychotherapy

(von Knorring et al., 2006). In addition, a worsening of

suicidal thoughts and a nonsignificant trend to a

higher incidence of suicide-related events was seen

more frequently in the placebo group.

10.2.1.1.2.5 Escitalopram

Wagner and colleagues conducted an 8-week RCT of

escitalopram, the S-isomer of citalopram, involving

264 young subjects aged 6–17 (Wagner et al., 2006).

Although the results across the entire sample did not

reveal significant differences, subgroup analysis re-

vealed a statistically significant drug versus placebo

benefit for adolescents. Rates of discontinuation due to

adverse events and rates of suicide-related behavior

were similar for drug and placebo.

10.2.1.1.2.6 Venlafaxine

Venlafaxine, an antidepressant that inhibits reuptake

of both serotonin and norepinephrine, has also been

evaluated as a treatment for depressed youth. In 1997,

Mandoki et al. published a trial involving 40 children

and adolescents (aged 8–18), who received relatively

low doses of venlafaxine (37.5 mg for children, 75 mg

for adolescents) or placebo; all subjects also received

weekly therapy with cognitive and behavioral el-

ements. After 6 weeks, substantial improvement was

noted in all subjects ; however, there was no significant

difference between the venlafaxine-treated subjects

and those who received placebo. No serious adverse

events were reported in the published paper ; how-

ever, one subject was hospitalized after developing

mania (Mandoki et al., 1997).

Emslie et al. conducted two RCTs of venlafaxine XR

in a total of 334 subjects with depressive disorders

aged 7–17; while unpublished, the results of these two

trials were analyzed together and described in a recent

review (Cheung et al., 2005). The combined analysis

did not identify any significant differences between

venlafaxine extended release (ER, XR) and placebo on

the primary outcome variable of CDRS-R endpoint.

Of note, when children (ages 7–11) and adolescent

(ages 12–17) subgroup analyses were conducted,

there was a suggestion of efficacy in the adolescent

group (Cheung et al., 2005). According to the CSM

report, more treatment-discontinuing adverse events,

including hostility and suicidality, were identified in

the group treated with venlafaxine.

10.2.1.1.2.7 Mirtazapine

Emslie et al. also conducted two RCTs of mirtazapine,

a noradrenergic and specific serotonergic agent. These

trials involved a total of 250 depressed youth (aged

7–17). While the results of these trials remain unpub-

lished, a recent review indicates that no significant

CDRS-R differences between mirtazapine and placebo

conditions were noted at the end of either 8-week trial

(Cheung et al., 2005). According to the CSM report,

one mirtazapine-treated subject reported suicidal

thoughts and one placebo-treated subject performed

an act of self-mutilation.

10.2.1.1.2.8 Nefazodone

Two RCTs of nefazodone, a serotonin-modulating

antidepressant, were conducted by Emslie and col-

leagues. While neither study has been published,

one trial involving 195 depressed 12- to 17-year-

olds was described in a recent review (Cheung et al.,

2005). In this study, beneficial effects for nefazodone

approached but did not achieve statistical

significance on CDRS-R primary outcome variables.

No nefazodone-related serious adverse events oc-

curred. The CSM report included no data regarding

this medication.

10.2.1.1.2.9 Bupropion

No RCTs have been conducted with this medication in

child and adolescent populations.

10.2.1.1.2.10 V-3 fatty acids

Benefits of V-3 fatty acids have been shown in a

16-week-long RCT (Nemets et al., 2006).

10.2.1.2 Regulatory action by the UK and US

In June 2003, after evaluating unpublished manufac-

turer data revealing increased suicidality associated

with paroxetine, the UK Committee on Safety of

Medicine (CSM) advised that paroxetine should not be

used to treat depressed youth. The FDA quickly fol-

lowed suit. In August 2003, the manufacturer of ven-

lafaxine sent letters to doctors explaining that, due to

lack of efficacy and potential for increases in suicid-

ality and hostility, the drug should not be used for

young people. By December 2003, the Medicines and

Healthcare products Regulatory Agency (MHRA)


warned against using all SSRIs, and the FDA urged

extreme caution when using any newer antidepressant

in pediatric populations (Leslie et al., 2005).

Given their concern regarding treatment-emergent

suicidality, the FDA conducted a review of indepen-

dently coded safety data from 24 studies of nine of

these antidepressants (fluoxetine, sertraline, parox-

etine, fluvoxamine, citalopram, bupropion, venla-

faxine, nefazodone and mirtazapine) in youth

populations. Of note, these medications were pre-

scribed in trials not only for depression but also for

anxiety disorders and attention-deficit hyperactivity

disorder. It is important to note that, among the 4400

patients treated with SSRIs or other newer anti-

depressants in these studies, there were no completed

suicides. However, when evaluated together, the risk

of ‘suicidality’ (defined as suicidal thinking and be-

havior) in the antidepressant trials was approximately

twice that of placebo: 4 versus 2%, respectively (risk

ratio 1.95, 95% CI 1.28–2.98), a finding that was sup-

ported by a recent re-analysis largely of the same

studies (Wohlfarth et al., 2006). There was also a sig-

nificant effect for treatment-emergent agitation and

hostility (Hammad, 2006).

When the FDA restricted its analysis to trials of de-

pressive disorders, statistically significant differences

in suicidality and treatment-emergent agitation

and hostility persisted (Hammad et al., 2006a; see

Table 23). Depressed youth treated with paroxetine

were most likely to experience treatment-emergent

agitation and hostility (relative risk 7.69, 95% CI

1.80–32.99). Those treated with venlafaxine XR were

most likely to experience suicidality (relative risk 8.84,

95% CI 1.12–69.51).

Based on the above analyses, the FDA concluded

that a true risk may exist for some youth. As a result,

in October 2004 the FDA issued a ‘black box’ warning

alerting health-care providers and consumers about

‘an increased risk of suicidality (suicidal thinking and

behavior) in children and adolescents’ who are taking

antidepressant medication (FDA Public Health

Advisory, 2004) (FDAwebsite). The FDA review panel

included all antidepressants in its warning due to

concern that limiting the black box to newer agents

would encourage the use of older medications with

narrower therapeutic windows and higher lethality in

overdose (Gibbons et al., 2005) ; however, fluoxetine

remains FDA-approved for the treatment of de-

pression in youth. In December 2004, the Committee

for Medicinal Products for Human Use of the

European Medicines Agency (EMEA) Scientific

Committee similarly advised that newer anti-

depressants ‘are not authorized Europe-wide for the

treatment of depression and anxiety disorders in chil-

dren and adolescents. These compounds should gen-

erally not be used in this age group because clinical

trials have shown an increased risk of suicidal behav-

ior (European Medicines Agency, 2004). In June 2006,

however, after further data reviews, the EMEA adop-

ted a more favorable position towards fluoxetine ; it

recommended extending fluoxetine’s indication to in-

clude children, ‘8 years of age or older who suffer

from moderate to severe depression and who do not

respond to psychological therapy (European Medi-

cines Agency, 2006)’ (EMEA website : http://www.

emea.eu.int/).

10.2.1.3 Investigations of other sources of evidence

Given the problems inherent in drawing conclusions

about suicidality from studies not designed or pow-

ered for such a purpose (Emslie et al., 2005), several

pharmaco-epidemiological and observational studies

have been undertaken in order to further examine the

link between newer antidepressants and suicide or

suicidal behavior.

10.2.1.4 Antidepressants and completed suicides

One frequently utilized pharmaco-epidemiologic

technique involves investigating whether regional

changes in rates of prescription of newer anti-

depressants correlate with changes in suicide rates.

Several of these large, retrospective studies have been

carried out (Gibbons et al., 2005 ; Gibbons et al., 2006;

Hall et al., 2003; Helgason et al., 2004 ; Ludwig and

Marcotte, 2005; Olfson et al., 2003 ; Olfson et al., 2006;

Sondergard et al., 2006). An Australian study found

substantially decreased rates of suicide in association

with exposure to antidepressants, especially in older

men and women, together with increased suicide rates

in adolescents and young adults aged 15–24 (Hall et al.,

2003). More recent studies by Olfson and colleagues

(Olfson et al., 2006), as well as a large FDA meta-

analysis found a similar age-dependent pattern of

antidepressant-associated suicide risk (US Food and

Drug Administration, 2007). Other American and

international studies indicate an inverse relationship

between rates of SSRI prescriptions and rates of

suicide in child and adolescent populations (Gibbons

et al., 2005 ; Ludwig and Marcotte, 2005 ; Olfson et al.,

2003). According to an analysis of WHO data per-

formed by the American College of Neuropsycho-

pharmacology (ACNP) Task Force on SSRIs and

Suicidal Behavior in Youth, over the past 14 years the

suicide rate for adolescents and young adults (aged

15–24) has decreased by an average of 33% across 15


countries (Mann et al., 2006a). While such analyses

are imperfect and subject to the ‘ecologic fallacy’

(Robinson, 1950), taken together, the reported studies

show mixed evidence of increased suicidality or sui-

cide rates among children and adolescents caused by

SSRI use.

In addition to pharmaco-epidemiologic studies,

others groups have used post-mortem toxicological

analyses as a means of investigating a link between

completed youth suicide and antidepressant medi-

cations. Evidence from a large-scale Swedish study

(Isacsson et al., 2005) and two smaller American stu-

dies (Moskos et al., 2005 ; Tardiff et al., 2002) does not

support an association between treating youth with

antidepressants and subsequent completed suicide.

10.2.1.5 Antidepressants and suicidal behavior or

non-fatal self-harm in depressed youth

In addition to completed suicides, information is also

available regarding suicidal behavior and non-fatal

self-harm. Several retrospective studies have in-

vestigated this potential link through queries of large

databases of patient information. The results of these

studies are mixed.

In 2004, Valuck et al. conducted a propensity-

adjusted cohort study to examine links between

antidepressant treatment and suicide attempts in

over 24000 adolescents (aged 12–18) who were

started on antidepressants after being newly diag-

nosed with depressive disorders. After adjusting for

severity of symptoms, the researchers found that

youth treated with SSRIs did not have statistically

significant increases in rates of suicide attempts

when compared with youth treated with other or

multiple medications. Youth who continued treatment

with any antidepressant for 6 months made signifi-

cantly fewer suicide attempts than those who re-

mained on medication for less than 8 weeks. (Valuck

et al., 2004).

Martinez et al. conducted a nested case-control

study comparing rates of fatal and non-fatal self-harm

for over 146000 individuals in a large UK general

practice database (Martinez et al., 2005). Identified

cases were prescribed TCAs, SSRIs or other newer

antidepressants for a depressive episode (unipolar

or bipolar) or dysthymia. In the 6 months following

index prescription, no suicides occurred in the 10- to

18-year-old cohort. However, compared with de-

pressed youth treated with TCAs, depressed youth

treated with SSRIs demonstrated ‘weak evidence’ for

increased rates of non-fatal self-harm (adjusted odds

ratio 1.59, 95% CI 1.01–2.50). Among the SSRIs evalu-

ated, the greatest risk for non-fatal self-harm was

associated with paroxetine. Jick and colleagues found

a near-significant signal for increased rates of self-

harm in paroxetine-treated youth (aged 10–19) in an

earlier study of the same database (Jick et al., 2004).

A potential criticism of these studies, but also of other

naturalistic databases, is the mixed cohort of unipolar

and bipolar patients. Antidepressants may induce

switching into mania, which in adolescents is charac-

teristically mixed in nature. Mixed episodes, however,

are strongly associated with suicidal ideation

(Dilsaver et al., 1994). In addition, the index episode in

bipolar patients is characteristically depressive, and

the age of onset of bipolar disorder is earlier than of

unipolar disorder, leading to a potential overrep-

resentation of bipolar patients in such a cohort. Thus,

the inclusion of bipolar adolescents may easily

Table 23. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents

Drug

Suicide-related events Treatment-emergent agitation or hostility

Relative risk 95% CI Relative risk 95% CI

Nefazodone No events n.a. 1.09 0.53–2.25

Citalopram 1.37 0.53–3.50 1.87 0.34–10.13

Fluoxetine 1.53 0.74–3.16 1.01* 0.40–2.55

Mirtazapine 1.58 0.06–38.37 0.52 0.03–8.27

Paroxetine 2.15 0.71–6.52 7.69 1.80–32.99

Sertraline 2.16 0.48–9.62 2.92 0.31–27.83

Venlafaxine XR 8.84 1.12–69.51 2.86 0.78–10.44

Total 1.66 1.02–2.68 1.79 1.16–2.76

* FDA analysis of treatment-emergent hostility and agitation did not include data from the TADS study.

Boldface=statistically significant results.


confound the results, making conclusions regarding

the risk of suicidal ideation in unipolar depressed

patients problematic (Berk and Dodd, 2005a; Berk

and Dodd, 2005b).

In a recent meta-analysis by Dubicka et al. (Dubicka

et al., 2006) the pooled risk of self-harm and suicidal

behavior from randomized trials of newer anti-

depressants was determined. Self-harm or suicide-

related events occurred in 71 of 1487 (4.8%) of de-

pressed youths treated with antidepressants versus

38 of 1254 (3.0%) of those given placebo (fixed-effect

odds ratio 1.70, 95% CI 1.13–2.54, p=0.01). There was

a trend for individual suicidal thoughts, attempts and

self-harm to occur more often in youth taking anti-

depressants than in those given placebo, but none of

these differences was statistically significant.

In a separate study, Simon and colleagues used a

large American database to retrospectively analyze

over 82000 index episodes of antidepressant treat-

ment, 5107 of which involved youth aged 5–18

(Simon et al., 2006). Six months after the diagnosis

of depressive disorders (coded as ICD-9 MDD,

Dysthymia or Depressive Disorder NOS) and after

initiating antidepressants, 3 youth and 28 adults com-

pleted suicide. Like Jick and colleagues, Simon

and colleagues found a significantly higher rate of

suicide attempts in the first week of treatment com-

pared with subsequent weeks. However, when com-

pared across the entire sample, there was no

statistically significant increased risk of completing

suicide the first month of treatment compared with

subsequent months. Additionally, rates of serious

suicide attempts, captured from 3 months before to

6 months after index antidepressant prescription,

were highest in the month before antidepressants

were initiated. When the newer antidepressants in-

cluded in the FDA review were compared with

older antidepressants not evaluated by the FDA, this

decrease in suicide attempts in the month after treat-

ment initiation was seen only with newer anti-

depressants. The authors state that these differences

may reflect a more timely therapeutic effect of newer

agents.

10.2.1.6 The use of antidepressants, and their risks

and benefits

Several recent studies have used a meta-analysis

to compare the risks and benefits of individual

antidepressant agents that have been subject

to randomized clinical trials in depressed youth

(Bridge et al., 2005 ; Wallace et al., 2006 ; Whittington

et al., 2004). The authors of each of these studies

conclude that the risk-benefit profile is most favorable

for fluoxetine. Two of the studies suggest that the

risk-benefit profile of citalopram is also positive

(Bridge et al., 2005; Wallace et al., 2006) ; one

study suggests that the benefits of sertraline may also

outweigh its risks when used in treating depressed

youth.

In sum, the evidence about safety and efficacy of

SSRIs is mixed. There is significant evidence for the

efficacy of fluoextine in treating depressed ado-

lescents. Fluoxetine is the only agent approved by

regulatory agencies in the US, UK and Europe for use

in depressed youth. Importantly, in the well-designed

TADS study, fluoextine was helpful in a group of

moderate to severely depressed youth that were

not significantly helped by CBT (March et al, 2004).

There is more limited evidence for the efficacy of

sertraline, citalopram and escitalopram. Regarding

safety, meta-analyses of RCTs suggest that SSRIs in-

crease suicide ideation compared with placebo, but

observational studies suggest that SSRIs do not in-

crease suicide risk more than older antidepressants

(Hall and Lucke, 2006). While there is no evidence of

completed suicide from reported RCTs, compared

with placebo, there is a higher incidence of self-harm

and aggressive or impulsive actions, especially with

paroxetine or venlafaxine treatment.

Based on all of the preceding data, the following

recommendations might be considered regarding di-

agnosis and treatment of youth with depressive dis-

orders (see also Box 11).

10.2.1.7 Conclusion

Although much is known about the effects of anti-

depressant medications in children and adolescents,

research is needed to further improve our ability to

treat depressed youth. In adolescents, high placebo

response rates have been reported, but there is

reasonable evidence for the effectiveness of fluoxetine.

Apart from V-3 fatty acids, there is no substantial

evidence that antidepressant medication is useful in

prepubertal children. The current evidence for pre-

pubertal efficacy of antidepressants is not robust : the

older postpubertal adolescents were in clinical trials,

the more likely was the response to antidepressants. In

addition, several questions regarding the safety of

newer antidepressants remain.

Regarding efficacy, more information is needed to

determine which children and adolescents respond to

which treatments. Current treatment studies have

been characterized by high placebo response rates

and suboptimal response rates. Important questions


regarding the effects of early intervention and long-

term treatment in both children and adolescents also

remain.

The debate over the safety of these medications will

also continue. If the risk is determined to be real, in-

vestigators must identify an etiology of self-harm

and suicidal behavior, and conclude whether these

behaviors can be predicted and neutralized. Given

the known morbidity and mortality associated with

untreated depression, all risks of treatment must be

balanced against the risk of withholding treatment.

Regardless of treatment status, all depressed children

and adolescents will require psychoeducation and

careful monitoring.

10.2.2 Antidepressant treatment in old age

10.2.2.1 General clinical considerations

The prevalence of depression appears to be indepen-

dent of age (Patten et al., 2001 ; Steffens et al., 2000),

Box 11. Useful clinical practice in the treatment of children and adolescents (and adults)

$ Carefully diagnosis the patient. Comorbidities or alternate diagnoses such as bipolar disorder may affect both the safety

and efficacy of drug treatment. Differentiate between depressive disorder and depressive distress in teenagers (for

screening purposes, the symptoms hopelessness, anhedonia and suicidality are the most important).$ After careful diagnosis, discuss the risks and benefits of treatment with antidepressants and/or psychotherapy. The

discussion should involve the parent(s) or guardian(s) and, whenever appropriate, the patient. The conversation should

reflect both the treatment-associated risks as well as the risk of untreated depression. Be aware of the better evidence for

the use of medication combined with psychotherapy.$ If depressive symptoms are mild or if the current episode is of new or recent onset, consider a period of intensive

psychosocial therapy, support and monitoring. Given the episodic nature of depression and the turbulence of youth,

particularly adolescence, some depressive episodes may respond to psychotherapy, simple supportive interventions or

may even remit spontaneously. However, even if symptoms remit, patients should be considered at risk for future de-

pressive episodes and receive regular monitoring. If symptoms worsen or persist for 6–8 weeks, an evidence-based

treatment with medication and/or a specific psychotherapy should also be initiated if only support has been offered up to

that point.60

$ Educate the patient and family61 about what to expect from drug treatment. It is important to let them know that they may

experience a drug’s side effects before they experience the benefits. Provide them with information about irritability,

akathisia, agitation and mania, and encourage them to call with questions. The Parent’s Med Guide is one useful resource

available on theWorldWideWeb (www.parentsmedguide.org) in English and Spanish. Ameasurement of side effects and

symptoms of depression, including suicidality, using rating scales is useful.$ Develop a safety plan with the patient and the responsible adult. Both the child and parent/guardian should have

numbers for the doctor/clinic as well as a plan for accessing emergency services. If the patient is experiencing suicidal

ideation but outpatient treatment is appropriate, provide only limited amounts of medication.$ When initiating medication, start low and monitor carefully. Based on current evidence, fluoxetine is the only drug

approved for clinical use and should be used as a first line agent. It is recommended that psychotherapy be co-

administered whenever possible. While starting low, children may be able to tolerate and sometimes require doses

similar to those for adults. Monitoring must be tailored to fit individual clinical situations. The FDA recommends the

monitoring schedule listed below, which was also used in the TADS study. Particularly in the initial weeks, in addition to

monitoring for suicidality, patients and families should be asked about medication compliance and changes in behavior.

# Every week for the first 4 weeks

# Every other week for the next 4 weeks

# After 12 weeks, then as necessary

$ If the patient responds, treatment should continue. ‘Continuation’ treatment for 3–6 months after remission helps reduce

rates of relapse. If children or adolescents have suffered previously from episodes of depression, a ‘maintenance’ phase of

1–3 years should be strongly considered. If a medication discontinuation trial is desired after a period of sustained re-

mission, it should be well-planned, slowly conducted and carefully monitored.$ If the patient does not respond, re-evaluate the diagnosis before moving on to an alternative drug strategy. If the

diagnosis is confirmed, consider a trial of a different medication.

60 The suggestions given are based more on clinical experience than

on evidence-based medicine.61 In countries where firearms are widely available, parents should

be encouraged to remove firearms or other dangerous equipment

from the house.


but a high rate of depressive symptoms requiring

treatment (Chopra et al., 2005) in old age has been

reported. In clinical work, prevalence rates may be

artificially low owing to standardized diagnostic

assessment procedures that are insufficiently adapted

for use in the elderly (Wittchen et al., 1994). Under-

detection of subthreshold depression, which shows a

high prevalence in the old age (Horowitz et al., 2005),

may be one explanation. The diagnosis of depression

may thus be relatively rare in elderly patients, whereas

subthreshold depression, which according to the

Diagnostic and Statistical Manual of Mental Disorders,

4th revision (DSM-IV), and the International Statisti-

cal Classification of Diseases and Related Health

Problems, 10th revision (ICD-10), also requires anti-

depressant treatment, may frequently be present.

However, epidemiological data show that the preva-

lence of depression in old age is in fact high, is often

underdiagnosed and undertreated, has a high rate

of recurrence and is associated with significantly in-

creased mortality (Katona, 1994). Because the preva-

lence of suicidal ideation is also relatively high in

the old age, effective suicide prevention is especially

needed for this age group (Pfaff and Almeida, 2005;

Raue et al., 2007). In addition, older patients experi-

ence more and longer major depressive episodes-

together with increased general medical comorbidities

(Husain et al., 2005). Considerable comorbidity exists

with dementia, stroke and Parkinson’s disease, where

patients often suffer from depressive symptoms. The

response to antidepressant treatment in the elderly

apparently does not differ from treatment response in

younger patients. However, relapse rates are higher,

and the longitudinal outcome is less favorable than for

middle age (Mitchell and Subramaniam, 2005). Very

few longitudinal studies follow the course of depress-

ive illness in elderly people. The meta-analysis of data

from 12 studies in primary care and in community

secondary care showed that after 2 years, 21% of

elderly depressed patients who were at least partially

diagnosed and treated by primary care physicians

had died. Among survivors, almost half remained

depressed (Cole et al., 1999). Moreover, inadequate

training in geriatrics may worsen this situation

(Bartels et al., 2003), whereas elderly patients who re-

ceive adequate antidepressant treatment experience

significantly better physical functioning (Callahan

et al., 2005). The more adverse longitudinal course in

old age may more plausibly be explained by medical

comorbidity (see also chapter 5.2.4), immobility and

psychosocial factors than by age itself (Mitchell and

Subramaniam, 2005). It is also generally accepted

that elderly depressed patients are particularly prone

to the side effects of antidepressants, particularly

cardiovascular side effects and treatment-related

cognitive dysfunction (Moskowitz and Burns, 1986).

Suboptimal regimes in 43.3% of elderly patients

treated with antidepressants have been reported.

These include both potentially hazardous (e.g. due to

high-dose treatment with anticholinergic agents) as

well as excessively low intensity and insufficient

treatments (Wang et al., 2005). It may also be import-

ant to distinguish between young-old (aged <75

years) and old-old (aged >75 years). Both groups

show marked differences in comorbidity (e.g. de-

mentia), lifestyle and rates of institutional care. How-

ever, in most antidepressant trials this distinction

has not been made, and patient samples in previous

studies are usually heterogeneous and termed

elderly, geriatric, senile or older adults, aged 55 or

over (Mottram et al., 2006).

10.2.2.2 Efficacy of antidepressants in old age

Numerous randomized controlled trials of anti-

depressant treatment in late-life depression have been

conducted, including all substance classes. The first

question is whether antidepressant pharmacotherapy

is effective at all in elderly patients, i.e. whether it

shows therapeutic efficacy superior to placebo treat-

ment. Roose and Schatzberg (2005) recently reviewed

five placebo-controlled trials that were selected based

on quality criteria in order to assess antidepressant

efficacy and effectiveness. Useful data on TCAs are

very limited because previous studies have often in-

volved inadequate dosages of TCAs (e.g. imipramine

and amitriptyline), which are not recommended

for the use in elderly patients (Mamdani et al., 2000).

Thus, four of these randomized controlled trials

(Rapaport et al., 2003 ; Roose et al., 2004 ; Schneider

et al., 2003 ; Tollefson et al., 1995) compared different

SSRIs (fluoxetine, sertraline, citalopram, paroxetine),

and one trial compared fluoxetine and venlafaxine

with placebo (Schatzberg et al., 2002). Three studies

demonstrated a statistically significant difference in

drug versus placebo response or remission rates

(Rapaport et al., 2003 ; Schneider et al., 2003; Tollefson

et al., 1995). The percentage of trials failing to

show a significant difference between verum and

placebo groups resembles results of non-geriatric

trials, where medication is found to be more effective

than placebo less than 50% of the time. In 1999, among

other general medical principles, the World Psy-

chiatric Association (WPA) recommended treating

depressive symptoms in the elderly with the aim

of complete remission. A more recent guideline of a


working group of the Royal College of Psychiatrists

from the UK (Baldwin et al., 2003) also supported the

efficacy of antidepressant drugs in elderly patients

based on a previous Cochrane review (Wilson et al.,

2001) and further meta-analyses (Gerson et al., 1999 ;

McCusker et al., 1998 ; Mittmann et al., 1997). In con-

trast, little is known about augmentation strategies in

elderly patients who have shown only modest im-

provement during previous treatment trials (Baldwin

et al., 2003).

Another question is whether one class of anti-

depressants is more favorable in old age than others.

Roose and Schatzberg (Roose and Schatzberg, 2005)

selected six trials that compared at least two different

antidepressants for further critical review. All random-

ized controlled trials in this review were comparison

trials of two SSRIs or one SSRI compared with a TCA

or mirtazapine (Bondareff et al., 2000 ; Navarro et al.,

2001 ; Newhouse et al., 2000 ; Roose et al., 2004 ;

Schatzberg et al., 2002). The response rates in these

comparison trials were consistently higher than those

seen with the same agents in placebo-controlled trials

(50–73% vs. 35–72%) and may better reflect the effec-

tiveness of medication in a clinical setting (Roose and

Schatzberg, 2005). These trials did not demonstrate

that one antidepressant is superior to another ; never-

theless, some experts recommend the low-dose use of

TCAs in the treatment of elderly patients. In a very

recent Cochrane analysis (Mottram et al., 2006), 29 out

of 163 identified trials were selected for further analy-

sis, and 14 studies were selected for contributing effi-

cacy data. Trials entering the meta-analysis of efficacy

had to compare at least two active antidepressant

drugs, because the meta-analysis aimed at comparing

the efficacy of antidepressant classes, withdrawal rates

and side-effect profiles in elderly patients. The trial

duration varied between 4 and 8 weeks, and only 2

trials (comparison of moclobemide with imipramine

and tianeptine) were conducted over 12 weeks or more

(Dunningham et al., 1994). No significant differences

in efficacy were found between classes of anti-

depressants (TCAs, TCA-related drugs, SSRIs, MAOIs

and atypical antidepressants). However, the trials

contained relatively small numbers of patients, poss-

ibly introducing a large type-2 error, which may ex-

plain the negative finding. Higher numbers of patients

withdrawn irrespective of reason or due to side effects

were observed during treatment with TCAs compared

with SSRIs.

Electroconvulsive therapy (ECT) has also been

shown to exert excellent effectiveness, which was

better in younger than in older geriatric patients

(Abrams, 2002; Greenberg and Fink, 1992; Oshima

and Higuchi, 1999). Despite specific side effects,

such as greater cognitive impairment, efficacy is

greater in older than in younger patients, and reduced

mortality in comparison with other treatments has

been shown (Philibert et al., 1995). Further progress in

understanding ECT and anesthesia has reduced the

risks of of the treatment. Some authors currently are

therefore of the opinion that there are no absolute

medical contraindications to the use of modified ECT

which is encouraged now also in geriatric patients and

in patients at particular medical risk (Abrams, 2002 ;

Fink, 1999).

There is a broad clinical consensus that it is appro-

priate to include both antidepressant medication,

specifically SSRIs, and nonpharmacological modalities

in treatment plans for severe depression in the elderly

(Alexopoulos et al., 2001).

10.2.2.3 Tolerability in elderly patients

The recent Cochrane analysis (Mottram et al., 2006) of

side effects showed a small increased risk of gastroin-

testinal (including the experience of ‘dry mouth’) and

neuropsychiatric side effects (drowsiness, dizziness,

lethargy) associated with classical TCAs. However,

further conclusions regarding the comparison of other

classes of substances have not been possible due to the

methodological limitation mentioned above. Thus,

only the pharmacological profiles of specific drugs

and their interactions with medical comorbidity and

concomitant medication can determine the choice of

antidepressants in elderly patients. In primary care,

newer drugs that provide a superior safety profile,

such as SSRIs, are gradually replacing TCAs as a first-

line treatment (Gareri et al., 1998 ; Mamdani et al.,

2000). Moreover, geriatric patients are more suscep-

tible to side effects such as orthostatic hypotension and

sedation. Cognitive disturbances, too, and even de-

lirious states induced by the anticholinergic action of

various antidepressants, e.g. TCAs, are more frequent.

Elderly patients are at especially high risk for adverse

drug reactions and drug-drug interactions (see also

chapter 9.1.1.1.5) due to multimedications (Borchelt,

1995). Some side effects that raise particular concerns

in younger patients, such as weight gain due to anti-

histaminergic effects, may be beneficial for elderly

patients, who often suffer from anorexia and weight

loss. In existing medical comorbidity, which may

complicate the management of late-life depression,

particular care should be paid in choosing an anti-

depressant. According to the guidelines from the

UK (Baldwin et al., 2003), SSRIs should be preferred

for depression that complicates vascular and


cerebrovascular disease, mainly because of safety and

tolerability. In dementia, TCAs, SSRIs and moclo-

bemide are effective ; however, newer drugs are better

tolerated and safer. For Parkinson’s disease no ad-

equate trial data are available. SSRIs may aggravate

parkinsonian symptoms, but this finding has not been

established (Baldwin et al., 2003).

10.2.2.4 Dosage and duration of antidepressant

treatment in old age

Comorbid medical conditions and concomitant medi-

cations require particular attention to pharmaco-

dynamic and pharmacokinetic interactions. Even if

no other medical disturbances are present, normal

aging leads to differences in hepatic and renal function

that require extraordinary awareness. Because of

reduced hepatic metabolism and renal elimination

rate in the elderly, appropriate dosages are lower

than in younger patients (Chiu, 1997). In frail patients

treatment should commence with a slow dosage

and titrate gradually to the therapeutic dosage range

(‘start low and go slow’). Moreover, the guidelines of

the American Psychiatric Association (APA) empha-

size that elderly patients typically require a lower

dosage than younger patients to reach a particular

blood level and tolerate a given blood level less

well. However, the blood levels at which anti-

depressant medications are maximally effective ap-

pear to be the same as for younger patients (American

Psychiatric Association, 2000 ; Wilson et al., 2001).

Another critical issue is the duration of treatment

in old age. Older patients apparently take longer to

recover from depression and recovery goes on up to

12 weeks, provided that there has been some early

improvement (Wilson et al., 2001). Currently at least

6 weeks of treatment is recommended to achieve

optimal therapeutic effects (Wilson et al., 2001).

However, little response (e.g. less than 25% recovery)

during the first 4 weeks of the same treatment is

associated with a low probability of remission

(Mottram et al., 2006). Similar to younger patients,

following remission, antidepressant medication

should be continued at the same dose for at least 6

months in the case of initial episodes and longer in the

case of recurrent illness, as described in Table 9

(Geddes et al., 2003).

11 Suicidality and antidepressants : depression

and suicide

About two-thirds of people committing suicide suffer

from depression. In 1970, Guze and Robins (Guze and

Robins, 1970) published a meta-analysis of studies

putting a lifetime suicide risk at 15%. This frequently

quoted figure may overestimate the suicide risk, as

it generalizes from high-risk hospitalized patients to

all depressed patients (Boardman and Healy,

2001). Suicide rates in depressed patients in longer

(>10 years) follow-up studies range from 4% to 10.6%

(Angst et al., 2005). A meta-analysis of 27 mortality

studies by Inskip (Inskip et al., 1998) using contem-

porary data and modern analytic techniques led to

an estimate of a lifetime suicide risk of 6% for affective

disorders. Recently, Bostwick and Pankratz (Bostwick

and Pankratz, 2000) found a hierarchy of lifetime

suicide prevalences : 8.6% in people ever admitted

for suicidality, 4% in patients admitted with affective

disorder but not specifically for suicidality, and 2.2%

in mixed inpatient and outpatient populations.

Diagnostic uncertainties may also obscure accurate

estimates of suicide rates for unipolar depression.

A meta-analysis by Harris and Barraclough (1998)

found a standard mortality ratio (SMR) of 21.24

for major depressive disorder that even exceeded

the one calculated for bipolar patients. Osby et al.

identified all patients with a hospital diagnosis of

bipolar (n=15386) or unipolar (n=39182) disorder in

Sweden from 1973 to 1995 from the inpatient register

and linked with the national cause-of-death register to

determine the date and cause of death. The SMRs for

suicide were 15.0 for males and 22.4 for females with

bipolar disorder, and 20.9 and 27.0, respectively, for

unipolar disorder (Osby et al., 2001).

A more precise estimate of suicide mortality may be

difficult due to methodological shortcomings, as out-

lined by Jules Angst and colleagues (Angst et al.,

2005).

$ The most severely ill, hospitalized patient samples

are selected, and these are not representative.$ Lifelong follow-up studies are lacking.$ The diagnoses in representative suicide samples are

retrospective.$ In order to compensate for the lack of decades-long

follow-up studies, risk estimates are based on ex-

posure years that assume an unproven time-related

linear risk.$ Perhaps the most significant methodological prob-

lem: bipolar disorder and unipolar depression aris-

ing from an under-diagnosis of hypomania leading

to an underestimate of bipolar II disorder.

The most definitive prospective, long-term, large

cohort study on suicide risk in affective disorders

may be that conducted by Angst et al. who followed

up 406 patients with mood disorder from 1963 to


2003 (Angst et al., 2005). By 2003, 11.1% of these

patients had committed suicide, with the highest

SMR being 26.4 for unipolar depressed patients. These

data underscore the prominent role of early diagnosis

and treatment of depression in suicide prevention.

Early diagnosis and public awareness have been

proven to be effective tools in reducing suicide at-

tempts and completed suicides in large, population-

based studies. This finding was first demonstrated in

a prospective, community-based trial in Gotland,

Sweden (Rihmer et al., 1995 ; Rutz et al., 1989). The

results were replicated recently (Henriksson and

Isacsson, 2006) and seem also to hold true for larger,

urban communities. For example, the Nurnberger

Bundnis gegen Depression (Nuremberg Alliance

against Depression) is a community-based, multi-

faceted, 2-year intervention that focuses on de-

pression. The number of suicidal acts (fatal and

non-fatal suicide attempts) showed a significant and

clinically relevant reduction compared with both a

1-year baseline and a control region (minus 24%)

(Althaus et al., 2006 ; Hegerl et al., 2006).

Patients with a history of suicidal behavior suffer

from a greater burden of depressive illness (Claassen

et al., 2006). As demonstrated by Balazs et al. (2006),

the presence of such clinical features as irritability,

distractibility and psychomotor agitation (‘mixed

depression’ as quoted by the authors) are, besides

hopelessness (Goldston et al., 2006 ; MacLeod et al.,

2005), strong predictors of suicide attempts even

in patients who do not otherwise fulfill diagnostic

criteria for bipolar disorder. On the basis of these

findings, Rihmer and Akiskal (2006) speculated that

in these patients the use of antidepressants without

concomitant mood stabilizers may exacerbate a pre-

existing mixed state or generate de novo mixed syn-

dromes, resulting in treatment resistance as well as

a worsening of depression that ultimately may pro-

voke suicidal behavior. In the context of this review, it

may be appropriate to recommend that special caution

should be exercised in patients with the symptoms of

hopelessness, irritability, distractibility and agitation

who are prescribed an SSRI, since agitation occurs

statistically significantly more frequently with SSRIs

than with other antidepressants, e.g. TCAs. In the fu-

ture, we may be even able to identify patients on

riks for suicidal behaviour on a gentic basis ; a recent

report demonstrated that markers within GRIK2 and

GRIA3 are associated with treatment-emergent suici-

dal ideation during citalopram therapy (Laje et al.,

2007).

Different claims about the use of antidepressants,

especially selective serotonin reuptake inhibitors

(SSRIs), and suicidality have been proposed. Antide-

pressants may decrease suicide rates on a population

basis (Ludwig and Marcotte, 2005), but at the same

time they may increase suicidality (or even suicide

events) in some individuals early in treatment (Healy

and Whitaker, 2003). Recent reviews by Hall and

Lucke (2006) and Moller (2006a, b), show some sup-

portive evidence for both views.

A study by Yerevanian et al. (2004) demonstrated

that long-term treatment with antidepressants (SSRIs

and tricyclic antidepressants (TCAs)), sometimes in

combination with benzodiazepines, significantly re-

duces the risk of both completed and attempted sui-

cide in more than 500 patients with major depression

and dysthymic disorder. In addition, a multitude of

epidemiological studies have demonstrated reduction

of suicidality in regional populations in association

with antidepressant prescription (Carlsten et al., 2001 ;

Hall et al., 2003 ; Isacsson et al., 1997 ; Isacsson, 2000 ;

Ohberg et al., 1998 ; Rihmer et al., 2000) ; for a short

overview see (Hall and Lucke, 2006 ; Isacsson and

Rich, 2005; Yerevanian et al., 2004). Investigating the

suicide mortality of the 27 countries with data on

annual sales of all SSRIs (and, of course, also other

antidepressants) between 1980 and 2000, Ludwig and

Marcotte (2005) found that after controlling for a var-

iety of sociodemographic factors, an increase of one

SSRI pill per capita in 2000 (a 13% increase over 1999

levels) was associated with a significant, 2.5% re-

duction in suicide rates in adults. As pointed out by

Rihmer and Akiskal (2006), this effect is most promi-

nent in countries with previous high suicide rates and

low rates of treated depression, and can be separated

from other covariables such as alcohol consumption or

unemployment rates. In Iceland (population 286000)

the relatively low suicide rate (around 30 suicides per

year) was not decreased despite a huge increase in the

use of antidepressants (Helgason et al., 2004).

When not properly conducted, however, open stu-

dies and population-based studies can easily be sub-

ject to several biases and errors in interpreting results

(Moller, 2006a). It should also not be neglected that

some of the recent epidemiological studies arose in

response to the concerns of regulatory agencies of po-

tential increased suicidality with antidepressants, and

due to their largely uncontrolled nature, there is

clearly room for an investigator bias. Randomized,

control group studies, especially when placebo con-

trolled, seem to be the best basis for statements about

the suicide risk of certain antidepressants. But because

suicide is, fortunately, a rare outcome in controlled

studies, it cannot be reliably assessed. To improve the

number of subjects and statistical power, pooled data


subjected to meta-analysis have been used (for the

general methodological problems of using meta-

analyses, please refer to chapter 4.4). To date, the

largest database from randomized controlled trials

(RCTs) is one assessed by Hammad et al. (Hammad

et al., 2006b). They evaluated the rate of suicide in

placebo- and active drug-treated groups of patients

with major depression and various anxiety disorders

participating in short-term RCTs. Data were available

for 207 trials conducted in patients with major de-

pressive disorder (MDD), including a total of 40028

patients, and 44 trials conducted in patients with

various anxiety disorders, including a total of 10972

patients. The use of neither placebo nor anti-

depressants in short-term RCTs was associated with

an increased risk of completed suicide among patients

with MDD or various anxiety disorders. Nonetheless,

as the authors conclude, because of the small numbers

of suicides in these trials and the subsequent lack of

statistical power, an increased risk of completed sui-

cide in association with either drug or placebo treat-

ment cannot be definitively excluded.

Thus, we can only assess other parameters that are

more frequent and are linked to suicide with various

degrees of certainty (and, of course, uncertainty ;

Klein, 2006). Even when softening the outcome cri-

terion towards ‘suicidality’, not completed suicide,

the results of such control group studies also have to

be viewed critically and considering the methodolo-

gical pitfalls inherent in the design of such studies. The

low basal prevalence of suicidal behavior has the

consequence that, for principal statistical reasons, it

is almost impossible to perform a control group study

with adequate statistical power to differentiate be-

tween the outcome results of two treatment groups,

as the number of these events in a medium-sized

or even a large control group study is small. This

drawback could possibly be overcome by an enriched

sample design; however, most of the respective con-

trol group studies on antidepressants do not deal with

samples in which the symptom suicidality/suicidal

thoughts is enriched. Indeed, the opposite is true:

most studies exclude at least patients with serious

suicidal thoughts. The principal ethical aim, i.e. to

avoid harm to the patients, conflicts with the scientific

objective of such studies. Thus the ideal control

group design to answer the question whether anti-

depressants reduce suicidality cannot be realized

for ethical reasons. The consequence of this dilemma

might be that any indications of efficacy do not reach

statistical significance and, in addition, are far re-

moved from actual efficacy in real-life conditions

(Moller, 2006a).

These limitations must be kept in mind when

assessing suicidal behavior in controlled studies,

both in those studies detecting a signal and those

that do not. A secondary analysis by Moller of a

6-week double-blind controlled study comparing

paroxetine and amitriptyline showed a marked re-

duction in suicidal thoughts for both medications

(Moller et al., 1998). Similarly, Szanto (Szanto et al.,

2003) demonstrated complete remission of suicidal

ideation in elderly depressed patients after 12 weeks

of either amitriptyline or paroxetine treatment. A re-

view of data from several controlled studies by Moller

(Moller, 2003) also demonstrated a greater benefit of

SSRIs compared with placebo in reducing suicidal

ideation.

But there is also conflicting evidence. Concerns

started in 1990 with the observation of intense suicidal

preoccupation during fluoxetine treatment in six

patients. (Teicher et al., 1990), obviously contrasting

neurobiological findings of decreased central seroton-

ergic neurotransmission in suicide victims (Asberg,

1976). By the end of 1991, at least four other publi-

cations appeared, expressing concerns about the

emergence of intense suicidality with fluoxetine. A

reanalysis of the first survey on this topic, conducted

by Fava and Rosenbaum (1991) suggested that the

emergence of suicidality was about three times more

likely with fluoxetine than with other antidepressants

(ACNP, 1992). More recently Healey and Whitaker

(2003) have argued that there is an increased risk of

suicidal behavior in controlled trials, although the risk

is relatively rare. In the Healey meta-analysis, this risk

seemed to be especially increased in juveniles and

adolescents as discussed previously in this review (see

chapter 10.2.1). This report raised considerable public

attention, especially in Great Britain and the US.

To clarify this issue, the US Food and Drug

Administration (FDA) commissioned an independent

group of investigators at Columbia University to re-

view all adverse events that suggested suicidal activity

in controlled trials of SSRIs in children and ado-

lescents. In 4400 depressed children and adolescents

in a total of 24 studies, there were no completed

suicides ; however, the risk of suicidal ideation or

activity was 4% on active medication and 2% on

placebo (US Food and Drug Administration, 2005).

The exact significance of this finding is not clear, and

the FDA did not make any conclusions regarding

causality. In addition, the methodological basis of the

consecutive FDA black box warning (FDA Public

Health Advisory, 2004) for marketed antidepressants

about the use of these agents in younger patients raises

questions, as outlined by Klein (2006).


A finding similar to the FDA warning was also re-

ported by a recent meta-analysis of 702 randomized

controlled trials including more than 87000 depressive

and other psychiatric patients, primarily adult pa-

tients. In this analysis Fergusson62 et al. (2005) showed

a significantly increased risk of suicide attempts (OR,

2.28), but not of completed suicides in patients taking

SSRIs compared with placebo. In the pooled analysis

of SSRIs versus TCAs, no difference was detected in

the odds ratio of suicide attempts. This contrasts with

another meta-analysis by Gunnell et al. (2005) of 277

randomized controlled trials of SSRIs compared with

placebo in 40000 adult patients submitted by phar-

maceutical companies to the safety review of the

Medicines and Healthcare products Regulatory

Agency (MHRA). The authors found no evidence that

SSRIs increase the risk of suicide. As a consequence of

the conflicting results in adults, the FDA recently

asked manufacturers to review their adult databases

on suicidal behavior in controlled antidepressant

trials.

In response to the FDA request, the first meta-

analyses of the specific suicide risk of newer anti-

depressants are now available. Acharya et al. (2006)

evaluated all completed duloxetine trials in major de-

pression until February 2004. The researchers com-

pared the incidence of suicide-related events with

duloxetine versus placebo in controlled trials, using

the Mantel-Haenszel incidence difference (MHID)

and exposure time-adjusted rate difference (MHRD)

methods, and analyzed changes in HAMD Item-3

(suicidality) scores. The planned primary meta-

analysis of differences in incidence (MHID) of suicidal

behaviors during randomized treatment with dulo-

xetine versus placebo did not indicate an association of

risk with treatment. Analyses using MHRD methods

and outcomes (completed suicide, non-fatal suicide

attempt and suicidal ideation) also failed to show

either increased or decreased risk of suicidal events

in association with duloxetine treatment. Changes in

HAMD Item-3 suicidality scores showed more im-

provement with duloxetine (MHID 9.56%, 95% CI

4.50–14.6, p<0.001) and less worsening of suicidal

ideation with duloxetine (MHID –4.25%, 95% CI –6.55

to –1.95, p<0.001). Cheung et al. have argued that ex-

trapolating data on antidepressants from adults to

adolescents is questionable (Cheung et al., 2006), but

the same is true in the opposite direction. Thus, mod-

eling of potential excess suicides in adults from data

generated in adolescents, as done, for example, by

Gunnell and Ashby (2004), is highly questionable, es-

pecially with more data now available of studies in

adult populations. Following up on FDA warnings,

Simon et al. (2006) analyzed computerized health plan

records from a total of 82285 episodes of anti-

depressant treatment between 1 January 1992 and 30

June 2003. Identifying death by suicide and serious

suicide attempts, they found that the risk of suicide

attempts was highest in the months before starting

antidepressant treatment and declined progressively

after starting medication. It was not significantly

higher in the months after starting medication than in

subsequent months. Comparing the 10 newer anti-

depressants included in the FDA black box warning

with older antidepressants revealed that an increase

in the risk of suicide was even more likely with the

older drugs than with the newer antidepressants. In

addition, a recent combined analysis of all placebo-

controlled depression and anxiety studies with

escitalopram found no signal for increased suicide risk

with active medication treatment. On the contrary,

suicidal ideation as measured with item 10 of the

MADRS became significantly lower from week 1 on-

wards with active treatment (Pedersen, 2005).

Other important arguments against increased sui-

cide rates with SSRIs are provided by epidemiological

and toxicological studies. A controlled toxicological

analysis of all suicide victims from 1992 to 1999 in

Sweden showed that SSRIs were underrepresented

compared with other antidepressants and that in

suicide victims under the age of 15 (n=52), different

antidepressants (but no SSRIs) were detected in seven

cases (Isacsson et al., 2005). In a study of the UK

General Practice Research Database, Jick et al. found

no suicides at all in 6976 depressed patients, 10–19

years old, who were prescribed antidepressants.

Indeed, over this entire age group the database re-

vealed 15 suicides, none of whom had been treated

with antidepressants (Jick et al., 2004).

Grunebaum et al. (2004) presented the results of a

methodologically very sound analysis of US-American

data for the years 1985–1999 that also took into account

unemployment and alcohol consumption as con-

founding factors in a multivariate approach. The

relationships between the suicide, antidepressant

prescription, unemployment and alcoholic beverage

consumption rates were studied using generalized

linear models. Suicide rates by antidepressant over-

dose were compared in SSRIs and TCAs. From 1985 to

62 In a series of workshops on problematic papers, the Canadian

Network for Mood and Anxiety Treatments (CANMAT) criticized

the lack of heterogeneity analysis before including studies in

patients whose diagnoses were unspecified. In addition, small

differences in the numbers of rare events such as suicides may lead

to misinterpretation of study results.


1999, the suicide rate fell 13.5%, with a greater decline

among women, and antidepressant prescription rates

increased over fourfold, with the increase mostly

due to SSRIs. Prescription rates for SSRIs and other

second-generation antidepressants were both in-

versely associated with suicide rates (p=0.03 and

p=0.02, respectively). In a multivariable analysis ad-

justing for unemployment and alcoholic beverage

consumption rates, SSRI antidepressant prescription

rates remained inversely associated with the national

suicide rate (p=0.03).

A similar analysis of suicide data from the US per-

formed by Gibbons et al. (2005) obtained somewhat

more differentiated results. This study focused on

the years 1996–1998 and categorized the national

county-level suicide rates according to age, sex,

income, race and antidepressant prescription rates

(expressed as number of pills prescribed). The overall

relationship between antidepressant medication pre-

scription and suicide rate was not significant. Within

individual classes of antidepressants, prescriptions

for SSRIs and other new-generation non-SSRI anti-

depressants (e.g. nefazodone hydrochloride, mirtaza-

pine, bupropion hydrochloride and venlafaxine

hydrochloride) were associated with lower suicide

rates (both within and between counties). A positive

association between TCA prescription and suicide

rates was observed, i.e. higher TCA prescription rates

were associated with a higher suicide risk (which may

be partially due to the higher toxicity of TCAs when

taken with suicidal intent). Results were adjusted for

age, sex, race, income and county-to-county variability

in suicide rates. Higher suicide rates in rural areas

were associated with fewer antidepressant prescrip-

tions, lower income and relatively more prescriptions

for TCAs. It should be noted that the authors also re-

port similar results in favor of SSRI prescription in

adolescents in a consecutive paper (Gibbons et al.,

2006).

Thus, on the basis of the cited and additional

studies and meta-analyses (Fergusson et al., 2005;

Martinez et al., 2005) Cipriani et al. (2005a) concluded

for depression in adults (not in children!) that ‘taking

into account these limitations, we can get some useful

insights for clinical practice. Firstly, current evidence

that indicates no clear relation between SSRIs and

suicide, together with available robust evidence of ef-

ficacy of treatment with antidepressant drugs in the

pharmacological management of moderate to severe

unipolar depression, should encourage doctors to

prescribe effective doses of these drugs in such

patients. Doctors should additionally be aware that

SSRIs, similarly to tricyclics, may induce or worsen

suicidal ideation and suicide attempts during the early

phases of treatment, possibly because they cause agi-

tation and activation particularly at that time. During

these early phases, doctors should plan frequent

follow-up visits and also consider a possible support-

ing role for family members and caregivers. ’ In ad-

dition, doctors should give patients a realistic view

about the time to onset of improvement ; over-

optimistic expectations of patients and doctors may

result in disappointment and consequently hope-

lessness and suicidality.

Besides antidepressants, other medications, includ-

ing lithium and antipsychotics, may also significantly

reduce suicides in patients with mood disorder, as

demonstrated by a meta-analysis of Baldessarini et al.

(2003) and a recent study of Angst et al. (2005). In the

analysis of data of the Zurich cohort study by Angst,

long-term medication treatment with antidepressants

alone or with a neuroleptic, or with lithium in combi-

nation with antidepressants and/or neuroleptics, sig-

nificantly lowered suicide rates even though the

subjects treated were more severely ill than those

without medication.

Weighing risks against the benefits of anti-

depressants, it also has been argued that overdosing of

antidepressants is potentially lethal, and thus it may

be risky to supply a depressed patient with a potential

means of suicide. Yet newer antidepressants especially

show a large safety margin that makes lethal intoxi-

cation difficult, and several studies have shown that

prescription medication is not commonly used as a

means of suicide (Bradvik and Berglund, 2005;

Henriksson et al., 2001; Isacsson et al., 1997). In

addition, it has been demonstrated that, with the

introduction of the newer antidepressants and the

decreased use of older tricyclics, the rate of fatal toxi-

cities of antidepressants has declined (Morgan et al.,

2004).

In summary, data on increased suicidal behaviors

from randomized controlled studies are conflicting,

but the overwhelming evidence from epidemiological

studies is in favor of reduced suicide rates with anti-

depressant treatment. Concerning the risk of using

prescribed antidepressants as a suicide tool, the risk of

lethal intoxication with antidepressants, although al-

ready rare, still declines with the replacement of the

classical antidepressants by newer agents. It appears

more evident that antidepressants are valuable tools in

preventing suicides in depression (Goldney, 2006) in-

stead of provoking it ; and summarized on the basis of

the available evidence, any increased risk of suicide

that antidepressants may produce in a subset of

(mostly adolescent) depressed patients appears to be


offset by the public health benefits of increased diag-

nosis and treatment of depression.

12 Other treatments for depression

12.1 Psychotherapy63

Empirically supported psychotherapies are potent

alternatives to and augmenters in combination

with antidepressant medications. Efficacious psy-

chotherapies may have particular benefits for de-

pressed patients, such as pregnant women, who prefer

to avoid medication. In non-industrialized countries,

such psychotherapies may be the only feasible,

affordable treatments for depression (Bolton et al.,

2003).

Interpersonal psychotherapy (IPT) is a time-limited,

diagnosis-focused treatment shown in repeated ran-

domized controlled trials to have efficacy as both an

acute and a maintenance treatment for major de-

pressive disorder (Weissman et al., 2000). IPT defines

depression as a treatable medical illness that is not the

patient’s fault. It focuses on the connection between

the patient’s mood and interpersonal life circum-

stances. It has been shown not only to relieve de-

pressive symptoms but to build social skills. IPT has

shown more modest benefit for dysthymic disorder

(Browne et al., 2002 ; Markowitz et al., 2005). One large

trial has indicated the efficacy of an adaptation of IPT

(Interpersonal Social Rhythms Therapy) as an adjunc-

tive treatment for bipolar disorder (Frank et al., 2005).

Other studies have found that interpersonal counsel-

ing (IPC), a short, dilute version of IPT, relieves

symptoms of subsyndromal depression (Weissman

et al., 2000). Cognitive and behavioral therapies (CBT)

have also demonstrated efficacy in repeated rando-

mized controlled trials for depression. Cognitive

therapy focuses on the ‘automatic ’ irrational thoughts

that arise in the depressed state, in particular the

‘cognitive triad’ of negative outlooks. This consists of

negative thoughts about oneself (‘ I’m no good’), the

environment (‘Things are overwhelming’), and the

future (‘It’s never going to get any better’) (Beck et al.,

1979). Patients learn to test the evidence for and

against negative thinking, and to substitute more

rational responses to the environment for overly

negative depressive thinking. Cognitive techniques

are frequently used in combination with behavioral

interventions such as scheduling pleasurable

activities. The two are used together in varying com-

binations, but CBT is generally more common

than either pure cognitive or pure behavioral therapy.

Cognitive therapy appears to have an ‘enduring

effect’ that protects persistently against relapse

even after acute treatment ends (Hollon et al.,

2005a,b). Cognitive Behavioral Analysis System of

Psychotherapy (CBASP; McCullough, 2000), an

amalgam of behavioral, cognitive, interpersonal, and

psychodynamic techniques developed specifically

to treat chronic depression, equalled nefazodone in

efficacy in one large trial, and the combination of

CBASP plus nefazodone surpassed either treatment

alone (Keller et al., 2000). As there was no placebo

control condition in this study, however, the efficacy of

CBASP requires further testing.

In addition to acute efficacy, cognitive therapies

have been shown to enhance the efficacy of anti-

depressants, especially in combination treatment,

possibly due to an influence on serotonin and nora-

drenaline levels (Gaszner, 2005).

Due to a relative lack of research funding, there

are far fewer trials of psychotherapy than of

pharmacotherapy for the treatment of depression.

Psychotherapy research is complicated by the need to

manualize the therapies, to train therapists to follow

these manuals, and to monitor therapist adherence in

treating patients during the trial by taping and rating

treatment sessions. Nonetheless, a series of ran-

domized trials have generally shown equipotence of

empirically-based psychotherapies with pharmaco-

therapy for non-delusional outpatients with major

depression. An early, key study was the NIMH

Treatment of Depression Collaborative Research

Program (Elkin et al., 1989), which compared imipra-

mine, pill placebo, IPT, and CBT in treating 250 out-

patients with major depression. In that 16 week trial,

all treatments showed equal overall benefits, but imi-

pramine and IPT had greater efficacy for patients with

more severe depression (HAMD >20) relative to pill

placebo with clinical management.

On the basis of their performance in controlled effi-

cacy trials, interpersonal psychotherapy, and cognitive

and behavioral therapies (CBTs) should be included

in algorithms of standard treatment for depressive

disorders. IPT and CBTs have already been included

in numerous professional and national treatment

guidelines (Karasu et al., 1993 ; Tylee, 2006 ; van den

Broek, 2005). For patients with chronic or severe de-

pression, the combination of pharmacotherapy and

one of these empirically validated psychotherapies

may be preferable to either monotherapy (Rush

and Thase, 1999). Also in a recently published

63 See chapter 19.8 for more detailed information in Annex 8 :

Additional information on psychotherapy.


meta-analysis the combined therapy outperformed

psychotherapy, but this was only true in moderate

chronic depression. No differences were found in non-

chronic depression (de Maat et al., 2007).

12.2 Electroconvulsive therapy64

Electroconvulsive therapy (ECT) is the safe induction

of a series of generalized epileptic seizures for thera-

peutic purposes using brief-pulse stimulation tech-

niques under anesthesia and muscle paralysis.

Informed consent65 of the patient or the responsible

legal guardian is mandatory (see also Box 12). Since

the first publications, the excellent therapeutic effec-

tiveness of this method in the treatment of depression

has been described in a variety of reviews and meta-

analyses (Abrams, 2002 ; Baghai et al., 2005; ECT

review group, 2003).

12.2.1 ECT as first-line treatment

In the case of refusal of food and drink, and severe

psychomotor retardation, ECT has been shown to be

one of the safest therapeutic options with the fastest

relief of symptoms (Gangadhar et al., 1982). Therefore,

depressive stupor and inanition, as in melancholic,

catatonic and/or psychotic depression, can be a first-

line indication for ECT before other treatments are

prescribed. If, due to other conditions, e.g. severe

psychotic symptoms and/or high suicide risk, rapid

improvement is crucial for the patient, ECT should

be considered earlier than other therapeutic options

(American Psychiatric Association Committee on

Electroconvulsive Therapy et al., 2001). In psychotic

depression, the remission rate for ECT approximates

90%, with relief experienced within 10–14 days

(Petrides et al., 2001). The risks of suicide that mark

severe psychiatric illnesses are quickly relieved by

ECT, although attention to continuation treatment is

essential to sustain the benefit (Kellner et al., 2005).

Also, with other acute psychiatric syndromes, e.g.

delirious mania and malignant catatonia, that mark

systemic illnesses such as lupus erythematosus,

neuroleptic malignant syndrome (NMS) and medi-

cation toxicitymay require ECT as a first-line treatment

(Abrams, 2002; Baghai et al., 2005), especially if it is

not possible to differentiate between NMS and malig-

nant catatonia. Intensive ECT, usually administered

daily (en bloc), relieves the high rates of mortality

associated with malignant catatonia and delirious

mania (Fink, 1999 ; Fink and Taylor, 2003). In addition,

when depression, mania and psychotic symptoms ac-

company systemic illnesses or are present during early

pregnancy or the post-partum breastfeeding period,

administration of medications is often precluded and

ECT becomes a useful treatment option. In the case of

severe and life-threatening adverse events of anti-

depressants, in psychotic depressed patients and also

in the case of severe adverse events due to anti-

psychotics, ECT monotherapy can be a safe first-line

treatment. This recommendation also holds for

patients suffering from severe somatic diseases, in-

cluding the risk of worsening due to antidepressant

and antipsychotic pharmacotherapy (Beliles and

Stoudemire, 1998 ; Franco-Bronson, 1996 ; Rothschild,

1996).

In addition, long duration and chronic course of

the index episode are negative outcome predictors in

depressive disorders that signal a higher risk for ther-

apy resistance to medication and ECT (Beliles and

Stoudemire, 1998 ; Prudic et al., 1990) ; more patients

should be informed about these possible response

rate modifiers as part of shared decision making

concerning their antidepressant treatment. Never-

theless, the primary use of ECT is handicapped by

Box 12. Administration of ECT according WHO recommendations (World Health Organization, 2005c)

$ According WHO recommendations, just as with any other treatment, ECT should only be administered after obtaining

informed consent.$ ECT should only be administered in the so-called modified form (which to date represents the standard procedure),

i.e. with the use of anesthesia and muscle relaxation.$ The practice of using unmodified ECT should be stopped, but up to now this method is still used in some countries for

traditional and financial reasons.


Additional information on electroconvulsive therapy.65 Exceptionally in the case of perilous disease, when there is no

possibility of obtaining informed consent due to the character of the

mental illness, ECT can also be administered after legal

authorization and informed consent of the patient’s legal

representative. Patients with stupor, manic excitement, catatonic

mutism and in acute paranoid states may not be able to give written

consent, and alternative consent processes, which vary with

jurisdictions in different countries, must be applied. It is useful for

physicians who are responsible for the more acute and severely ill

psychiatric patients to consider ECT as a primary indication and to

be acquainted with all the means for proper consent for treatment

within their jurisdiction.


severe stigma and even legal restrictions against

its use in some jurisdictions (Ottoson and Fink,

2004).

12.2.2 ECT as second-line treatment

The most common use of ECT is in patients for whom

medications have failed to elicit remission or in whom

medication toxicity has interrupted the course of

therapy (Abrams, 2002 ; Baghai et al., 2005).

Nevertheless, patients rarely receive ECT after the first

two medication treatment failures, which are often

used as a criterion for pharmacotherapy resistance

(Moller, 1997 ; Prudic et al., 1996 ; Sackeim, 2001;

Warneke, 1993). Use of ECT significantly enhances

response rates (Davidson et al., 1978 ; Folkerts et al.,

1997 ; Kroessler, 1985). This finding is especially true in

patients suffering from psychotic depression, even if

antipsychotic therapies have been applied adequately

before (American Psychiatric Association Committee

on Electroconvulsive Therapy et al., 2001 ; Folkerts

et al., 1997). Intolerable side effects of antidepressant

medications, somatic comorbidities emerging during

the pharmacological treatment (American Psychiatric


et al., 2001 ; Rasmussen et al., 2002) or worsening of

depressive symptoms, including severe suicidality

during antidepressant pharmacotherapy, can also be

the reason for initiating an ECT treatment course


Electroconvulsive Therapy et al., 2001).

12.2.3 Maintenance and continuation ECT66

As described in chapter 9.2 in addition to pharmaco-

logic and psychotherapeutic continuation therapies,

especially after pharmacotherapy treatment failures,

ECT, too, can be an efficacious prophylactic tool

(Kellner et al., 2005 ; Sartorius and Henn, 2005a,b),

even given the absence of controlled studies. Con-

tinuation ECT should be considered when depressive

symptoms recur, especially when adequate pharma-

cologic therapy fails. Even when the prior history of an

individual patient shows an enhanced risk for recur-

rence of depression during continued pharmaco-

therapy, including both antidepressants and mood

stabilizers, C-ECT should be a part of the treatment

plan (Frey et al., 2001 ; McCall, 2001 ; Rabheru and

Persad, 1997). The usual clinical procedure is to

prolong the treatment intervals according to individ-

ual clinical requirements. During acute treatment, a

patient usually receives two or three treatments per

week. Afterwards, usually one treatment per week is

applied for 4–8 weeks, then one treatment every

2 weeks and then one treatment every 4 weeks. This

frequency should be maintained for at least 6 months.

A frequently used alternative strategy (the so-called

cafeteria style) is the individual decision whether to

administer C-ECT treatment when the first signs of

recurring depressive symptoms are reported (Abrams,

2002 ; Fink et al., 1996). Regular weekly evaluations

help to judge the necessity to shorten treatment-

free intervals on an individual basis. The same evalu-

ation is necessary during the attempt to stop

ECT treatment after 6 months. As soon as depressive

symptoms recur, prolongation of C-ECT should go

into effect.

12.2.4 Side effects

Varying with the anesthetic, the most frequent

immediate unpleasant effects of ECT are headache,

nausea and vomiting. On rare occasions, prolonged

seizures that require anticonvulsant treatment may

also occur (American Psychiatric Association Com-

mittee on Electroconvulsive Therapy et al., 2001).

Due to predisposition of the patients or pharmaco-

logical interactions (lithium), the effect of muscle

relaxants may be enhanced, requiring a longer period

of assisted respiration (Hill et al., 1977 ; Reimherr et al.,

1977). In bipolar depression ECT may induce hypo-

mania or mania (‘switch’) (Angst et al., 1992).

All patients may be confused on awakening after a

seizure. In addition, typical side effects that are

more prominent in bilateral than in unilateral and in

high-dose than in lower-dose ECT (ECT review

group, 2003) are transient cognitive disturbances.

These include short-term memory disturbances

(van Waarde and Stek, 2001), a prolonged postictal

reorientation period, memory disturbances that in-

clude anterograde or retrograde amnesia and rarely

occurring effects on autobiographic long-term mem-

ory (Lisanby et al., 2000). Nearly all patients report

amelioration of cognitive impairment after finish-

ing the course of ECT treatment (Devanand et al.,

1991).

66 The terms ‘continuation treatment ’ and ‘continuation ECT’

(C-ECT) are predominantly used to characterize maintenance

treatment after successful treatment of the index phase. They are

sometimes distinguished from ‘maintenance treatment ’ and

‘maintenance ECT’ (M-ECT) (Sartorius and Henn, 2005a) based on

theoretical considerations regarding switching to prophylactic

treatment to prevent new episodes of depression. Because for

individual patients this time point cannot be precisely defined, in

the following text only the term ‘C-ECT’ is used.


Nevertheless, recent improvements in the use of

ECT include methods to maintain good therapeutic

efficacy together with better tolerability vis-a-vis

cognitive disturbances. Using modified ECT tech-

niques (Ghaziuddin et al., 2000), including unilateral

or bifrontal pulse wave stimulation, anesthesia with

muscle relaxation and sufficient oxygenation, these

risks could be substantially reduced (Ghaziuddin

et al., 2000; Sackeim et al., 1993 ; Sackeim et al.,

2000).

A variety of case reports, case series and controlled

studies confirm that ECT does not cause long-lasting

functional (Krause et al., 1988) or any structural dam-

age of the central nervous system (CNS) (Devanand

et al., 1991 ; Krause et al., 1988 ; Lisanby et al., 2003b).

But more research is needed to investigate the longer-

term cognitive side effects of ECT (Greenhalgh et al.,

2005).

12.2.5 Safety

In general, ECT is one of the best-tolerated anti-

depressant therapies, with low risk for severe compli-

cations, even lower than TCA. The mortality rate

during ECT varies between 1:50000 and 1:25000

treatments (Abrams, 2002 ; American Psychiatric


et al., 2001). Severe complications that warrant special

attention are seen in less than 1:10000 treatments


Electroconvulsive Therapy et al., 2001 ; Nuttall et al.,

2004 ; Shiwach et al., 2001).

12.3 Other non-pharmacological treatments

12.3.1 Introduction

Besides new pharmacological antidepressant treat-

ment strategies, during the last decade several new

biophysical approaches have been under investigation

for the treatment of major depressive illness : repetitive

transcranial magnetic stimulation (rTMS), vagus nerve

stimulation (VNS), magnetoconvulsive therapy (MST)

and, very recently, deep brain stimulation (DBS).

These methods have in common that they directly

or indirectly target brain regions that play a role in the

pathophysiology of depressive disorders. All methods

except MST differ from ECT in their presumed mech-

anisms of action, though they have often been dis-

cussed in comparison with ECT. rTMS was originally

found to improve mood in patients suffering from

Parkinson’s disease. This led to trials in the treatment

of depression. rTMS, VNS, MST and DBS have been

further developed in a hypothesis-driven manner

based on the current view that depressive disorders

affect integrated pathways that link select cortical,

subcortical and limbic sites and their related neuro-

transmitter and molecular mediators (Padberg and

Moller, 2003). However, these brain-stimulation

methods use different ‘windows’ to access the

anatomically defined pathways that show functional

changes during the acute episode and attempt to

modulate the system in the direction of a normal

regulation of mood and emotions. rTMS is currently

mainly targeted to cortical prefrontal sites (George

et al., 2003; Padberg and Moller, 2003), whereas

VNS enters the system by vagal afferents to the

vagal nucleus and the nucleus tractus solitarius in

the brain stem that are linked to regions of the brain

involved in mood regulation, such as the amygdala,

hippocampus and locus coeruleus (George et al.,

2003).

MST employs the ECT approach of inducing

generalized therapeutic convulsions in order to treat

depression. However, the method induces a lower

current in the CNS and attempts to be more focal

compared with ECT to minimize side effects and

particularly exerts its effect on frontal and prefrontal

cortical and subcortical sites (Lisanby et al., 2003b).

Very recently, interesting data have been presented

using DBS to stimulate a subgenual cingulate region

(Brodmann area 25) that is metabolically overactive

in treatment-resistant depression and shows normal-

ization in activity after recovery (Greenblatt et al.,

1964 ; Lisanby et al., 2003b). However, other regions in

the basal ganglia and their pathways to prefrontal

limbic areas may also be putative targets in future

studies.

Psychosurgical interventions, such as stereo-

tactically applied bilateral orbitomedial lesions for

resistant severe depression, posssibly show similar

therapeutic effects ; however, at present they are of

marginal clinical significance (Sachdev and Sachdev,

2005). Moxibustion must also be mentioned among

physical treatment options for depression. But em-

pirical data regarding this intervention are insufficient,

and it mainly plays a role in traditional Chinese

medicine (Cheng et al., 2005).

Due to the fact that placebo response rates can be

high in the treatment of depression, it is sometimes

difficult to approve new antidepressant treatments.

Nevertheless, new non-pharmacological treatments

have already been approved in some countries for the

treatment of depression : TMS has been approved in

Canada and Israel, and VNS is approved by the US

Food and Drug Administration (FDA) as an add-on

treatment for depression.


12.3.2 Repetitive transcranial magnetic stimulation67

Repetitive transcranial magnetic stimulation (rTMS)

was originally introduced in 1985 by Barker et al. as a

non-invasive tool to electromagnetically stimulate the

primary motor cortex in humans (Lisanby et al.,

2003b). It has turned out to be a powerful research tool

in neurophysiology and cognitive neuroscience. As an

antidepressant intervention rTMS is usually targeted

to the dorsolateral prefrontal cortex (DLPFC) based on

well-replicated findings that show reversible func-

tional changes in this region. The majority of studies

focus on the left prefrontal cortex based on the ob-

served asymmetry of prefrontal function associated

with major depression (Lisanby et al., 2003b). A large

number of different stimulation parameters, e.g. fre-

quency and intensity of stimulation, have been ap-

plied in studies (Padberg and Moller, 2003), and the

usual treatment duration has been 1–4 weeks of treat-

ment.

About 25 randomized placebo-controlled clinical

trials, including about 750 patients suffering from

major depressive episodes, have been conducted to

date investigating the safety and efficacy of rTMS as an

antidepressant intervention (Berman et al., 2000b;

Dolberg et al., 2002; Garcia-Toro et al., 2001a; Garcia-

Toro et al., 2001b; Kauffmann et al., 2004 ; Loo et al.,

2003 ; Miniussi et al., 2005 ; Mosimann et al., 2004 ;

Nahas et al., 2003 ; Padberg et al., 1999; Padberg et al.,

2002 ; Padberg and Moller, 2003 ; Pascual-Leone et al.,

1996 ; Rossini et al., 2005). In the majority of these

trials, significant placebo/verum differences have

been observed, with antidepressant effects ranging

from modest to substantial. Due to the methodological

limitations of many of these trials stemming from

rather small sample sizes, the difficulty of controlling

sham rTMS and short observation periods, the current

assessment of its efficacy in the wake of initial en-

thusiasm about its treatment potential is more sober.

Several meta-analyses have been conducted (Berman

et al., 2000b; Burt et al., 2002 ; Couturier, 2005 ; Dolberg

et al., 2002 ; Ebmeier et al., 2006 ; Garcia-Toro et al.,

2001a; Martin et al., 2003 ; Pascual-Leone et al., 1996 ;

Schulze-Rauschenbach et al., 2005) that support the

antidepressant efficacy of rTMS, but clinical effects are

not very strong, and the clinical significance may be

questionable. rTMS has also been directly compared

with ECT in five parallel design trials (Grunhaus et al.,

2000 ; Grunhaus et al., 2003 ; Pridmore et al., 2000 ;

Schulze-Rauschenbach et al., 2005). In these trials,

rTMS was found to be as effective as ECT in patients

suffering from major depressive episodes without

psychotic features, but to be inferior for psychotic de-

pression (Grunhaus et al., 2000). Four trials have in-

vestigated combined treatment with active rTMS plus

antidepressant compared with sham rTMS plus anti-

depressant to answer the question whether rTMS

augments the effect of antidepressant medication

(Lisanby et al., 2001b; Rumi et al., 2005). But only one

study that combined rTMS with amitriptyline found a

significant superiority of combined active treatment

(Rumi et al., 2005). Apart from single studies and

case reports, little is known regarding the stability

of effects and potential maintenance treatment stra-

tegies (Pascual-Leone et al., 1996), and the largest

body of evidence points to transient effects following

completion of rTMS treatment (Pascual-Leone et al.,

1996 ; Schule et al., 2003). rTMS appears to be

safe and well tolerated by patients within a range

of parameters defined according to a consensus

(Wassermann, 1998).

In conclusion, there is considerable evidence for

the antidepressant efficacy of high-frequency rTMS

over the left dorsolateral prefrontal cortex applied

over 2–4 weeks, and rTMS may be applied success-

fully as adjuvant antidepressant intervention. How-

ever, the antidepressant efficacy of rTMS has still

not been sufficiently proven owing to the methodo-

logical limitations of previous clinical trials. Up to

now solely in Canada and in Israel it has been ap-

proved for the treatment of depression by the auth-

orities.

12.3.3 Transcranial direct current stimulation

Transcranial direct current stimulation (tDCS) is a

stimulation technique with potential benefits in the

treatment of depression which is currently used in

investigational settings. A placebo controlled RCT in

40 depressed patients suggested beneficial effects of

tDCS of the left dorsolateral prefrontal cortex which

persisted one month after the end of the treatment

(Boggio et al., 2007b). During the treatment there was

no necessity for anesthesia and the overall tolerability

was excellent. In addition an improvement of cogni-

tive performance has been reported (Boggio et al.,

2007a). In spite of the increasing interest in the new

non-pharmacological treatment strategies (Rau et al.,

2007) to date tDCS is at a very early stage of develop-

ment in the treatment of depression and the reports

about antidepressant effectiveness are awaiting their

replication.

67 See chapter 19.4 for more detailed information in for more

detailed information in Annex 4 : Additional information on

transcranial magnetic stimulation.


12.3.4 Magnetic seizure therapy

MST is a variant of rTMS that uses stronger stimu-

lation parameters (40% more intensity compared with

standard rTMS stimulation, higher frequency and a

prolonged impulse of about 0.4 ms) to intentionally

induce an epileptic seizure for therapeutic purposes.

It is hypothesized that MST might be a kind of con-

vulsive therapy that retains the therapeutic efficacy of

ECTwith an improved side-effect profile. Indeed, MST

should induce a secondary generalized seizure more

focally in relevant brain regions (Lisanby et al., 2003b),

as the magnetic field can penetrate scalp and skull

without hindrance. Animal studies and safety data of

clinical pilot studies in depression have been pub-

lished supporting this notion (Lisanby et al., 2001c;

Lisanby et al., 2003a; Moscrip et al., 2005). Its anti-

depressant efficacy is currently under investigation,

and so far only case reports are available (Kosel et al.,

2003 ; Lisanby et al., 2001a; Moscrip et al., 2005). MST

is still at an early stage of development (Lisanby et al.,

2003a) and is therefore restricted in most counties to

use in experimental treatment designs.

12.3.5 Vagus nerve stimulation68

In the 1980s and 1990s vagus nerve stimulation (VNS)

was developed in animal models for its putative anti-

convulsant action. It was introduced into the routine

treatment of therapy-resistant focal epilepsies about

a decade ago. It has been approved by the FDA.

Theoretical considerations regarding the functional

anatomy of the vagus nerve, which projects to areas of

the brain relevant for generation and control of mood

and emotions, as well as observations of mood chan-

ges in epilepsy patients undergoing VNS have trig-

gered the application of VNS in depressive disorders

(George et al., 2003). VNS has been investigated in

a series of open and controlled clinical trials in

depressed patients participating in an industrial de-

velopment program, and recently the data of the

complete trial set have been published (George et al.,

2005 ; Nahas et al., 2005 ; Rush et al., 2000 ; Rush et al.,

2005b; Rush et al., 2005a; Sackeim et al., 2001b).

The results of an open pilot study (Rush et al., 2000;

Sackeim et al., 2001b) led to a double-blind rando-

mized placebo-controlled multicenter trial that in-

cluded 235 patients who received either active or

placebo stimulation over a 10-week period (Rush et al.,

2005a). Following the acute treatment period, all

patients received continuous treatment, and long-

term data have been published on 205 patients after

12 months of stimulation (Rush et al., 2005b). In the

acute study, no difference in primary and secondary

outcome measures between VNS and placebo treat-

ment groups was observed (Rush et al., 2005a). To fa-

cilitate interpretation of the clinical meaning of the

long-term data in terms of efficacy, a post hoc com-

parison study with the same inclusion criteria as the

controlled VNS study was initiated, including 124

patients who received ‘treatment as usual’ (TAU)

(George et al., 2005). After 12 months, a clinical re-

sponse was found in 29.8% of the patients included in

the VNS study, whereas only 12.5% responded in the

TAU study; remission was achieved in 17.1% of the

VNS study compared with 6.7% of the TAU study

(George et al., 2005). Concerning the safety of VNS, the

results of the studies in epilepsy were essentially con-

firmed. VNS carries significant health risks, including

voice alteration, cough, dyspnea, neck pain, dys-

phagia, laryngismus, paraesthesia and pharyngitis

(Rush et al., 2005a), which may improve gradually

during treatment (Rush et al., 2005b).

Based on the efficacy and safety data, the VNS

therapy system was recently approved by the FDA for

the adjunctive long-term treatment of chronic and re-

current depression for patients 18 years of age or older

who are experiencing a major depressive episode and

have not had an adequate response to four or more

adequate antidepressant treatments. Despite this ap-

proval, to date it is not known whether VNS exerts

antidepressant effects superior to placebo or other

treatments, and further controlled, parallel-design

long-term trials are urgently needed. Because of its

invasive nature, VNS should be strictly reserved for

exceptional cases where the patient’s demand for this

treatment is high, other interventions have failed and a

clinical benefit is likely. In addition, although contro-

versial (Annegers et al., 2000 ; Schachter, 2006), a con-

nection has been suggested between VNS (used to

treat treatment-refractory epilepsy) and sudden death.

12.3.6 Deep brain stimulation

Deep brain stimulation (DBS) is a well-established

treatment for intractable Parkinson’s disease (PD) and

other movement disorders, where usually the sub-

thalamic nucleus, the globus pallidus internus or the

thalamus is stimulated (Mayberg et al., 2005). An im-

plantable stimulation system like the VNS system

is used to stereotactically target relevant brain areas

and generate a functional lesion in regions that are

generators of symptoms of PD and other movement


Additional information on vagus nerve stimulation.


disorders. For psychiatric disorders, published reports

of treatment with DBS have been limited to cases of

obsessive compulsive disorder and Gilles de la

Tourette syndrome (Mayberg et al., 2005). Very re-

cently, Mayberg and colleagues (2005) published six

cases of patients treated with DBS of the subgenual

cingulate cortex, hypothetically driven by previous

studies showing the consistent involvement of this

region in acute sadness in healthy volunteers and

antidepressant treatment effects in depressed patients

(Kopell et al., 2004 ; Mayberg et al., 1999 ; Mayberg

et al., 2005). The authors found a striking and sus-

tained remission of depressive symptoms in four of

the six patients, associated with a marked reduction

in local cerebral blood flow as well as changes in

downstream limbic and cortical sites demonstrated

by positron emission tomography (Mayberg et al.,

2005).

DBS treatment is thus far only an experimental in-

tervention in depression, and further extensive meth-

odological research is needed to develop this approach

towards a clinically applicable treatment (Schlaepfer

and Lieb, 2005).

12.3.7 Total or partial sleep deprivation69

(wakefulness therapy)

Total sleep deprivation (TSD) is a non-pharmacologi-

cal intervention that exerts rapid antidepressant ef-

fects in about 60–70% of depressed patients who

stayed awake one complete night and the consecutive

day (Benedetti et al., 2005; Wirz-Justice et al., 2005 ;

Wu and Bunney, 1990) despite the fact that sometimes

it is difficult to keep patients awake. During late-night

sleep deprivation (partial sleep deprivation, PSD)

patients are awakened between 1 and 2 a.m. and stay

awake during the second half of the night and the

complete consecutive day until at least 8 p.m. PSD is as

effective and rapid as TSD and better accepted by de-

pressed patients (Schilgen and Tolle, 1980). In contrast,

early night sleep deprivation (SD) is ineffective in

the treatment of depression (Wu and Bunney, 1990).

To date, in addition to chronotherapeutic mechanisms,

the induction of hippocampal neurogenesis has also

been discussed as a possible mechanism of action

(Grassi et al., 2006).

The clinical relevance of TSD is limited, since re-

lapse after sleep deprivation is a frequent phenom-

enon observed in most patients with depression (Wu

and Bunney, 1990). Different strategies for relapse

prevention after SD are combination with lithium

(Benedetti et al., 1999 ; Grube and Hartwich, 1990),

pindolol (Smeraldi et al., 1999), bright light therapy

(Colombo et al., 2000 ; Neumeister et al., 1996) or the

serial administration of PSD up to twice (or thrice) a

week (Kuhs et al., 1996 ; Kuhs et al., 1998). It was re-

cently shown in several clinical trials that a ‘phase

advance’ of the sleep period after SD can be used to

prevent relapse in about 60% of responders (Kuhs

et al., 1996 ; Lee and Chan, 1999). Nevertheless, due

to the overall lower effectiveness in comparison

with other antidepressant treatments and its transient

effects, sleep deprivation is used in clinical routine

predominantly as an augmentation strategy.

12.3.8 Bright light therapy (phototherapy)

In seasonal affective disorders (SADs), bright

white light therapy shows some usefulness in the

treatment of depressive symptoms (Lee and Chan,

1999 ; Rosenthal et al., 1985). For other indications,

such as non-seasonal depressive disorder, further re-

search will be needed to determine the usefulness of

phototherapy (Benedetti et al., 2001 ; Compton and

Nemeroff, 2000 ; Prasko et al., 2002). Some studies re-

port a good benefit in depressed patients receiving

bright light therapy to augment antidepressant phar-

macotherapy (Benedetti et al., 2003 ; Loving et al.,

2002). In recent reports, phototherapy was also sug-

gested as an efficacious adjunctive treatment in non-

seasonal unipolar and bipolar depression (Martiny

et al., 2005a; Martiny et al., 2005b; Terman and

Terman, 2005). Nevertheless, due to the fact that some

reports on the efficacy of light therapy are not based on

rigorous study designs, more randomized controlled

trials are necessary to adequately evaluate the thera-

peutic impact of phototherapy on non-seasonal de-

pression (Golden et al., 2005). Because of these

somewhat controversial results, due to the results of

several RCTs (Lam et al., 2006 ; Ruhrmann et al., 1998)

phototherapy could be considered in SAD as a first-

line therapy, whereas in other forms of depression

it can be tried as an augmentation strategy.

12.3.9 Exercise

A variety of publications have discussed the theoreti-

cal background of the beneficial effects of physical ex-

ercise in the treatment of depressive disorders. In

addition, reviews report on and recommend exercise

as a promising behavioral intervention, at least as an

adjunct treatment of depression (Craft and Perna,

69 See chapter 19.7 for more detailed information Annex 7 :

Additional information on chronotherapeutics : light and wake

therapy.


2004; North et al., 1990). Even long-term changes and

antidepressant effectiveness of exercise during

20 weeks of treatment have been reported (Singh et al.,

2001). Nevertheless, detailed reviews and a meta-

analysis showed that the effectiveness of exercise

in reducing symptoms of depression cannot yet be

concluded owing to methodological weaknesses in

studies published to date (Barbour and Blumenthal,

2005 ; Lawlor and Hopker, 2001). Preliminary evidence

reported recently shows exercise to be an effective

lower-cost augmentation strategy that reduces

depressive symptoms in partial responders to anti-

depressant medication (Trivedi et al., 2006b; Trivedi

et al., 2006c). For now, exercise can only be re-

commended as a supplemental therapeutic option

during antidepressant therapies, with additional

health benefits especially in the case of longer-term

use. In addition, limited evidence supports the effec-

tiveness of yoga breathing exercises as a complemen-

tary treatment of depression (Jorm et al., 2002), but at

this time it is impossible to quantitatively assess its

benefit.

12.3.10 Acupuncture70

Because the use of complementary and alternative

therapies is overrepresented in patients suffering from

depressive syndromes (Kessler et al., 2001), the actual

knowledge about the main therapeutic options in this

field needs to be evaluated. Acupuncture has a long

history in Eastern culture, and traditional Chinese

medicine describes its influence on the body’s balance

of health and energy. Traditional acupuncture in-

volves inserting needles into specific trigger points at

different parts of the body.

Despite a variety of published studies in this field, a

recent review reports insufficient evidence for de-

termining the efficacy of acupuncture in compari-

son with pharmacological antidepressant treatment

(Smith and Hay, 2005). Also, adequate blinding of

physicians and patients in clinical trials together with

standardized outcome measures are necessary before

clinical and scientific recommendations can be made

(Smith and Hay, 2005).

An overall good safety and tolerability of acupunc-

ture has been described. Especially in trials comparing

TCA with acupuncture, the typical side effects were

much less in the acupuncture groups (Luo et al., 1998).

Studies comparing modern and better- tolerated anti-

depressants have not been published to date.

13 Antidepressant drugs in the treatment of

anxiety disorders71

The proven efficacy of antidepressant drugs in reliev-

ing anxiety symptoms in patients with depressive

disorders led naturally to investigations of their

potential to relieve symptoms and reduce associated

disability in patients with anxiety disorders, including

generalized anxiety disorder (GAD), panic disorder,

social phobia (also known as social anxiety disorder),

post-traumatic stress disorder (PTSD) and obsessive-

compulsive disorder (OCD). In clinical practice, the

need for treatment should be determined by the

severity and persistence of symptoms, and the level of

disability and impact on social functioning; choice of

treatment is influenced by patient characteristics (such

as previous response, concomitant medication and

contraindications), the evidence base supporting its

use, patient and physician preference, and the local

availability of the proposed intervention (Baldwin and

Polkinghorn, 2005).

14 Health economics : the cost of illness

14.1 Background

The primary and central objectives of mental health

services are the alleviation of symptoms and the pro-

motion of quality of life. However, it is also widely

recognized that economic considerations need to be

taken into account. One reason is the widespread re-

cognition that the costs of mental health problems can

be substantial, and that they fall widely : on those who

are ill, their families, the health-care system, other

service systems and the wider national economy.

Costs vary across countries for a number of reasons,

including different means of calculating them, differ-

ences in health systems and differences in economies,

including currencies. Thus, costs cannot be easily ex-

trapolated from one country to another, particularly

from developed to developing countries.

A second reason for paying more attention to

economic issues is the apparently growing cost of

treatment. Some of the newer modes of treatment for

mental health problems – including the newer medi-

cations for depression – are marketed at higher prices

than the older treatments they could potentially re-

place. This has raised questions about whether the

newer treatments are cost-effective. Third, in many


Additional information on acupuncture.


Additional information on antidepressant drugs in the treatment of

anxiety disorders.


countries there is a better understanding of the inter-

connections between mental health problems, em-

ployment and social exclusion (and of the potential for

effective treatments to have impacts across many areas

of life), and hence growing interest in mental health

among ministries responsible for employment and

finance.

But the fundamental, pervasive, durable and most

important reason for being interested in the economics

of depression is that the professional, pharmaceutical

and other resources required to provide treatment

and support are not enough to meet the needs. Scarcity

is a permanent feature of all health systems, indeed

of all societies. In the face of such scarcity, choices

have to be made among alternative uses of the

same resource or service. Economics – and, in par-

ticular, economic evaluation –– aims to provide de-

cision makers with data that can inform and assist

their decisions about how to allocate available re-

sources.

14.2 The broad costs of depression

The cost of depression to a society is usually measured

in a ‘cost-of-illness study’, which estimates the value

of resources incurred as a result of an illness. The

economic cost of an illness or condition is driven by a

number of factors :

$ prevalence$ treatment and service support rates$ effects of the illness on ability to work.

The costs measured in a cost-of-illness study are

therefore usually separated into direct and indirect

costs. Direct costs include the costs of treating the ill-

ness ; in the case of depression these would include the

cost of primary and secondary care contacts and the

cost of antidepressant medication. Indirect costs in-

clude the economic impact of premature mortality

(estimated in terms of lost productivity from lost life

years) and the lost productivity from economic inac-

tivity (non-availability for work – how many people

with depression are unemployed or otherwise inactive

because of their illness), absenteeism (days taken off

work as a result of depression) and presenteeism

(time at work but with reduced productivity because

of depression-related symptoms). The output of a cost-

of-illness study is expressed in monetary terms and is

an estimate of the total burden of a particular disease

to society. Such estimates are helpful, but they are

not evaluative – they tell us nothing about whether

treatment is needed or which treatment is most cost-

effective.

There have been numerous cost-of-illness studies

for depression. Here we summarize just a few to il-

lustrate the main economic impacts of the illness.

$ In England, unipolar depression was estimated to

cost over £9000 million in 2000, of which only £370

million was direct treatment costs. The largest cost

element was productivity losses : over 1 year, 109.7

million lost working days and 2615 deaths were

attributed to depression (Thomas and Morris,

2003). Depression is a substantial financial burden

compared with coronary heart disease, and is the

leading single cause of death in the UK. In 1999, the

estimated economic burden of depression was

around £7000 million (Liu et al., 2002). Throughout

Europe, 23% of the years of healthy life lost and 50%

of years lived with disability (YLD) are caused by

brain diseases. Thirty-five per cent of disability-

adjusted life years (DALYs), a measure of lost

health, are considered to be due to brain disease

(Olesen and Leonardi, 2003). In addition, in Europe

depression is undertreated, and antidepressant

treatments are underused (Henriksson et al., 2006 ;

Taleb et al., 2006).$ The cost of affective disorders (including both bi-

polar depression and unipolar depression) in the 25

countries of the European Union plus Iceland,

Norway and Switzerland was modeled by Andlin-

Sobocki and colleagues (Andlin-Sobocki et al., 2005)

and estimated at E10,566 million in 2004. Never-

theless, the need for a pan-European epidemi-

ological study to collect more complete data

about the real costs of depression in Europe has

been recommended (Andlin-Sobocki and Wittchen,

2005).$ The cost of depression in the Asia-Pacific region has

also been examined. Hu et al. reviewed existing

evidence and reported that the total cost of de-

pression in Australia was US$1800 million in 1997,

of which 22% was direct treatment costs, and

US$1400 million in Taiwan in 1994, of which a

quarter was direct treatment costs (Hu, 2004).

Another study by Hu et al. that estimates the cost of

depression in China is currently in press. In

Pakistan, the high cost of depression prevents the

majority of depressed patients from seeking treat-

ment, which contributes to suffering from the illness

and an associated loss of productivity (Gadit, 2004).$ The economic burden of depression in the US was

relatively stable between 1990 and 2000, despite an

increase in the proportion of sufferers receiving

treatment. The total cost in 2000 was US$8310

million, of which almost a third was in direct


medical treatment costs (Greenberg et al., 2003). The

burden of depression appears to be less than the

economic cost of diabetes in the US, estimated at

US$13,200 million in 2001 (American Diabetes

Association, 2003).

There is a dearth of cost-of-illness studies from Africa,

Asia, Eastern Europe, and Latin America (Hu, 2006).

The cost-of-illness literature thus reminds us that de-

pression places a financial burden not only on health

and social services but also on the broader economy

from days lost from work and productivity losses

more generally (see 19.2 – Annex 2: Additional in-

formation on the types of economic evaluation).

Moreover, the impact of depression on work – days

absent and reduced productivity while at work – has

income and career progression implications for in-

dividuals with the illness. Less readily measured –

certainly not easily expressed in monetary terms – but

of considerable importance are the effects of de-

pression on performance of family and social role

(Brown and Harris, 1978). In addition, the psycho-

logical distress of caregivers together with a higher

intensity of depressive symptoms in patients may in-

crease use of primary care services and, presumably,

costs (Perlick et al., 2005).

It is therefore important that evaluations of costs

and outcomes take a wide cost perspective that in-

cludes not only health service costs, and social and

non-statutory service costs, but also losses to the eco-

nomy and to the individual and family. For example,

the direct cost of depression in England (Thomas and

Morris, 2003) included the cost of hospital contacts,

general practice consultations and drug consumption,

while indirect costs included morbidity costs mea-

sured in terms of absenteeism and mortality costs in

terms of the number of deaths due to suicide. Private

costs to family and carers were excluded in this study.

Thomas et al. found that a relatively small proportion

of total costs were direct treatment costs and that total

costs are driven by the ability of patients to return to

work (morbidity costs). However, we will see that

analyses that include morbidity and mortality costs

are relatively rare. Instead, most economic evaluations

tend to take a health systems approach, including only

costs of primary and secondary care and medication.

The need for this wider perspective is illustrated by

Simon et al. (Simon et al., 2000a), who reported sec-

ondary analyses of a randomized controlled trial

(RCT) of an SSRI. They found that patients across both

arms (SSRI and TCA) whose symptoms had improved

12 months after the start of the trial were more likely to

continue in paid employment (if working at baseline)

or to return to work (if not originally employed) com-

pared with patients whose symptoms had not chan-

ged. Clinical improvement was also associated with

fewer work days lost though illness, but not with the

typical number of hours worked per week. For people

whose symptoms improved, there was a marginally

significant reduction in health-care costs, although not

until the second year after initiating antidepressant

treatment. The impact on employment was therefore

both larger and more immediate than the impact

on health service costs. Another study shows that

the impact of symptom alleviation on workplace

performance can be rapid (Berndt et al., 1998). At-

work performance in this US study improved for

chronically depressed people as the severity of their

symptoms reduced. Over two-thirds of the observed

improvement in work performance was found to have

occurred in the first 4 weeks after initiating treatment

with an antidepressant. In Canada, Dewa et al. found

that the use of recommended antidepressants at re-

commended doses improved symptoms and in turn

improved employment outcomes for a large sample

of workers (Dewa et al., 2003). Similarly, the large-

sample, six-country Longitudinal Investigation of

Depression Outcomes (LIDO) study found that pa-

tients with improved depression symptoms had less

absenteeism (Simon et al., 2002). These employment

changes are all the more significant in the face of end-

ing stigma and discrimination by employers against

people with mental health problems (McDaid et al.,

2005).

14.3 Methodology: economic evaluation72

14.3.1 Core questions

Decision makers face two central questions when

considering whether to use or recommend a particular

treatment for depression. The first is the clinical ques-

tion, which asks whether an antidepressant is effective

in improving patient health, or – when considering

two or more treatment options – which of them has the

better or best outcomes. Once the decision maker

knows that a particular treatment is effective, she or

he wants an answer to the second question : Is it cost-

effective? That is, does the treatment achieve the im-

proved outcomes or quality of life at a cost that is

worth paying?

These two questions (Is the treatment effective? Is it

worth it?) sit at the heart of cost-effectiveness analysis.


Additional information on the types of economic evaluation.


While it is always going to be necessary to reformulate

these questions in ways that make them answerable

with empirical research, their simplicity should never

be forgotten. However, providing answers to these

questions is obviously not that simple.

It must also be emphasized that cost-effectiveness

analysis does what its name suggests : it looks at both

costs and effectiveness (outcomes). So, comparing the

costs of one treatment with another, without any evi-

dence on outcomes, does not constitute an economic

evaluation. Such an exercise might be a helpful

description of service utilization patterns and

associated costs, as we have just seen in looking at the

cost-of-illness evidence, but it does not provide

enough information to assist service professionals,

managers or others facing the choice between two or

more alternatives. Similarly, calculating the costs

and outcomes of a single service could be interesting

but cannot be classed as an economic evaluation

unless those costs and outcomes are compared with

equivalent data for another service, or even compared

with the option of ‘doing nothing’, and so again the

study cannot tell us whether the service is worth pro-

viding. Uncontrolled mirror design studies often run

into this problem.

It is important to emphasize – as we will note again

below – that an intervention’s cost-effectiveness is

relative to the comparator in the evaluation, which

makes the choice of comparator crucial.

14.3.2 Types of economic evaluation

There are a number of different modes of economic

evaluation, each with their associated data needs,

advantages, disadvantages and uses. Good accounts

of health economic evaluation methods (although

with very few mental health examples) are given by

Drummond et al. (Drummond et al., 2005) and

Drummond and McGuire (Drummond and McGuire,

2001). The methods used in health economic evalu-

ations are developing quite rapidly, and consequently

some of the techniques mentioned later in this report

have been in use in empirical studies for only a short

time.

A detailed account of the methods for economic

evaluation is given in Annex 2: Additional infor-

mation on the types of economic evaluation. In

brief, cost-effectiveness analysis combines costs with

a single disease-specific outcome measure such as

a depression symptom scale. The incremental cost-

effectiveness ratio (ICER) is computed as the differ-

ence in cost between the two treatments divided

by the difference in outcomes. In a cost-utility analysis,

effectiveness is reduced to a single outcome index of

utility such as the quality-adjusted life year (QALY) or

DALY. Incremental cost-utility ratios can thus be cal-

culated and compared over different conditions and

disease areas, allowing strategic decision makers in a

health system to judge whether resources are most

effectively deployed in, say, treating depression

or treating breast cancer. Cost-benefit analysis gen-

erates monetary valuations of outcomes to compare

costs and benefits directly, which in principle opens

up a wider set of comparisons for decision makers, in-

cluding non-health-care options. In cost-consequence

analysis, costs are reported alongside a range of

outcome measures in an attempt to capture the

broader picture of the impact of the intervention.

Finally, cost-minimization analysis involves assess-

ment of costs only, given the already established

equality of outcomes. A summary of methods for

economic evaluation is given in Table 24.

14.3.3 Search strategy

We carried out a systematic review, searching on

Medline, EMBASE and PsycINFO for the period

January 1985 to November 2005. The search was re-

stricted to articles with the key words ‘depression’ or

‘depressive disorder’ and ‘cost and cost analysis ’, or

‘cost-effectiveness’ or ‘economic’. Following the

search of the databases, a manual search of the refer-

ences of included articles was undertaken to identify

any relevant studies.

Information on the articles was recorded using a

structured form included consideration of the follow-

ing criteria :

$ focused on adults with depression;$ included comparative analysis of alternative inter-

ventions ;$ undertaken within a randomized controlled trial

(RCT), non-random comparison or modeling study;$ considered the cost-effectiveness of antidepressants,

or of care or case management when in combination

with, or compared with antidepressants or of

physical treatments ;$ included the systematic assessment of both

costs and outcomes, including cost-effectiveness,

cost-utility, cost-benefit, cost-consequence and cost-

minimization analysis.

14.4 Economic evidence for pharmacological

treatment options

The literature search retrieved almost 3000 references,

although only 50 are included in the final review.


Papers were excluded because they did not focus on

depression, they did not include costs or they did not

compare two or more alternative interventions.

The relative cost-effectiveness of antidepressants is

determined by a number of factors, most importantly

their relative efficacy. The SSRIs and other newer anti-

depressants have a considerably higher purchase price

than the TCAs, and higher drug costs can lead to

higher total costs. However, it is unclear how long this

trend will continue, as many of the SSRIs and newer

antidepressants are now coming off patent and in

many countries (though not all) are then sold generi-

cally at a lower price : for example, in March 2000 a 30-

day supply of fluoxetine (Prozac1) in the UK cost

£19.34, but by March 2005 the equivalent generic

fluoxetine price was £2.11. Cost-effectiveness is also

influenced by patient adherence. Adherence is gener-

ally low and dropout rates high among individuals

commencing antidepressant treatment, which has an

impact on the effectiveness of the drug. One expla-

nation for poor adherence is the unpleasant side ef-

fects associated with the drugs ; these include as dry

mouth, sedation, blurred vision and sexual dysfunc-

tion (see chapter 9.1.1.3). If the SSRIs and the other

newer antidepressants have better side-effect profiles

than the TCAs, the newer preparations may improve

adherence and outcomes and thus also improve cost-

effectiveness.

14.4.1 Selective serotonin reuptake inhibitors

We identified 32 papers that appraised the cost-

effectiveness of selective serotonin reuptake inhibitors

(SSRIs) for depression, though only 7 used data from

prospective trials or naturalistic settings, with the re-

maining evidence coming from models.

Simon and colleagues (Simon et al., 1996 ; Simon

et al., 1999a) carried out a prospective, naturalistic,

randomized trial with economic evaluation comparing

alternative antidepressant therapies. Patients attend-

ing primary care clinics in the US and initiating anti-

depressant treatment were randomized to fluoxetine

(an SSRI) or desipramine or imipramine (TCAs). In the

short term (6 months) treatment dropout was lower,

there were fewer adverse effects and achievement of a

therapeutic dose was more likely among patients ran-

domized to receive fluoxetine. However, there were

no significant differences in clinical outcomes or

quality of life, nor were there any significant differ-

ences in cost, because the higher drug acquisition cost

of fluoxetine was offset by lower outpatient and in-

patient service use. A similar pattern of results was

found at the 2-year follow-up. The authors concluded

that restricting the first-line use of fluoxetine in pri-

mary care would probably not reduce overall treat-

ment costs due to the lower hospital service utilization

in that group.

Other RCTs have compared SSRIs with other anti-

depressants and psychological therapies. One com-

pared the costs and outcomes of fluoxetine, citalopram

and amitriptyline for major depression in central

Europe and found no significant differences in cost or

outcome between interventions (Hosak et al., 2000).

The authors concluded that amitriptyline was no less

expensive or more effective than citalopram or fluoxe-

tine and advised that there was no advantage to

Table 24. Methods for economic evaluation

Type of analysis Outcome Advantages Disadvantages

Cost-effectiveness Disease-specific outcome such

as depression scale

Meaningful and understandable

analysis

Cannot compare across diseases

Cost-utility Single outcome such as QALY

or DALY

Can compare across diseases Not suitable in all disease areas,

particularly mental health,

because of difficulties of utility

measurement

Cost-benefit Monetary Understandable and simple

analysis

Difficult to convert health

outcomes into monetary terms

Cost-consequence Specific range of disease and

other relevant outcome

dimensions

Includes range of outcomes in

analysis

Difficult to draw firm conclusions

if outcomes move in different

directions

Cost-minimization Outcomes must be identical to

the treatment alternatives

Understandable and simple

analysis

Can rarely be used because

outcomes are rarely known

with certainty to be equal


restricting patients from treatment with SSRIs.

Another compared SSRIs, placebo and psychological

treatment for common mental disorders, includ-

ing depression, in Goa, India (Patel et al., 2003).

Psychiatric outcomes were significantly better with

antidepressant than placebo at 2 months, but no sig-

nificant difference was detected at 12 months. Costs

were lower in the SSRI group, suggesting that anti-

depressants are more cost-effective than placebo.

Psychological treatment resulted in worse outcomes

and higher total costs than placebo. The authors ar-

gued that affordable antidepressants such as fluox-

etine should be the treatment of choice for common

mental disorders in general health-care settings in

India, since they are associated with improved clinical

and economic outcomes, particularly in the long term.

Retrospective analysis of existing data was used to

measure the cost-effectiveness of sertraline and TCAs

for depression in primary care in the UK (Forder et al.,

1996). The average cost of treatment was slightly

greater for those receiving TCAs due to greater use of

psychiatric services. In terms of cost-effectiveness,

sertraline was found to dominate TCAs for all defini-

tions of costs and outcomes.

In an attempt to clarify the relative cost-effectiveness

of antidepressants as a first choice treatment for de-

pression in primary care, Peveler and colleagues

(2005) carried out a randomized controlled trial com-

paring TCAs, SSRIs and the TCA-related anti-

depressant lofepramine. The UK-based study found

no significant difference in costs or outcomes between

groups. However, for values placed on an additional

QALY of over £5000 – the approach taken in examin-

ing net benefits or plotting a cost-effectiveness ac-

ceptability curve – treatment with SSRIs was likely to

be the most cost-effective strategy.

The evidence from RCTs and retrospective analyses

suggests that SSRIs may be more cost-effective treat-

ments for depression than TCAs and are more cost-

effective than placebo. Despite higher acquisition

costs, SSRIs do not appear to increase overall treat-

ment costs, as SSRIs result in reductions in subsequent

health service utilization. In addition, SSRIs may gen-

erate better outcomes.

In comparison to the limited availability of econ-

omic evaluations from naturalistic settings and RCTs,

there are a plethora of studies using modeling tech-

niques to estimate the cost-effectiveness of SSRIs for

depression. These models tend to use data from exist-

ing evidence for clinical effectiveness and outcomes,

but expert opinion on costs and transition through the

model, and are based in a variety of health systems

and settings. The studies vary substantially in the

quality of the data used, the robustness of assump-

tions employed, the techniques used to test them and

generate findings, and consequently their usefulness

for this review.

Assumptions need to be employed because there is

inadequate data on some aspect of how the drugs will

influence outcomes, service use and costs.

A decision-analytic model was used to analyze the

cost-effectiveness and cost utility of SSRIs and TCAs

in various combinations for depressive disorders in

Canada and is a good example of how the evidence

on the relative cost-effectiveness of the two types

of antidepressants can be summarized (Canadian

CoordinatingOffice for Health TechnologyAssesment,

1997). The meta-analysis of available clinical evidence

showed that there were no statistically significant dif-

ferences between the efficacy, completion rates and

dropout rates of the antidepressants considered. The

perspective of the economic evaluation was that of the

health-care system, so only direct health-care costs

(inpatient contacts, primary care contacts and drug

costs) were included. The study suggested that from a

Canadian perspective both TCAs and SSRIs should be

part of an effective treatment strategy and that further

research, preferably from RCTs, was needed to inves-

tigate the long-term cost-effectiveness of treatment for

depressive disorders.

In an early model Jonsson and Bebbington (Jonsson

and Bebbington, 1994) compared the cost-effectiveness

of paroxetine and imipramine in people with de-

pression in the UK. The 12-month cost per successfully

treated patient was lower with paroxetine than imi-

pramine, indicating that paroxetine was the more cost-

effective. The results were sensitive to assumptions

concerning the relative efficacy of the drugs, particu-

larly treatment failure, and the authors concluded

that although paroxetine had a high cost per day

when patient adherence and the total cost of treatment

are taken into account, it was the more cost-effective

option. However, these findings were questioned a

few years later when the model was reassessed with

some key assumptions challenged and changed

(Woods and Rizzo, 1997). With revised assumptions

the model demonstrated that the TCA was at least

equally if not more cost-effective than the SSRI. The

authors advised that a policy of using TCAs as a first

choice antidepressant, with SSRIs reserved for those

patients not doing well, appears more cost-effective

than the reverse sequence. The two studies use the

same data but generate different results, confusing

the issue of cost-effectiveness and highlighting the

importance of the assumptions made in economic

models.


Other modeling studies present evidence of the

cost-effectiveness of SSRIs compared with TCAs (Le

Pen et al., 1994 ; Nuijten et al., 1995) and compared

with usual care (Nuijten et al., 1998), although no

statistically significant differences in costs are re-

ported. However, there is evidence suggesting that

SSRIs are more costly and more effective than usual

care (Kind and Sorensen, 1995). When maintenance

treatment with SSRIs is compared with episodic

treatment with a TCA, there are improved outcomes,

but alongside higher costs (Hatziandreu et al., 1994).

Evidence of the cost-effectiveness of escitalopram

compared with SSRIs and other newer antidepressants

is accumulating. However, the majority of the

evidence is from one economic model, applied to dif-

ferent health systems. In Austria, Belgium, Sweden,

Norway and Finland, escitalopram was the dominant

treatment strategy, achieving better outcomes with

lower costs, both when health-care and broader

societal costs are considered for patients with severe

depression (Demyttenaere et al., 2005 ; Francois et al.,

2002 ; Francois et al., 2003 ; Hemels et al., 2004a;

Lothgren et al., 2004). It was also cost-effective in

treating severe depression in Austria (Hemels et al.,

2004b). When the model was applied in the UK, esci-

talopram was found to be a cost-effective option com-

pared with generic citalopram (Wade et al., 2005a;

Wade et al., 2005b) and had a cost-effectiveness profile

comparable to the newer antidepressant venlafaxine.

Only one prospective evaluation of escitalopram has

been carried out as part of an RCT. Fernandez et al.

(2005) demonstrated that escitalopram had similar

efficacy to venlafaxine and patient costs were lower in

the escitalopram group, though not significantly so. In

both the models and the RCT, the reduction in costs

was due to reduced hospitalization in the escitalopram

group.

14.4.2 Selective serotonin and noradrenaline reuptake

inhibitors

In common with evidence of the cost-effectiveness

of SSRIs, decision and Markov models dominate

economic evaluations for the newer antidepressants.

The cost-effectiveness of venlafaxine for major de-

pressive disorder has been estimated using models in

a number of health-care systems: Germany, Italy,

Netherlands, Poland, Spain, Sweden, Switzerland,

UK, US and Venezuela (Casciano et al., 2001 ; Doyle

et al., 2001). Using results from meta-analyses, venla-

faxine had the highest expected success rate and the

greatest number of symptom-free days in all countries.

It yielded a lower expected cost in all countries except

Poland in the inpatient setting, and Italy and Poland

in the outpatient setting. The authors concluded

that venlafaxine is a more cost-effective treatment than

the alternatives and suggested that increased utiliz-

ation of the compound in most settings across Europe

and the Americas would have favorable impacts on

health-care payer budgets. The model was re-analyzed

when new data became available on the probability

of relapse with different antidepressants (Casciano,

2003). The revised study disputed the treatment

dominance of venlafaxine and concluded that venla-

faxine was more effective than SSRIs but also more

expensive.

The cost-effectiveness of venlafaxine for people in

the acute phase of major depressive disorder was

evaluated in a UK outpatient setting (Freeman et al.,

2000). The model demonstrated that venlafaxine

offered statistically significant improvements in de-

pression-free days and that, from a health care per-

spective, the cost per depression-free day was lower

for venlafaxine than for SSRIs or TCAs. Lenox-Smith

and colleagues (2004) updated the Freeman model

using revised data on costs and outcomes. They found

that using venlafaxine as a first-line treatment strat-

egy, and switching to an SSRI if necessary, was a

dominant treatment strategy over first-line treatment

with an SSRI, resulting in better outcomes with lower

costs. A similar evaluation was undertaken in Italy

(Casciano et al., 1999). The results suggested that

venlafaxine was more cost-effective compared with

SSRIs and TCAs for both inpatients and outpatients

with respect to cost per successfully treated patient

and cost per symptom-free day. Extended-release

venlafaxine was found to be a cost-effective strategy

among people with depression in Austria (Howard

and Knight, 2004).

Finally, venlafaxine for people with major depress-

ive disorder has been evaluated in both inpatient

and outpatient settings in Canada and the US

(Einarson et al., 1995 ; Einarson et al., 1997 ; Trivedi

et al., 2004 ; van Baardewijk et al., 2005). Results from

these studies suggested that venlafaxine was more

effective, but costs were either more, less or the same

as with treatment with other antidepressants. The

results of all the models above are highly sensitive to

the assumptions made and the unit costs used. At

present, and on the basis of available evidence, it

is difficult to draw firm conclusions regarding the

cost-effectiveness of venlafaxine for depression. In

the case of duloxetine, both acute and maintenance

treatment seem to be cost-effective alternatives

to SSRIs and TCAs (Dardennes et al., 1999 ; Lafuma

et al., 1999).


14.4.3 Noradrenergic and specific serotonergic

antidepressant

Only one study prospectively collected and analyzed

data on cost-effectiveness, focusing on mirtazapine

versus paroxetine in UK primary care attenders with

depression (Romeo et al., 2004). Mirtazapine treatment

resulted in significantly greater improvements in

quality of life than paroxetine at 26 weeks. Although

no significant cost differences were observed between

the two groups, societal costs were lower with mirta-

zapine than with paroxetine. The results suggest that

mirtazapine may be a cost-effective treatment choice

for depression in a primary care setting.

Mirtazapine for people with moderate to severe

depression has been investigated in modeling studies

for the UK and Austria. In the UK study Borghi and

Guest (Borghi and Guest, 2000) demonstrated that

mirtazapine was both more effective and less costly

compared with amitriptyline and fluoxetine. The

higher acquisition costs of the preparation were

offset by the lower costs of managing adverse

events and lower health service utilization. In Austria,

Brown and colleagues (Brown et al., 1999) estab-

lished the cost-effectiveness of mirtazapine despite

the differences in acquisition costs compared with

other antidepressants such as amitriptyline and

fluoxetine.

14.4.4 Serotonin-modulating antidepressants

Two models have evaluated the cost utility of nefazo-

done in depression, from the perspective of a US

managed care organization (Revicki et al., 1997) and a

Canadian health insurance organization (Anton and

Revicki, 1995). In both models, cost-effectiveness was

estimated for a 30-year-old woman with active de-

pression, and in both studies the findings suggested

that nefazodone is a cost-effective treatment compared

with imipramine (a TCA) and fluoxetine (an SSRI).

The results were highly sensitive to the assumptions

made in the model, particularly those concerning effi-

cacy and dropout.

14.5 Evidence on the cost-effectiveness of

antidepressants and care management

Care management involves patient education, shared

decision making and monitoring. The way in which

individuals starting antidepressant treatment are

managed clinically may influence their outcomes and

thus the cost-effectiveness of the antidepressants.

Three studies have investigated the cost-effectiveness

of care management versus usual care in patients

starting antidepressant treatment. In two trials clinical

outcomes suggest there are no significant differences

in depression-free days or in health-care costs (Simon

et al., 2000b; Simon et al., 2002), whereas one describes

superiority of care management (Wells et al., 2000).

Although education alone of primary care physicians

does not seem to improve patient outcomes (Gask

et al., 2004 ; Thompson et al., 2000), care management

or collaborative care involving doctor education,

patient education and monitoring by an additional

mental health worker can improve patient outcomes at

modest costs (Simon et al., 2000b; Simon et al., 2002 ;

Wells et al., 2000). In additon, identification and treat-

ment of depression among patients with a history of

high medical expenditures can decrease service use,

improve depression outcomes and increase work

productivity, though the cost of screening is high

(Katzelnick et al., 1997; Von Korff et al., 1998). A de-

cision-analytic model suggested that an increase in

the appropriateness of care as seen in a care man-

agement program is likely to improve functioning

outcomes and increase the value of health-care

spending in terms of health benefits (Sturm andWells,

1995).

14.6 Economic evidence for pharmacological

treatment options

The economic evidence has some limitations. First,

results from clinical trials are frequently inconclusive

due to short follow-up periods and inadequate power

to demonstrate differences in costs. Second, the results

from economic models are strongly influenced by the

assumptions made; in many cases conclusions change

when new evidence becomes available, or when

medication prices change or when a different view

has been taken on the likelihood of an assumption

(this is true particularly in modeling studies ; a dif-

ferentiation between analyses performed with an

industrial sponsor and analyses independent of

the pharmaceutical industry has been suggested).

Third, the results of economic evaluations tend to

be country-specific, as nations have different health

systems and economic conditions. Notwithstanding

these points, it is possible to identify some trends

in the results, as well as some areas where further re-

search is needed.

Evidence of the cost-effectiveness of SSRIs com-

pared with TCAs is persuasive (Barbui et al., 2003).

Many studies have demonstrated that SSRIs have

higher acquisition costs, but lower subsequent health

service costs, a pattern that may increase as SSRIs

become available generically at much lower prices.


Evidence of the cost-effectiveness of the SSRI

escitalopram is accumulating. Although it has a higher

cost than the now generic citalopram, models have

demonstrated that it achieves better outcomes and

decreases the likelihood of an inpatient stay, resulting

in lower costs.

Newer antidepressants have entered a crowded

market, and except in one instance, real-life (RCT

or observational) comparisons to existing anti-

depressants have yet to be undertaken (or at least

published). In common with other evidence from

economic models, it is difficult to summarize the

cost-effectiveness of these interventions. In many

cases, the models that have been constructed have

relied entirely on expert views to project the costs,

and the precise methods used by the expert panels

to arrive at their resource use estimates are often

not described fully or clearly in the literature. These

inadequacies limit the generalizability and applica-

bility of these studies and make it difficult to draw

firm conclusions. On the basis of available evidence,

however, the SNRIs venlafaxine (Freeman et al., 2000)

and duloxetine or (Dardennes et al., 1999 ; Lafuma

et al., 1999) the NaSSA mirtazapine (Borghi and

Guest, 2000) appear to be cost-effective alternatives to

SSRIs.

14.7 Implications : economic evidence for

pharmacological treatment options

Growing awareness of the need to improve not

only the effectiveness but also the cost-effectiveness

of health-care interventions has produced various

streams of demand for economic evidence. Two are

relevant here. There are requests for measures of the

overall resource or cost impact of a particular health

problem, leading to cost-of-illness and ‘global burden’

studies. Much attention has recently focused on some

of the non-health-care costs – which, as we have seen,

can be very large for many people with depression.

While cost-of-illness calculations can be helpful in

raising awareness of the scale and breadth of impact

of mental health problems, they are no substitute for

evaluations that look at both costs and outcomes.

There are also demands for economic evaluations

of particular treatments or policies, generating cost-

effectiveness and similar analyses, either carried out

within clinical trials or using routinely collected,

naturalistic data. Well-conducted economic evalu-

ations can contribute pertinent evidence to the dis-

cussion and development of policy and practice. They

can support decisions relating to the funding and

provision of services and can help to improve the

efficiency with which scarce health-care and related

resources are allocated.

In this chapter we have reviewed the economic

evaluation evidence on antidepressant medications,

drawing on a new systematic search of the inter-

national literature. The quality of many studies is dis-

appointing. Among the methodological weaknesses

are (for summary see Box 13) :

$ small sample sizes, leaving studies underpowered

to test economic hypotheses ;$ narrow measurement of costs ;$ the relative rarity of randomized controlled

trials, and hence few studies with strong internal

validity ;

Box 13. Summary of economic evidence on antidepressant treatments

What we know:

$ Some, but not all analyses suggest that SSRI treatment is more cost-effective than treatment with TCAs.$ On the basis of available evidence, venlafaxine and mirtazapine appear to be cost-effective alternatives to SSRIs.$ A new way of care, called care management, has demonstrated its value in enhancing the effectiveness of antidepressants

in one out of three studies.

What we do not know:

$ Evidence of the cost-effectiveness of the new SSRI escitalopram compared with other SSRIs is accumulating.$ Large-scale real-life (RCT or observational) comparisons of newer antidepressants, such as NARIs, SNRIs or NaSSAs to

SSRIs have yet to be undertaken.$ Modeled analyses have limited application because of the quality of the data on which they are based and the assumptions

made.$ Most studies are based in developed countries, and given the fundamental differences in health systems across the world,

it is difficult to know whether their findings can be generalized to other countries. Cultural factors may impact on patients’

adherence, prescription habits and finally on cost-effectiveness.


$ few large observational studies with appropriate

standardization, and hence limitations on the exter-

nal validity of some evidence ;$ the scarcity of cost-utility analyses and cost-

benefit analyses, making it impossible to use the

existing evidence base to make comparisons of

resource efficiency outside the mental health sys-

tem;$ widespread use of economic models that may not

accurately reflect the true clinical cost situation.

In many areas the economic evidence relied entirely

on economic modeling. These models are based in

many cases on expert views to project costs, and

the precise methods used by the expert panels to

arrive at their resource use estimates are not describ-

ed fully and clearly in the literature. These in-

adequacies limit the generalizability and applicability

of these studies and make it difficult to draw firm

conclusions.

Economic evaluations of antidepressant treatment

for depression are inherently context-bound. These

evaluations describe the consequences of both the ill-

ness and its treatment for service systems and social

relations, and these latter will vary from country to

country, and often from locality to locality. Also, the

economic value of work varies across different coun-

tries and cultures. Making generalizations across

countries is therefore more difficult than with, say,

clinical evaluations. The almost complete absence of

economic evidence on depression treatments for all

but a very few health systems of the world is therefore

a further limitation.

14.8 Economic evidence for psychological

treatment options

Depression is widely treated with psychological

therapies, including cognitive behavioral therapy

(CBT), interpersonal psychotherapy (IPT), counseling

and other forms of psychotherapy. Psychological

therapies such as CBT and IPT have proven effective-

ness in depression (see chapter 12.1), so economic

evaluations essentially aim to investigate whether

high initial treatment costs are offset by potentially

lower drug costs and fewer visits to other health care

professionals (the cost-offset question) or whether the

additional costs are worth paying because of im-

proved outcomes (the cost-effectiveness question). In

standard care, psychological treatments generally tend

to be delivered alongside treatment as usual, which

may or may not include an antidepressant and this

is reflected in the evaluative literature. In some

instances, however, antidepressants have been di-

rectly compared with psychological therapies and we

concentrate on this literature here.

In an early economic analysis, 120 patients initiating

treatment for depression were randomized to one of

four interventions : CBT by a clinical psychologist,

counseling and case work by a social worker,

amitriptyline prescribed by a psychiatrist and usual

care from a general practitioner (Scott and Freeman,

1992). After 16 weeks, there were improvements

in depressive symptoms in all treatment groups, but

total treatment costs were twice as much in the

specialist treatment groups compared with routine

care. With such a short period of follow-up, it was

difficult to draw conclusions, and the authors re-

commended a full economic evaluation with longer

follow-up and one that included a wider definition

of cost.

More recently, Miller and colleagues (2003) com-

pared counseling and antidepressant therapy for the

treatment of mild to moderate depression in primary

care. At 12-month follow-up, there were no significant

differences in outcomes and costs. Bootstrap analysis

showed that the antidepressant intervention was the

dominant cost-effective strategy for the majority of

patients, indicating that the cost-effectiveness of

counseling compared with treatment with an anti-

depressant for depression in primary care has not been

proven.

The cost-effectiveness of psychotherapy and medi-

cation was investigated in trials in Canada, the US

and the UK. In one study, patients with dysthymia

were randomized to interpersonal psychotherapy

(IPT) (Klerman and Weissmann, 1987), IPT with

sertraline (an SSRI) or sertraline alone in an RCT

in primary care (Browne et al., 2002). Clinical out-

comes at 2-year follow-up demonstrated that there

were no statistically significant differences between

sertraline alone and sertraline plus IPT, but both

were significantly more effective than IPT alone in re-

ducing depressive symptoms. Societal costs were sig-

nificantly lower in the IPT group, but there was

no synthesis of costs and effects, so the incremental

cost-effectiveness of the treatment is not known. The

authors stressed the importance and potential econ-

omic value of combining psychotherapy and pharma-

cotherapy.

IPT, pharmacotherapy with nortriptyline (a TCA) or

usual care were compared in a cost-effectiveness

analysis in the US (Lave et al., 1998). Both IPT and the

pharmacotherapy generated better outcomes than

usual care at follow-up, although the pharmaco-

therapy group did slightly better than those assigned


to IPT. Costs were higher in the IPT and

pharmacotherapy groups compared with usual care.

The incremental cost per QALY gained was US$11695

for nortriptyline and US$15358 for IPT. Although the

differences were not statistically significant, from a

decision-making perspective there is a preference for

the drug treatment.

A modeled cost-utility analysis compared IPT,

imipramine (a TCA), a combination of the two, and

placebo in patients with recurrent depression (Kamlet

et al., 1995). Modeling and simulation methods

were used to estimate the costs and benefits associated

with each maintenance therapy, and the authors

demonstrated that the drug maintenance treatment

was cost-effective. Among patients with depression

who had a partner with a criticizing attitude, signifi-

cant improvements in outcomes were found in

patients randomized to couples therapy compared

with those randomized to antidepressants (Leff

et al., 2000). There were higher treatment costs in

the therapy group, but the higher costs were moder-

ated by decreased use of other services, resulting in

no significant differences in cost at follow-up. The

authors warned that the results could not be general-

ized beyond individuals with depression who are

living with a heterosexual partner and that con-

clusions were limited by large amounts of missing

data in the economic evaluation. Cost-effectiveness

studies concerning the role of family care are lacking,

but there is a broad consensus about the importance

and value of family care during the treatment of de-

pressive disorders.

Psychotherapy is cost-effective in some patient

groups (Table 25), but when compared directly with

antidepressants, their cost-effectiveness needs further

evaluation. The economic value of combining psycho-

therapy with pharmacotherapy also needs further

examination.

Finally, new care arrangements have demonstrated

their value in enhancing the effectiveness of anti-

depressants, but studies have only taken place in the

US and – given the fundamental differences in health

systems across the world – it is difficult to know whe-

ther their findings can be generalized to other coun-

tries.

The economic discussion to this point principally

addresses acute treatment costs. In the very short run,

psychotherapies are more labor-intensive and costly

than pharmacotherapies. Over time, however, the ful-

crum may shift : daily pharmacotherapy which might

be continued indefinitely to maintain prophylaxis

against depressive relapse and recurrence, whereas

psychotherapy may either be discontinued, with ‘en-

during effect’ (Hollon et al., 2005), or continued in

less frequent (e.g. monthly) sessions. Empirically

validated psychotherapies may also arguably help

patients to neutralize psychosocial stressors (e.g.,

marital difficulties) that might provoke a future

Table 25. Summary of cost-effectiveness of psychological treatments for depression

Psychotherapeutic

method Cost-effectiveness Reference

IPT Depends on the treatment setting ; may be cost-effective

(better outcomes no difference in cost) in secondary care but

evidence from primary care less clear. When compared

head-to-head with an SSRI, no evidence of cost-effectiveness

Browne et al., 2002 ; Guthrie et al., 1999 ;

Kamlet et al., 1995

CBT Not yet proven. Evidence from primary care of improved

outcomes is always accompanied by substantially higher

costs. Some evidence that self-help CBT and computerized

CBT may be cost-effective

Bower et al., 2000 ; Kaltenthaler et al.,

2002 ; Richards et al., 2003 ; Scott and

Freeman, 1992 ; Scott et al., 2003

Counseling No significant differences in costs or outcomes in clinical

trials, though meta-analysis suggests counseling will

produce significantly better outcomes for significantly

higher costs

Bower et al., 2002 ; Bower and Rowland,

2006 ; Friedli et al., 2000 ; Harvey et al.,

1998 ; Miller et al., 2003 ; Scott and

Freeman, 1992 ; Simpson et al., 2003

Problem solving Cost-effective from a societal perspective, but higher costs in

intervention group from a health-care perspective.

Additional costs of problem-solving treatment are offset by

fewer days off work in the intervention group

Mynors-Wallis et al., 1997


depressive episode. Thus over the longer duration of

the treatment of this usually chronic illness, it is poss-

ible that antidepressant psychotherapy might have

cost advantages relative to pharmacotherapy. Studies

to assess this, however, are lacking.

15 Conclusions and implications73

The Executive Committee and the Council of the Col-

legium Internationale Neuropsychopharmacologicum

have considered the information contained in this

report as well as other information available to its

members and adopted a Consensus Statement about

the use of antidepressants in the treatment of de-

pressive disorders. The Consensus Statement is given

here as a concluding summary of the review. In ad-

dition to providing a summary of the main findings of

the review, the Consensus Statement also indicates

future action that CINP will take in this area and

makes a series of recommendations to governments,

professional and non-professional organizations and

the media.

Antidepressant Medications in the Treatment ofDepressive Disorders: A Consensus Statementby the Collegium InternationaleNeuropsychopharmacologicum

The International College of

Neuropsychopharmacology,

Aware of the major public health importance of depressive

disorders and of the suffering that these disorders cause to

people who have them and their families ;

Cognizant that even in highly industrialized countries only

a small proportion of people with depression who could

benefit from qualified help contact health-care services and

receive adequate treatment ;

Given that medical practitioners may fail to recognize de-

pressive disorders in people who come to them seeking help

and that their knowledge about the treatment of depression

may be insufficient ;

Concerned by the findings that the general population and

health-care workers still attach stigma to depressive dis-

orders ;

Aware of the risks of suicide and physical illness that are

elevated in people with depressive disorders ;

Deeply concerned also by the tendency to consider depress-

ive disorders to be minor ills of living and not illnesses that

should be given appropriate care ;

Considering that the potential benefits of these medications

used in the treatment of depressive disorders outweigh the

risks presented by the side effects of their application ;

Stressing that the application of adequate treatment not

only helps the persons who have the disease and their fam-

ilies, but also brings significant social and economic benefits

to society ;

Stressing also that the treatment of depressive disorders is a

process in which the application of antidepressant medi-

cations, social support and psychological help and treatment

must be used in a manner that will correspond to the needs

of the individuals who are being treated, and of their re-

latives and other carers ;

Recognizing that new information and knowledge about the

treatment of depressive disorders is not reaching those en-

gaged in health-care and that the general public is still in-

sufficiently informed about the frequency of depressive

disorders and possibilities of their effective treatment ;

DECIDES

1. To publish the CINP Task Force report based on a review

of Evidence about Antidepressant Medications and other

Treatments of Depressive Disorders and employ it as a

platform for the development of training programs and

guidelines concerning the recognition and treatment of

depressive disorders ;

2. To develop specific guidelines concerning the use of

antidepressant medications in the treatment of de-

pressive disorders and to undertake all that is necess-

ary to bring them to the attention of medical

practitioners worldwide, engaging the World Health

73 The CINP consensus statement has been adopted to the actual

knowledge about antidepressant treatments. Due to the nature of the

constant scientific progress it is planned to actualize the information

presented in the review on a regular basis.


Organization and other institutions and organizations

in this process ;

3. To develop materials that will be suitable for the correct

information of the general public about depressive dis-

orders and the possibilities of their treatment.

AND RECOMMENDS

1. To governments to introduce educational programs

concerning depressive disorders in all schools of health

personnel and in in-service training of health staff to

ensure that people with depressive disorders receive ad-

equate help and treatment ; these programs should in-

clude families as well.

2. To professional societies in the field of mental health to

participate in the development of comprehensive treat-

ment and rehabilitation programs for people with de-

pressive disorders ;

3. To non-governmental organizations of patients and their

families to participate in the development of training

materials and collaborate in other ways with professional

organizations and institutions engaged in the programs

designed to improve the treatment of people with mental

disorders ;

4. To the media to collaborate with professional organiz-

ations in the effort to bring well-balanced information

about depressive disorders to the general public.

16 Acknowledgements

Work on this review has been supported by unre-

stricted grants made to the CINP by the following

companies : Bristol-Myers Squibb Company, Eli Lilly

and Company, Forest Laboratories, GlaxoSmithKline,

H. Lundbeck A/S, Les Laboratoires Servier and

Wyeth. The funds received served to organize and

cover the expenses of travel and accommodation for

meetings of the Task Force as well as national and re-

gional meetings of experts. The funds were also used

for administrative support in producing the review.

None of the members of the Task Force nor any of the

advisers received any fees nor honoraria for their

work.

Prof. Xiao Zeping, President of the Shanghai Mental

Health Center in Shanghai, China, Prof. Nikolaj

Nesnanov, Director of the Bekhterev Psychoneuro-

logical Institute in St. Petersburg, Russia, and Dr Edgar

Belfort, Administrative Secretary of the Association

of Psychiatrists of Latin America (APAL) in Caracas,

Venezuela, organized and hosted regional meetings

related to the project.

Prof. Moller, Chairman of the Psychiatric De-

partment of the Ludwig-Maximilians-Universitat

Munchen in Germany hosted one of the regional

meetings and enabled two of the editors (Dr T. C.

Baghai and Prof. H. Grunze) to carry out their work on

the review.

Numerous individuals, institutions and the com-

panies listed above provided the Task Force with

publications and other relevant scientific materials. To

all of them we express our most sincere and cordial

gratitude.

17 Statement of Interest

Thomas C. Baghai accepted paid speaking engagements

in satellite symposia and acted as a consultant for

Janssen-Cilag, Organon, Pfizer and Servier.

David Baldwin acted as a consultant to and/or ac-

cepted paid speaking engagements in satellite sym-

posia from a number of companies with an interest in

anxiety and depressive disorders (Asahi, Cephalon,

Eli Lilly, GlaxoSmithKline (GSK), Lundbeck, Pfizer,

Organon, Pharmacia, Pierre Fabre, Roche, Servier,

Sumitomo, Wyeth). He holds or has held research

grants (on behalf of his employer) from a number of

companies with an interest in anxiety and depressive

disorders (Cephalon, Eli Lilly, GSK, Lundbeck,

Organon, Pfizer, Pharmacia, Roche, Wyeth).

Barbara Barrett has acted as an independent con-

sultant to Servier for the development of an economic

model of agomelatine in the UK.

Pierre Baumann has served on the advisory boards of

Pfizer and Lundbeck in Switzerland. He has been

sponsored by almost all pharmaceutical companies

involved in psychopharmacology in Switzerland to

carry out studies, participate in symposia and organ-

ize congresses. He has stocks in Novartis and Roche.

Ursula Brand has no conflicting interests.

Max Fink has no commercial contracts or appoint-

ments and receives no funding from industry sources

that may influence the conclusions of his contributions

to the review.

Wolfgang Fleischhacker discloses that he received

speaking/consultancy honoraria from Bristol-Myers

Squibb (BMS)/Otsuka, AstraZeneca, Janssen-Cilag,

Lundbeck, Pfizer, Servier and Wyeth. He also holds

or has held research support from BMS/Otsuka,

Janssen and Servier.

Konstantinos Fountoulakis has received support con-

cerning travel and accommodation expenses from

various pharmaceutical companies in order to partici-

pate in medical congresses. He has also received hon-

oraria for lectures from AstraZeneca, Janssen-Cilag,

Eli Lilly and a research grant from the Pfizer

Foundation.


Toshiaki Furukawa has received research funds and

speaking fees from Asahi Kasei, Astellas, Dai-Nippon,

Eisai, Eli Lilly, GSK, Janssen, Kyowa Hakko, Meiji,

Organon, Pfizer, Tsumura, Yoshitomi and Zelia. The

Japanese Ministry of Education, Science and

Technology, and the Japanese Ministry of Health,

Labor and Welfare have also funded his research.

Karim Ghalib has no conflicts of interest.

Guy M. Goodwin received grants from Sanofi-

Aventis, Servier and honoraria from AstraZeneca,

BMS, Eisai, Lilly, Lundbeck, Pfizer, Sanofi-Aventis,

Servier and Wyeth. He serves on the advisory boards

of Lilly, Lundbeck, P1Vital, Sanofi-Aventis, Servier,

Wyeth. He has no shares in pharmaceutical compa-

nies. He holds or has held research grants from Sanofi-

Aventis, Lilly, Stanley MRI, the Bailey-Thomas Trust

and the MRC (UK).

Heinz Grunze receives research grants from

Novartis, AstraZeneca, UCB Belgium and Pfizer. He

occasionally supplies services as a consultant and/or

paid speaker for AstraZeneca, Sanofi-Aventis, Desitin,

Lilly, Janssen-Cilag, BMS and Pfizer.

Peter Jensen currently receives investigator-initiated

grants from McNeil Pharmaceuticals and unrestricted

educational grants from Pfizer, Lilly and McNeil,

participates in speakers’ bureaus for CMED, the Union

Chimique Belge Pharma, PsychCME, Continuing

Medical Education Outfitters and the Neuroscience

Education Institute, and consults to Best Practice, Inc.,

Janssen Pharma, Novartis and the Union Chimique

Belge Pharma.

Shigenobu Kanba Grants or contracts : Lilly, GSK,

Pfizer, Asahi-Kasei, Janssen, Tsumura, Ajinomoto,

Yoshitomi, Meiji, Kyowa-Hakko, Sumitomo, Organon,

Otsuka. Consultant : Lilly, Pfizer, Mitsubishi, Ono,

Astellas, Otsuka.

Martin Knapp discloses the following consulting

services and research grants from the pharmaceutical

industry pertinent to this review: Servier, Lilly,

Organon, Sanofi-Aventis, Pfizer, Novartis.

Jeffrey Liebermann discloses that he holds or has held

research grants from BMS/Otsuka, GSK, Janssen,

Pfizer andAcadia. He is also patent holder of Repligen.

John C. Markowitz was a consultant in 2006 for Ono

Pharmaceuticals ; in the past he has received speaker’s

honoraria and/or consulting fees from Pfizer, BMS

and Forest.

Yoshibumi Nakane is a supervisor of The Japanese

Committee of Prevention and Treatment for De-

pression sponsored by Eli Lilly and Shionogi.

Frank Padberg has no conflicts of interests.

Roger Pinder was a full-time employee of Organon

until June 2004. Since then he has received honoraria

and/or travel support from Organon for chairing and

speaking at symposia. He also acts as non-executive

Chairman of NeuroCure Ltd. (Dublin) and as a con-

sultant to Cypress Bioscience Inc. (San Diego),

Daniolabs Ltd. (Cambridge, UK), Nomura Phase4

Ventures (London) and Organon International Inc.

(New Jersey, USA).

Anita Riecher-Rossler discloses that she received

speaking/consultancy honoraria or research grants

from BMS, AstraZeneca, Janssen-Cilag, Eli Lilly and

Sanofi-Synthelabo.

Norman Sartorius acted as consultant and/or re-

ceived honoraria for presentations at meetings and

symposia organized by Eli Lilly, Janssen, Lundbeck,

Pfizer, Servier and Wyeth.

Alan Schatzberg acted as a consultant to and/or

accepted paid speaking engagements in satellite

symposia from Abbott, Aventis, BrainCells, BMS,

Corcept, Eli Lilly, Forest Labs, GSK, Janssen-Cilag,

Neuronetics, Organon, Pfizer, Somaxon, Somerset

and Wyeth. He holds or has held research grants

from Somerset and Wyeth and holds equities from

BrainCells, Corcept, Merck, Organon, Pfizer and

Somaxon.

Jaromır Svestka acted as a consultant to and/or ac-

cepted paid speaking engagements in satellite sym-

posia from AstraZeneca, Sanofi-Aventis, BMS, Desitin,

Eli Lilly, Janssen-Cilag, KrkaPfizer, Zenziva. He

received support for participation in international

congresses from BMS, Eli Lilly, Janssen-Cilag, Pfizer

and Zentiva.

18 References

Aarre TF, Bugge P (2002). ECT for patients taking

lamotrigine. European Psychiatry 17 (Suppl. 1), 135.

Abrams R (2002). Electroconvulsive Therapy. Oxford : Oxford

University Press.

Acharya N, Rosen AS, Polzer JP, D’Souza DN, Perahia DG,

Cavazzoni PA, Baldessarini RJ (2006). Duloxetine : meta-

analyses of suicidal behaviors and ideation in clinical trials

for major depressive disorder. Journal of Clinical

Psychopharmacology 26, 587–594.

Ackerman DL, Greenland S (2002). Multivariate meta-

analysis of controlled drug studies for obsessive-

compulsive disorder. Journal of Clinical Psychopharmacology

22, 309–317.

Adli M, Baethge C, Heinz A, Langlitz N, Bauer M (2005).

Is dose escalation of antidepressants a rational strategy

after a medium-dose treatment has failed? A systematic

review. European Archives of Psychiatry and Clinical

Neuroscience 255, 387–400.

Adli M, Berghofer A, Linden M, Helmchen H,

Muller-Oerlinghausen B, Mackert A, Stamm T,


Bauer M (2002). Effectiveness and feasibility of a

standardized stepwise drug treatment regimen algorithm

for inpatients with depressive disorders : results of a 2-year

observational algorithm study. Journal of Clinical Psychiatry

63, 782–790.

Adli M, Rush AJ, Moller HJ, Bauer M (2003). Algorithms for

optimizing the treatment of depression : making the right

decision at the right time. Pharmacopsychiatry 36 (Suppl. 3),

S222–S229.

Agency for Health Care Policy and Research (1993).

Depression Guideline Panel : Depression in Primary Care.

Rockville, MD: U.S. Department of Health and Human

Services.

AHCPR (Agency for Health Care Policy and Research)

(1999). Evidence Report on Treatment of Depression : Newer

Pharmacotherapies. Washington DC: AHCPR.

Aichhorn W, Whitworth AB, Weiss U, Stuppaeck C (2004).

Mirtazapine and breast-feeding. American Journal of

Psychiatry 161, 2325.

Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA,

Amini H, Fallah-Pour H, Jamshidi AH, Khani M

(2005). Crocus sativus L. in the treatment of mild to

moderate depression : a double-blind, randomized

and placebo-controlled trial. Phytotherapy Research 19,

148–151.

Akiskal H, Bourgeois ML, Angst J, Post R, Moller HJ,

Hirschfeld RM (2000). Re-evaluating the prevalence of

and diagnostic composition within the broad clinical

spectrum of bipolar disorders. Journal of Affective Disorders

59 (Suppl. 1), 5–30.

Akiskal HS, Benazzi F (2006). The DSM-IV and ICD-10

categories of recurrent [major] depressive and bipolar II

disorders : evidence that they lie on a dimensional

spectrum. Journal of Affective Disorders 92, 45–54.

Alarcon RD, Westermeyer J, Foulks EF, Ruiz P (1999).

Clinical relevance of contemporary cultural psychiatry.

Journal of Nervous and Mental Disease 187, 465–471.

Alexopoulos GS, Katz IR, Reynolds CF, III, Carpenter D,

Docherty JP (2001). The expert consensus guideline

series. Pharmacotherapy of depressive disorders in

older patients. Postgrad. Med. Spec No Pharmacotherapy,

1–86.

Alfonso J, Frick LR, Silberman DM, Palumbo ML, Genaro

AM, Frasch AC (2006). Regulation of hippocampal gene

expression is conserved in two species subjected to

different stressors and antidepressant treatments. Biological

Psychiatry 59, 244–251.

Allen JJB, Schnyer RN (1998). The efficacy of acupuncture in

the treatment of major depression in women. Psychological

Science 9, 397–402.

Alonso J, Angermeyer MC, Bernert S, Bruffaerts R, Brugha

TS, Bryson H, de Girolamo G, Graaf R, Demyttenaere K,

Gasquet I, Haro JM, Katz SJ, Kessler RC, Kovess V,

Lepine JP, Ormel J, Polidori G, Russo LJ, Vilagut G,

Almansa J, Arbabzadeh-Bouchez S, Autonell J, Bernal M,

Buist-Bouwman MA, Codony M, Domingo-Salvany A,

Ferrer M, Joo SS, Martinez-Alonso M, Matschinger H,

Mazzi F, Morgan Z, Morosini P, Palacin C, Romera B,

Taub N, Vollebergh WA (2004). Prevalence of mental

disorders in Europe: results from the European Study of

the Epidemiology of Mental Disorders (ESEMeD) project.

Acta Psychiatrica Scandinavica. Supplementum 21–27.

Altar CA (1999). Neurotrophins and depression. Trends in

Pharmacological Sciences 20, 59–61.

Althaus D, Niklewski G, Schmidtke A, Hegerl U

(2006). [Changes in the frequency of suicidal behaviour

after a 2-year intervention campaign.]. Nervenarzt.

10.1007/s00115-005-2031-5.

Altshuler LL, Bauer M, Frye MA, Gitlin MJ, Mintz J, Szuba

MP, Leight KL, Whybrow PC (2001). Does thyroid

supplementation accelerate tricyclic antidepressant

response? A review and meta-analysis of the literature.

American Journal of Psychiatry 158, 1617–1622.

Ambrosini PJ (2000). A review of pharmacotherapy of major

depression in children and adolescents. Psychiatric Services

51, 627–633.

American Diabetes Association (2003). Economic cost of

diabetes in the US in 2002. Diabetes Care 26, 917–932.

American Diabetes Association (2005). Antidepressants

AssociatedWith Increased Risk of Diabetes in Pre-Diabetes

(www.diabetes.org). Accessed 10 November 2006.

American Psychiatric Association (1994). Diagnostic and

Statistical Manual of Mental Disorders. Washington DC:

American Psychiatric Press.

American Psychiatric Association (2000). Practice guideline

for the treatment of patients with major depressive

disorder (revision). American Journal of Psychiatry 157, 1–45.

American Psychiatric Association Committee on

Electroconvulsive Therapy, Weiner RD, Coffey CE, Folk

J, Fochtmann LJ, Greenberg RM, Isenberg KE, Kellner

CH, Sackeim HA, Moench LM (2001). The Practice of

Electroconvulsive Therapy. Washington : American

Psychiatric Association.

Amore M, Jori MC (2001). Faster response on amisulpride

50 mg versus sertraline 50–100 mg in patients with

dysthymia or double depression : a randomized,

double-blind, parallel group study. International Clinical


Amsterdam JD (2003). A double-blind, placebo-controlled

trial of the safety and efficacy of selegiline transdermal

system without dietary restrictions in patients with major

depressive disorder. Journal of Clinical Psychiatry 64,

208–214.

Amsterdam JD, Bodkin JA (2006). Selegiline transdermal

system in the prevention of relapse of major depressive

disorder : a 52-week, double-blind, placebo-substitution,

parallel-group clinical trial. Journal of Clinical

Psychopharmacology 26 (6), 579–586.

Amsterdam JD, Shults J (2005). MAOI efficacy and safety in

advanced stage treatment-resistant depression-A

retrospective study. Journal of Affective Disorders 89,

183–188.

Anand A, Malison RT, McDougle CJ, Price LH (1995).

Antiglucocorticoid treatment of refractory depression with

ketoconazole : a case report. Biological Psychiatry 37,

338–340.


Ananth J (1998). Treatment-resistant depression.

Psychotherapy and Psychosomatics 67, 61–70.

Anderson IM (1998). SSRIS versus tricyclic antidepressants

in depressed inpatients : a meta-analysis of efficacy

and tolerability. Depression & Anxiety 7 (Suppl. 1), 11–7.,

11–17.

Anderson IM (2000). Selective serotonin reuptake inhibitors

versus tricyclic antidepressants : a meta-analysis of efficacy

and tolerability. Journal of Affective Disorders 58, 19–36.

Anderson CS, Hackett ML, House AO (2004). Interventions

for preventing depression after stroke. Cochrane Database of

Systematic Reviews. CD003689.

Anderson IM (1998). SSRIS versus tricyclic antidepressants

in depressed inpatients : a meta-analysis of efficacy

and tolerability. Depression and Anxiety 7 (Suppl. 1), 11–17.

Anderson IM (2000a). Selective serotonin reuptake inhibitors

versus tricyclic antidepressants : a meta-analysis of

efficacy and tolerability. Journal of Affective Disorders 58,

19–36.

Anderson IM, Nutt DJ, Deakin JF (2000). Evidence-based

guidelines for treating depressive disorders with

antidepressants : a revision of the 1993 British Association

for Psychopharmacology guidelines. British Association

for Psychopharmacology. Journal of Psychopharmacology 14,

3–20.

Anderson J (2000b). On variability of effects for a

metaanalysis of rheumatoid arthritis radiographic

progression. Journal of Rheumatology 27, 540–542.

Andersson HI, Ejlertsson G, Leden I, Rosenberg C (1993)

Chronic pain in a geographically defined general

population : studies of differences in age, gender, social

class, and pain localization. Clinical Journal of Pain 9,

174–182.

Andlin-Sobocki P, Jonsson B, Wittchen H-U, Olesen J

(2005). Cost of brain disorders in Europe. European Journal

of Neurology 12, S1–S27.

Andlin-Sobocki P, Wittchen HU (2005). Cost of affective

disorders in Europe. European Journal of Neurology 12

(Suppl. 1), 34–38.

Andrade L, Caraveo-Anduaga JJ, Berglund P, Bijl RV, de

Graaf R, Vollebergh W, Dragomirecka E, Kohn R, Keller

M, Kessler RC, Kawakami N, Kilic C, Offord D, Ustun

TB, Wittchen HU (2003). The epidemiology of major

depressive episodes : results from the International

Consortium of Psychiatric Epidemiology (ICPE) Surveys.

International Journal of Methods in Psychiatric Research 12,

3–21.

Andrade RJ, Lucena MI, Fernandez MC, Pelaez G,

Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B,

Gonzalez-Grande R, Pizarro A, Duran JA, Jimenez M,

Rodrigo L, Romero-Gomez M, Navarro JM, Planas R,

Costa J, Borras A, Soler A, Salmeron J, Martin-Vivaldi R

(2005). Drug-induced liver injury : an analysis of 461

incidences submitted to the Spanish registry over a 10-year

period. Gastroenterology 129, 512–521.

Andrews JM, Nemeroff CB (1994). Contemporary

management of depression.American Journal of Medicine 97,

24S–32S.

Anghelescu I, Klawe C, Dahmen N (2002). Venlafaxine in a

patient with idiopathic leukopenia and mirtazapine-

induced severe neutropenia. Journal of Clinical Psychiatry

63, 838.

Angst F, Stassen HH, Clayton PJ, Angst J (2002a).

Mortality of patients with mood disorders : follow-

up over 34-38 years. Journal of Affective Disorders 68,

167–181.

Angst J (2006). Do many patients with depression suffer from

bipolar disorder? Canadian Journal of Psychiatry 51, 3–5.

Angst J, Angst F, Gerber-Werder R, Gamma A (2005).

Suicide in 406 mood-disorder patients with and without

long-term medication : a 40 to 44 years’ follow-up. Archives

of Suicide Research 9, 279–300.

Angst J, Angst K, Baruffol I, Meinherz-Surbeck R (1992).

ECT-induced and drug-induced hypomania. Convulsive

Therapy 8, 179–185.

Angst J, Dobler-Mikola A (1985). The Zurich Study: a

prospective epidemiological study of depressive, neurotic

and psychosomatic syndromes. IV. Recurrent and

nonrecurrent brief depression. European Archives of

Psychiatry and Neurological Science 234, 408–416.

Angst J, Gamma A, Gastpar M, Lepine JP, Mendlewicz J,

Tylee A (2002b). Gender differences in depression.

Epidemiological findings from the European DEPRES I

and II studies. European Archives of Psychiatry and Clinical


Annegers JF, Coan SP, Hauser WA, Leestma J (2000).

Epilepsy, vagal nerve stimulation by the NCP system,

all-cause mortality, and sudden, unexpected,

unexplained death. Epilepsia 41, 549–553.

Anon. (2001). Extrapyramidal effects of SSRI antidepressants.

Prescrire International 10, 118–119.

Anon. (2002). Factors impacting on quality of life in

Parkinson’s disease : results from an international survey.

Movement Disorders 17, 60–67.

Anon. (2004). Mirtazapine : seizures and neutropenia.

Prescrire International 13, 58.

Ansorge MS, Zhou M, Lira A, Hen R, Gingrich JA (2004).

Early-life blockade of the 5-HT transporter alters emotional

behavior in adult mice. Science 306, 879–881.

Anton RF, Burch EA (1990). Amoxapine versus amitriptyline

combined with perphenazine in the treatment of

psychotic depression. American Journal of Psychiatry 147,

1203–1208.

Anton SF, Revicki DA (1995). The use of decision analysis in

the pharmacoeconomic evaluation of an antidepressant :

a cost-effectiveness study of nefazodone.

Psychopharmacology Bulletin 31, 249–258.

Appelberg BG, Syvalahti EK, Koskinen TE, Mehtonen OP,

Muhonen TT, Naukkarinen HH (2001). Patients with

severe depression may benefit from buspirone

augmentation of selective serotonin reuptake inhibitors :

results from a placebo-controlled, randomized,

double-blind, placebo wash-in study. Journal of Clinical


Aranow RB, Hudson JI, Pope HG, Grady TA, Laage TA,

Bell IR, Cole JO (1989). Elevated antidepressant plasma


levels after addition of fluoxetine. American Journal of


Arinami T, Li L, Mitsushio H, Itokawa M, Hamaguchi H,

ToruM (1996). An insertion/deletion polymorphism in the

angiotensin converting enzymegene is associatedwith both

brain substance P contents and affective disorders.

Biological Psychiatry 40, 1122–1127.

Arinzon ZH, Lehman YA, Fidelman ZG, Krasnyansky II

(2002). Delayed recurrent SIADH associated with SSRIs.

Annals of Pharmacotherapy 36, 1175–1177.

Armstrong SC, Cozza KL (2000). Consultation-liaison

psychiatry drug-drug interactions update. Psychosomatics

41, 155–156.

Aronson R, Offman HJ, Joffe RT, Naylor CD (1996).

Triiodothyronine augmentation in the treatment of

refractory depression. A meta-analysis. Archives of General


Arroll B, Goodyear-Smith F, Kerse N, Fishman T, Gunn J

(2005). Effect of the addition of a ‘help’ question to two

screening questions on specificity for diagnosis of

depression in general practice : diagnostic validity study.

British Medical Journal 331, 884.

Artigas F, Adell A, Celada P (2006). Pindolol augmentation

of antidepressant response. Current Drug Targets 7,

139–147.

Artigas F, Celada P, Laruelle M, Adell A (2001). How does

pindolol improve antidepressant action? Trends in


Asnis GM, De La Garza R, II (2006). Interferon-induced

depression in chronic hepatitis C : a review of its

prevalence, risk factors, biology, and treatment

approaches. Journal of Clinical Gastroenterology 40, 322–335.

Audinot V, Mailliet F, Lahaye-Brasseur C, Bonnaud A, Le

Gall A, Amosse C, Dromaint S, Rodriguez M, Nagel N,

Galizzi JP, Malpaux B, Guillaumet G, Lesieur D,

Lefoulon F, Renard P, Delagrange P, Boutin JA (2003).

New selective ligands of human cloned melatonin MT1

and MT2 receptors. Naunyn-Schmiedeberg’s Archives of

Pharmacology 367, 553–561.

Avery DH, Norden MJ (1998). Dawn stimulation and bright

light therapy in subsyndromal seasonal affective disorder.

In : Lam R (Ed.), Seasonal Affective Disorder and Beyond : Light

Treatment for SAD and Non-SAD Conditions. Washington,

DC: American Psychiatric Press.

Avila A, Cardona X, Martin-Baranera M, Maho P, Sastre F,

Bello J (2003). Does nefazodone improve both depression

and Parkinson disease? A pilot randomized trial. Journal of

Clinical Psychopharmacology 23, 509–513.

Baboolal NS (2004). Venlafaxine withdrawal syndrome:

report of seven cases in Trinidad. Journal of Clinical


Baca E, Garcia-Garcia M, Porras-Chavarino A (2004). Gender

differences in treatment response to sertraline versus

imipramine in patients with nonmelancholic depressive

disorders. Progress in Neuro-Psychopharmacology and


Baghai TC, Binder EB, Schule C, Salyakina D, Eser D,

Lucae S, Zwanzger P, Haberger C, Zill P, Ising M,

Deiml T, Uhr M, Illig T, Wichmann HE, Modell S,

Nothdurfter C, Holsboer F, Muller-Myhsok B, Moller HJ,

Rupprecht R, Bondy B (2006a). Polymorphisms in the

angiotensin-converting enzyme gene are associated with

unipolar depression, ACE activity and hypercortisolism.

Molecular Psychiatry 11, 1003–1115.

Baghai TC, Eser D, Schule C, Nothdurfter C, Moller HJ,

Rupprecht R (2005). Elektrokonvulsionstherapie bei

depressiven Storungen. Journal Fur Neurologie,

Neurochirurgie Und Psychiatrie 4/2005, 20–28.

Baghai TC, Marcuse A, Brosch M, Schule C, Eser D,

Nothdurfter C, Steng Y, Noack I, Pietschmann K,

Moller HJ, Rupprecht R (2006b). The influence of

concomitant antidepressant medication on safety,

tolerability and clinical effectiveness of electroconvulsive

therapy. World Journal of Biological Psychiatry 7, 82–90.

Baghai TC, Moller HJ, Rupprecht R (2006c). Recent progress

in pharmacological and non-pharmacological treatment

options of major depression. Current Pharmaceutical Design

12, 503–515.

Baghai TC, Schule C, Zill P, Deiml T, Eser D, Zwanzger P,

Ella R, Rupprecht R, Bondy B (2004). The angiotensin I

converting enzyme insertion/deletion polymorphism

influences therapeutic outcome in major depressed

women, but not in men. Neuroscience Letters 363, 38–42.

Baghai TC, Schule C, Zwanzger P, Minov C, Schwarz MJ,

de Jonge S, Rupprecht R, Bondy B (2001). Possible

influence of the insertion/deletion polymorphism in the

angiotensin I-converting enzyme gene on therapeutic

outcome in affective disorders. Molecular Psychiatry 6,

258–259.

Baghai TC, Schule C, Zwanzger P, Minov C, Zill P, Ella R,

Eser D, Oezer S, Bondy B, Rupprecht R (2002).

Hypothalamic-pituitary-adrenocortical axis dysregulation

in patients with major depression is influenced by

the insertion/deletion polymorphism in the angiotensin

I-converting enzyme gene. Neuroscience Letters 328,

299–303.

Baghai TC, Schule C, Zwanzger P, Zill P, Ella R, Eser D,

Deiml T, Minov C, Rupprecht R, Bondy B (2003).

Influence of a functional polymorphism within the

angiotensin I-converting enzyme gene on partial sleep

deprivation in patients with major depression.Neuroscience

Letters 339, 223–226.

Balazs J, Benazzi F, Rihmer Z, Rihmer A, Akiskal KK,

Akiskal HS (2006). The close link between suicide

attempts and mixed (bipolar) depression: implications

for suicide prevention. Journal of Affective Disorders 91,

133–138.

Baldessarini RJ, Tondo L, Hennen J (2003). Lithium

treatment and suicide risk in major affective disorders :

update and new findings. Journal of Clinical Psychiatry 64

(Suppl. 5), 44–52.

Baldwin DS (2002). Escitalopram: efficacy and tolerability in

the treatment of depression. Hospital Medicine 63, 668–671.

Baldwin DS, Birtwistle J (1998). The side effect burden

associated with drug treatment of panic disorder. Journal of

Clinical Psychiatry 59 (Suppl. 8), 39–44.


Baldwin DS, Montgomery SA, Nil R, Lader M (2005).

Discontinuation symptoms in depression and anxiety

disorders. International Journal of Neuropsychopharmacology.

10.1017/S1461145705006358.

Baldwin DS, Polkinghorn C (2005). Evidence-based

pharmacotherapy of Generalized Anxiety Disorder.

International Journal of Neuropsychopharmacology 8, 293–302.

Baldwin RC, Anderson D, Black S, Evans S, Jones R,

Wilson K, Iliffe S (2003). Guideline for the management

of late-life depression in primary care. International

Journal of Geriatric Psychiatry 18, 829–838.

Ballesteros J, Callado LF (2004). Effectiveness of pindolol

plus serotonin uptake inhibitors in depression : a meta-

analysis of early and late outcomes from randomised

controlled trials. Journal of Affective Disorders 79, 137–147.

Bambauer KZ, Adams AS, Zhang F, Minkoff N, Grande A,

Weisblatt R, Soumerai SB, Ross-Degnan D (2006).

Physician alerts to increase antidepressant adherence : fax

or fiction? Arch. Intern. Med. 166, 498–504.

Ban TA (2001). Pharmacotherapy of depression: a historical

analysis. Journal of Neural Transmission 108, 707–716.

Ban TA, Healy D, Shorter E (1998). The rise of

Psychopharmacology and The story on CINP. Animula

Publishing House (Hungary).

Ban TA (2006a). A history of the Collegium Internationale

Neuro-Psychopharmacologicum (1957–2004). Progress in

Neuro-Psychopharmacology and Biological Psychiatry 30,

599–616.

Ban TA (2006b). Academic psychiatry and the

pharmaceutical industry. Progress in Neuro-

Psychopharmacology and Biological Psychiatry 30, 429–441.

Bano S, Akhter S, Afridi MI (2004). Gender based response

to fluoxetine hydrochloride medication in endogenous

depression. Journal of the College of Physicians and

Surgeons – Pakistan 14, 161–165.

Barbee JG, Conrad EJ, Jamhour NJ (2004). The effectiveness

of olanzapine, risperidone, quetiapine, and ziprasidone as

augmentation agents in treatment-resistant major


975–981.

Barbee JG, Jamhour NJ (2002). Lamotrigine as an

augmentation agent in treatment-resistant depression.

Journal of Clinical Psychiatry 63, 737–741.

Barbey JT, Roose SP (1998). SSRI safety in overdose.

Journal of Clinical Psychiatry 59 (Suppl. 15), 42–48.

Barbosa L, Berk M, Vorster M (2003). A double-

blind, randomized, placebo-controlled trial of

augmentation with lamotrigine or placebo in patients

concomitantly treated with fluoxetine for resistant major

depressive episodes. Journal of Clinical Psychiatry 64,

403–407.

Barbour KA, Blumenthal JA (2005). Exercise training

and depression in older adults. Neurobiology of Aging 26

(Suppl. 1), 119–123.

Barbui C, Hotopf M, Freemantle N, Boynton J, Churchill R,

Eccles MP, Geddes JR, Hardy R, Lewis G, Mason JM

(2000). Selective serotonin reuptake inhibitors versus

tricyclic and heterocyclic antidepressants : comparison of

drug adherence. Cochrane Database of Systematic Reviews.

CD002791.

Barbui C, Guaiana G, Garattini S (2001). Regulatory issues

in Europe. Journal of Clinical Psychopharmacology 21,

545–548.

Barbui C, Percudani M, Hotopf M (2003). Economic

evaluation of antidepressive agents : a systematic

critique of experimental and observational studies.

Journal of Clinical Psychopharmacology 23, 145–154.

Barden N, Reul JM, Holsboer F (1995). Do antidepressants

stabilize mood through actions on the hypothalamic-

pituitary-adrenocortical system? Trends in Neurosciences 18,

6–11.

Barkin RL, Barkin S (2005). The role of venlafaxine and

duloxetine in the treatment of depression with

decremental changes in somatic symptoms of pain,

chronic pain, and the pharmacokinetics and clinical

considerations of duloxetine pharmacotherapy.

American Journal of Therapeutics 12, 431–438.

Barlow DH, Gorman JM, Shear MK, Woods SW (2000).

Cognitive-behavioral therapy, imipramine, or their

combination for panic disorder : a randomized controlled

trial. Journal of the American Medical Association 283,

2529–2536.

Bartels SJ, Dums AR, Oxman TE, Schneider LS, Arean PA,

Alexopoulos GS, Jeste DV (2003). Evidence-based

practices in geriatric mental health care : an overview

of systematic reviews and meta-analyses. Psychiatric

Clinics of North America 26, 971–990, x–xi.

Bauer M, Adli M, Baethge C, Berghofer A, Sasse J, Heinz A,

Bschor T (2003). Lithium augmentation therapy in

refractory depression : clinical evidence and

neurobiological mechanisms. Canadian Journal of Psychiatry

48, 440–448.

Bauer M, Baur H, Berghofer A, Strohle A, Hellweg R,

Muller-Oerlinghausen B, Baumgartner A (2002a).

Effects of supraphysiological thyroxine administration

in healthy controls and patients with depressive disorders.

Journal of Affective Disorders 68, 285–294.

Bauer M, Bschor T, Kunz D, Berghofer A, Strohle A,

Muller-Oerlinghausen B (2000). Double-blind,

placebo-controlled trial of the use of lithium to augment

antidepressant medication in continuation treatment of

unipolar major depression. American Journal of Psychiatry

157, 1429–1435.

Bauer M, Dopfmer S (1999). Lithium augmentation in

treatment-resistant depression: meta-analysis of placebo-

controlled studies. Journal of Clinical Psychopharmacology 19,

427–434.

Bauer M, Hellweg R, Graf KJ, Baumgartner A (1998).

Treatment of refractory depression with high-dose

thyroxine. Neuropsychopharmacology 18, 444–455.

Bauer M, London ED, Rasgon N, Berman SM, Frye MA,

Altshuler LL, Mandelkern MA, Bramen J, Voytek B,

Woods R, Mazziotta JC, Whybrow PC (2005).

Supraphysiological doses of levothyroxine alter regional

cerebral metabolism and improve mood in bipolar

depression. Molecular Psychiatry 10, 456–469.


Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ

(2002b). World Federation of Societies of Biological

Psychiatry (WFSBP) Guidelines for Biological Treatment of

Unipolar Depressive Disorders. Part 2. Maintenance

treatment of major depressive disorder and treatment of

chronic depressive disorders and subthreshold

depressions. World Journal of Biological Psychiatry 3, 69–86.

Bauer M, Whybrow PC, Angst J, Versiani M, Moller HJ,

WFSBP Task Force on Tretment Guidelines for Unipolar

Depressive Disorders (2002c). World Federation of

Societies of Biological Psychiatry (WFSBP) Guidelines for

Biological Treatment of unipolar depressive disorder.

Part 1. Acute and continuation treatment of major

depressive disorder. World Journal of Biological Psychiatry

3, 4–43.

Baumann P (1996). Pharmacokinetic-pharmacodynamic

relationship of the selective serotonin reuptake inhibitors.

Clinical Pharmacokinetics 31, 444–469.

Baumann P, Broly F, Kosel M, Eap CB (1998). Ultrarapid

metabolism of clomipramine in a therapy-resistant

depressive patient, as confirmed by CYP2 D6 genotyping.

Pharmacopsychiatry 31, 72.

Baumann P, Eap CB (2001). Enantiomeric antidepressant

drugs should be considered on individual merit. Human

Psychopharmacology 16, S85–S92.

Baumann P, Hiemke C, Ulrich S, Eckermann G, Gaertner I,

Kuss HJ, Laux G, Muller-Oerlinghausen B, Rao ML,

Riederer P, Zernig G (2004). The AGNP-TDM expert

group consensus guidelines : therapeutic drug monitoring

in psychiatry. Pharmacopsychiatry 37, 243–265.

Baumann P, Ulrich S, Eckermann G, Gerlach M, Kuss HJ,

Laux G, Muller-Oerlinghausen B, Rao ML, Riederer P,

Zernig G, Hiemke C (2005). The AGNP-TDM Expert

Group Consensus Guidelines : focus on therapeutic

monitoring of antidepressants. Dialogues in Clinical


Baumann P, Zullino DF, Eap CB (2002). Enantiomers’

potential in psychopharmacology: a critical analysis with

special emphasis on the antidepressant escitalopram.

European Neuropsychopharmacology 12, 433–444.

Baxter K (2006). Stockley’s Drug Interactions : a Source Book of

Interactions, Their Mechanisms, Clinical Importance and

Management. London : Pharmaceutical Press.

Bech P, Tanghoj P, Cialdella P, Andersen HF, Pedersen AG

(2004). Escitalopram dose-response revisited : an

alternative psychometric approach to evaluate

clinical effects of escitalopram compared to citalopram and

placebo in patients with major depression. International

Journal of Neuropsychopharmacology 7, 283–290.

Beck AT (1967). Depression : Clinical, Experimental and

Theoretical Aspects. New York : Harper & Row.

Beck AT, Rush AJ, Shaw BF, Emery G (1979). Cognitive

Therapy of Depression. New York : Guilford.

Beckman SE, Sommi RW, Switzer J (2000). Consumer use of

St. John’s wort : a survey on effectiveness, safety, and

tolerability. Pharmacotherapy 20, 568–574.

Behnke K, Jensen GS, Graubaum HJ, Gruenwald J

(2002). Hypericum perforatum versus fluoxetine in

the treatment of mild to moderate depression.

Advances in Therapy 19, 43–52.

Belanoff JK, Flores BH, KalezhanM, Sund B, Schatzberg AF

(2001). Rapid reversal of psychotic depression using

mifepristone. Journal of Clinical Psychopharmacology 21,

516–521.

Belanoff JK, Rothschild AJ, Cassidy F, DeBattista C,

Baulieu EE, Schold C, Schatzberg AF (2002).

An open label trial of C-1073 (mifepristone) for psychotic

major depression. Biological Psychiatry 52, 386–392.

Belloeuf L, Le JC, Hugues FC (2000). [Paroxetine

withdrawal syndrome]. Annales de Medecine Interne (Paris)

151 (Suppl. A), A52–A53.

Beliles K, Stoudemire A (1998). Psychopharmacologic

treatment of depression in the medically ill.

Psychosomatics 39, S2–19.

Bell C, Abrams J, Nutt D (2001). Tryptophan depletion

and its implications for psychiatry. British Journal of


Bellantuono C, Migliarese G, Imperadore G (2006).

[Pharmacologic therapy of depression during pregnancy].

Recenti Progressi in Medicina 97, 94–107.

Ben-Arie O, George GC (1979). A case of tranylcypromine

(‘Parnate’) addiction. British Journal of Psychiatry 135,

273–274.

Benedetti F, Barbini B, Fulgosi MC, Colombo C,

Dallaspezia S, Pontiggia A, Smeraldi E (2005). Combined

total sleep deprivation and light therapy in the treatment of

drug-resistant bipolar depression: acute response and

long-term remission rates. Journal of Clinical Psychiatry 66,

1535–1540.

Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E

(1999). Ongoing lithium treatment prevents relapse after

total sleep deprivation. Journal of Clinical


Benedetti F, Colombo C, Barbini B, Campori E, Smeraldi E

(2001). Morning sunlight reduces length of hospitalization

in bipolar depression. Journal of Affective Disorders 62,

221–223.

Benedetti F, Colombo C, Pontiggia A, Bernasconi A, Florita

M, Smeraldi E (2003). Morning light treatment hastens the

antidepressant effect of citalopram: a placebo-controlled

trial. Journal of Clinical Psychiatry 64, 648–653.

Benedetti F, Wirz-Justice A, Terman M (2006). Personal

communication.

Benkert O, Grunder G, Wetzel H, Hackett D (1996). A

randomized, double-blind comparison of a rapidly

escalating dose of venlafaxine and imipramine in

inpatients with major depression and melancholia. Journal

of Psychiatric Research 30, 441–451.

Benkert O, Muller M, Szegedi A (2002). An overview of the

clinical efficacy of mirtazapine. Human Psychopharmacology

17 (Suppl. 1), S23–S26.

Benkert O, Szegedi A, Kohnen R (2000). Mirtazapine

compared with paroxetine in major depression. Journal of

Clinical Psychiatry 61, 656–663.

Benkert O, Szegedi A, Philipp M, Kohnen R, Heinrich C,

Heukels A, van der Vegte-Senden M, Baker RA,


Simmons JH, Schutte AJ (2006). Mirtazapine orally

disintegrating tablets versus venlafaxine extended release :

a double-blind, randomized multicenter trial comparing

the onset of antidepressant response in patients with major

depressive disorder. Journal of Clinical Psychopharmacology

26, 75–78.

Bennett DS, Ambrosini PJ, Kudes D, Metz C, Rabinovich H

(2005). Gender differences in adolescent depression : do

symptoms differ for boys and girls? Journal of Affective

Disorders 89, 35–44.

Bennett HG, Wyllie AM (1999). Paroxetine and acute angle-

closure glaucoma. Eye 13 (Pt 5), 691–692.

Berard R, Fong R, Carpenter DJ, Thomason C, Wilkinson C

(2006). An international, multicenter, placebo-controlled

trial of paroxetine in adolescents with major depressive

disorder. Journal of Child and Adolescent Psychopharmacology

16, 59–75.

Berg AO (2002). Screening for depression : recommendations

and rationale. American Journal of Nursing 102, 77–80.

Berger M, van Calker D, Riemann D (2003). Sleep and

manipulations of the sleep-wake rhythm in depression.

Acta Psychiatrica Scandinavica. Supplementum 83–91.

Berk M, Dodd S (2005a). Antidepressants and adolescents :

the bipolar confound? Human Psychopharmacology 20, 1–2.

Berk M, Dodd S (2005b). Are treatment emergent

suicidality and decreased response to antidepressants in

younger patients due to bipolar disorder being

misdiagnosed as unipolar depression? Medical Hypotheses

65, 39–43.

Berkman LF, Blumenthal J, Burg M, Carney RM, Catellier

D, Cowan MJ, Czajkowski SM, DeBusk R, Hosking J,

Jaffe A, Kaufmann PG, Mitchell P, Norman J, Powell LH,

Raczynski JM, Schneiderman N (2003). Effects of treating

depression and low perceived social support on clinical

events after myocardial infarction : the Enhancing

Recovery in Coronary Heart Disease Patients (ENRICHD)

Randomized Trial. Journal of the American Medical

Association 289, 3106–3116.

Berlim MT, Turecki G (2007). What is the meaning of

treatment resistant/refractory major depression (TRD)? A

systematic review of current randomized trials. European

Neuropsychopharmacology 17, 696–707.

Berman RM, Cappiello A, Anand A, Oren DA, Heninger

GR, Charney DS, Krystal JH (2000a). Antidepressant

effects of ketamine in depressed patients. Biological


Berman RM, Narasimhan M, Sanacora G, Miano AP,

Hoffman RE, Hu XS, Charney DS, Boutros NN (2000b).

A randomized clinical trial of repetitive transcranial

magnetic stimulation in the treatment of major depression.


Berndt ER (2005). To inform or persuade? Direct-to-

consumer advertising of prescription drugs. New England

Journal of Medicine 352, 325–328.

Berndt ER, Finkelstein SN, Greenberg PE, Howland RH,

Keith A, Rush AJ, Russell J, Keller MB (1998). Workplace

performance effects from chronic depression and its

treatment. Journal of Health Economics 17, 511–535.

Bertilsson L, Aberg-Wistedt A, Gustafsson LL, Nordin C

(1985). Extremely rapid hydroxylation of debrisoquine : a

case report with implication for treatment with

nortriptyline and other tricyclic antidepressants.

Therapeutic Drug Monitoring 7, 478–480.

Bertilsson L, Dahl ML, Dalen P, Al Shurbaji A (2002).

Molecular genetics of CYP2D6: clinical relevance with

focus on psychotropic drugs. British Journal of Clinical


Bertilsson L, Mellstrom B, Sjoqvist F, Martensson B,

Asberg M (1981). Slow hydroxylation of nortriptyline

and concomitant poor debrisoquine hydroxylation :

clinical implications. Lancet i, 560–561.

Bertschy G, Vandel S, Vandel B, Allers G, Volmat R (1991).

Fluvoxamine-tricyclic antidepressant interaction : an

accidental finding. European Journal of Clinical Pharmacology

40, 119–120.

Beutler LE, Clarkin JF, Bongar B (2000). Guidelines for the

Systematic Treatment of the Depressed Patient. New York :

Oxford University Press.

Bezchlibnyk-Butler K, Aleksic I, Kennedy SH (2000).

Citalopram: a review of pharmacological and

clinical effects. Journal of Psychiatry and Neuroscience 25,

241–254.

Bickel A, Kornhuber J, Maihofner C, Ropohl A (2005).

Exacerbation of migraine attacks during treatment with

the selective serotonin reuptake inhibitor sertraline.

A case report. Pharmacopsychiatry 38, 327–328.

Bielski RJ, Ventura D, Chang CC (2004). A double-blind

comparison of escitalopram and venlafaxine extended

release in the treatment of major depressive disorder.


Binder EB, Salyakina D, Lichtner P, Wochnik GM, Ising M,

Putz B, Papiol S, Seaman S, Lucae S, Kohli MA, Nickel T,

Kunzel HE, Fuchs B, Majer M, Pfennig A, Kern N,

Brunner J, Modell S, Baghai T, Deiml T, Zill P, Bondy B,

Rupprecht R, Messer T, Kohnlein O, Dabitz H, Bruckl T,

Muller N, Pfister H, Lieb R, Mueller JC, Lohmussaar E,

Strom TM, Bettecken T, Meitinger T, Uhr M, Rein T,

Holsboer F, Muller-Myhsok B (2004). Polymorphisms in

FKBP5 are associated with increased recurrence of

depressive episodes and rapid response to antidepressant

treatment. Nature Genetics 36, 1319–1325.

Birkenhager TK, Renes JW, Pluijms EM (2004). One-year

follow-up after successful ECT: a naturalistic study in

depressed inpatients. Journal of Clinical Psychiatry 65, 87–91.

Birmaher B, Brent DA, Benson RS (1998). Summary of the

practice parameters for the assessment and treatment of

children and adolescents with depressive disorders.

American Academy of Child and Adolescent Psychiatry.

Journal of the American Academy of Child and Adolescent


Bitran D, Hilvers RJ, Kellogg CK (1991). Anxiolytic effects of

3a-hydroxy-5a[b]-pregnan-20-one : endogenous

metabolites of progesterone that are active at the GABAA

receptor. Brain Research 561, 157–161.

Bjerkenstedt L, Edman GV, Alken RG, Mannel M (2005).

Hypericum extract LI 160 and fluoxetine in mild to


moderate depression : a randomized, placebo-controlled

multi-center study in outpatients. European Archives of

Psychiatry and Clinical Neuroscience 255, 40–47.

Black DW, Winokur G, Nasrallah A (1993). A multivariate

analysis of the experience of 423 depressed inpatients

treated with electroconvulsive therapy. Convulsive Therapy

9, 112–120.

Blakely RD (2001). Physiological genomics of antidepressant

targets : keeping the periphery in mind. Journal of


Blanco C, Raza MS, Schneier FR, Liebowitz MR (2003).

The evidence-based pharmacological treatment of social

anxiety disorder. International Journal of


Blier P (2001). Pharmacology of rapid-onset antidepressant

treatment strategies. Journal of Clinical Psychiatry 62

(Suppl. 15), 12–17.

Blier P (2003). The pharmacology of putative early-onset

antidepressant strategies. European


Blier P (2006). Pregnancy, depression, antidepressants and

breast-feeding. Journal of Psychiatry and Neuroscience 31,

226–228.

Blier P, Bergeron R (1995). The safety of concomitant use

of sumatriptan and antidepressant treatments. Journal of


Blier P, Saint-Andre E, Hebert C, de Montigny C, Lavoie N,

Debonnel G (2006). Effects of different doses of

venlafaxine on serotonin and norepinephrine reuptake in

healthy volunteers. International Journal of

Neuropsychopharmacology 1–10.

Blier P, Ward NM (2003). Is there a role for 5-HT1A agonists

in the treatment of depression? Biological Psychiatry 53,

193–203.

Boardman AP, Healy D (2001). Modelling suicide risk in

affective disorders. European Psychiatry 16, 400–405.

Bodkin JA, Amsterdam JD (2002). Transdermal selegiline in

major depression : a double-blind, placebo-controlled,

parallel-group study in outpatients. American Journal of

Psychiatry 159, 1869–1875.

Boerner RJ, Moller HJ (1999). The importance of new

antidepressants in the treatment of anxiety/depressive

disorders. Pharmacopsychiatry 32, 119–126.

Bogdanowicz E, Kalinowski A, Swiecicki L (1991).

[Treatment of depression with intravenous infusions of

clomipramine and maprotiline]. Psychiatria Polska 25,

19–24.

Bogetto F, Bellino S, Revello RB, Patria L (2002).

Discontinuation syndrome in dysthymic patients treated

with selective serotonin reuptake inhibitors : a clinical

investigation. CNS Drugs 16, 273–283.

Boggio PS, Bermpohl F, Vergara AO, Muniz AL, Nahas FH,

Leme PB, Rigonatti SP, Fregni F (2007a). Go-no-go

task performance improvement after anodal transcranial

DC stimulation of the left dorsolateral prefrontal cortex in

major depression. Journal of Affective Disorders 101, 91–98.

Boggio PS, Rigonatti SP, Ribeiro RB, Myczkowski ML,

Nitsche MA, Pascual-Leone A, Fregni F (2007b). A

randomized, double-blind clinical trial on the efficacy of

cortical direct current stimulation for the treatment of

major depression. International Journal of

Neuropsychopharmacology 1–6.

Bolton P, Bass J, Neugebauer R, Verdeli H, Clougherty KF,

Wickramaratne P, Speelman L, Ndogoni L, Weissman M

(2003). Group interpersonal psychotherapy for depression

in rural Uganda: a randomized controlled trial. Journal of

the American Medical Association 289, 3117–3124.

Bolton P, Wilk CM, Ndogoni L (2004). Assessment of

depression prevalence in rural Uganda using symptom

and function criteria. Social Psychiatry and Psychiatric

Epidemiology 39, 442–447.

Bondareff W, Alpert M, Friedhoff AJ, Richter EM,

Clary CM, Batzar E (2000). Comparison of sertraline and

nortriptyline in the treatment of major depressive

disorder in late life. American Journal of Psychiatry 157,

729–736.

Bondy B, Baghai TC, Zill P, Schule C, Eser D, Deiml T,

Zwanzger P, Ella R, Rupprecht R (2005). Genetic variants

in the angiotensin I-converting-enzyme (ACE) and

angiotensin II receptor (AT1) gene and clinical outcome in

depression. Progress in Neuro-Psychopharmacology and


Bonnabry P, Sievering J, Leemann T, Dayer P (2001).

Quantitative drug interactions prediction system

(Q-DIPS) : a dynamic computer-based method to assist in

the choice of clinically relevant in vivo studies. Clinical

Pharmacokinetics 40, 631–640.

Bonnet U (2003). Moclobemide : therapeutic use and clinical

studies. CNS Drug Reviews 9, 97–140.

Borchelt M (1995). [Potential side-effects and interactions in

multiple medication in elderly patients : methodology and

results of the Berlin Study of Aging]. Zeitschrift Fur

Gerontologie Und Geriatrie 28, 420–428.

Borghi J, Guest JF (2000). Economic impact of using

mirtazapine compared to amitriptyline and fluoxetine in

the treatment of moderate and severe depression in the

UK. European Psychiatry 15, 378–387.

Bosker FJ, Westerink BH, Cremers TI, Gerrits M, van der

Hart MG, Kuipers SD, van der Pompe G, ter Horst GJ,

Den Boer JA, Korf J (2004). Future antidepressants : what

is in the pipeline and what is missing? CNS Drugs 18,

705–732.

Bostic JQ, Rubin DH, Prince J, Schlozman S (2005).

Treatment of depression in children and adolescents.

Journal of Psychiatric Practice 11, 141–154.

Bostwick JM, Pankratz VS (2000). Affective disorders

and suicide risk : a reexamination. American Journal of

Psychiatry 157, 1925–1932.

Bouali S, Evrard A, Chastanet M, Lesch KP, Hamon M,

Adrien J (2003). Sex hormone-dependent desensitization

of 5-HT1A autoreceptors in knockout mice deficient in

the 5-HT transporter. European Journal of Neuroscience 18,

2203–2212.

Boulenger JP, Huusom AK, Florea I, Baekdal T,

SarchiaponeM (2006). A comparative study of the efficacy

of long-term treatment with escitalopram and paroxetine


in severely depressed patients. Current Medical Research

and Opinion 22, 1331–1341.

Bower P, Byford S, Sibbald B, Ward E, King M, Lloyd M,

Gabbay M (2000). Randomised controlled trial of

non-directive counselling, cognitive-behaviour therapy,

and usual general practitioner care for patients with

depression. II : cost effectiveness. British Medical Journal

321, 1389–1392.

Bower P, Rowland N (2006). Effectiveness and cost

effectiveness of counselling in primary care. Cochrane

Database of Systematic Reviews 3, CD001025.

Bower P, Rowland N, Mellor C, Heywood P, Godfrey C,

Hardy R (2002). Effectiveness and cost effectiveness of

counselling in primary care. Cochrane Database of Systematic

Reviews CD001025.

Boyer EW, Shannon M (2005). The serotonin syndrome.

New England Journal of Medicine 352, 1112–1120.

Bradvik L, Berglund M (2005). Suicide in severe

depression related to treatment : depressive

characteristics and rate of antidepressant overdose.

European Archives of Psychiatry and Clinical Neuroscience 255,

245–250.

Bramness JG, Skurtveit S, Morland J (2003). Testing for

benzodiazepine inebriation–relationship between

benzodiazepine concentration and simple clinical tests for

impairment in a sample of drugged drivers. European

Journal of Clinical Pharmacology 59, 593–601.

Breivik T, Gundersen Y, Myhrer T, Fonnum F, Osmundsen

H, Murison R, Gjermo P, von HS, Opstad PK (2006).

Enhanced susceptibility to periodontitis in an animal

model of depression: reversed by chronic treatment with

the anti-depressant tianeptine. Journal of Clinical

Periodontology 33, 469–477.

Brenner R, Azbel V, Madhusoodanan S, Pawlowska M

(2000). Comparison of an extract of hypericum (LI 160)

and sertraline in the treatment of depression: a

double-blind, randomized pilot study. Clinical Therapeutics

22, 411–419.

Breslau N, Schultz L, Peterson E (1995). Sex differences in

depression : a role for preexisting anxiety. Psychiatry

Research 58, 1–12.

Bridge JA, Iyengar S, Salary CB, Barbe RP, Birmaher B,

Pincus HA, Ren L, Brent DA (2007). Clinical response and

risk for reported suicidal ideation and suicide attempts in

pediatric antidepressant treatment : a meta-analysis of

randomized controlled trials. Journal of the American

Medical Association 297, 1683–1696.

Bridge JA, Salary CB, Birmaher B, Asare AG, Brent DA

(2005). The risks and benefits of antidepressant treatment

for youth depression. Annals of Medicine 37, 404–412.

Briggs NC, Jefferson JW, Koenecke FH (1990).

Tranylcypromine addiction : a case report and review.


Briley M (1998). Specific serotonin and noradrenaline

reuptake inhibitors (SNRIs). A review of their

pharmacology, clinical efficacy and tolerability.

Human Psychopharmacology : Clinical and Experimental 13,

99–111.

Brion S, Audrain S, de Bodinat C (1996). [Major depressive

episodes in patients over 70 years of age. Evaluation of the

efficiency and acceptability of tianeptine and mianserin].

Presse Medicale 25, 461–468.

Brøsen K (1996). Drug-metabolizing enzymes and

therapeutic drug monitoring in psychiatry. Therapeutic

Drug Monitoring 18, 393–396.

Brown C, Battista DR, Bruehlman R, Sereika SS, Thase ME,

Dunbar-Jacob J (2005). Beliefs about antidepressant

medications in primary care patients : relationship to self-

reported adherence. Medical Care 43, 1203–1207.

Brown CS, Bryant SG (1988). Monoamine oxidase inhibitors :

safety and efficacy issues. Drug Intelligence and Clinical

Pharmacy 22, 232–235.

Brown GK, Beck AT, Steer RA, Grisham JR (2000). Risk

factors for suicide in psychiatric outpatients : a 20-year

prospective study. Journal of Consulting and Clinical

Psychology 68, 371–377.

Brown GW, Harris T (1978). Social Origins of Depression : a

Study of Psychiatric Disorder in Women. London : Tavistock

Publications.

Brown MC, Nimmerrichter AA, Guest JF (1999). Cost-

effectiveness of mirtazapine compared to amitriptyline and

fluoxetine in the treatment of moderate and severe

depression in austria. European Psychiatry 14, 230–244.

Browne G, Steiner M, Roberts J, Gafni A, Byrne C, Dunn E,

Bell B, Mills M, Chalklin L, Wallik D, Kraemer J (2002).

Sertraline and/or interpersonal psychotherapy for patients

with dysthymic disorder in primary care : 6-month

comparison with longitudinal 2-year follow-up of

effectiveness and costs. Journal of Affective Disorders 68,

317–330.

Bruck P, Antao CA, Henry JA (1992). Generic prescribing of

antidepressants. Journal of the Royal Society of Medicine 85,

682–685.

Brunello N, Mendlewicz J, Kasper S, Leonard B,

Montgomery S, Nelson J, Paykel E, Versiani M,

Racagni G (2002). The role of noradrenaline and

selective noradrenaline reuptake inhibition in depression.


Brunnauer A, Laux G, Geiger E, Soyka M, Moller HJ (2006).

Antidepressants and driving ability : results from a clinical

study. J. Clin. Psychiatry 67, 1776–1781.

Bschor T, Bauer M (2006). Efficacy and mechanisms

of action of lithium augmentation in refractory

major depression. Current Pharmaceutical Design 12,

2985–2992.

Bschor T, Berghofer A, Strohle A, Kunz D, Adli M, Muller-

Oerlinghausen B, Bauer M (2002). How long should the

lithium augmentation strategy be maintained? A 1-year

follow-up of a placebo-controlled study in unipolar

refractory major depression. Journal of Clinical


Bump GM, Mulsant BH, Pollock BG, Mazumdar S, Begley

AE, Dew MA, Reynolds CF, III. (2001). Paroxetine versus

nortriptyline in the continuation and maintenance

treatment of depression in the elderly. Depress. Anxiety. 13,

38–44.


Burgess S, Geddes J, Hawton K, Townsend E, Jamison K,

Goodwin G (2001a). Lithium for maintenance treatment of

mood disorders. Cochrane Database of Systematic Reviews

CD003013.

Burgess S, Geddes J, Hawton K, Townsend E, Jamison K,

Goodwin G (2001b). Lithium for maintenance treatment of

mood disorders [Update]. Cochrane Database of Systematic

Reviews CD003013.

BurkeMJ, Preskorn SH (1995). Short term treatment of mood

disorders with standard antidepressants. In : Bloom FE,

Kupfer DJ (Eds.), Psychopharmacology : The Fourth

Generation of Progress (pp. 1053–1065). New York : Raven

Press.

Burke MJ, Preskorn SH (1999). Therapeutic drug monitoring

of antidepressants : cost implications and relevance to

clinical practice. Clinical Pharmacokinetics 37, 147–165.

Burn DJ (2002). Beyond the iron mask : towards better

recognition and treatment of depression associated with

Parkinson’s disease. Movement Disorders 17, 445–454.

Burrows GD (1992). Long-term clinical management of

depressive disorders. Journal of Clinical Psychiatry 53

(Suppl.), 32–35.

Burrows GD, Davies B, Scoggins BA (1972). Plasma

concentration of nortriptyline and clinical response in

depressive illness. Lancet 2, 619–623.

Burrows GD, Hughes I, Norman T (1981). Cardiotoxicity of

Antidepressants : Experimental Background. In : Wheatly

D (Ed.), Stress and the Heart (pp. 131–171). New York :

Raven Press.

Burrows GD, Maguire KP, Norman TR (1998).

Antidepressant efficacy and tolerability of the selective

norepinephrine reuptake inhibitor reboxetine : a review.


Burrows GD, Norman TR (1997). Antidepressants : clinical

aspects. Stress Medicine 13, 167–172.

Burrows GD, Norman TR, Judd FK (1993). Long-term

management of depressive disorders. Current Therapeutic

Research 54, 832–837.

Burrows GD, Norman TR, Judd FK (1994). Definition

and differential diagnosis of treatment-resistant

depression. International Clinical Psychopharmacology 9

(Suppl. 2), 5–10.

Burrows GD, Norman TR, Maguire KP, Rubinstein G,

Scoggins BA, Davies B (1977). A new antidepressant

butriptyline : plasma levels and clinical response. Medical

Journal of Australia 2, 604–606.

Burrows GD, Vohra J, Hunt D, Sloman JG, Scoggins BA,

Davies B (1976). Cardiac effects of different tricyclic

antidepressant drugs. British Journal of Psychiatry 129,

335–341.

Burt T, Lisanby SH, Sackeim HA (2002). Neuropsychiatric

applications of transcranial magnetic stimulation: a meta

analysis. International Journal of Neuropsychopharmacology 5,

73–103.

Burt VK, Suri R, Altshuler L, Stowe Z, Hendrick VC,

Muntean E (2001). The use of psychotropic medications

during breast-feeding. American Journal of Psychiatry 158,

1001–1009.

Butt AA, Evans R, Skanderson M, Shakil AO (2006).

Comorbid medical and psychiatric conditions and

substance abuse in HCV infected persons on dialysis.

Journal of Hepatology 44, 864–868.

Bymaster FP, Dreshfield-Ahmad LJ, Threlkeld PG, Shaw JL,

Thompson L, Nelson DL, Hemrick-Luecke SK, Wong DT

(2001). Comparative affinity of duloxetine and venlafaxine

for serotonin and norepinephrine transporters in vitro

and in vivo, human serotonin receptor subtypes, and other

neuronal receptors. Neuropsychopharmacology 25, 871–880.

Calil HM (2001). Fluoxetine : a suitable long-term treatment.


Callahan CM, Kroenke K, Counsell SR, Hendrie HC,

Perkins AJ, Katon W, Noel PH, Harpole L, Hunkeler EM,

Unutzer J (2005). Treatment of depression improves

physical functioning in older adults. Journal of the American

Geriatrics Society 53, 367–373.

Campo-Arias A (2004). [Antidepressants in migraine

prophylaxis : an approximation]. Revista De Neurologia 38,

864–868.

Canadian Coordinating Office for Health Technology

Assesment (1997). Selective Serotonin Reuptake Inhibitors

(SSRI’s) for Major Depresion. Part 2. The Cost-Effectiveness

of SSRI’s in Treatment of Depression. Ottawa:

Canadian Coordinating Office for Health Technology

Assesment.

Canadian Psychiatric Association and Canadian Network

for Mood and Anxiety Treatments (CANMAT) (2001).

Clinical guidelines for the treatment of depressive

disorders. Canadian Journal of Psychiatry 46 (Suppl. 1),

5S–90S.

Carlsten A, Waern M, Ekedahl A, Ranstam J (2001).

Antidepressant medication and suicide in Sweden.

Pharmacoepidemiology and Drug Safety 10, 525–530.

Carney RM, Blumenthal JA, Freedland KE, Youngblood M,

Veith RC, Burg MM, Cornell C, Saab PG, Kaufmann PG,

Czajkowski SM, Jaffe AS (2004). Depression and late

mortality after myocardial infarction in the Enhancing

Recovery in Coronary Heart Disease (ENRICHD) study.

Psychosomatic Medicine 66, 466–474.

Carrasco GA, Barker SA, Zhang Y, Damjanoska KJ,

Sullivan NR, Garcia F, D’Souza DN, Muma NA,

van De Kar LD (2004). Estrogen treatment increases the

levels of regulator of G protein signaling-Z1 in the

hypothalamic paraventricular nucleus : possible role in

desensitization of 5-hydroxytryptamine1A receptors.


Casciano J, Arikian S, Tarride JE, Doyle JJ, Casciano R

(1999). A pharmacoeconomic evaluation of major

depressive disorder (Italy). Epidemiologia e Psichiatria

Sociale 8, 220–231.

Casciano J, Doyle J, Arikian S, Casciano R (2001). The health

economic impact of antidepressant usage from a payer’s

perspective : a multinational study. International Journal of

Clinical Practice 55, 292–299.

Casciano R (2003). Effectiveness measures of major

depressive disorder in pharmacoeconomic evaluations.

Managed Care Interface (Suppl. B), 14–15.


Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW,

Harrington H, McClay J, Mill J, Martin J, Braithwaite A,

Poulton R (2003). Influence of life stress on depression:

moderation by a polymorphism in the 5-HTT gene. Science

301, 386–389.

Cassano GB, Jori MC (2002). Efficacy and safety of

amisulpride 50 mg versus paroxetine 20 mg in major

depression : a randomized, double-blind, parallel group

study. International Clinical Psychopharmacology 17, 27–32.

Cassano GB, Musetti L, Perugi G, Soriani A, Mignani V,

McNair DM, Akiskal HS (1988). A proposed new

approach to the clinical subclassification of depressive

illness. Pharmacopsychiatry 21, 19–23.

Castren E (2005). Is mood chemistry? Nature Reviews.


Ceskova E, Nahunek K, Rysanek R, Svestka J (1983).

[Clinical experience with clomipramine (Hydiphen) and

desipramine (Petytyl) by parenteral administration in the

treatment of endogenous depression with signs of

pharmacoresistance]. Cesk. Psychiatr. 79, 94–101.

Chambers CD, Anderson PO, Thomas RG, Dick LM, Felix

RJ, Johnson KA, Jones KL (1999). Weight gain in infants

breastfed by mothers who take fluoxetine. Pediatrics 104,

e61.

Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler

MM, Louik C, Jones KL, Mitchell AA (2006). Selective

serotonin-reuptake inhibitors and risk of persistent

pulmonary hypertension of the newborn. New England

Journal of Medicine 354, 579–587.

Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL

(1996). Birth outcomes in pregnant women taking

fluoxetine. New England Journal of Medicine 335, 1010–1015.

Charney DS, Grothe DR, Smith SL, Brady KT, Kaltsounis-

Puckett J, Wright CW, Laird LK, Rush AJ (2002).

Overview of psychiatric disorders and the role of newer

antidepressants. Journal of Clinical Psychiatry 63, 3–9.

Chatterjee U, Poddar A, Ameen S (2006). Evidence-Based

Psychotherapy (http://www.psyplexus.com/mhr/

evidence_based_psychotherapy.html). Accessed 10

February 2007).

Cheeta S, Schifano F, Oyefeso A, Webb L, Ghodse AH

(2004). Antidepressant-related deaths and antidepressant

prescriptions in England and Wales, 1998-2000. British

Journal of Psychiatry 184, 41–47.

Chen F, Larsen MB, Sanchez C, Wiborg O (2005). The

S-enantiomer of R,S-citalopram increases inhibitor binding

to the human serotonin transporter by an allosteric

mechanism. Comparison with other serotonin transporter

inhibitors. European Neuropsychopharmacology 15, 193–198.

Chen S, Chou WH, Blouin RA, Mao Z, Humphries LL,

Meek C, Neill JR, Martin WL, Hays LR, Wedlund PJ

(1996). The cytochrome P450 2D6 (CYP2D6) enzyme

polymorphism: screening costs and influence on clinical

outcomes in psychiatry. Clinical Pharmacology and

Therapeutics 60, 522–534.

Cheng K, Yan H, Duan KJ (2005). [Advances in clinical and

mechanism studies of acupuncture and moxibustion for

treatment of depression]. Zhongguo Zhen Jiu 25, 221–223.

Cheung AH, Emslie GJ, Mayes TL (2005). Review of the

efficacy and safety of antidepressants in youth depression.

Journal of Child Psychology and Psychiatry, and Allied

Disciplines 46, 735–754.

Cheung AH, Emslie GJ, Mayes TL (2006). The use of

antidepressants to treat depression in children and

adolescents. Canadian Medical Association Journal 174,

193–200.

Chisholm D, Healey A, Knapp M (1997). QALYs and

mental health care. Social Psychiatry and Psychiatric


Chiu E (2004). Epidemiology of depression in the Asia

Pacific region. Australasian Psychiatry 12 (Suppl.), S4–10.

Chiu HF (1997). Antidepressants in the elderly. International

Journal of Clinical Practice 51, 369–374.

Chopra MP, Zubritsky C, Knott K, Have TT, Hadley T,

Coyne JC, Oslin DW (2005). Importance of subsyndromal

symptoms of depression in elderly patients. American

Journal of Geriatric Psychiatry 13, 597–606.

Cipriani A, Barbui C, Brambilla P, Furukawa TA, Hotopf

M, Geddes JR (2006). Are all antidepressants really the

same? The case of fluoxetine : a systematic review. Journal

of Clinical Psychiatry 67, 850–864.

Cipriani A, Barbui C, Geddes JR (2005a). Suicide,

depression, and antidepressants. British Medical Journal

330, 373–374.

Cipriani A, Brambilla P, Furukawa T, Geddes J, Gregis M,

Hotopf M, Malvini L, Barbui C (2005b). Fluoxetine

versus other types of pharmacotherapy for depression.

Cochrane Database of Systematic Reviews CD004185.

Ciusani E, Zullino DF, Eap CB, Brawand-Amey M,

Brocard M, Baumann P (2004). Combination therapy

with venlafaxine and carbamazepine in depressive

patients not responding to venlafaxine : pharmacokinetic

and clinical aspects. Journal of Psychopharmacology 18,

559–566.

Claassen CA, Trivedi MH, Rush AJ, Husain MM, Zisook S,

Young E, Leuchter A, Wisniewski SR, Balasubramani

GK, Alpert J (2006). Clinical differences among depressed

patients with and without a history of suicide attempts :

Findings from the STAR*D trial. Journal of Affective


Claghorn JL and Feighner JP. (1993). A double-blind

comparison of paroxetine with imipramine in the

long-term treatment of depression. Journal of Clinical

Psychopharmacology 13, 23S–27S.

Clark RE, Xie H, Brunette MF (2004). Benzodiazepine

prescription practices and substance abuse in persons

with severe mental illness. Journal of Clinical Psychiatry 65,

151–155.

Clayton AH, Zajecka J, Ferguson JM, Filipiak-Reisner JK,

Brown MT, Schwartz GE (2003). Lack of sexual

dysfunction with the selective noradrenaline reuptake

inhibitor reboxetine during treatment for major depressive

disorder. International Clinical Psychopharmacology 18,

151–156.

Clement Jerdi M, Daali Y, Kondo Oestreicher M, Cherkaoui

S, Dayer P (2005). A simplified analytical method for a


phenotyping cocktail of major CYP450 biotransformation

routes. Journal of Pharmaceutical and Biomedical Analysis

35, 1203–1212.

Clerc GE, Ruimy P, Verdeau-Palles J (1994). A double-blind

comparison of venlafaxine and fluoxetine in patients

hospitalized for major depression and melancholia. The

Venlafaxine French Inpatient Study Group. International


Cohen LS, Nonacs R, Viguera AC, Reminick A (2004).

Diagnosis and treatment of depression during pregnancy.

CNS Spectrums 9, 209–216.

Cole MG, Bellavance F, Mansour A (1999). Prognosis of

depression in elderly community and primary care

populations : a systematic review and meta-analysis.


Coleman CC, Cunningham LA, Foster VJ, Batey SR,

Donahue RM, Houser TL, Ascher JA (1999).

Sexual dysfunction associated with the treatment of

depression : a placebo-controlled comparison of bupropion

sustained release and sertraline treatment. Annals of


Coleman CC, King BR, Bolden-Watson C, Book MJ,

Segraves RT, Richard N, Ascher J, Batey S, Jamerson B,

Metz A (2001). A placebo-controlled comparison of the

effects on sexual functioning of bupropion sustained

release and fluoxetine. Clinical Therapeutics 23, 1040–1058.

Collantes-Estevez E, Fernandez-Perez C (2003). Improved

control of osteoarthritis pain and self-reported health

status in non-responders to celecoxib switched to

rofecoxib : results of PAVIA, an open-label post-marketing

survey in Spain. Current Medical Research and Opinion 19,

402–410.

Colombo C, Benedetti F, Barbini B, Campori E, Smeraldi E

(1999). Rate of switch from depression into mania after

therapeutic sleep deprivation in bipolar depression.

Psychiatry Research 86, 267–270.

Colombo C, Lucca A, Benedetti F, Barbini B, Campori E,

Smeraldi E (2000). Total sleep deprivation combined with

lithium and light therapy in the treatment of bipolar

depression : replication of main effects and interaction.

Psychiatry Research 95, 43–53.

Committee for Proprietary Medicinal Products (2002)

Concept paper on the revision of the committee for

proprietary medicinal products (CPMP) note for guidance

on medicinal products for the treatment of depression.

Document id : cpmp/ewp/518/97 (http://

www.emea.eu.int). Accessed 22 June 2007.

Commitee on Safety of Medicines (2004). Report of the

CSM Expert Working Group on the Safety of Selective

Serotonin Reuptake Inhibitor Antidepressants. (http://

www.mhra.gov.uk/home/groups/pl-p/documents/

drugsafetymessage/con019472.pdf). Accessed 24 January

2006.

Compton MT, Nemeroff CB (2000). The treatment of bipolar

depression. Journal of Clinical Psychiatry 61 (Suppl. 9),

57–67.

Compton SN, March JS, Brent D, Albano AM, Weersing R,

Curry J (2004). Cognitive-behavioral psychotherapy for

anxiety and depressive disorders in children and

adolescents : an evidence-based medicine review. Journal

of the American Academy of Child and Adolescent Psychiatry

43, 930–959.

Conus P, Bondolfi G, Eap CB, Macciardi F, Baumann P

(1996). Pharmacokinetic fluvoxamine-clomipramine

interaction with favorable therapeutic consequences in

therapy-resistant depressive patient. Pharmacopsychiatry

29, 108–110.

Conway CR, McGuire JM, Baram VY (2004). Nefazodone-

induced liver failure. Journal of Clinical Psychopharmacology

24, 353–354.

Coppen A (2000). Lithium in unipolar depression and the

prevention of suicide. Journal of Clinical Psychiatry 61

(Suppl. 9), 52–56.

Coppen A, Bailey J (2000). Enhancement of the

antidepressant action of fluoxetine by folic acid : a

randomised, placebo controlled trial. Journal of Affective


Corrigan MH, Denahan AQ, Wright CE, Ragual RJ,

Evans DL (2000). Comparison of pramipexole, fluoxetine,

and placebo in patients with major depression. Depression

and Anxiety 11, 58–65.

Corruble E, Guelfi JD (2000). Does increasing dose

improve efficacy in patients with poor antidepressant

response : a review. Acta Psychiatrica Scandinavica 101,

343–348.

Coryell W (1996). Psychotic depression. Journal of Clinical

Psychiatry 57 (Suppl. 3), 27–31.

Coryell W (1998). The treatment of psychotic depression.


Coryell W, Pfohl B, Zimmerman M (1985). Outcome

following electroconvulsive therapy: a comparison of

primary and secondary depression. Convulsive Therapy 1,

10–14.

Couturier JL (2005). Efficacy of rapid-rate repetitive

transcranial magnetic stimulation in the treatment of

depression : a systematic review and meta-analysis. Journal

of Psychiatry and Neuroscience 30, 83–90.

Cozza KL, Armstrong SC (2005). Concise Guide to the

Cytochrome P450 System. Drug Interaction Principles for

Medical Practice. Washington : Amer Psychiatric Pub Inc.

Craft LL, Perna FM (2004). The benefits of exercise for the

clinically depressed. Primary Care Companion to the Journal


Croft H, Settle EJ, Houser T, Batey SR, Donahue RM,

Ascher JA (1999). A placebo-controlled comparison of the

antidepressant efficacy and effects on sexual functioning of

sustained-release bupropion and sertraline. Clinical


Cui C, Yang M, Yao Z, Cao B, Luo Z, Xu Y, Chen Y (1995).

[Antidepressant active constituents in the roots of

Morinda officinalis How]. Zhongguo Zhong Yao Za Zhi 20,

36–3.

Cullen M, Mitchell P, Brodaty H, Boyce P, Parker G, Hickie

I, Wilhelm K (1991). Carbamazepine for treatment-

resistant melancholia. Journal of Clinical Psychiatry 52,

472–476.


Culman J, Klee S, Ohlendorf C, Unger T (1997). Effect of

tachykinin receptor inhibition in the brain on

cardiovascular and behavioral responses to stress. Journal

of Pharmacology and Experimental Therapeutics 280, 238–246.

Cummings JL, Masterman DL (1999). Depression in patients

with Parkinson’s disease. International Journal of Geriatric


Cunningham LA, Borison RL, Carman JS, Chouinard G,

Crowder JE, Diamond BI, Fischer DE, Hearst E (1994). A

comparison of venlafaxine, trazodone, and placebo in

major depression. Journal of Clinical Psychopharmacology 14,

99–106.

Curran S (1995). Effect of paroxetine on seizure length during

electroconvulsive therapy. Acta Psychiatrica Scandinavica

92, 239–240.

Curry JF (2001). Specific psychotherapies for childhood and

adolescent depression. Biological Psychiatry 49, 1091–1100.

Curtin F, Berney P, Kaufmann C (2002). Moclobemide

discontinuation syndrome predominantly presenting with

influenza-like symptoms. J Psychopharmacol. 16, 271–272.

Cuzzell JZ (2006). Paroxetine may increase risk for congenital

malformations. Dermatology Nursing 18, 68.

Cyr M, Brown CS (1996). Nefazodone : its place among

antidepressants. Annals of Pharmacotherapy 30, 1006–1012.

Czekalla J, Gastpar M, Hubner WD, Jager D (1997). The

effect of hypericum extract on cardiac conduction as seen

in the electrocardiogram compared to that of imipramine.

Pharmacopsychiatry 30 (Suppl. 2), 86–88.

Dam J, Ryde L, Svejso J, Lauge N, Lauritsen B, Bech P

(1998). Morning fluoxetine plus evening mianserin versus

morning fluoxetine plus evening placebo in the acute

treatment of major depression. Pharmacopsychiatry 31,

48–54.

Danish University Antidepressant Group (1986).

Citalopram: clinical effect profile in comparison with

clomipramine. A controlled multicenter study. Danish

University Antidepressant Group. Psychopharmacology 90,

131–138.


Paroxetine : a selective serotonin reuptake inhibitor

showing better tolerance, but weaker antidepressant effect

than clomipramine in a controlled multicenter study.

Danish University Antidepressant Group. Journal of

Affective Disorders 18, 289–299.


Moclobemide : a reversible MAO-A-inhibitor showing

weaker antidepressant effect than clomipramine in a

controlled multicenter study. Danish University

Antidepressant Group. Journal of Affective Disorders 28,

105–116.

Dantzer R (2004). Cytokine-induced sickness behaviour : a

neuroimmune response to activation of innate immunity.

European Journal of Pharmacology 500, 399–411.

Darcourt G, Souetre E, Pringuey D, Robert P, Feuillade P,

Belugou JL (1992). [Disorders of circadian rhythms in

depression]. Encephale 18 Spec No. 4, 473–478.

Dardennes R, Berdeaux G, Lafuma A, Fagnani F (1999).

Comparison of the cost-effectiveness of milnacipran

(a SNRI) with TCAs and SSRIs : a modeling approach.

European Psychiatry 14, 152–162.

Dardennes RM, Even C, Ballon N, Bange F (1998). Serotonin

syndrome caused by a clomipramine-moclobemide

interaction. Journal of Clinical Psychiatry 59, 382–383.

Davidson J, McLeod M, Law-Yone B, Linnoila M (1978). A

comparison of electroconvulsive therapy and combined

phenelzine-amitriptyline in refractory depression. Archives

of General Psychiatry 35, 639–642.

Davidson J, Pearlstein T, Londborg P, Brady KT, Rothbaum

B, Bell J, Maddock R, Hegel MT, Farfel G (2001). Efficacy

of sertraline in preventing relapse of posttraumatic stress

disorder : results of a 28-week double-blind, placebo-

controlled study. American Journal of Psychiatry 158,

1974–1981.

Davidson J, Pelton S (1986). Forms of atypical depression

and their response to antidepressant drugs. Psychiatry

Research 17, 87–95.

Davidson JR, Connor KM, Hertzberg MA, Weisler RH,

Wilson WH, Payne VM (2005). Maintenance therapy with

fluoxetine in posttraumatic stress disorder : a placebo-

controlled discontinuation study. Journal of Clinical


Davidson JR, McLeod MN, Turnbull CD, Miller RD

(1981). A comparison of phenelzine and imipramine in

depressed inpatients. Journal of Clinical Psychiatry 42,

395–397.

Davis JM, Wang Z, Janicak PG (1993). A quantitative

analysis of clinical drug trials for the treatment

of affective disorders. Psychopharmacol. Bull. 29,

175–181.

Davis LL, Frazier E, Husain MM, Warden D, Trivedi M,

Fava M, Cassano P, McGrath PJ, Balasubramani GK,

Wisniewski SR, Rush AJ (2006). Substance use disorder

comorbidity in major depressive disorder : a confirmatory

analysis of the STAR*D cohort. American Journal on

Addictions 15, 278–285.

Davis LL, Kabel D, Patel D, Choate AD, Foslien-Nash C,

Gurguis GN, Kramer GL, Petty F (1996). Valproate as an

antidepressant in major depressive disorder.


Dawling S, Lynn K, Rosser R, Braithwaite R (1982).

Nortriptyline metabolism in chronic renal failure :

metabolite elimination. Clinical Pharmacology and


Dawson LA, Nguyen HQ (2000). The role of 5-HT(1A) and

5-HT(1B/1D) receptors on the modulation of acute

fluoxetine-induced changes in extracellular 5-HT: the

mechanism of action of (+/x)pindolol.

Neuropharmacology 39, 1044–1052.

De la Gandara J, Aguera L, Rojo JE, Ros S, de Pedro JM

(2005a). Use of antidepressant combinations : which, when

and why? Results of a Spanish survey. Acta Psychiatrica

Scandinavica. Supplementum 32–36.

De la Gandara J, Rojo JE, Ros S, Aguera L, de Pedro JM

(2005b). Neuropharmacological basis of combining

antidepressants. Acta Psychiatrica Scandinavica.

Supplementum 11–13, 36.


De Leon J (2006). AmpliChip CYP450 test : personalized

medicine has arrived in psychiatry. Expert Review of

Molecular Diagnostics 6, 277–286.

De Leon J, Armstrong SC, Cozza KL (2006). Clinical

guidelines for psychiatrists for the use of pharmacogenetic

testing for CYP450 2D6 and CYP450 2C19. Psychosomatics

47, 75–85.

De Leon J, Susce MT, Murray-Carmichael E (2006b). The

AmpliChip CYP450 genotyping test : Integrating a new

clinical tool. Molecular Diagnosis & Therapy 10, 135–151.

De Maat SM, Dekker J, Schoevers RA, de JF (2007). Relative

efficacy of psychotherapy and combined therapy in the

treatment of depression : a meta-analysis. European


De Mello MF, de Jesus Mari J, Bacaltchuk J, Verdeli H,

Neugebauer R (2005). A systematic review of research

findings on the efficacy of interpersonal therapy for

depressive disorders. European Archives of Psychiatry and

Clinical Neuroscience 255, 75–82.

Dean AJ (2002). Are antidepressants addictive? Drug and

Alcohol Review 21, 317–319.

DeBattista C, Belanoff J, Glass S, Khan A, Horne RL, Blasey

C, Carpenter LL, Alva G (2006). Mifepristone versus

placebo in the treatment of psychosis in patients with

psychotic major depression. Biological Psychiatry 60,

1343–1349.

Defrance R, Marey C, Kamoun A (1988). Antidepressant

and anxiolytic activities of tianeptine : an overview of

clinical trials. Clinical Neuropharmacology 11 (Suppl. 2),

S74–S82.

Degner D, Grohmann R, Kropp S, Ruther E, Bender S,

Engel RR, Schmidt LG (2004). Severe adverse drug

reactions of antidepressants : results of the German

multicenter drug surveillance program AMSP.

Pharmacopsychiatry 37 (Suppl. 1), S39–S45.

Delgado PL (2004). How antidepressants help depression:

mechanisms of action and clinical response. Journal of


Delgado PL, Miller HL, Salomon RM, Licinio J, Krystal JH,

Moreno FA, Heninger GR, Charney DS (1999).

Tryptophan-depletion challenge in depressed patients

treated with desipramine or fluoxetine : implications for

the role of serotonin in the mechanism of antidepressant

action. Biological Psychiatry 46, 212–220.

Deltito J, Beyer D (1998). The scientific, quasi-scientific and

popular literature on the use of St. John’s Wort in the

treatment of depression. Journal of Affective Disorders 51,

345–351.

Demolis JL, Angebaud P, Grange JD, Coates P, Funck-

Brentano C, Jaillon P (1996). Influence of liver cirrhosis

on sertraline pharmacokinetics. British Journal of Clinical


Demyttenaere K (1998). Noncompliance with

antidepressants : who’s to blame? International Clinical

Psychopharmacology 13 (Suppl. 2), S19–S25.

Demyttenaere K, Bruffaerts R, Posada-Villa J, Gasquet I,

Kovess V, Lepine JP, Angermeyer MC, Bernert S, de

Girolamo G, Morosini P, Polidori G, Kikkawa T,

Kawakami N, Ono Y, Takeshima T, Uda H, Karam EG,

Fayyad JA, Karam AN, Mneimneh ZN, Medina-Mora

ME, Borges G, Lara C, de Graaf R, Ormel J, Gureje O,

Shen Y, Huang Y, Zhang M, Alonso J, Haro JM, Vilagut

G, Bromet EJ, Gluzman S, Webb C, Kessler RC,

Merikangas KR, Anthony JC, Von Korff MR, Wang PS,

Brugha TS, Aguilar-Gaxiola S, Lee S, Heeringa S,

Pennell BE, Zaslavsky AM, Ustun TB, Chatterji S (2004).

Prevalence, severity, and unmet need for treatment of

mental disorders in the World Health Organization

World Mental Health Surveys. Journal of the American


Demyttenaere K, Enzlin P, DeweW, Boulanger B, De BJ, De

TW, Mesters P (2001a). Compliance with antidepressants

in a primary care setting, 1 : Beyond lack of efficacy and

adverse events. Journal of Clinical Psychiatry 62 (Suppl. 22),

30–33.

Demyttenaere K, Enzlin P, Dewe W, Boulanger B, De BJ,

De TW, Mesters P (2001b). Compliance with

antidepressants in a primary care setting, 2 : the influence

of gender and type of impairment. Journal of Clinical


Demyttenaere K, Hemels ME, Hudry J, Annemans L (2005).

A cost-effectiveness model of escitalopram, citalopram,

and venlafaxine as first-line treatment for major depressive

disorder in Belgium. Clinical Therapeutics 27, 111–124.

Depression Guideline Panel (1993). Depression in Primary

Care : Detection and Diagnosis. Rockville, MD: Agency for

Health Care Policy and Research.

Derouesne C, Lacomblez L (2004). [Depression and

dementia]. Psychologie et Neuropsychiatrie Du Vieillissement

2 (Suppl. 1), S35–S42.

DeRubeis RJ, Gelfand LA, Tang TZ, Simons AD (1999).

Medications versus cognitive behavior therapy for

severely depressed outpatients : mega-analysis of four

randomized comparisons. American Journal of Psychiatry

156, 1007–1013.

DeRubeis RJ, Hollon SD, Amsterdam JD, Shelton RC,

Young PR, Salomon RM, O’Reardon JP, Lovett ML,

Gladis MM, Brown LL, Gallop R (2005). Cognitive

therapy vs medications in the treatment of moderate to

severe depression. Archives of General Psychiatry 62,

409–416.

Descamps-Francois C, Yous S, Chavatte P, Audinot V,

Bonnaud A, Boutin JA, Delagrange P, Bennejean C,

Renard P, Lesieur D (2003). Design and synthesis of

naphthalenic dimers as selective MT1 melatoninergic

ligands. Journal of Medicinal Chemistry 46, 1127–1129.

Detke MJ, Lu Y, Goldstein DJ, Hayes JR, Demitrack MA

(2002). Duloxetine, 60 mg once daily, for major

depressive disorder : a randomized double-blind

placebo-controlled trial. Journal of Clinical Psychiatry 63,

308–315.

Detke MJ, Wiltse CG, Mallinckrodt CH, McNamara RK,

DemitrackMA, Bitter I (2004). Duloxetine in the acute and

long-term treatment of major depressive disorder : a

placebo- and paroxetine-controlled trial. European



Devanand DP, Sackeim HA, Prudic J (1991).

Electroconvulsive therapy in the treatment-resistant

patient. Psychiatric Clinics of North America 14, 905–923.

DeVane CL (2003). Immediate-release versus controlled-

release formulations : pharmacokinetics of newer

antidepressants in relation to nausea. Journal of Clinical


Dewa CS, Hoch JS, Lin E, Paterson M, Goering P (2003).

Pattern of antidepressant use and duration of

depression-related absence from work. British Journal of


Diaz-Olavarrieta C, Cummings JL, Velazquez J, Garcia de la

Cadena C (1999). Neuropsychiatric manifestations of

multiple sclerosis. Journal of Neuropsychiatry and Clinical

Neurosciences 11, 51–57.

Dilsaver SC (1988). Monoamine oxidase inhibitor

withdrawal phenomena: symptoms and pathophysiology.

Acta Psychiatrica Scandinavica 78, 1–7.

Dilsaver SC, Chen YW, Swann AC, Shoaib AM, Krajewski

KJ (1994). Suicidality in patients with pure and depressive

mania. American Journal of Psychiatry 151, 1312–1315.

DiMascio A, Weissman MM, Prusoff BA, Neu C, Zwilling

M, Klerman GL (1979). Differential symptom reduction by

drugs and psychotherapy in acute depression. Archives of

General Psychiatry 36, 1450–1456.

Dingemanse J, Kneer J, Fotteler B, Groen H, Peeters PA,

Jonkman JH (1995). Switch in treatment from tricyclic

antidepressants to moclobemide : a new generation

monoamine oxidase inhibitor. Journal of Clinical


Dingemanse J, Wallnofer A, Gieschke R, Guentert T,

Amrein R (1998). Pharmacokinetic and pharmacodynamic

interactions between fluoxetine and moclobemide in the

investigation of development of the ‘serotonin syndrome’.

Clinical Pharmacology and Therapeutics 63, 403–413.

Dodd S, Buist A, Norman TR (2000). Antidepressants and

breast-feeding : a review of the literature. Paediatric Drugs

2, 183–192.

Dodd S, Horgan D, Malhi GS, Berk M (2005). To

combine or not to combine? A literature review of

antidepressant combination therapy. Journal of Affective


Dolberg OT, Dannon PN, Schreiber S, Grunhaus L (2002).

Transcranial magnetic stimulation in patients with bipolar

depression : a double blind, controlled study. Bipolar

Disorders 4 (Suppl. 1), 94–95.

Doogan DP, Caillard V (1992). Sertraline in the

prevention of depression. British Journal of Psychiatry 160,

217–222.

Doyle JJ, Casciano J, Arikian S, Tarride JE, Gonzalez MA,

Casciano R (2001). A multinational pharmacoeconomic

evaluation of acute major depressive disorder (MDD) : a

comparison of cost-effectiveness between venlafaxine,

SSRIs and TCAs. Value in Health 4, 16–31.

Drago F, Motta A, Grossi E (1983). Intravenous maprotiline

in severe and resistant primary depression: a double-blind

comparison with clomipramine. Journal of International

Medical Research 11, 78–84.

Drummond M, McGuire A (2001). Economic Evaluation in

Health Care : Merging Theory With Practice. Oxford : Oxford

University Press.

Drummond M, Sculpher MJ, Torrance GW, O’Brien BJ,

Stoddart GL (2005). Methods for the Economic Evaluation of

Health Care Programmes. Oxford : Oxford University Press.

Dubicka B, Hadley S, Roberts C (2006). Suicidal behaviour

in youths with depression treated with new-generation

antidepressants : meta-analysis. British Journal of Psychiatry

189, 393–8., 393–398.

Dugbartey AT, Dugbartey MT, Apedo MY (1998). Delayed

neuropsychiatric effects of malaria in Ghana. Journal of

Nervous and Mental Disease 186, 183–186.

Duggal HS, Gates C, Pathak PC (2004). Olanzapine-induced

neutropenia : mechanism and treatment. Journal of Clinical


Duman RS, Monteggia LM (2006). A neurotrophic model for

stress-related mood disorders. Biological Psychiatry 59,

1116–1127.

Dunner DL (1998). Lithium carbonate : maintenance studies

and consequences of withdrawal. Journal of Clinical

Psychiatry 59 (Suppl. 6), 48–55 ; discussion 56.

DunninghamW, de Aguiar WM, de Lourdes Costa Pinto M

(1994). A double-blind Brazilian study of efficacy and

safety of moclobemide versus imipramine in the treatment

of patients with geriatric depression. Arquivos Brasileiros De

Medicina 68, 402–405.

Eaton WW (2002). Epidemiologic evidence on the

comorbidity of depression and diabetes. Journal of

Psychosomatic Research 53, 903–906.

Eaton WW, Armenian H, Gallo J, Pratt L, Ford DE (1996).

Depression and risk for onset of type II diabetes. A

prospective population-based study. Diabetes Care 19,

1097–1102.

Ebmeier KP, Donaghey C, Steele JD (2006). Recent

developments and current controversies in depression.

Lancet 367, 153–167.

ECT review group (2003). Efficacy and safety of

electroconvulsive therapy in depressive disorders :

a systematic review and meta-analysis. Lancet 361,

799–808.

Edwards JG, Anderson I (1999). Systematic review and guide

to selection of selective serotonin reuptake inhibitors.

Drugs 57, 507–533.

Egger T, Dormann H, Ahne G, Pahl A, Runge U,

Azaz-Livshits T, Neubert A, Criegee-Rieck M,

Gassmann KG, Brune K (2005). Cytochrome P450

polymorphisms in geriatric patients : impact on

adverse drug reactions : a pilot study. Drugs and Aging

22, 265–272.

Einarson TR, Addis A, Iskedjian M (1997).

Pharmacoeconomic analysis of venlafaxine in the

treatment of major depressive disorder. Pharmacoeconomics

12, 286–296.

Einarson TR, Arikian S, Sweeney S, Doyle J (1995). A model

to evaluate the cost-effectiveness of oral therapies in the

management of patients with major depressive disorders.

Clinical Therapeutics 17, 136–153.


Einarson TR, Einarson A (2005). Newer antidepressants

in pregnancy and rates of major malformations : a

meta-analysis of prospective comparative studies.

Pharmacoepidemiology and Drug Safety 14, 823–827.

Eker SS, Akkaya C, Akgoz S, Sarandol A, Kirli S (2005).

[Comparison of reboxetine and sertraline in terms of

efficacy and safety in major depressive disorder]. Turk

Psikiyatri Dergisi 16, 153–163.

Elkin I, Shea MT, Watkins JT, Imber SD, Sotsky SM,

Collins JF, Glass DR, Pilkonis PA, Leber WR,

Docherty JP (1989). National Institute of Mental Health

Treatment of Depression Collaborative Research Program.

General effectiveness of treatments. Archives of General


Ellingrod VL, Perry PJ (1995). Nefazodone : a new

antidepressant. American Journal of Health-System Pharmacy

52, 2799–2812.

Ellis P (2004). Australian and New Zealand clinical

practice guidelines for the treatment of depression.

Australian and New Zealand Journal of Psychiatry 38,

389–407.

Emslie GJ, Heiligenstein JH, Hoog SL, Wagner KD,

Findling RL, McCracken JT, Nilsson ME, Jacobson JG

(2004). Fluoxetine treatment for prevention of relapse

of depression in children and adolescents : a double-

blind, placebo-controlled study. Journal of the

American Academy of Child and Adolescent Psychiatry 43,

1397–1405.

Emslie GJ, Heiligenstein JH, Wagner KD, Hoog SL,

Ernest DE, Brown E, Nilsson M, Jacobson JG (2002).

Fluoxetine for acute treatment of depression in children

and adolescents : a placebo-controlled, randomized clinical

trial. Journal of the American Academy of Child and Adolescent


Emslie GJ, Rush AJ, Weinberg WA, Kowatch RA,

Hughes CW, Carmody T, Rintelmann J (1997). A

double-blind, randomized, placebo-controlled trial

of fluoxetine in children and adolescents with

depression. Archives of General Psychiatry 54,

1031–1037.

Emslie GJ, Ryan ND, Wagner KD (2005). Major depressive

disorder in children and adolescents : clinical trial design

and antidepressant efficacy. Journal of Clinical Psychiatry 66

(Suppl. 7), 14–20.

Emslie GJ, Wagner KD, Kutcher S, Krulewicz S, Fong R,

Carpenter DJ, Lipschitz A, Machin A, Wilkinson C

(2006). Paroxetine treatment in children and adolescents

with major depressive disorder : a randomized,

multicenter, double-blind, placebo-controlled trial. Journal

of the American Academy of Child and Adolescent Psychiatry

45, 709–719.

Ensom MHH, Chang TKH, Patel P (2001).

Pharmacogenetics : the therapeutic drug monitoring of

the future? Clinical Pharmacokinetics 40, 783–802.

DeVane CL (2003). Immediate-release versus controlled-

release formulations : pharmacokinetics of newer

antidepressants in relation to nausea. Journal of Clinical


Ernst CL, Goldberg JF (2002). The reproductive safety profile

of mood stabilizers, atypical antipsychotics, and broad-

spectrum psychotropics. Journal of Clinical Psychiatry 63

(Suppl. 4), 42–55.

European Medicines Agency CfMPfHU (2004). CHMP

Meeting on Paroxetine and Other SSRIs (http://

www.emea.europa.eu/pdfs/human/press/pr/

19257004en.pdf). Accessed 7 January 2007.

Evans DL, Charney DS, Lewis L, Golden RN, Gorman JM,

Krishnan KR, Nemeroff CB, Bremner JD, Carney RM,

Coyne JC, DeLong MR, Frasure-Smith N, Glassman AH,

Gold PW, Grant I, Gwyther L, Ironson G, Johnson RL,

Kanner AM, KatonWJ, Kaufmann PG, Keefe FJ, Ketter T,

Laughren TP, Leserman J, Lyketsos CG, McDonald WM,

McEwen BS, Miller AH, Musselman D, O’Connor C,

Petitto JM, Pollock BG, Robinson RG, Roose SP,

Rowland J, Sheline Y, Sheps DS, Simon G, Spiegel D,

Stunkard A, Sunderland T, Tibbits PJ, Valvo WJ

(2005). Mood disorders in the medically ill : scientific

review and recommendations. Biological Psychiatry 58,

175–189.

Fakra E, Fonseca DD, Livolsi S, Destoppeleire C, Lancon C

(2006) Long term studies of depression: what is relevant

for the physician? European Journal Psychiatry 20, 242–257.

Fallon BA, Liebowitz MR, Campeas R, Schneier FR,

Marshall R, Davies S, Goetz D, Klein DF (1998).

Intravenous clomipramine for obsessive-compulsive

disorder refractory to oral clomipramine : a placebo-

controlled study. Archives of General Psychiatry 55, 918–924.

Fallon BA, Nields JA (1994). Lyme disease : a

neuropsychiatric illness. American Journal of Psychiatry 151,

1571–1583.

Fan XD (1992). [Function of lymphocyte beta-adrenergic

receptor in depression]. Zhonghua Shen Jing Jing Shen Ke Za

Zhi 25, 322–4, 382.

Farah A (1997). Mirtazapine and ECT combination therapy.

Convulsive Therapy 13, 116–117.

Farmer R (1990). Mianserin and agranulocytosis. Lancet 336,

1010.

Fattaccini CM, Bolanos-Jimenez F, Gozlan H, Hamon M

(1990). Tianeptine stimulates uptake of 5-

hydroxytryptamine in vivo in the rat brain.


Fava GA (2003a). Can long-term treatment with

antidepressant drugs worsen the course of depression?


Fava GA, Ruini C (2002). The sequential approach to relapse

prevention in unipolar depression. World Psychiatry 1,

10–15.

Fava M (2001). Augmentation and combination strategies in

treatment-resistant depression. Journal of Clinical Psychiatry

62 (Suppl. 18), 4–11.

Fava M (2002). Somatic symptoms, depression, and

antidepressant treatment. Journal of Clinical Psychiatry 63,

305–307.

Fava M (2003b). Diagnosis and definition of

treatment-resistant depression. Biological Psychiatry 53,

649–659.


Fava M (2003c). The role of the serotonergic and

noradrenergic neurotransmitter systems in the treatment of

psychological and physical symptoms of depression.


Fava M (2006). Prospective studies of adverse events related

to antidepressant discontinuation. Journal of Clinical


Fava M, Alpert J, Nierenberg AA, Mischoulon D, Otto MW,

Zajecka J, Murck H, Rosenbaum JF (2005a). A

double-blind, randomized trial of St John’s wort,

fluoxetine, and placebo in major depressive disorder.


Fava M, Davidson KG (1996). Definition and epidemiology

of treatment-resistant depression. Psychiatric Clinics of

North America 19, 179–200.

Fava M, Mulroy R, Alpert J, Nierenberg AA, Rosenbaum JF

(1997). Emergence of adverse events following

discontinuation of treatment with extended-release

venlafaxine. American Journal of Psychiatry 154, 1760–1762.

Fava GA, Ruini C, Belaise C (2007). The concept of recovery

in major depression. Psychol. Med. 37, 307–317.

Fava M, Rush AJ, Trivedi MH, Nierenberg AA, Thase ME,

Sackeim HA, Quitkin FM, Wisniewski S, Lavori PW,

Rosenbaum JF, Kupfer DJ (2003). Background and

rationale for the sequenced treatment alternatives to

relieve depression (STAR*D) study. Psychiatric Clinics of

North America 26, 457–94. x.

Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert

JE, McGrath PJ, Thase ME, Warden D, Biggs M, Luther

JF, Niederehe G, Ritz L, TrivediMH (2006). A comparison

of mirtazapine and nortriptyline following two

consecutive failed medication treatments for depressed

outpatients : a STAR*D report. American Journal of

Psychiatry 163, 1161–1172.

Fava M, Thase ME, DeBattista C (2005b). A multicenter,

placebo-controlled study of modafinil augmentation in

partial responders to selective serotonin reuptake

inhibitors with persistent fatigue and sleepiness. Journal of


FDA Public Health Advisory (2004). Suicidality in Children

and Adolescents Being Treated With Antidepressant

Medications. (http://www.fda.gov/cder/drug/

antidepressants/SSRIPHA200410.htm). Accessed 7

January 2007).

Feiger AD (1996). A double-blind comparison of gepirone

extended release, imipramine, and placebo in the

treatment of outpatient major depression.


Feiger AD, Heiser JF, Shrivastava RK, Weiss KJ, Smith WT,

Sitsen JM, Gibertini M (2003). Gepirone extended-release :

new evidence for efficacy in the treatment of major


243–249.

Feiger AD, Rickels K, Rynn MA, Zimbroff DL, Robinson

DS (2006). Selegiline transdermal system for the treatment

of major depressive disorder : an 8-week, double-blind,

placebo-controlled, flexible-dose titration trial. Journal of

Clinical Psychiatry 67(9), 1354–1361.

Feighner J, Hendrickson G, Miller L, Stern W (1986).

Double-blind comparison of doxepin versus bupropion in

outpatients with a major depressive disorder. Journal of


Feighner JP, Gardner EA, Johnston JA, Batey SR,

Khayrallah MA, Ascher JA, Lineberry CG (1991). Double-

blind comparison of bupropion and fluoxetine in depressed

outpatients. Journal of Clinical Psychiatry 52, 329–335.

Feighner JP, Herbstein J, Damlouji N (1985). Combined

MAOI, TCA, and direct stimulant therapy of treatment-

resistant depression. Journal of Clinical Psychiatry 46,

206–209.

Feinstein A, O’Connor P, Gray T, Feinstein K (1999).

Pathological laughing and crying in multiple sclerosis : a

preliminary report suggesting a role for the prefrontal

cortex. Multiple Sclerosis 5, 69–73.

Feng BL, Wang QC, Li ZY (2004). [Influence of Jieyu Huoxue

Decoction on rehabilitation of patients with depression

after cerebral infarction]. Zhong Xi Yi Jie He Xue Bao 2,

182–184.

Ferguson JM (2001). SSRI antidepressant medications :

adverse effects and tolerability. Primary Care Companion to

the Journal of Clinical Psychiatry 3, 22–27.

Fergusson D, Doucette S, Glass KC, Shapiro S, Healy D,

Hebert P, Hutton B (2005). Association between suicide

attempts and selective serotonin reuptake inhibitors :

systematic review of randomised controlled trials. British

Medical Journal 330, 396.

Fernandez JL, Montgomery S, Francois C (2005). Evaluation

of the cost effectiveness of escitalopram versus venlafaxine

XR in major depressive disorder. Pharmacoeconomics 23,

155–167.

Ferreri M, Lavergne F, Berlin I, Payan C, Puech AJ

(2001). Benefits from mianserin augmentation of

fluoxetine in patients with major depression non-

responders to fluoxetine alone. Acta Psychiatrica

Scandinavica 103, 66–72.

Fineberg NA, Gale TM (2005). Evidence-based

pharmacotherapy of obsessive-compulsive disorder.


Finfgeld DL (2003). SSRI-related hyponatremia among aging

adults. Journal of sychosocial Nursing and Mental Health

Services 41, 12–16.

Fink M (1990). Is catatonia a primary indication for ECT?

Convulsive Therapy 6, 1–4.

Fink M (1992). Catatonia and DSM-IV. Convulsive Therapy 8,

159–162.

Fink M (1999). Electroshok : Restoring the Mind. New York :


Fink M, Abrams R, Bailine S, Jaffe R (1996). Ambulatory

electroconvulsive therapy: report of a task force of the

association for convulsive therapy. Association for

Convulsive Therapy. Convulsive Therapy 12, 42–55.

Fink M, Sackeim HA (1996). Convulsive therapy in

schizophrenia? Schizophrenia Bulletin 22, 27–39.

Fink M, Taylor MA (2003). Catatonia : a Clinician’s Guide to

Diagnosis and Treatment. Cambridge : Cambridge

University Press.


Finkelstein FO, Watnick S, Finkelstein SH, Wuerth D

(2002). The treatment of depression in patients

maintained on dialysis. Journal of Psychosomatic Research 53,

957–960.

Fleck MP, Lafer B, Sougey EB, Del Porto JA, Brasil MA,

Juruena MF (2003). [Guidelines of the Brazilian Medical

Association for the treatment of depression (complete

version)]. Revista Brasileira De Psiquiatria 25, 114–122.

Foley KF, DeSanty KP, Kast RE (2006). Bupropion :

pharmacology and therapeutic applications. Expert Review

of Neurotherapeutics 6, 1249–1265.

Folkerts HW, Michael N, Tolle R, Schonauer K, Mucke S,

Schulze-Monking H (1997). Electroconvulsive therapy vs.

paroxetine in treatment-resistant depression: a

randomized study. Acta Psychiatrica Scandinavica 96,

334–342.

Forder J, Kavanagh S, Fenyo A (1996). A comparison of the

cost-effectiveness of sertraline versus tricyclic

antidepressants in primary care. Journal of Affective


Foulkes NS, Borjigin J, Snyder SH, Sassone-Corsi P

(1997). Rhythmic transcription : the molecular basis of

circadian melatonin synthesis. Trends in Neurosciences 20,

487–492.

Fountoulakis KN, Iacovides A, Nimatoudis I, Kaprinis G,

Ierodiakonou C (1999). Comparison of the diagnosis of

melancholic and atypical features according to DSM-IV

and somatic syndrome according to ICD-10 in patients

suffering from major depression. European Psychiatry 14,

426–433.

Fountoulakis KN, Iacovides A, St Kaprinis G (2004).

Combined oral venlafaxine and intravenous

clomipramine-A: successful temporary response in a

patient with extremely refractory depression. Canadian


Fountoulakis KN, Vieta E, Bouras C, Notaridis G,

Giannakopoulos P, Kaprinis G, Akiskal HS (2006).

Lithium toxicity. A systematic review of existing data.

Annals of General Psychiatry 4, S329.

Frampton JE and Plosker GL (2007). Selegiline transdermal

system: in the treatment of major depressive disorder.

Drugs 67, 257–65.

Franchini L, Gasperini M, Perez J, Smeraldi E, Zanardi R.

(1997). A double-blind study of long-term treatment with

sertraline or fluvoxamine for prevention of highly

recurrent unipolar depression. J Clin Psychiatry. 58,

104–107.

Franchini L, Gasperini M, Perez J, Smeraldi E, Zanardi R

(1998). Dose-response efficacy of paroxetine in

preventing depressive recurrences : a randomized,

double-blind study. Journal of Clinical Psychiatry 59,

229–232.

Franco-Bronson K (1996). The management of treatment-

resistant depression in the medically ill. Psychiatric Clinics

of North America 19, 329–350.

Francois C, Sinronen H, Toumi M (2002). Introduction

of escitalopram, a new SSRI in Finland: comparison of

cost-effectiveness between the other SSRs and SNRI

for the treatment of depression and estimation of

the budgetary impact. Journal of Medical Economics 5,

91–107.

Francois C, Toumi M, Aakhus AM, Hansen K (2003). A

pharmacoeconomic evaluation of escitalopram, a new

selective serotonin reuptake inhibitor. Comparison of

cost-effectiveness between escitalopram, citalopram,

fluoxetine, and venlafaxine for the treatment of

depression in Norway. European Journal of Health Economics

4, 12–19.

Frank E, Carpenter LL, Kupfer DJ (1988). Sex differences in

recurrent depression : are there any that are significant?


Frank E, Kupfer DJ, Perel JM, Cornes C, Jarrett DB,

Mallinger AG, Thase ME, McEachran AB, Grochocinski

VJ (1990). Three-year outcomes for maintenance therapies

in recurrent depression. Archives of General Psychiatry 47,

1093–1099.

Frank E, Kupfer DJ, Thase ME, Mallinger AG, Swartz HA,

Fagiolini AM, Grochocinski V, Houck P, Scott J,

Thompson W, Monk T (2005). Two-year outcomes for

interpersonal and social rhythm therapy in individuals

with bipolar I disorder. Archives of General Psychiatry 62,

996–1004.

Frasure-Smith N, Lesperance F, Julien P (2004). Major

depression is associated with lower omega-3 fatty acid

levels in patients with recent acute coronary syndromes.


Frasure-Smith N, Lesperance F, Talajic M (1993).

Depression following myocardial infarction. Impact on

6-month survival. Journal of the American Medical


Frazer A (2001). Serotonergic and noradrenergic reuptake

inhibitors : prediction of clinical effects from in vitro

potencies. Journal of Clinical Psychiatry 62, 16–23.

Freeman H, Arikian S, Lenox-Smith A (2000).

Pharmacoeconomic analysis of antidepressants for major

depressive disorder in the United Kingdom.

Pharmacoeconomics 18, 143–148.

Freeman MP, Hibbeln JR, Wisner KL, Brumbach BH,

Watchman M, Gelenberg AJ (2006). Randomized

dose-ranging pilot trial of omega-3 fatty acids for

postpartum depression. Acta Psychiatrica Scandinavica 113,

31–35.

Frey R, Schreinzer D, Heiden A, Kasper S (2001). [Use of

electroconvulsive therapy in psychiatry]. Nervenarzt 72,

661–676.

Frey R, Schreinzer D, Stimpfl T, Vycudilik W, Berzlanovich

A, Kasper S (2002). [Fatal poisonings with antidepressive

drugs and neuroleptics. Analysis of a correlation with

prescriptions in Vienna 1991 to 1997]. Nervenarzt 73,

629–636.

Friedli K, King MB, Lloyd M (2000). The economics of

employing a counsellor in general practice : analysis of

data from a randomised controlled trial. British Journal of

General Practice 50, 276–283.

Fromm MF (2000). P-glycoprotein : a defense mechanism

limiting oral bioavailability anad CNS accumulation of


drugs. International Journal of Clinical Pharmacology and


Furey ML and Drevets WC (2006). Antidepressant efficacy of

the Antimuscarinic drug scopolamine : a randomized,

placebo.-controlled clinical trial. Archives of General


Furlong RA, Ho L, Rubinsztein JS, Walsh C, Paykel ES,

Rubinsztein DC (1999). Analysis of the monoamine

oxidase A (MAOA) gene in bipolar affective disorder by

association studies, meta-analyses, and sequencing of the

promoter. American Journal of Medical Genetics 88, 398–406.

Furukawa T, McGuire H, Barbui C (2003). Low dosage

tricyclic antidepressants for depression. Cochrane Database

of Systematic Reviews CD003197.

Furukawa T, Streiner DL, Young LT (2000). Antidepressant

plus benzodiazepine for major depression. Cochrane

Database of Systematic Reviews CD001026.

Furukawa TA, Streiner DL, Young LT (2001a).

Antidepressant plus benzodiazepine for major depression.

Cochrane Database of Systematic Review.s CD001026.

Furukawa TA, Streiner DL, Young LT (2001b). Is

antidepressant-benzodiazepine combination therapy

clinically more useful? A meta-analytic study. Journal of


Furukawa TA, Watanabe N, Churchill R (2006).

Psychotherapy plus antidepressant for panic disorder with

or without agoraphobia : systematic review. British Journal

of Psychiatry 188, 305–312.

Gadit AA (2004). Out-of-pocket expenditure for depression

among patients attending private community psychiatric

clinics in Pakistan. Journal of Mental Health Policy and

Economics 7, 23–28.

Gallagher P, Young AH (In Press). Mifepristone (RU-486)

treatment for depression and psychosis : a review of the

therapeutic implications. Neuropsychiatric Disease and

Treatment.

Gallagher SM, Allen JJ, Hitt SK, Schnyer RN, Manber R

(2001). Six-month depression relapse rates among women

treated with acupuncture. Complementary Therapies in

Medicine 9, 216–218.

Gallarda T (1999). [Alzheimer’s disease and depression].

Encephale 25 Spec No. 5, 14–17.

Gallinat J, Boetsch T, Padberg F, Hampel H, Herrmann

WM,Hegerl U (2000). Is the EEG helpful in diagnosing and

monitoring lithium intoxication? A case report and review

of the literature. Pharmacopsychiatry 33, 169–173.

Gangadhar BN, Kapur RL, Kalyanasundaram S (1982).

Comparison of electroconvulsive therapy with imipramine

in endogenous depression : a double blind study. British


Garcia-Toro M, Mayol A, Arnillas H, Capllonch I, Ibarra O,

Crespi M, Mico J, Lafau O, Lafuente L (2001a). Modest

adjunctive benefit with transcranial magnetic stimulation

in medication-resistant depression. Journal of Affective


Garcia-Toro M, Pascual-Leone A, Romera M, Gonzalez A,

Mico J, Ibarra O, Arnillas H, Capllonch I, Mayol A,

Tormos JM (2001b). Prefrontal repetitive transcranial

magnetic stimulation as add on treatment in depression.

Journal of Neurology, Neurosurgery and Psychiatry 71,

546–548.

Gardiner SJ, Begg EJ (2005). Pharmacogenetic testing for

drug metabolizing enzymes : is it happening in practice?

Pharmacogenetics and Genomics 15, 365–369.

Gardiner SJ, Begg EJ (2006). Pharmacogenetics, drug-

metabolizing enzymes, and clinical practice.

Pharmacological Reviews 58, 521–590.

Gardner DM, Lynd LD (1998). Sumatriptan

contraindications and the serotonin syndrome. Annals of

Pharmacotherapy 32, 33–38.

Gareri P, Stilo G, Bevacqua I, Mattace R, Ferreri G, De Sarro

G (1998). Antidepressant drugs in the elderly. General


Garner EM, Kelly MW, Thompson DF (1993). Tricyclic

antidepressant withdrawal syndrome. Annals of


Gask L, Dowrick C, Dixon C, Sutton C, Perry R,

Torgerson D, Usherwood T (2004). A pragmatic cluster

randomized controlled trial of an educational intervention

for GPs in the assessment and management of depression.

Psychological Medicine 34, 63–72.

Gastpar M, Ngo KT, Gilsdorf U, Baumann P (1986).

Comparison of oral and intravenous treatment of

depressive states : preliminary results of a WHO

collaborative study. Clinical Neuropharmacology 9 (Suppl. 4),

434–436.

Gastpar M, Singer A, Zeller K (2005). Efficacy and

tolerability of hypericum extract STW3 in long-term

treatment with a once-daily dosage in comparison with

sertraline. Pharmacopsychiatry 38, 78–86.

Gaszner P (2005). About the menopausal depression.

Neuropsychopharmacologia Hungarica 7, 208–214.

Geddes JR, Carney SM, Davies C, Furukawa TA,

Kupfer DJ, Frank E, Goodwin GM (2003). Relapse

prevention with antidepressant drug treatment in

depressive disorders : a systematic review. Lancet 361,

653–661.

Geddes JR, Freemantle N, Mason J, Eccles MP, Boynton J

(2000). SSRIs versus other antidepressants for

depressive disorder. Cochrane Database of Systematic

Reviews CD001851.

Geerlings MI, Schoevers RA, Beekman AT, Jonker C, Deeg

DJ, Schmand B, Ader HJ, Bouter LM, Van TW (2000).

Depression and risk of cognitive decline and Alzheimer’s

disease. Results of two prospective community-based

studies in The Netherlands. British Journal of Psychiatry 176,

568–575.

Gendreau RM, Thorn MD, Gendreau JF, Kranzler JD,

Ribeiro S, Gracely RH, Williams DA, Mease PJ, McLean

SA, Clauw DJ (2005). Efficacy of milnacipran in patients

with fibromyalgia. Journal of Rheumatology 32, 1975–1985.

Gentile S (2005). The safety of newer antidepressants in

pregnancy and breastfeeding. Drug Safety 28, 137–152.

George MS, Rush AJ, Marangell LB, Sackeim HA,

Brannan SK, Davis SM, Howland R, Kling MA,

Moreno F, Rittberg B, Dunner D, Schwartz T,


Carpenter L, Burke M, Ninan P, Goodnick P (2005).

A one-year comparison of vagus nerve stimulation with

treatment as usual for treatment-resistant depression.


George MS, Rush AJ, Sackeim HA, Marangell LB (2003).

Vagus nerve stimulation (VNS) : utility in neuropsychiatric

disorders. International Journal of Neuropsychopharmacology

6, 73–83.

Georgotas A, McCue RE, Hapworth W, Friedman E,

Kim OM, Welkowitz J, Chang I, Cooper TB (1986).

Comparative efficacy and safety of MAOIs versus TCAs

in treating depression in the elderly. Biological Psychiatry

21, 1155–1166.

Gerson S, Belin TR, Kaufman A, Mintz J, Jarvik L (1999).

Pharmacological and psychological treatments for

depressed older patients : a meta-analysis and overview

of recent findings. Harvard Review of Psychiatry 7, 1–28.

Ghadirian AM, Engelsmann F, Dhar V, Filipini D, Keller R,

Chouinard G, Murphy BEP (1995). The psychotropic

effects of inhibitors of steroid biosynthesis in depressed

patients refractory to treatment. Biological Psychiatry 37,

369–375.

Ghaziuddin N, Laughrin D, Giordani B (2000). Cognitive

side effects of electroconvulsive therapy in adolescents.

Journal of Child and Adolescent Psychopharmacology 10,

269–276.

Gibbons RD, Brown CH, Hur K, Marcus SM, Bhaumik DK,

Erkens JA, Herings RM, Mann JJ (2007). Early evidence

on the effects of regulators’ suicidality warnings on SSRI

prescriptions and suicide in children and adolescents.


Gibbons RD, Hur K, Bhaumik DK, Mann JJ (2005). The

relationship between antidepressant medication use and

rate of suicide. Archives of General Psychiatry 62, 165–172.

Gibbons RD, Hur K, Bhaumik DK, Mann JJ (2006). The

relationship between antidepressant prescription rates and

rate of early adolescent suicide. American Journal of

Psychiatry 163, 1898–1904.

Gibson AC (1974). Letter : Agranulocytosis after treatment

with clomipramine infusion. British Journal of Psychiatry

125, 111–112.

Gijsman HJ, Geddes JR, Rendell JM, Nolen WA, Goodwin

GM (2004). Antidepressants for bipolar depression : a

systematic review of randomized, controlled trials.


Gilaberte I, Montejo AL, de la GJ, Perez-Sola V, Bernardo

M, Massana J, Martin-Santos R, Santiso A, Noguera R,

Casais L, Perez-Camo V, Arias M, Judge R. (2001).

Fluoxetine in the prevention of depressive recurrences : a

double-blind study. Journal of Clinical Psychopharmacology

21, 417–424.

Gilbody S, Whitty P, Grimshaw J, Thomas R (2003a).

Educational and organizational interventions to improve

the management of depression in primary care : a

systematic review. Journal of the American Medical


Gilbody SM, Whitty PM, Grimshaw JM, Thomas RE

(2003b). Improving the detection and management of

depression in primary care.Quality and Safety in Health Care

12, 149–155.

GilmerWS, TrivediMH, Rush AJ, Wisniewski SR, Luther J,

Howland RH, Yohanna D, Khan A, Alpert J (2005).

Factors associated with chronic depressive episodes : a

preliminary report from the STAR-D project. Acta

Psychiatrica Scandinavica 112, 425–433.

Girard M (1990). Mianserin side-effects. Lancet 336, 1439.

Glassman A, Shapiro PA, Ford DE, Culpepper L, Finkel

MS, Swenson JR, Bigger JT, Rollman BL, Wise TN (2003).

Cardiovascular health and depression. Journal of Psychiatric

Practice 9, 409–421.

Glassman AH (2005). Does treating post-myocardial

infarction depression reduce medical mortality? Archives of


Glassman AH, Bigger JT, Gaffney M, Shapiro PA, Swenson

JR (2006). Onset of major depression associated with acute

coronary syndromes : relationship of onset, major

depressive disorder history, and episode severity to

sertraline benefit. Archives of General Psychiatry 63,

283–288.

Goforth HW, Holsinger T (2007). Rapid relief of severe

major depressive disorder by use of preoperative

ketamine and electroconvulsive therapy. Journal of ECT 23,

23–25.

Goldberg D, Lecrubier Y (1995). Form and frequency of

mental disorders across centres. In : Ustun TB, Sartorius N

(Eds.), Mental Illness in General Health Care : an International

Study (pp. 323–334). Chichester : John Wiley.

Goldberg JF (2003). When do antidepressants worsen the

course of bipolar disorder? Journal of Psychiatric Practice 9,

181–194.

Goldberg JF, Burdick KE, Endick CJ (2004). Preliminary

randomized, double-blind, placebo-controlled trial of

pramipexole added to mood stabilizers for treatment-

resistant bipolar depression. American Journal of Psychiatry

161, 564–566.

Goldberg MR, Lowry RC, Musson DG, Birk KL, Fisher A,

De Puy ME, Shadle CR (1999). Lack of pharmacokinetic

and pharmacodynamic interaction between rizatriptan

and paroxetine. Journal of Clinical Pharmacology 39, 192–199.

Golden RN, Gaynes BN, Ekstrom RD, Hamer RM, Jacobsen

FM, Suppes T, Wisner KL, Nemeroff CB (2005). The

efficacy of light therapy in the treatment of mood

disorders : a review and meta-analysis of the evidence.


Golden RN, Hsiao JK, Lane E, Ekstrom D, Rogers S, Hicks

R, Potter WZ (1990). Abnormal neuroendocrine

responsivity to acute i.v. clomipramine challenge in

depressed patients. Psychiatry Research 31, 39–47.

Goldney RD (2006). Suicide and antidepressants : what is the

evidence? Australian and New Zealand Journal of Psychiatry

40, 381–385.

Goldstein BJ, Goodnick PJ (1998). Selective serotonin

reuptake inhibitors in the treatment of affective

disorders – III. Tolerability, safety and

pharmacoeconomics. Journal of Psychopharmacology 12,

S55–S87.


Goldstein DJ, Lu Y, Detke MJ, Wiltse C, Mallinckrodt C,

Demitrack MA (2004). Duloxetine in the treatment of

depression : a double-blind placebo-controlled comparison

with paroxetine. Journal of Clinical Psychopharmacology 24,

389–399.

Goldston DB, Reboussin BA, Daniel SS (2006). Predictors of

suicide attempts : state and trait components. Journal of

Abnormal Psychology 115, 842–849.

Gonzalez-Pinto A, Gutierrez M, Gonzalez N, Elizagarate E,

Perez DeHeredia JL, Mico JA (2002). Efficacy and safety of

venlafaxine-ECT combination in treatment-resistant

depression. Journal of Neuropsychiatry and Clinical

Neurosciences 14, 206–209.

Goodwin FK, Fireman B, Simon GE, Hunkeler EM, Lee J,

Revicki D (2003). Suicide risk in bipolar disorder during

treatment with lithium and divalproex. Journal of the

American Medical Association 290, 1467–1473.

Goodwin GM (2003). Evidence-based guidelines for treating

bipolar disorder : recommendations from the British

Association for Psychopharmacology. Journal of


Gould TD, Manji HK (2004). The molecular medicine

revolution and psychiatry : bridging the gap between basic

neuroscience research and clinical psychiatry. Journal of


Grasmader K, Verwohlt PL, Rietschel M, Dragicevic A,

Muller M, Hiemke C, Freymann N, Zobel A, Maier W,

Rao ML (2004). Impact of polymorphisms of cytochrome-

P450 isoenzymes 2C9, 2C19 and 2D6 on plasma

concentrations and clinical effects of antidepressants in a

naturalistic clinical setting. European Journal of Clinical


Grassi ZG, Cipriani S, Balgkouranidou I, Scattoni R (2006).

‘One night’ sleep deprivation stimulates hippocampal

neurogenesis. Brain Research Bulletin 69, 375–381.

Gravenor DS, Leclerc JR, Blake G (1986). Tricyclic

antidepressant agranulocytosis. Canadian Journal of

Psychiatry 31, 661.

Green B (2003). Focus on paroxetine. Current Medical Research

and Opinion 19, 13–21.

Green RC, Cupples LA, Kurz A, Auerbach S, Go R,

Sadovnick D, Duara R, Kukull WA, Chui H, Edeki T,

Griffith PA, Friedland RP, Bachman D, Farrer L (2003).

Depression as a risk factor for Alzheimer disease : the

MIRAGE Study. Archives of Neurology 60, 753–759.

Greenberg L, Fink M (1992). The use of electroconvulsive

therapy in geriatric patients. Clinics in Geriatric Medicine 8,

349–354.

Greenberg PE, Kessler RC, Birnbaum HG, Leong SA, Lowe

SW, Berglund PA, Corey-Lisle PK (2003). The economic

burden of depression in the United States : how did it

change between 1990 and 2000? Journal of Clinical


Greenblatt M, Grosser GH, Wechsler HA (1964). Differential

response of hospitalized depressed patients in somatic

therapy. American Journal of Psychiatry 935–943.

Greenhalgh J, Knight C, Hind D, Beverley C, Walters S

(2005). Clinical and cost-effectiveness of electroconvulsive

therapy for depressive illness, schizophrenia, catatonia

and mania : systematic reviews and economic modelling

studies. Health Technology Assessment 9, 1–56, iii–iv.

Griffith JD, Carranza J, Griffith C, Miller LL (1983).

Bupropion: clinical assay for amphetamine-like

abuse potential. Journal of Clinical Psychiatry 44,

206–208.

Grigoriadis S, Kennedy SH, Srinivisan J, McIntyre RS,

Fulton K (2005). Antidepressant augmentation with

raloxifene. Journal of Clinical Psychopharmacology 25, 96–98.

Grogan R, Wagner DR, Sullivan T, Labar D (1995).

Generalized nonconvulsive status epilepticus after

electroconvulsive therapy. Convulsive Therapy 11, 51–56.

Grote NK, Frank E (2003). Difficult-to-treat depression: the

role of contexts and comorbidities. Biological Psychiatry 53,

660–670.

Grube M, Hartwich P (1990). Maintenance of antidepressant

effect of sleep deprivation with the help of lithium.


60–61.

Grundemar L, Hakanson R (1994). Neuropeptide Y effector

systems: perspectives for drug development. Trends in


Grunebaum MF, Ellis SP, Li S, Oquendo MA, Mann JJ

(2004). Antidepressants and suicide risk in the United

States, 1985–1999. Journal of Clinical Psychiatry 65,

1456–1462.

Grunhaus L, Dannon PN, Schreiber S, Dolberg OH, Amiaz

R, Ziv R, Lefkifker E (2000). Repetitive transcranial

magnetic stimulation is as effective as electroconvulsive

therapy in the treatment of nondelusional major

depressive disorder : an open study. Biological Psychiatry

47, 314–324.

Grunhaus L, Pande AC, Brown MB, Greden JF (1994).

Clinical characteristics of patients with concurrent major

depressive disorder and panic disorder. American Journal of


Grunhaus L, Rabin D, Greden JF (1986). Simultaneous panic

and depressive disorder : response to antidepressant

treatments. Journal of Clinical Psychiatry 47, 4–7.

Grunhaus L, Schreiber S, Dolberg OT, PolakD, Dannon PN

(2003). A randomized controlled comparison of

electroconvulsive therapy and repetitive transcranial

magnetic stimulation in severe and resistant

nonpsychotic major depression. Biological Psychiatry 53,

324–331.

Grunze H, Kasper S, Goodwin G, Bowden C, Baldwin D,

Licht R, Vieta E, Moller HJ (2002). World Federation of

Societies of Biological Psychiatry (WFSBP) guidelines for

biological treatment of bipolar disorders. Part I. Treatment

of bipolar depression. World Journal of Biological Psychiatry

3, 115–124.

Guelfi JD, Ansseau M, Timmerman L, Korsgaard S (2001).

Mirtazapine versus venlafaxine in hospitalized severely

depressed patients with melancholic features. Journal of


Guelfi JD, Bouhassira M, Bonett-Perrin E, Lancrenon S

(1999). [The study of the efficacy of fluoxetine versus


tianeptine in the treatment of elderly depressed

patients followed in general practice]. Encephale 25,

265–270.

Guelfi JD, Pichot P, Dreyfus JF (1989). Efficacy of tianeptine

in anxious-depressed patients : results of a controlled

multicenter trial versus amitriptyline. Neuropsychobiology

22, 41–48.

Guelfi JD, Strub N, Loft H (2000). Efficacy of intravenous

citalopram compared with oral citalopram for severe

depression. Safety and efficacy data from a double-blind,

double-dummy trial. Journal of Affective Disorders 58,

201–209.

Guillem E, Lepine JP (2003). [Does addiction to

antidepressants exist ? About a case of one addiction to

tianeptine]. Encephale 29, 456–459.

Guma M, Clemente F, Segura A, Costa J (1999). [The

serotoninergic syndrome: moclobemide and citalopram].

Medicina Clınica 113, 677–678.

Gunnell D, Ashby D (2004). Antidepressants and suicide :

what is the balance of benefit and harm. British Medical

Journal 329, 34–38.

Gunnell D, Saperia J, Ashby D (2005). Selective serotonin

reuptake inhibitors (SSRIs) and suicide in adults :

meta-analysis of drug company data from placebo

controlled, randomised controlled trials submitted

to the MHRA’s safety review. British Medical Journal 330,

385.

Gureje O, Lasebikan VO, Kola L, Makanjuola VA (2007).

Lifetime and 12-month prevalence of mental disorders in

the Nigerian Survey of Mental Health and Wellbeing.

British Journal of Psychiatry.

Guthrie E, Moorey J, Margison F, Barker H, Palmer S,

McGrath G, Tomenson B, Creed F (1999). Cost-

effectiveness of brief psychodynamic-interpersonal

therapy in high utilizers of psychiatric services. Archives of


Guze SB, Robins E (1970). Suicide and primary affective

disorders. British Journal of Psychiatry 117, 437–438. DOI :

10.1016/j.jad.2006.09.023.

Hackett ML, Anderson CS, House AO (2004). Interventions

for treating depression after stroke. Cochrane Database of

Systematic Reviews CD003437.

Haddad P (1998). The SSRI discontinuation syndrome.

Journal of Psychopharmacology 12, 305–313.

Haddad P (1999). Do antidepressants have any potential

to cause addiction? Journal of Psychopharmacology 13,

300–307.

Haddad PM (2001). Antidepressant discontinuation

syndromes. Drug Safety 24, 183–197.

Haddjeri N, Blier P, de Montigny C (1998). Long-term

antidepressant treatments result in a tonic activation of

forebrain 5-HT1A receptors. Journal of Neuroscience 18,

10150–10156.

Hager ED, Dziambor H, Winkler P, Hohmann D, Macholdt

K (2002). Effects of lithium carbonate on hematopoietic

cells in patients with persistent neutropenia following

chemotherapy or radiotherapy. Journal of Trace Elements in

Medicine and Biology 16, 91–97.

Halbreich U, Kahn LS (2006). Atypical depression, somatic

depression and anxious depression in women: Are they

gender-preferred phenotypes? Journal of Affective Disorders

Hall WD, Lucke J (2006). How have the selective serotonin

reuptake inhibitor antidepressants affected suicide

mortality? Australian and New Zealand Journal of Psychiatry

40, 941–950.

Hall WD, Mant A, Mitchell PB, Rendle VA, Hickie IB,

McManus P (2003). Association between antidepressant

prescribing and suicide in Australia, 1991–2000: trend

analysis. British Medical Journal 326, 1008.

Hameed U, Schwartz TL, Malhotra K, West RL, Bertone F

(2005). Antidepressant treatment in the primary care office :

outcomes for adjustment disorder versus major

depression. Annals of Clinical Psychiatry 17, 77–81.

Hamilton JA, Grant M, Jensvold MF (1995). Sex and the

treatment of depression: when does it matter? In : Jensvold

MF, Halbreich U, Hamilton JA (Eds.), Psychopharmacology

of Women: Sex, Gender and Hormonal Considerations.

Washington DC: American Psychiatric Press.

Hamilton M (1960). A rating scale for depression. Journal of

Neurology, Neurosurgery and Psychiatry 23, 56–62.

Hamilton M (1967). Development of a rating scale for

primary depressive illness. British Journal of Social and

Clinical Psychology 6, 278–296.

Hammad TA (2006). Relationship Between Psychotropic

Drugs and Pediatric Suicidality (http://www.fda.gov/

ohrms/dockets/ac/04/briefing/2004-4065B1-10-TAB08-

Hammads-Review.pdf). Accessed 24 January 2006.

Hammad TA, Laughren T, Racoosin J (2006a). Suicidality in

pediatric patients treated with antidepressant drugs.

Archives of General Psychiatry 63, 332–339.

Hammad TA, Laughren TP, Racoosin JA (2006b). Suicide

rates in short-term randomized controlled trials of newer

antidepressants. Journal of Clinical Psychopharmacology 26,

203–207.

Hansen RA, Gartlehner G, Lohr KN, Gaynes BN, Carey TS

(2005). Efficacy and safety of second-generation

antidepressants in the treatment of major depressive

disorder. Annals of Internal Medicine 143, 415–426.

Hantz P, Caradoc-Davies G, Caradoc-Davies T, Weatherall

M, Dixon G (1994). Depression in Parkinson’s disease.


Harkin A, Kelly JP, Leonard BE (2006). A review of the

relevance and validity of olfactory bulbectomy as a model

of depression. Clinical Neuroscience Research 3, 253–262.

Harris EC, Barraclough B (1998). Excess mortality of mental

disorder. British Journal of Psychiatry 173 :11–53., 11–53.

Harvey BH, McEwen BS, Stein DJ (2003). Neurobiology of

antidepressant withdrawal : implications for the

longitudinal outcome of depression. Biological Psychiatry

54, 1105–1117.

Harvey I, Nelson SJ, Lyons RA, Unwin C, Monaghan S,

Peters TJ (1998). A randomized controlled trial and

economic evaluation of counselling in primary care. British

Journal of General Practice 48, 1043–1048.

Hasegawa S, Watanabe A, Nguyen KQ, Debonnel G, Diksic

M (2005). Chronic administration of citalopram in


olfactory bulbectomy rats restores brain 5-HT synthesis

rates : an autoradiographic study. Psychopharmacology

(Berlin) 179, 781–790.

Hasin DS, Goodwin RD, Stinson FS, Grant BF (2005).

Epidemiology of major depressive disorder : results from

the National Epidemiologic Survey on Alcoholism and

Related Conditions. Archives of General Psychiatry 62,

1097–1106.

Hasler G, Drevets WC, Manji HK, Charney DS (2004).

Discovering endophenotypes for major depression.


Hatziandreu EJ, Brown RE, Revicki DA, Turner R,

Martindale J, Levine S, Siegel JE (1994). Cost utility of

maintenance treatment of recurrent depression with

sertraline versus episodic treatment with dothiepin.


Hatzinger M, Hemmeter UM, Baumann K, Brand S,

Holsboer-Trachsler E (2002). The combined

DEX-CRH test in treatment course and long-term

outcome of major depression. Journal of Psychiatric

Research 36, 287–297.

Hazell P, O’Connell D, Heathcote D, Henry D (2002).

Tricyclic drugs for depression in children and

adolescents. Cochrane Database of Systematic Reviews.

CD002317.

Healy D (2006). Manufacturing consensus. Culture, Medicine

and Psychiatry 30, 135–156.

Healy D, Whitaker C (2003). Antidepressants and suicide :

risk-benefit conundrums. Journal of Psychiatry and


Hebenstreit GF, Fellerer K, Fichte K, Fischer G, Geyer N,

Meya U, Hernandez M, Schony W, Schratzer M,

Soukop W (1989). Rolipram in major depressive disorder :

results of a double-blind comparative study with

imipramine. Pharmacopsychiatry 22, 156–160.

Hegerl U, Althaus D, Schmidtke A, Niklewski G (2006).

The alliance against depression : 2-year evaluation of a

community-based intervention to reduce suicidality.


Helgason T, Tomasson H, Zoega T (2004). Antidepressants

and public health in Iceland. Time series analysis of

national data. British Journal of Psychiatry 184, 157–162.

Helmchen H (1974). Symptomatology of therapy-resistant

depressions. Pharmakopsychiatrie, Neuro-

Psychopharmakologie 7, 145–155.

Hemels ME, Kasper S, Walter E, Einarson TR (2004a).

Cost-effectiveness analysis of escitalopram: a new SSRI

in the first-line treatment of major depressive disorder

in Austria. Current Medical Research and Opinion 20,

869–878.

Hemels ME, Kasper S, Walter E, Einarson TR (2004b).

Cost-effectiveness of escitalopram versus citalopram

in the treatment of severe depression. Annals of


Henderson L, Yue QY, Bergquist C, Gerden B, Arlett P

(2002). St John’s wort (Hypericum perforatum) : drug

interactions and clinical outcomes. British Journal of Clinical


Hendset M, Haslemo T, Rudberg I, Refsum H, Molden E

(2006). The complexity of active metabolites in therapeutic

drug monitoring of psychotropic drugs.

Pharmacopsychiatry 39, 121–127.

Henkel V, Mergl R, Allgaier AK, Kohnen R, Moller HJ,

Hegerl U (2006). Treatment of depression with atypical

features : a meta-analytic approach. Psychiatry Research 141,

89–101.

Henkel V, Moller HJ (2005). What Are the Most Effective

Diagnostic and Therapeutic Strategies for the anagement of

Depression in Specialist Care? A Health Evidence

Network Report (http://www.euro.who.int/document/

e86602.pdf). Accessed 24 May 2005.

Hennessy M, Kelleher D, Spiers JP, Barry M, Kavanagh P,

Back D, Mulcahy F, Feely J (2002). St Johns wort increases

expression of P-glycoprotein : implications for drug

interactions. British Journal of Clinical Pharmacology 53,

75–82.

Henriksson S, Asplund R, Boethius G, Hallstrom T,

Isacsson G (2006). Infrequent use of antidepressants in

depressed individuals (an interview and prescription

database study in a defined Swedish population

2001–2002). European Psychiatry 21, 355–360.

Henriksson S, Boethius G, Isacsson G (2001). Suicides are

seldom prescribed antidepressants : findings from a

prospective prescription database in Jamtland county,

Sweden, 1985–95. Acta Psychiatrica Scandinavica 103,

301–306.

Henriksson S, Isacsson G (2006). Increased antidepressant

use and fewer suicides in Jamtland county, Sweden, after

a primary care educational programme on the treatment

of depression. Acta Psychiatrica Scandinavica 114, 159–167.

Heres S, Davis J, Maino K, Jetzinger E, KisslingW, Leucht S

(2006). Why olanzapine beats risperidone, risperidone

beats quetiapine, and quetiapine beats olanzapine : an

exploratory analysis of head-to-head comparison studies

of second-generation antipsychotics. American Journal of


Heresco-Levy U, Javitt DC, Gelfin Y, Gorelik E, Bar M,

Blanaru M, Kremer I (2006). Controlled trial of

D-cycloserine adjuvant therapy for treatment-resistant

major depressive disorder. Journal of Affective Disorders 93,

239–243.

Heuser I, Deuschle M, Luppa P, Schweiger U, Standhardt

H, Weber B (1998). Increased diurnal plasma

concentrations of dehydroepiandrosterone in depressed

patients. Journal of Clinical Endocrinology and Metabolism 83,

3130–3133.

Hibbeln JR (1998). Fish consumption and major depression.

Lancet 351, 1213.

Hickie I, Scott E, Naismith S, Ward PB, Turner K, Parker G,

Mitchell P, Wilhelm K (2001). Late-onset depression :

genetic, vascular and clinical contributions. Psychological

Medicine 31, 1403–1412.

Hildebrandt MG, Steyerberg EW, Stage KB, Passchier J,

Kragh-Soerensen P (2003). Are gender differences

important for the clinical effects of antidepressants?



Hill GE, Wong KC, Hodges MR (1976). Potentiation of

succinylcholine neuromuscular blockade by lithium

carbonate. Anesthesiology 44, 439–442.

Hill GE, Wong KC, Hodges MR (1977). Lithium carbonate

and neuromuscular blocking agents. Anesthesiology 46,

122–126.

Himmelhoch JM, Thase ME, Mallinger AG, Houck P

(1991). Tranylcypromine versus imipramine in anergic

bipolar depression. American Journal of Psychiatry 148,

910–916.

Hirschfeld RM (2000). Antidepressants in long-term

therapy : a review of tricyclic antidepressants and

selective serotonin reuptake inhibitors. Acta Psychiatrica

Scandinavica. Supplementum 403, 35–38.

Hirschfeld RM (2001). Clinical importance of long-term

antidepressant treatment. British Journal of Psychiatry

(Suppl.), 42, S4–S8.

Hirschfeld RM, Montgomery SA, Aguglia E, Amore M,

Delgado PL, Gastpar M, Hawley C, Kasper S, Linden M,

Massana J, Mendlewicz J, Moller HJ, Nemeroff CB,

Saiz J, Such P, Torta R, Versiani M (2002). Partial

response and nonresponse to antidepressant therapy :

current approaches and treatment options. Journal of


Hirschfeld RM, Montgomery SA, Keller MB, Kasper S,

Schatzberg AF, Moller HJ, Healy D, Baldwin D,

Humble M, Versiani M, Montenegro R, Bourgeois M

(2000). Social functioning in depression: a review. J Clin.


Hirschfeld RM, Vornik LA (2004). Newer antidepressants :

review of efficacy and safety of escitalopram and

duloxetine. Journal of Clinical Psychiatry 65 (Suppl. 4),

46–52.

Hochstrasser B, Isaksen PM, Koponen H, Lauritzen L,

Mahnert FA, Rouillon F, Wade AG, Andersen M,

Pedersen SF, Swart JC, Nil R (2001). Prophylactic effect

of citalopram in unipolar, recurrent depression :

placebo-controlled study of maintenance therapy.

British Journal of Psychiatry. 178 :304–10., 304–310.

Hoenig J (1980). The early manifestations of depression:

Diagnostic hints. In : Ayd FJ (Ed.), Clinical Depression :

Diagnostic and Therapeutic Challenges (pp. 1–21). Baltimore :

Ayd Medical Communications.

Hollon SD, DeRubeis RJ, Shelton RC, Amsterdam JD,

Salomon RM, O’Reardon JP, Lovett ML, Young PR,

Haman KL, Freeman BB, Gallop R (2005). Prevention of

relapse following cognitive therapy vs medications in

moderate to severe depression. Archives of General


Hollon SD, Jarrett RB, Nierenberg AA, Thase ME,

Trivedi M, Rush AJ (2005). Psychotherapy

and medication in the treatment of adult and

geriatric depression : which monotherapy or

combined treatment? Journal of Clinical Psychiatry 66,

455–468.

Hollon SD, Thase ME, Markowitz JC (2002). Treatment

and prevention of depression. Psychological Science in the

Public Interest 3, 39–77.

Holsboer F (2001). Antidepressant drug discovery in the

postgenomic era. World Journal of Biological Psychiatry 2,

165–177.

Holsboer F, Barden N (1996). Antidepressants and

hypothalamic-pituitary-adrenocortical regulation.

Endocrine Reviews 17, 187–205.

Horne RL, Ferguson JM, Pope HGJ, Hudson JI, Lineberry

CG, Ascher J, Cato A (1988). Treatment of bulimia with

bupropion: a multicenter controlled trial. Journal of Clinical


Horowitz A, Reinhardt JP, Kennedy GJ (2005). Major and

subthreshold depression among older adults seeking

vision rehabilitation services. American Journal of Geriatric


Hosak L, Tuma I, Hanus H, Straka L (2000). Costs and

outcomes of use of amitriptyline, citalopram and

fluoxetine in major depression : exploratory study. Acta

Medica (Hradec Kralove) 43, 133–137.

Hotopf M, Hardy R, Lewis G (1997). Discontinuation rates of

SSRIs and tricyclic antidepressants : a meta-analysis and

investigation of heterogeneity. British Journal of Psychiatry

170, 120–127.

Howard P, Knight C (2004). A clinical and cost-effectiveness

comparison of venlafaxine and selective serotonin

reuptake inhibitors (SSRIs) in the management of patients

with major depresive disorders from the perspective of an

Austrian sickness fund. Journal of Medical Economics 7,

93–106.

Hu TW (2004). The economic burden of depression and

reimbursement policy in the Asia Pacific region.

Australasian Psychiatry 12 (Suppl.), S11–S15.

Hu TW (2006). Perspectives : an international review of the

national cost estimates of mental illness, 1990–2003. Journal

of Mental Health Policy and Economics 9, 3–13.

Huizink AC, Mulder EJ, Buitelaar JK (2004). Prenatal

stress and risk for psychopathology : specific effects or

induction of general susceptibility? Psychol. Bull. 130,

115–142.

Hung CI, Liu CY, Fuh JL, Juang YY, Wang SJ (2006).

Comorbidmigraine is associated with a negative impact on

quality of life in patients with major depression. Cephalalgia

26, 26–32.

Husain MM, Rush AJ, Fink M, Knapp R, Petrides G,

Rummans T, Biggs MM, O’Connor K, Rasmussen K,

Litle M, Zhao W, Bernstein HJ, Smith G, Mueller M,

McClintock SM, Bailine SH, Kellner CH (2004). Speed of

response and remission in major depressive disorder with

acute electroconvulsive therapy (ECT) : a Consortium for

Research in ECT (CORE) report. Journal of Clinical


Husain MM, Rush AJ, Sackeim HA, Wisniewski SR,

McClintock SM, Craven N, Holiner J, Mitchell JR,

Balasubramani GK, Hauger R (2005). Age-related

characteristics of depression : a preliminary

STAR*D report. American Journal of Geriatric Psychiatry 13,

852–860.

Hutton HE, Lyketsos CG, Zenilman JM, Thompson RE,

Erbelding EJ (2004). Depression and HIV risk behaviors


among patients in a sexually transmitted disease clinic.


Imbarlina MJ, Sarkar S, Marwah S, Parepally H, Johnston

PR, Brar JS, Chengappa KN (2004). Leukopenia in

clozapine treated patients may be induced by other drugs :

a case series. European Psychiatry 19, 506–509.

Ingelman-Sundberg M, Oscarson M, McLellan RA (1999).

Polymorphic human cytochrome P450 enzymes: an

opportunity for individualized drug treatment. Trends in


Inskip HM, Harris EC, Barraclough B (1998). Lifetime risk of

suicide for affective disorder, alcoholism and

schizophrenia. British Journal of Psychiatry 172, 35–37.

Invernizzi G, Aguglia E, Bertolino A, Casacchia M, Ciani N,

Marchesi GF, Nardini M, Rapisarda V (1994). The efficacy

and safety of tianeptine in the treatment of depressive

disorder : results of a controlled double-blind multicentre

study vs. amitriptyline. Neuropsychobiology 30, 85–93.

Isacsson G (2000). Suicide prevention: a medical

breakthrough? Acta Psychiatrica Scandinavica 102, 113–117.

Isacsson G, Holmgren P, Ahlner J (2005). Selective serotonin

reuptake inhibitor antidepressants and the risk of suicide :

a controlled forensic database study of 14,857 suicides.

Acta Psychiatrica Scandinavica 111, 286–290.

Isacsson G, Holmgren P, Druid H, Bergman U (1997). The

utilization of antidepressants : a key issue in the prevention

of suicide : an analysis of 5281 suicides in Sweden during

the period 1992–1994. Acta Psychiatrica Scandinavica 96,

94–100.

Isacsson G, Rich CL (2005). Antidepressant drug use and

suicide prevention. International Review of Psychiatry 17,

153–162.

Isbister GK, Dawson A, Whyte IM, Prior FH, Clancy C,

Smith AJ (2001). Neonatal paroxetine withdrawal

syndrome or actually serotonin syndrome? Archives of

Disease in Childhood. Fetal and Neonatal Edition 85,

F147–F148.

Ising M, Horstmann S, Kloiber S, Lucae S, Binder EB, Kern

N, Kunzel HE, Pfennig A, Uhr M, Holsboer F (2006).

Combined dexamethasone/corticotropin releasing

hormone test predicts treatment response in major

depression : a potential biomarker? Biological Psychiatry.

10.1016/j.biopsych.2006.07.039.

Israel JA (2006). Remission in depression: definition and

initial treatment approaches. Journal of Psychopharmacology

20, 5–10.

Izzo AA, Ernst E (2001). Interactions between herbal

medicines and prescribed drugs : a systematic review.

Drugs 61, 2163–2175.

Jacobson NS, Dobson KS, Truax PA, Addis ME, Koerner K,

Gollan JK, Gortner E, Prince SE (1996). A component

analysis of cognitive-behavioral treatment for

depression. Journal of Consulting and Clinical Psychology 64,

295–304.

Jaffe AS, Krumholz HM, Catellier DJ, Freedland KE, Bittner

V, Blumenthal JA, Calvin JE, Norman J, Sequeira R,

O’Connor C, Rich MW, Sheps D, Wu C (2006). Prediction

of medical morbidity and mortality after acute myocardial

infarction in patients at increased psychosocial risk in the

Enhancing Recovery in Coronary Heart Disease Patients

(ENRICHD) study. American Heart Journal 152, 126–135.

Jahn H, Schick M, Kiefer F, Kellner M, Yassouridis A,

WiedemannK (2004). Metyrapone as additive treatment in

major depression : a double-blind and placebo-controlled

trial. Archives of General Psychiatry 61, 1235–1244.

Janicak PG, Davis JM, Gibbons RD, Ericksen S, Chang S,

Gallagher P (1985). Efficacy of ECT: a meta-analysis.


Jansson M, Gatz M, Berg S, Johansson B, Malmberg B,

McClearn GE, Schalling M, Pedersen NL (2004). Gender

differences in heritability of depressive symptoms in the

elderly. Psychological Medicine 34, 471–479.

Jaquenoud Sirot E, van der Velden JW, Rentsch K, Eap CB,

Baumann P (2006). Therapeutic Drug Monitoring and

Pharmacogenetic Tests as Tools in Pharmacovigilance.

Drug Safety 29, 735–768.

Jesberger JA, Richardson JS (1988). Brain output

dysregulation induced by olfactory bulbectomy: an

approximation in the rat of major depressive disorder in

humans? International Journal of Neuroscience 38, 241–265.

Jick H, Kaye JA, Jick SS (2004). Antidepressants and the risk

of suicidal behaviors. Journal of the American Medical


Jin H, Hampton AJ, Yu X, Heaton RK, Shi C, Marcotte TP,

Young C, Sadek J, Wu Z, Grant I (2006). Depression and

suicidality in HIV/AIDS in China. Journal of Affective


Joffe P, Larsen FS, Pedersen V, Ring-Larsen H, Aaes-

Jorgensen T, Sidhu J (1998). Single-dose pharmacokinetics

of citalopram in patients with moderate renal insufficiency

or hepatic cirrhosis compared with healthy subjects.

European Journal of Clinical Pharmacology 54, 237–242.

Joffe RT, Singer W (1990). A comparison of triiodothyronine

and thyroxine in the potentiation of tricyclic

antidepressants. Psychiatry Research 32, 241–251.

Joffe RT, Singer W, Levitt AJ, MacDonald C (1993). A

placebo-controlled comparison of lithium and

triiodothyronine augmentation of tricyclic antidepressants

in unipolar refractory depression. Archives of General


Johne A, Brockmoller J, Bauer S, Maurer A, Langheinrich

M, Roots I (1999). Pharmacokinetic interaction of digoxin

with an herbal extract from St John’s wort (Hypericum

perforatum). Clinical Pharmacology and Therapeutics 66,

338–345.

Jonsson A, Holmgren P, Ahlner J (2004). Fatal intoxications

in a Swedish forensic autopsy material during 1992–2002.

Forensic Science International 143, 53–59.

Jonsson B, Bebbington PE (1994). What price depression?

The cost of depression and the cost-effectiveness of

pharmacological treatment. British Journal of Psychiatry 164,

665–673.

Jorge RE, Robinson RG, Arndt S, Starkstein S (2003).

Mortality and poststroke depression : a placebo-controlled

trial of antidepressants. American Journal of Psychiatry 160,

1823–1829.


Jorm AF, Christensen H, Griffiths KM, Rodgers B (2002).

Effectiveness of complementary and self-help treatments

for depression. Medical Journal of Australia 176 (Suppl.),

S84–S96.

Joyce PR, Mulder RT, Luty SE, McKenzie JM, Miller AL,

Rogers GR, Kennedy MA (2003). Age-dependent

antidepressant pharmacogenomics : polymorphisms of the

serotonin transporter and G protein beta3 subunit as

predictors of response to fluoxetine and nortriptyline.


Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J,

Coryell W, PaulusMP, Kunovac JL, Leon AC, Mueller TI,

Rice JA, Keller MB (1998a). A prospective 12-year study of

subsyndromal and syndromal depressive symptoms in

unipolar major depressive disorders. Archives of General


Judd LL, Akiskal HS, Maser JD, Zeller PJ, Endicott J,

Coryell W, PaulusMP, Kunovac JL, Leon AC, Mueller TI,

Rice JA, Keller MB (1998b). Major depressive disorder : a

prospective study of residual subthreshold depressive

symptoms as predictor of rapid relapse. Journal of Affective


Judge R, Parry MG, Quail D, Jacobson JG (2002).

Discontinuation symptoms: comparison of brief

interruption in fluoxetine and paroxetine treatment.

International Clinical Psychopharmacology 17, 217–225.

Kahn LS, Halbreich U (2005). The effect of estrogens on

depression. In : Bergemann N, Riecher-Rossler A (Eds.),

Estrogen Effects in Psychiatric Disorders (pp. 145–173). Wien :

Springer.

Kahn RS, van Praag HM (1992). Panic disorder : a biological

perspective. European Neuropsychopharmacology 2(1), 1–20.

Kalb R, Trautmann-Sponsel RD, Kieser M (2001). Efficacy

and tolerability of hypericum extract WS 5572 versus

placebo in mildly to moderately depressed patients. A

randomized double-blind multicenter clinical trial.


Kaltenthaler E, Shackley P, Stevens K, Beverley C, Parry G,

Chilcott J (2002). A systematic review and economic

evaluation of computerised cognitive behaviour therapy

for depression and anxiety. Health Technology Assessment 6,

1–89.

Kamlet MS, Paul N, Greenhouse J, Kupfer D, Frank E,

Wade M (1995). Cost utility analysis of maintenance

treatment for recurrent depression. Controlled Clinical Trials

16, 17–40.

Kanba S, Yamada K, Mizushima H, Asai M (1998). Use of

herbal medicine for treating psychiatric disorders in Japan.

Psychiatry and Clinical Neurosciences 52 (Suppl.), S331–S333.

Kanba S, Yamada K, Mizushima H, Murata T, Asai M

(1999). Use of herbal medicine for treating psychiatric

disorders in Japan. In : Kanba S, Richelson E (Eds.),

Herbal Medicine in Mental Health. New York :

Brunner-Mazel.

Kanner AM (2003). When did neurologists and psychiatrists

stop talking to each other? Epilepsy and Behavior 4, 597–601.

Kanner AM (2005a). Depression in epilepsy: a neurobiologic

perspective. Epilepsy Currents 5, 21–27.

Kanner AM (2005b). Should neurologists be trained to

recognize and treat comorbid depression of neurologic

disorders? Yes. Epilepsy and Behavior 6, 303–311.

Karasu TB, Docherty JP, Gelenberg A, Kupfer DJ, Merriam

AE, Shadoan R (1993). Practice guideline for major

depressive disorder in adults.American Journal of Psychiatry

150, 1–26.

Karp JF, Scott J, Houck P, Reynolds CF, III, Kupfer DJ,

Frank E (2005). Pain predicts longer time to remission

during treatment of recurrent depression. Journal of Clinical


Kasper S (2001). Hypericum perforatum: a review of clinical

studies. Pharmacopsychiatry 34 (Suppl. 1), S51–S55.

Kasper S, Dienel A (2002). Cluster analysis of symptoms

during antidepressant treatment with Hypericum extract

in mildly to moderately depressed out-patients. A meta-

analysis of data from three randomized, placebo-

controlled trials. Psychopharmacology 164, 301–308.

Kasper S, Muller-Spahn F (2002). Intravenous

antidepressant treatment : focus on citalopram. European

Archives of Psychiatry and Clinical Neuroscience 252, 105–109.

Kasper S, Olie JP (2002). A meta-analysis of randomized

controlled trials of tianeptine versus SSRI in the short-term

treatment of depression. European Psychiatry 17 (Suppl. 3),

331–340.

Kasper S, Rogers SL, Madden PA, Joseph-Vanderpool JR,

Rosenthal NE (1990). The effects of phototherapy in the

general population. Journal of Affective Disorders 18,

211–219.

Kasper S, Schulz V (1999). [High dose St. John’s wort extract

as a phytogenic antidepressant]. Wiener Medizinische

Wochenschrift 149, 191–196.

Kasper S, Spadone C, Verpillat P, Angst J (2006). Onset of

action of escitalopram compared with other

antidepressants : results of a pooled analysis. International


Kato T (2001). Molecular genetics of bipolar disorder.

Neuroscience Research 40, 105–113.

Katona CL (1994). Approaches to the management of

depression in old age. Gerontology 40 (Suppl. 1), 5–9.

Katona CL (1997). Depression and Physical Illness. Chichester,

England: John Wiley.

Katona CL, Abou-Saleh MT, Harrison DA, Nairac BA,

Edwards DR, Lock T, Burns RA, Robertson MM (1995).

Placebo-controlled trial of lithium augmentation of

fluoxetine and lofepramine. British Journal of Psychiatry 166,

80–86.

Katz MM, Tekell JL, Bowden CL, Brannan S, Houston JP,

Berman N, Frazer A (2004). Onset and early behavioral

effects of pharmacologically different antidepressants and

placebo in depression. Neuropsychopharmacology 29,

566–579.

Katzelnick DJ, KobakKA, Greist JH, Jefferson JW, HenkHJ

(1997). Effect of primary care treatment of depression on

service use by patients with high medical expenditures.

Psychiatric Services 48, 59–64.

Kauffmann CD, Cheema MA, Miller BE (2004). Slow

right prefrontal transcranial magnetic stimulation as


a treatment for medication-resistant depression: a

double-blind, placebo-controlled study. Depression and

Anxiety 19, 59–62.

Kavoussi RJ, Segraves RT, Hughes AR, Ascher JA,

Johnston JA (1997). Double-blind comparison of

bupropion sustained release and sertraline in depressed


Kelder J, Funke C, De Boer T, Delbressine L, Leysen D,

Nickolson V (1997). A comparison of the physicochemical

and biological properties of mirtazapine and mianserin.

Journal of Pharmacy and Pharmacology 49, 403–411.

Keller MB (1999). The long-term treatment of depression.

Journal of Clinical Psychiatry 60 (Suppl. 17), 41–45,

discussion 46–48.

Keller MB, Boland RJ (1998). Implications of failing to

achieve successful long-term maintenance treatment of

recurrent unipolar major depression. Biological Psychiatry

44, 348–360.

Keller MB, Kocsis JH, Thase ME, Gelenberg AJ, Rush AJ,

Koran L, Schatzberg A, Russell J, Hirschfeld R, Klein D,

McCullough JP, Fawcett JA, Kornstein S, LaVange L,

Harrison W (1998). Maintenance phase efficacy of

sertraline for chronic depression: a randomized controlled

trial. Journal of the American Medical Association 280,

1665–1672.

Keller MB, McCullough JP, Klein DN, Arnow B,

Dunner DL, Gelenberg AJ, Markowitz JC,

Nemeroff CB, Russell JM, Thase ME, Trivedi MH,

Zajecka J (2000). A comparison of nefazodone, the

cognitive behavioral-analysis system of psychotherapy,

and their combination for the treatment of chronic

depression. New England Journal of Medicine 342,

1462–1470.

Keller MB, Ryan ND, Strober M, Klein RG, Kutcher SP,

Birmaher B, Hagino OR, Koplewicz H, Carlson GA,

Clarke GN, Emslie GJ, Feinberg D, Geller B, Kusumakar

V, Papatheodorou G, SackWH, SweeneyM,Wagner KD,

Weller EB, Winters NC, Oakes R, McCafferty JP (2001).

Efficacy of paroxetine in the treatment of adolescent major

depression : a randomized, controlled trial. Journal of the

American Academy of Child and Adolescent Psychiatry 40,

762–772.

Kellner CH, Fink M, Knapp R, Petrides G, Husain M,

Rummans T, Mueller M, Bernstein H, Rasmussen K,

O’Connor K, Smith G, Rush AJ, Biggs M, McClintock S,

Bailine S, Malur C (2005). Relief of expressed suicidal

intent by ECT: a consortium for research in ECT study.


Kendler KS (1998). Gender differences in the genetic

epidemiology of major depression. Journal of Gender-

Specific Medicine 1, 28–31.

Kennedy SH, Andersen HF, Lam RW (2006). Efficacy of

escitalopram in the treatment of major depressive disorder

compared with conventional selective serotonin reuptake

inhibitors and venlafaxine XR: a meta-analysis. Journal of

Psychiatry and Neuroscience 31, 122–131.

Kennedy SH, Emsley R (2006). Placebo-controlled

trial of agomelatine in the treatment of major

depressive disorder. European Neuropsychopharmacology 16,

93–100.

Kennedy SH, Lam RW, Cohen NL, Ravindran AV (2001).

Clinical guidelines for the treatment of depressive

disorders. IV. Medications and other biological treatments.

Canadian Journal of Psychiatry 46 (Suppl. 1), 38S–58S.

Kent JM (2000). SNaRIs, NaSSAs, and NaRIs : new agents for

the treatment of depression. Lancet 355, 911–918.

Kessler RC (2003). Epidemiology of women and depression.


Kessler RC, Berglund P, Demler O, Jin R, Koretz D,

Merikangas KR, Rush AJ, Walters EE, Wang PS (2003).

The epidemiology of major depressive disorder : results

from the National Comorbidity Survey Replication

(NCS-R). Journal of the American Medical Association 289,

3095–3105.

Kessler RC, Soukup J, Davis RB, Foster DF, Wilkey SA, Van

Rompay MI, Eisenberg DM (2001). The use of

complementary and alternative therapies to treat anxiety

and depression in the United States. American Journal of


Khan A, Brodhead AE, Schwartz KA, Kolts RL, Brown WA

(2005). Sex differences in antidepressant response in

recent antidepressant clinical trials. Journal of Clinical


Khisti RT, Chopde CT, Jain SP (2000). Antidepressant-like

effect of the neurosteroid 3a-hydroxy-5a-pregnan-20-one

in mice forced swim test. Pharmacology, Biochemistry and

Behavior 67, 137–143.

Khouzam HR, Emes R, Gill T, Raroque R (2003). The

antidepressant sertraline : a review of its uses in a range

of psychiatric and medical conditions. Comprehensive

Therapy 29, 47–53.

Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG,

Carroll BJ (2000). Serotonin transporter gene

polymorphism and antidepressant response. Neuroreport

11, 215–219.

Kim HL, Streltzer J, Goebert D (1999). St. John’s wort for

depression : a meta-analysis of well-defined clinical trials.

Journal of Nervous and Mental Disease 187, 532–538.

Kim RB (2006). Transporters and drug discovery : why, when

and how. Molecular Pharmaceutics 3, 26–32.

Kimmel PL, Peterson RA (2005). Depression in end-stage

renal disease patients treated with hemodialysis : tools,

correlates, outcomes, and needs. Seminars in Dialysis 18,

91–97.

Kind P, Sorensen J (1995). Modelling the cost-effectiveness of

the prophylactic use of SSRIs in the treatment of

depression. International Clinical Psychopharmacology 10

(Suppl. 1), 41–48.

King DE, Finestone DH, Peden JG (1994). Combination

antidepressant therapy in primary care. Archives of Family

Medicine 3, 1088–1092.

King RA, Riddle MA, Chappell PB, Hardin MT,

Anderson GM, Lombroso P, Scahill L (1991). Emergence

of self-destructive phenomena in children and adolescents

during fluoxetine treatment. Journal of the American

Academy of Child and Adolescent Psychiatry 30, 179–186.


Kirchheiner J, Brøsen K, Dahl ML, Gram LF, Kasper S,

Roots I, Sjoqvist F, Spina E, Brockmoller J (2001).

CYP2D6 and CYP2C19 genotype-based dose

recommendations for antidepressants : a first step towards

subpopulation-specific dosages. Acta Psychiatrica


Kirchheiner J, Nickchen K, Bauer M, Wong ML, Licinio J,

Roots I, Brockmoller J (2004). Pharmacogenetics of

antidepressants and antipsychotics : the contribution of

allelic variations to the phenotype of drug response.

Molecular Psychiatry 9, 442–473.

Kissling W, Moller HJ, Lauter H, Binz U, Wendt G (1985).

Double-blind comparison of intravenous versus oral

maprotiline : antidepressant activity, plasma levels, side

effects. Pharmacopsychiatry 15, 96–97.

Kitada M (2003). Genetic polymorphism of cytochrome P450

enzymes in Asian populations : focus on CYP2D6.

International Journal of Clinical Pharmacology Research 23,

31–35.

Klein DF (2006). The flawed basis for FDA post-marketing

safety decisions : the example of anti-depressants and

children. Neuropsychopharmacology 31, 689–699.

Klerman GL, Cole JO (1965). Clinical pharmacology of

imipramine and related antidepressant compounds.

Pharmacological Reviews 17, 101–141.

Klerman GL, Weissmann MM (1987). Interpersonal

psychotherapy (IPT) and drugs in the treatment of

depression. Pharmacopsychiatry 20, 3–7.

Klysner R, Bent-Hansen J, Hansen HL, Lunde M,

Pleidrup E, Poulsen DL, AndersenM, Petersen HE (2002).

Efficacy of citalopram in the prevention of recurrent

depression in elderly patients : placebo-controlled study of

maintenance therapy. British Journal of Psychiatry 181,

29–35.

Knuuttila JE, Toronen P, Castren E (2004). Effects of

antidepressant drug imipramine on gene expression in rat

prefrontal cortex. Neurochemical Research 29, 1235–1244.

Kole MH, Swan L, Fuchs E (2002). The antidepressant

tianeptine persistently modulates glutamate receptor

currents of the hippocampal CA3 commissural

associational synapse in chronically stressed rats. European

Journal of Neuroscience 16, 807–816.

Konstantinidis A, Stastny J, Ptak-Butta J, Hilger E, Winkler

D, Barnas C, Neumeister A, Kasper S (2002). Intravenous

mirtazapine in the treatment of depressed inpatients.


Kopell BH, Greenberg B, Rezai AR (2004). Deep brain

stimulation for psychiatric disorders. Journal of Clinical

Neurophysiology 21, 51–67.

Koran LM, Pallanti S, Paiva RS, Quercioli L (1998). Pulse

loading versus gradual dosing of intravenous

clomipramine in obsessive-compulsive disorder. European


Kornstein SG, Sloan DM, Thase ME (2002). Gender-specific

differences in depression and treatment response.


Kosel M, Frick C, Lisanby SH, Fisch HU, Schlaepfer TE

(2003). Magnetic seizure therapy improves mood in

refractory major depression. Neuropsychopharmacology 28,

2045–2048.

Koski A, Vuori E, Ojanpera I (2005). Newer antidepressants :

evaluation of fatal toxicity index and interaction with

alcohol based on Finnish postmortem data. International

Journal of Legal Medicine 119, 344–348.

Kramer MS (2002). Clinical update : substance P antagonists

in patients with major depression. European Psychiatry

17, 10.

Kramer MS, Cutler N, Feighner J, Shrivastava R, Carman J,

Sramek JJ, Reines SA, Liu G, Snavely D, Wyatt-Knowles

E, Hale JJ, Mills SG, MacCoss M, Swain CJ, Harrison T,

Hill RG, Hefti F, Scolnick EM, Cascieri MA, Chicchi GG,

Sadowski S, Williams AR, Hewson L, Smith D,

Carlson EJ, Hargreaves RJ, Rupniak NMJ (1998). Distinct

mechanism for antidepressant activity by blockade

of central substance P receptors. Science 281, 1640–1645.

Kramer MS, Winokur A, Kelsey J, Preskorn SH, Rothschild

AJ, Snavely D, Ghosh K, Ball WA, Reines SA, Munjack

D, Apter JT, Cunningham L, Kling M, Bari M, Getson A,

Lee Y (2004). Demonstration of the efficacy and safety

of a novel substance P (NK1) receptor antagonist in

major depression. Neuropsychopharmacology 29, 385–392.

Krauchi K, Cajochen C, Mori D, Graw P, Wirz-Justice A

(1997). Early evening melatonin and S-20098 advance

circadian phase and nocturnal regulation of core body

temperature. American Journal of Physiology 272,

R1178–R1188.

Krause P, Genz A, Knorr W (1988). [Prospective study of the

late sequelae of electroconvulsive treatment]. Psychiatrie,

Neurologie Und Medizinische Psychologie 40, 532–536.

Kripke DF (1998). Light treatment for nonseasonal

depression : speed, efficacy, and combined treatment.


Krishnan KR, McDonald WM (1995). Arteriosclerotic

depression. Medical Hypotheses 44, 111–115.

Kroessler D (1985). Relative efficacy rates for therapies of

delusional depression. Convulsive Therapy 1, 173–182.

Krupnick JL, Sotsky SM, Simmens S, Moyer J, Elkin I,

Watkins J, Pilkonis PA (1996). The role of the therapeutic

alliance in psychotherapy and pharmacotherapy outcome:

findings in the National Institute of Mental Health

Treatment of Depression Collaborative Research

Program. Journal of Consulting and Clinical Psychology 64,

532–539.

Krystal J (2007). Ketamine and the potential role for

rapid-acting antidepressant medications. Swiss Medical

Weekly 137, 215–216.

Krystal AD, Coffey CE (1997). Neuropsychiatric

considerations in the use of electroconvulsive therapy.

Journal of Neuropsychiatry and Clinical Neurosciences 9,

283–292.

Kuehner C (2003). Gender differences in unipolar

depression : an update of epidemiological findings and

possible explanations. Acta Psychiatrica Scandinavica 108,

163–174.

Kugaya A, Seneca NM, Snyder PJ, Williams SA, Malison

RT, Baldwin RM, Seibyl JP, Innis RB (2003). Changes in


human in vivo serotonin and dopamine transporter

availabilities during chronic antidepressant

administration. Neuropsychopharmacology 28, 413–420.

Kuhs H, Farber D, Borgstadt S, Mrosek S, Tolle R (1996).

Amitriptyline in combination with repeated late sleep

deprivation versus amitriptyline alone in major

depression. A randomised study. Journal of Affective


Kuhs H, Kemper B, Lippe-Neubauer U, Meyer-Dunker J,

Tolle R (1998). Repeated sleep deprivation once versus

twice a week in combination with amitriptyline. Journal of


Kuhs H, Tolle R (1991). Sleep deprivation therapy. Biological


Kupfer DJ (1991). Long-term treatment of depression. Journal

of Clinical Psychiatry 52 (Suppl.), 28–34.

Kupfer DJ (2005). The pharmacological management of

depression. Dialogues in Clinical Neuroscience 7, 191–205.

Kupfer DJ, Charney DS (2003). Difficult-to-treat depression.


Kupfer DJ, Frank E, Perel JM, Cornes C, Mallinger AG,

Thase ME, McEachran AB, Grochocinski VJ (1992). Five-

year outcome for maintenance therapies in recurrent

depression. Archives of General Psychiatry 49, 769–773.

Kupfer DJ, Pollock BG, Perel JM, Jarrett DB, McEachran

AB, Miewald JM (1991). Immediate effects of intravenous

clomipramine on sleep and sleep-related secretion in

depressed patients. Psychiatry Research 36, 279–289.

Kupfer DJ, Rush AJ (1983). Recommendations for depression

publications. Archives of General Psychiatry 40, 1031.

Laakmann G, Faltermaier-Temizel M, Bossert-Zaudig S,

Baghai T (1996). Are benzodiazepines antidepressants?


LaakmannG, Schule C, Baghai T, Kieser M (1998). St. John’s

wort in mild to moderate depression: the relevance of

hyperforin for the clinical efficacy. Pharmacopsychiatry 31

(Suppl. 1), 54–59.

Lader MH (1996). Tolerability and safety : essentials in

antidepressant pharmacotherapy. Journal of Clinical


Lafuma A, Dardennes R, Fagnani F, Pribil C, Bisserbe JC,

Berdeaux G (1999). [Clinico-economic assessment of

milnacipran in the prevention of depressive episodes].

Encephale 25, 401–407.

Laje G, Paddock S, Manji H, Rush AJ, Wilson AF,

Charney D, McMahon FJ (2007). Genetic markers of

suicidal ideation emerging during citalopram treatment of

major depression. American Journal of Psychiatry 164,

1530–1538.

Lam R, Levitt AJ, Kraus RP, Rudradeo CB, Morehouse RL,

Hasey G, Levitan RD (1999). Management issues. In : Lam

R, Levitt AJ (Eds.), Canadian Consensus Guidelines for the

Treatment of Seasonal Affective Disorder (pp. 96–114).

Vancouver, BC: Clinical and Academic Publishing.

Lam RW, Levitt AJ, Levitan RD, Enns MW, Morehouse R,

Michalak EE, Tam EM (2006). The Can-SAD study: a

randomized controlled trial of the effectiveness of light

therapy and fluoxetine in patients with winter seasonal

affective disorder. American Journal of Psychiatry 163,

805–812.

Lam RW, Levitan RD, Tam EM, Yatham LN, Lamoureux S,

Zis AP (1997). L-tryptophan augmentation of light therapy

in patients with seasonal affective disorder. Canadian


Lambert MT, Trutia C, Petty F (1998). Extrapyramidal

adverse effects associated with sertraline. Progress in

Neuro-Psychopharmacology and Biological Psychiatry 22,

741–748.

Landauer AA, Milner G, Patman J (1969). Alcohol and

amitriptyline effects on skills related to driving behavior.

Science 163, 1467–1468.

Landen M, Bjorling G, Agren H, Fahlen T (1998). A

randomized, double-blind, placebo-controlled trial of

buspirone in combination with an SSRI in patients with

treatment-refractory depression. Journal of Clinical


Larsen JK (1988). MAO inhibitors : pharmacodynamic

aspects and clinical implications. Acta Psychiatrica


Launay D, Queyrel V, Hatron PY, Michon-Pasturel U,

Caron J, Hachulla E, Devulder B (2000). [Agranulocytosis

connected with the taking of mianserin : a complication to

be feared in the aged]. Revue De Medecine Interne 21,

642–643.

Lauritzen L, Odgaard K, Clemmesen L, LundeM, Ohrstrom

J, Black C, Bech P (1996). Relapse prevention by means of

paroxetine in ECT-treated patients with major depression :

a comparison with imipramine and placebo in medium-

term continuation therapy. Acta Psychiatrica Scandinavica

94, 241–251.

Laux G (2001). Driving performance under antidepressants.

World Journal of Biological Psychiatry 2, 186.

Laux G (2002). [Psychiatric disorders and fitness to

drive an automobile. An overview]. Nervenarzt 73,

231–238.

Laux G, Reimer F (1979). [Treatment of therapy resistant

depressions with high dose clomipramine]. International


Lave JR, Frank RG, Schulberg HC, Kamlet MS (1998).

Cost-effectiveness of treatments for major depression in

primary care practice. Archives of General Psychiatry 55,

645–651.

Lawlor DA, Hopker SW (2001). The effectiveness of exercise

as an intervention in the management of depression :

systematic review and meta-regression analysis of

randomised controlled trials. British Medical Journal 322,

763–767.

Le Pen C, Levy E, Ravily V, Beuzen JN, Meurgey F (1994).

The cost of treatment dropout in depression. A cost-benefit

analysis of fluoxetine vs. tricyclics. Journal of Affective


Learned-Coughlin SM, Bergstrom M, Savitcheva I, Ascher

J, Schmith VD, Langstrom B (2003). In vivo activity of

bupropion at the human dopamine transporter as

measured by positron emission tomography. Biological



Lecrubier Y (2007). Widespread underrecognition and

undertreatment of anxiety and mood disorders : results

from 3 European studies. Journal of Clinical Psychiatry

68(2), :36–41.

Lecrubier Y, Clerc G, Didi R, Kieser M (2002). Efficacy of St.

John’s wort extract WS 5570 in major depression : a double-

blind, placebo-controlled trial. American Journal of

Psychiatry 159, 1361–1366.

Lederbogen F, Deuschle M, Heuser I (1999). [Depression : a

cardiovascular risk factor]. Internist 40, 1119–1121.

Lederbogen F, Gilles M, Maras A, Hamann B, Colla M,

Heuser I, Deuschle M (2001). Increased platelet

aggregability in major depression? Psychiatry Research 102,

255–261.

LeDoux JE (2000). Emotion circuits in the brain. Annual

Review of Neuroscience 23, 155–184.

LeDrew K, Phillips L, Hogan M, MacCallum A (2005).

Lamotrigine-induced neutropenia. Canadian Journal of

Psychiatry 50, 242.

Lee MS, Lim SW, Cha JH, Chung SK, Kim KS, Kasper S,

Executive Committee for the Korean Medication

Algorithm Project for Major Depressive Disorder (2006).

Korean medication algorithm for major depressive

disorder. International Journal of Psychiatry in Clinical

Practice 10, 186–194.

Lee TM, Chan CC (1999). Dose-response relationship of

phototherapy for seasonal affective disorder : a meta-

analysis. Acta Psychiatrica Scandinavica 99, 315–323.

Leff J, Vearnals S, Brewin CR, Wolff G, Alexander B,

Asen E, Dayson D, Jones E, Chisholm D, Everitt B

(2000). The London Depression Intervention Trial :

randomised controlled trial of antidepressants v. couple

therapy in the treatment and maintenance of people with

depression living with a partner : clinical outcome and

costs. British Journal of Psychiatry 177, 95–100.

Leinonen E, Skarstein J, Behnke K, Agren H, Helsdingen JT

(1999). Efficacy and tolerability of mirtazapine versus

citalopram: a double-blind, randomized study in patients

with major depressive disorder. Nordic Antidepressant

Study Group. International Clinical Psychopharmacology 14,

329–337.

Lejoyeux M, Rodiere-Rein C, Ades J (1992). [Withdrawal

syndrome from antidepressive drugs. Report of 5 cases].

Encephale 18, 251–255.

Lemke MR (2002). Effect of reboxetine on depression in

Parkinson’s disease patients. Journal of Clinical Psychiatry

63, 300–304.

Lemke MR, Fuchs G, Gemende I, Herting B, Oehlwein C,

Reichmann H, Rieke J, Volkmann J (2004). Depression

and Parkinson’s disease. Journal of Neurology 251 (Suppl. 6),

VI/24–VI/27.

Lenox-Smith A, Conway P, Knight C (2004). Cost

effectiveness of representatives of three classes of

antidepressants used in major depression in the UK.


Leonard BE (1988). Biochemical aspects of therapy-

resistant depression. British Journal of Psychiatry 152,

453–459.

Leonard BE (2001). Brain cytokines and the psychopathology

of depression. In : Leonard BE (Ed.), Antidepressants

(pp. 109–120). Basel : Birkaeuser.

Leonard BE, Myint A (2006a). Changes in the immune

system in depression and dementia : causal or

coincidental effects? Dialogues in Clinical Neuroscience 8,

163–174.

Leonard BE, Myint AM (2006b). Inflammation and

depression : is there a causal connection with dementia?

Neurotoxicity Research 10, 1–12.

Leonard BE, Song C (1999). Stress, depression, and the role of

cytokines. Advances in Experimental Medicine & Biology 461,

251–265.

Leonard BE, Song C (2002). Changes in the immune system

in rodent models of depression. International Journal of


Lepine JP, Altamura C, Ansseau M, Gutierrez JL, Bitter I,

Lader M, Waintraub L (2001). Tianeptine and paroxetine

in major depressive disorder, with a special focus on

the anxious component in depression : an international,

6-week double-blind study dagger. Human


Lepine JP, Caillard V, Bisserbe JC, Troy S, Hotton JM,

Boyer P (2004). A randomized, placebo-controlled trial of

sertraline for prophylactic treatment of highly recurrent

major depressive disorder. American Journal of Psychiatry

161, 836–842.

Lepola U, Wade A, Andersen HF (2004). Do equivalent doses

of escitalopram and citalopram have similar efficacy? A

pooled analysis of two positive placebo-controlled studies

in major depressive disorder. International Clinical


Leproult R, Van Onderbergen A, L’hermite-Baleriaux M,

Van Cauter E, Copinschi G (2005). Phase-shifts of 24-h

rhythms of hormonal release and body temperature

following early evening administration of the melatonin

agonist agomelatine in healthy older men. Clinical

Endocrinology 63, 298–304.

Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD,

Petri S, Benjamin J, Muller CR, Hamer DH, Murphy DL

(1996). Association of anxiety-related traits with a

polymorphism in the serotonin transporter gene

regulatory region. Science 274, 1527–1531.

Lesch KP, Gutknecht L (2004). Focus on The 5-HT1A

receptor : emerging role of a gene regulatory variant in

psychopathology and pharmacogenetics. International

Journal of Neuropsychopharmacology 7, 381–385.

Lesieur D, Leclerc V, Chavatte P, Marcot C, Renard P,

Guardiola-Lemaitre B (1998). Melatonin : a pertinent

prototype for therapeutic intervention. Therapie 53,

429–437.

Leslie LK, Newman TB, Chesney PJ, Perrin JM (2005). The

Food and Drug Administration’s deliberations on

antidepressant use in pediatric patients. Pediatrics 116,

195–204.

Leterme L, Singlan YS, Auclair V, Le BR, Frimas V (2003).

[Misuse of tianeptine : five cases of abuse]. Annales De

Medecine Interne 154 Spec No. 2, S58–S63.


Levin OS (2006). [Coaxil (tianeptine) in the treatment of

depression in Parkinson’s disease]. Zhurnal Nevrologii i

Psikhiatrii Imeni S. S. Korsakova 106, 20–25.

Lexchin J, Bero LA, Djulbegovic B, Clark O (2003).

Pharmaceutical industry sponsorship and research

outcome and quality : systematic review. British Medical

Journal 326, 1167–1170.

Lexchin J, Light DW (2006). Commercial influence and the

content of medical journals. British Medical Journal 332,

1444–1447.

Li YF, Yuan L, Xu YK, Yang M, Zhao YM, Luo ZP (2001).

Antistress effect of oligosaccharides extracted from

Morinda officinalis in mice and rats. Acta Pharmacologica

Sinica 22, 1084–1088.

Lieberman A (2006). Depression in Parkinson’s disease : a

review. Acta Neurologica Scandinavica 113, 1–8.

Liebrenz M, Borgeat A, Leisinger R, Stohler R (2007).

Intravenous ketamine therapy in a patient with a

treatment-resistant major depression. Swiss. Med. Wkly.

137, 234–236.

Lin JH (2003). Drug-drug interaction mediated by inhibition

and induction of P-glycoprotein. Advanced Drug Delivery

Reviews 55, 53–81.

Linde K, Berner M, Egger M, Mulrow C (2005). St John’s

wort for depression: meta-analysis of randomised

controlled trials. British Journal of Psychiatry 186, 99–107.

Linkowski P, Mendlewicz J, Kerkhofs M, Leclerq R,

Goldstein J, Brasseur M, Copinschi G, Van Cauter E

(1987). 24-hour profiles of adrenocorticotropin, cortisol,

and growth hormone in major depressive illness : effect

of antidepressant treatment. Journal of Clinical

Endocrinology and Metabolism 65, 141–152.

Linnoila M, Virkkunen M, Scheinin M, Nuutila A,

Rimon R, Goodwin FK (1983). Low cerebrospinal fluid

5-hydroxyindoleacetic acid concentration differentiates

impulsive from nonimpulsive violent behavior. Life Science

33, 2609–2614.

Lisanby SH, Luber B, Finck AD, Schroeder C, Sackeim HA

(2001a). Deliberate seizure induction with repetitive

transcranial magnetic stimulation in nonhuman primates.


Lisanby SH, Luber B, Schlaepfer TE, Sackeim HA (2003a).

Safety and feasibility of magnetic seizure therapy (MST) in

major depression : randomized within-subject comparison

with electroconvulsive therapy. Neuropsychopharmacology

28, 1852–1865.

Lisanby SH, Maddox JH, Prudic J, Devanand DP, Sackeim

HA (2000). The effects of electroconvulsive therapy on

memory of autobiographical and public events. Archives of


Lisanby SH, Morales O, Payne N, Kwon E, Fitzsimons L,

Luber B, Nobler MS, Sackeim HA (2003b). New

developments in electroconvulsive therapy and magnetic

seizure therapy. CNS Spectrums 8, 529–536.

Lisanby SH, Pascual-Leone A, Sampson SM, Boylan LS,

Burt T, Sackeim HA (2001b). Augmentation of sertraline

antidepressant treatment with transcranial magnetic

stimulation. Biological Psychiatry 49, 81S.

Lisanby SH, Schlaepfer TE, Fisch HU, Sackeim HA (2001c).

Magnetic seizure therapy of major depression. Archives of


Liston HL, Markowitz JS, DeVane CL (2001). Drug

glucuronidation in clinical psychopharmacology. Journal of


Liu JLY, Maniadakis N, Gray A, Rayner M (2002). The

economic burden of coronary heart disease in the UK.

Heart 88, 597–603.

Livingston MG, Livingston HM (1996). Monoamine oxidase

inhibitors. An update on drug interactions. Drug Safety 14,

219–227.

Llorca PM, Azorin JM, Despiegel N, Verpillat P (2005).

Efficacy of escitalopram in patients with severe

depression : a pooled analysis. International Journal of

Clinical Practice 59, 268–275.

Loo CK, Mitchell PB, Croker VM, Malhi GS, Wen W,

Gandevia SC, Sachdev PS (2003). Double-blind controlled

investigation of bilateral prefrontal transcranial magnetic

stimulation for the treatment of resistant major depression.


Loo H, Deniker P (1988). Position of tianeptine among

antidepressive chemotherapies. Clinical Neuropharmacology

11 (Suppl. 2), S97–102.

Loo H, Hale A, D’haenen H (2002). Determination of

the dose of agomelatine, a melatoninergic agonist

and selective 5-HT(2C) antagonist, in the treatment of

major depressive disorder : a placebo-controlled dose

range study. International Clinical Psychopharmacology 17,

239–247.

LooH, Saiz-Ruiz J, Costa e Silva JA, AnsseauM, Herrington

R, Vaz-Serra A, Dilling H, De Risio S (2001). Efficacy and

safety of tianeptine in the treatment of depressive

disorders in comparison with fluoxetine. Human

Psychopharmacology 16, S31–S38.

Lothgren M, Hemels M, Francois C, Jonsson B (2004). A

cost-effectiveness analysis of escitalopram as first line

treatment of depression in Sweden. Primary Care Psychiatry

9, 161.

Lotufo-Neto F, Trivedi M, Thase ME (1999). Meta-analysis

of the reversible inhibitors of monoamine oxidase

type A moclobemide and brofaromine for the

treatment of depression. Neuropsychopharmacology 20,

226–247.

Louwerens JW, Brookhuis KA, O’Hanlon JF (1984). The

Effects of the Antidepressants Oxaprotiline, Mianserin,

Amitriptyline and Doxepin Upon Actual Driving Performance.

Groningen, The Netherlands : Traffic Research Centre.

Loving RT, Kripke DF, Shuchter SR (2002). Bright light

augments antidepressant effects of medication and wake

therapy. Depression and Anxiety 16, 1–3.

Lucena MI, Carvajal A, Andrade RJ, Velasco A (2003).

Antidepressant-induced hepatotoxicity. Expert Opinion on


Lucht MJ, Kleinschmidt R, Maier W, Rietschel M (2000).

Agranulocytosis during treatment with mianserin and

venlafaxine. Journal of Clinical Psychopharmacology 20,

490–491.


Ludwig J, Marcotte DE (2005). Anti-depressants, suicide, and

drug regulation. Journal of Policy Analysis and Management

24, 249–272.

Luo H, Jia Y, Feng X, Zhao X, Tang LC (1995). Advances in

clinical research on common mental disorders with

computer controlled electro-acupuncture treatment.

Neurochemistry in Clinical Application 109–122.

Luo H, Jia Y, Li Z (1985). Electro-acupuncture vs.

amitriptyline in the treatment of depressive states. Journal

of Traditional Chinese Medicine 5, 3–8.

Luo H, Jia YK, Wu X, Dai W (1990a). Electro-acupuncture in

the treatment of depressive psychosis. International Journal

of Clinical Acupuncture 1, 7–13.

Luo H, Meng F, Jia Y, Zhao X (1998). Clinical research on the

therapeutic effect of the electro-acupuncture treatment in

patients with depression. Psychiatry and Clinical

Neurosciences 52, S338–S340.

Luo H, Shen Y, Jia Y (1988). [Clinical study of electro-

acupuncture on 133 patients with depression in

comparison with tricyclic amitriptyline]. Zhong Xi Yi Jie He

Za Zhi 8, 77–80, 68.

Luo H, Shen Y, Zhou D, Jia Y (1990b). A comparative study

of the treatment of depression by electroacupuncture and

amitriptyline. Acupuncture 1, 20–26.

Luo L, Nong WJ, Kong LD, Jiang QG, Tan RX (2000).

Antidepressant effects of Banxia Houpu decoction, a

traditional Chinese medicinal empirical formula. Journal of

Ethnopharmacology 73, 277–281.

Mace S, Taylor D (2000). Selective serotonin reuptake

inhibitors : a review of efficacy and tolerability in

depression. Expert Opinion on Pharmacotherapy 1, 917–933.

MacLeod AK, Tata P, Tyrer P, Schmidt U, Davidson K,

Thompson S (2005). Hopelessness and positive and

negative future thinking in parasuicide. British Journal of

Clinical Psychology 44, 495–504.

MacMillan HL, Patterson CJ, Wathen CN, Feightner JW,

Bessette P, Elford RW, Feig DS, Langley J, Palda VA,

Patterson C, Reeder BA, Walton R (2005). Screening

for depression in primary care : recommendation

statement from the Canadian Task Force on Preventive

Health Care. Canadian Medical Association Journal 172,

33–35.

Magyar J, Rusznak Z, Harasztosi C, Kortvely A, Pacher P,

Banyasz T, Pankucsi C, Kovacs L, Szucs G, Nanasi PP,

Kecskemeti V (2003). Differential effects of fluoxetine

enantiomers in mammalian neural and cardiac tissues.

International Journal of Molecular Medicine 11, 535–542.

Maj M, Starace F, Sartorius N (1993). Mental Disorders in

HIV-1 Infection and AIDS. Bern : Huber.

Malagie I, Deslandes A, Gardier AM (2000). Effects of acute

and chronic tianeptine administration on serotonin

outflow in rats : comparison with paroxetine by using in

vivo microdialysis. European Journal of Pharmacology 403,

55–65.

Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000).

Chronic antidepressant treatment increases neurogenesis

in adult rat hippocampus. Journal of Neuroscience 20,

9104–9110.

Malhotra AK, Murphy GMJ, Kennedy JL (2004).

Pharmacogenetics of psychotropic drug response.


Malison RT, Anand A, Pelton GH, Kirwin P, Carpenter L,

McDougle CJ, Heninger GR, Price LH (1999). Limited

efficacy of ketoconazole in treatment-refractory major

depression. Journal of Clinical Psychopharmacology 19,

466–470.

Mamdani MM, Parikh SV, Austin PC, Upshur RE (2000).

Use of antidepressants among elderly subjects : trends and

contributing factors. American Journal of Psychiatry 157,

360–367.

Manber R, Allen JJ, Morris MM (2002). Alternative

treatments for depression : empirical support and relevance

to women. Journal of Clinical Psychiatry 63, 628–640.

Manber R, Schnyer RN, Allen JJ, Rush AJ, Blasey CM

(2004). Acupuncture : a promising treatment for

depression during pregnancy. Journal of Affective Disorders

83, 89–95.

Mancama D, Kerwin RW (2003). Role of pharmacogenomics

in individualising treatment with SSRIs. CNS Drugs 17,

143–151.

MandokiMW, TapiaMR, Tapia MA, Sumner GS, Parker JL

(1997). Venlafaxine in the treatment of children and

adolescents with major depression. Psychopharmacology

Bulletin 33, 149–154.

Manji HK, Drevets WC, Charney DS (2001). The cellular

neurobiology of depression. Nature Medicine 7, 541–547.

Manji HK, Lenox RH (1999). Ziskind-Somerfeld Research

Award. Protein kinase C signaling in the brain : molecular

transduction of mood stabilization in the treatment of

manic-depressive illness. Biological Psychiatry 46,

1328–1351.

Manji HK, Quiroz JA, Sporn J, Payne JL, Denicoff K, Gray

A, Zarate CAJ, Charney DS (2003). Enhancing neuronal

plasticity and cellular resilience to develop novel,

improved therapeutics for difficult-to-treat depression.


Mann JJ, Aarons SF, Wilner PJ, Keilp JG, Sweeney JA,

Pearlstein T, Frances AJ, Kocsis JH, Brown RP (1989).

A controlled study of the antidepressant efficacy and

side effects of (-)-deprenyl. A selective monoamine

oxidase inhibitor. Archives of General Psychiatry 46, 45–50.

Mann JJ, Emslie G, Baldessarini RJ, Beardslee W,

Fawcett JA, Goodwin FK, Leon AC, Meltzer HY,

Ryan ND, Shaffer D, Wagner KD (2006a). ACNP Task

Force report on SSRIs and suicidal behavior in youth.


Mann K, Hiemke C, Schmidt LG, Bates DW (2006b).

Appropriateness of therapeutic drug monitoring for

antidepressants in routine psychiatric inpatient care.

Therapeutic Drug Monitoring 28, 83–88.

Manning DW, Markowitz JC, Frances AJ (1992). A Review

of Combined Psychotherapy and Pharmacotherapy in

the Treatment of Depression. J Psychother Pract Res 1,

103–116.

March J, Silva S, Petrycki S, Curry J, Wells K, Fairbank J,

Burns B, Domino M, McNulty S, Vitiello B, Severe J


(2004). Fluoxetine, cognitive-behavioral therapy, and their

combination for adolescents with depression : treatment

for Adolescents With Depression Study (TADS)

randomized controlled trial. Journal of the American Medical


Marcus SM, Young EA, Kerber KB, Kornstein S, Farabaugh

AH, Mitchell J, Wisniewski SR, Balasubramani GK,

Trivedi MH, Rush AJ (2005). Gender differences in

depression : findings from the STAR*D study. Journal of


Markowitz JC (1993). Psychotherapy of the Postdysthymic

Patient. The Journal of Psychotherapy Practice and Research 2,

157–163.

Markowitz JC, Kocsis JH, Bleiberg KL, Christos PJ, SacksM

(2005). A comparative trial of psychotherapy and

pharmacotherapy for ‘pure’ dysthymic patients. Journal of


Martell CR, Addis ME, Jacobson NS (2001). Depression in

Context : Strategies for Guided Action. New York : W. W.

Norton.

Martenyi F, Brown EB, Zhang H, Koke SC, Prakash A

(2002). Fluoxetine v. placebo in prevention of relapse in

post-traumatic stress disorder. British Journal of Psychiatry

181, 315–320.

Martin JL, Barbanoj MJ, Schlaepfer TE, Thompson E, Perez

V, Kulisevsky J (2003). Repetitive transcranial magnetic

stimulation for the treatment of depression. Systematic

review and meta-analysis. British Journal of Psychiatry 182,

480–491.

Martinez C, Rietbrock S, Wise L, Ashby D, Chick J,

Moseley J, Evans S, Gunnell D (2005). Antidepressant

treatment and the risk of fatal and non-fatal self harm in

first episode depression : nested case-control study. British

Medical Journal 330, 389.

Martiny K (2004). Adjunctive bright light in non-seasonal

major depression. Acta Psychiatrica Scandinavica.

Supplementum 7–28.

Martiny K, Lunde M, Unden M, Dam H, Bech P (2005a).

Adjunctive bright light in non-seasonal major depression :

results from clinician-rated depression scales. Acta


Martiny K, Lunde M, Unden M, Dam H, Bech P (2005b).

Adjunctive bright light in non-seasonal major depression :

results from patient-reported symptom and well-being

scales. Acta Psychiatrica Scandinavica 111, 453–459.

Martiny K, Lunde M, Unden M, Dam H, Bech P (2006).

The lack of sustained effect of bright light in

non-seasonal major depression. Psychological Medicine

1247–1252.

Marzolini C, Paus E, Buclin T, Kim RB (2004).

Polymorphisms in human MDR1 (P-glycoprotein) : recent

advances and clinical relevance. Clinical Pharmacology and


Mason J, Freemantle N, Eccles M (2000). Fatal toxicity

associated with antidepressant use in primary care.

British Journal of General Practice 50, 366–370.

Massana J, Moller HJ, Burrows GD,Montenegro RM (1999).

Reboxetine : a double-blind comparison with fluoxetine

in major depressive disorder. International Clinical


Mattia C, Paoletti F, Coluzzi F, Boanelli A (2002). New

antidepressants in the treatment of neuropathic pain.

A review. Minerva Anestesiologica 68, 105–114.

Maurer-Spurej E, Pittendreigh C, Solomons K (2004). The

influence of selective serotonin reuptake inhibitors on

human platelet serotonin. Thrombosis and Haemostasis 91,

119–128.

Mayberg HS, Liotti M, Brannan SK, McGinnis S,

Mahurin RK, Jerabek PA, Silva JA, Tekell JL, Martin CC,

Lancaster JL, Fox PT (1999). Reciprocal limbic-cortical

function and negative mood: converging PET findings in

depression and normal sadness. American Journal of


Mayberg HS, Lozano AM, Voon V, McNeely HE,

Seminowicz D, Hamani C, Schwalb JM, Kennedy SH

(2005). Deep brain stimulation for treatment-resistant

depression. Neuron 45, 651–660.

McCall WV (2001). Electroconvulsive therapy in the era of

modern psychopharmacology. International Journal of


McCall WV, Reboussin DM, Weiner RD, Sackeim HA

(2000). Titrated moderately suprathreshold vs fixed

high-dose right unilateral electroconvulsive therapy:

acute antidepressant and cognitive effects. Archives of


McCullough JP (2000). Treatment for chronic depression:

Cognitive Behavioral Analysis System of Psychotherapy.

New York : Guilford Press.

McCullough JP (2003). Treatment for chronic depression

using Cognitive Behavioral Analysis System of

Psychotherapy (CBASP). Journal of Clinical Psychology 59,

833–846.

McCusker J, ColeM, Keller E, Bellavance F, Berard A (1998).

Effectiveness of treatments of depression in older

ambulatory patients. Archives of Internal Medicine 158,

705–712.

McDaid D, Curran C, Knapp M (2005). Promoting

mental well-being in the workplace : a European policy

perspective. International Review of Psychiatry 17, 365–373.

McDonald WM, Richard IH, DeLong MR (2003).

Prevalence, etiology, and treatment of depression in

Parkinson’s disease. Biological Psychiatry 54, 363–375.

McEwen BS, Olie JP (2005). Neurobiology of mood, anxiety,

and emotions as revealed by studies of a unique

antidepressant : tianeptine. Molecular Psychiatry 10,

525–537.

McGrath PJ, Stewart JW, Fava M, Trivedi MH, Wisniewski

SR, Nierenberg AA, Thase ME, Davis L, Biggs MM,

Shores-Wilson K, Luther JF, Niederehe G, Warden D,

Rush AJ (2006). Tranylcypromine versus venlafaxine plus

mirtazapine following three failed antidepressant

medication trials for depression : a STAR*D report.


Medawar C, Hardon A (2004). Medicines Out of Control?

Antidepressants and the Conspiracy of Goodwill. Amsterdam:

Aksant Academic Publisher.


Medicines and Healthcare products Regulatory Agency

(2006). Updated Prescribing Advice for Venlafaxine :

Information for Healthcare Professionals (http://

www.mhra.gov.uk/home/idcplg?IdcService=SS_

GET_PAGE&ssDocName=CON2023846&

ssSourceNodeId=242&ssTargetNodeId=221). Accessed

26 October 2006.

Medicines Control Council (2007). Guidelines for the

Registration of Medicines (http://www.mccza.com/

showdocument.asp?Cat=17&Desc=Guidelines%20-

%20Human%20Medicines). Accessed 2 November 2007.

Medina-Mora ME, Borges G, Lara Munoz C, Benjet C,

Blanco Jaimes J, Fleiz Bautista C, Villatoro Velazquez J,

Rojas Guiot E, Zambrano Ruiz J, Casanova Rodas L,

Aguillar-Gaxiola S (2003). Prevalencia de trastornos

mentales y uso de servicios : Resultados de la Encuesta

Nacional de Epidemiologıa Psiquiatrica en Mexico. Salud

Mental 26, 1–16.

Meijer WEE, Bouvy ML, Heerdink ER, Urquhart J,

Leufkens HGM (2001). Spontaneous lapses in dosing

during chronic treatment with selective serotonin reuptake

inhibitors. British Journal of Psychiatry 179, 519–522.

Melfi CA, Chawla AJ, Croghan TW, HannaMP, Kennedy S,

Sredl K (1998). The effects of adherence to antidepressant

treatment guidelines on relapse and recurrence of


Menecier P, Menecier-Ossia L, Bern P (1997). [Fluoxetine

dependence and tolerance. Apropos of a case]. Encephale

23, 400–401.

Meng F, Luo H, Shen Y, Shu L, Liu J (1994). Plasma NE

concentration and 24 hours urinary MHPG-SO4 excretion

changes after electro-acupuncture treatment in

endogenous depression. World Journal of Acupuncture 4,

218–225.

Meng QF, Luo HC, Halbreich U (2002). Concepts,

techniques, and clinical applications of acupuncture.

Psychiatric Annals 32, 45–49.

Mennini T, Mocaer E, Garattini S (1987). Tianeptine, a

selective enhancer of serotonin uptake in rat brain.

Naunyn-Schmiedeberg’s Archives of Pharmacology 336,

478–482.

Menza M (2006). STAR*D: the results begin to roll in.

American Journal of Psychiatry 163, 1123.

Menza M, Marin H, Kaufman K, Mark M, Lauritano M

(2004). Citalopram treatment of depression in Parkinson’s

disease : the impact on anxiety, disability, and cognition.


315–319.

Mercante JP, Peres MF, Guendler V, Zukerman E, Bernik

MA (2005). Depression in chronic migraine : severity and

clinical features. Arquivos De Neuro-Psiquiatria 63, 217–220.

Meyer JH, Goulding VS, Wilson AA, Hussey D,

Christensen BK, Houle S (2002). Bupropion occupancy of

the dopamine transporter is low during clinical treatment.


Miklowitz DJ, George EL, Richards JA, Simoneau TL,

Suddath RL (2003). A randomized study of family-focused

psychoeducation and pharmacotherapy in the outpatient

management of bipolar disorder. Archives of General


Millan MJ, Brocco M, Gobert A, Dekeyne A (2005).

Anxiolytic properties of agomelatine, an antidepressant

with melatoninergic and serotonergic properties : role of

5-HT2C receptor blockade. Psychopharmacology 177,

448–458.

Millan MJ, Gobert A, Lejeune F, Dekeyne A,

Newman-Tancredi A, Pasteau V, Rivet JM, Cussac D

(2003). The novel melatonin agonist agomelatine

(S20098) is an antagonist at 5-hydroxytryptamine2C

receptors, blockade of which enhances the activity of

frontocortical dopaminergic and adrenergic pathways.

Journal of Pharmacology and Experimental Therapeutics 306,

954–964.

Millan MJ, Gobert A, Newman-Tancredi A, Lejeune F,

Cussac D, Rivet JM, Audinot V, Adhumeau A, Brocco M,

Nicolas JP, Boutin JA, Despaux N, Peglion JL (2000).

S18327 (1-[2-[4-(6-fluoro-1, 2-benzisoxazol-3-yl)piperid-1-

yl]ethyl]3-phenyl imidazolin-2-one), a novel, potential

antipsychotic displaying marked antagonist properties

at alpha(1)- and alpha(2)-adrenergic receptors : I.

Receptorial, neurochemical, and electrophysiological

profile. Journal of Pharmacology and Experimental


Miller L, Griffith J (1983). A comparison of bupropion,

dextroamphetamine, and placebo in mixed-substance

abusers. Psychopharmacology 80, 199–205.

Miller P, Chilvers C, Dewey M, Fielding K, Gretton V,

Palmer B, Weller D, Churchill R, Williams I, Bedi N,

Duggan C, Lee A, Harrison G (2003). Counseling versus

antidepressant therapy for the treatment of mild to

moderate depression in primary care : economic analysis.

International Journal of Technology Assessment in Health Care

19, 80–90.

Miniussi C, Bonato C, Bignotti S, Gazzoli A, Gennarelli M,

Pasqualetti P, Tura GB, Ventriglia M, Rossini PM (2005).

Repetitive transcranial magnetic stimulation (rTMS) at

high and low frequency : an efficacious therapy for major

drug-resistant depression? Clinical Neurophysiology 116,

1062–1071.

Miovic M, Block S (2007). Psychiatric disorders in advanced

cancer. Cancer 110, 1665–1676.

Misri S, Kostaras X (2002). Benefits and risks to mother and

infant of drug treatment for postnatal depression. Drug

Safety 25, 903–911.

Mitchell AJ, SubramaniamH (2005). Prognosis of depression

in old age compared to middle age : a systematic review of

comparative studies. American Journal of Psychiatry 162,

1588–1601.

Mitchell PB (2000). Therapeutic drug monitoring of

psychotropic medications. British Journal of Clinical


Mitchell PB (2004). Therapeutic drug monitoring of

non-tricyclic antidepressant drugs. Clinical Chemistry and

Laboratory Medicine 42, 1212–1218.

Mitte K, Noack P, Steil R, Hautzinger M (2005). A

meta-analytic review of the efficacy of drug treatment in


generalized anxiety disorder. Journal of Clinical


Mittmann N, Herrmann N, Einarson TR, Busto UE,

Lanctot KL, Liu BA, Shulman KI, Silver IL, Narango CA,

Shear NH (1997). The efficacy, safety and tolerability of

antidepressants in late life depression: a meta-analysis.


Moller HJ (1997). Therapieresistenz unter Antidepressiva :

Definition, Epidemiologie undRisikofaktoren. In : BauerM,

Berghofer A (Eds.), Therapieresistente Depressionen

(pp. 3–15). Berlin, Heidelberg : Springer.

Moller HJ (2000). Are all antidepressants the same? Journal

of Clinical Psychiatry 61 (Suppl. 6), 24–28.

Moller HJ (2002). Anxiety associated with comorbid


22–26.

Moller HJ (2003). Suicide, suicidality and suicide prevention

in affective disorders. Acta Psychiatrica Scandinavica.

Supplementum 73–80.

Moller HJ (2006a). Evidence for beneficial effects of

antidepressants on suicidality in depressive patients : a

systematic review. European Archives of Psychiatry and


Moller HJ (2006b). Is there evidence for negative effects

of antidepressants on suicidality in depressive patients?

A systematic review. European Archives of Psychiatry and


Moller HJ, Gallinat J, Hegerl U, Arato M, Janka Z, Pflug B,

Bauer H (1998). Double-blind, multicenter comparative

study of sertraline and amitriptyline in hospitalized

patients with major depression. Pharmacopsychiatry 31,

170–177.

Moller HJ, Grunze H, Broich K (2006). Do recent efficacy

data on the drug treatment of acute bipolar depression

support the position that drugs other than antidepressants

are the treatment of choice? A conceptual review.


1–16.

Moller HJ, Kasper S, Muller H, Kissling W, Fuger J,

Ruhrmann S (1995). A controlled study of the efficacy and

safety of mianserin and amitriptyline in depressive

inpatients. Pharmacopsychiatry 28, 249–252.

Monroe SM, Simons AD (1991). Diathesis-stress theories

in the context of life stress research : implications for

the depressive disorders. Psychological Bulletin 110,

406–425.

Montejo-Gonzalez AL, Llorca G, Izquierdo JA, Ledesma A,

Bousono M, Calcedo A, Carrasco JL, Ciudad J, Daniel E,

de la Gandara J, Derecho J, Franco M, Gomez MJ,

Macias JA, Martin T, Perez V, Sanchez JM, Sanchez S,

Vicens E (1997). SSRI-induced sexual dysfunction :

fluoxetine, paroxetine, sertraline, and fluvoxamine in

a prospective, multicenter, and descriptive clinical study

of 344 patients. Journal of Sex and Marital Therapy 23,

176–194.

Montgomery DB, Roberts A, Green M, Bullock T, Baldwin

D, Montgomery SA (1994). Lack of efficacy of fluoxetine

in recurrent brief depression and suicidal attempts.


211–215.

Montgomery JH, Byerly M, Carmody T, Li B, Miller DR,

Varghese F, Holland R (2004a). An analysis of the effect

of funding source in randomized clinical trials of second

generation antipsychotics for the treatment of

schizophrenia. Controlled Clinical Trials 25, 598–612.

Montgomery SA (1992). The advantages of paroxetine in

different subgroups of depression. International Clinical

Psychopharmacology 6 (Suppl. 4), 91–100.

Montgomery SA (1995). Safety of mirtazapine : a review.

International Clinical Psychopharmacology 10 (Suppl. 4),

37–45.

Montgomery SA (1998). Chairman’s overview. The place of

reboxetine in antidepressant therapy. Journal of Clinical


Montgomery SA (1999). New developments in the treatment

of depression. Journal of Clinical Psychiatry 60 (Suppl. 14),

10–15.

Montgomery SA (2005). Antidepressants and seizures :

emphasis on newer agents and clinical implications.

International Journal of Clinical Practice 59, 1435–1440.

Montgomery SA (2006). Guidelines in major depressive

disorder, and their limitations. International Journal of

Psychiatry in Clinical Practice 10, 3–9.

Montgomery SA, Andersen HF (2006). Escitalopram versus

venlafaxine XR in the treatment of depression. International


Montgomery SA, Asberg M (1979). A new depression scale

designed to be sensitive to change. British Journal of


Montgomery SA, Dufour H, Brion S, Gailledreau J,

Laqueille X, Ferrey G, Moron P, Parant-Lucena N,

Singer L, Danion JM (1988). The prophylactic efficacy of

fluoxetine in unipolar depression. British Journal of

Psychiatry (Suppl.) 69–76.

Montgomery SA, Huusom AK, Bothmer J (2004b). A

randomised study comparing escitalopram with

venlafaxine XR in primary care patients with major

depressive disorder. Neuropsychobiology 50, 57–64.

Montgomery SA, Kennedy SH, Burrows GD, Lejoyeux M,

Hindmarch I (2004c). Absence of discontinuation

symptoms with agomelatine and occurrence of

discontinuation symptomswith paroxetine : a randomized,

double-blind, placebo-controlled discontinuation

study. International Clinical Psychopharmacology 19, 271–280.

Montgomery SA, Prost JF, Solles A, BrileyM (1996). Efficacy

and tolerability of milnacipran : an overview. International

Clinical Psychopharmacology 11 (Suppl. 4), 47–51.

Montgomery SA, Reimitz PE, ZivkovM. (1998). Mirtazapine

versus amitriptyline in the long-term treatment of

depression : a double-blind placebo-controlled study. Int

Clin Psychopharmacol. 13, 63–73.

Moore N, Verdoux H, Fantino B (2005). Prospective,

multicentre, randomized, double-blind study of the

efficacy of escitalopram versus citalopram in outpatient

treatment of major depressive disorder. International



Moreno FA, Gelenberg AJ, Bachar K, Delgado PL (1997).

Pindolol augmentation of treatment-resistant depressed

patients. Journal of Clinical Psychiatry 58, 437–439.

Morgan PT (2007). Treatment-resistant depression :

response to low-dose transdermal but not oral selegiline.


Morgan ML, Cook IA, Rapkin AJ, Leuchter AF (2005).

Estrogen augmentation of antidepressants in

perimenopausal depression : a pilot study. Journal of


Morgan O, Griffiths C, Baker A, Majeed A (2004). Fatal

toxicity of antidepressants in England and Wales,

1993–2002. Health Statistics Quarterly 18–24.

Morilak DA, Frazer A (2004). Antidepressants and brain

monoaminergic systems: a dimensional approach to

understanding their behavioural effects in depression and

anxiety disorders. International Journal of


Morrison A, Levy R (2004). Toward individualized

pharmaceutical care of East Asians : the value of genetic

testing for polymorphisms in drug-metabolizing genes.

Pharmacogenomics 5, 673–689.

Moscicki EK (1999). Epidemiology of suicide. In : Jacobs D

(Ed.), The Harvard Medical School Guide to Suicide

Assessment and Intervention (pp. 40–51). San Francisco :

Jossey-Bass.

Moscrip TD, Terrace HS, Sackeim HA, Lisanby SH (2005).

Randomized controlled trial of the cognitive side-effects of

magnetic seizure therapy (MST) and electroconvulsive

shock (ECS). International Journal of


Mosimann UP, Schmitt W, Greenberg BD, Kosel M,

Muri RM, Berkhoff M, Hess CW, Fisch HU,

Schlaepfer TE (2004). Repetitive transcranial magnetic

stimulation : a putative add-on treatment for major

depression in elderly patients. Psychiatry Research 126,

123–133.

Moskos M, Olson L, Halbern S, Keller T, Gray D (2005).

Utah youth suicide study: psychological autopsy. Suicide

and Life-Threatening Behavior 35, 536–546.

Moskowitz H, Burns M (1986). Cognitive performance in

geriatric subjects after acute treatment with

antidepressants. Neuropsychobiology 15 (Suppl. 1), 38–43.

Mosolov SN (1998). [Clinical pharmacology

of antidepressants (review)]. Terapevticheskii Arkhiv 70,

71–76.

Mottram P, Wilson K, Strobl J (2006). Antidepressants for

depressed elderly. Cochrane Database of Systematic Reviews.

CD003491.

Moukaddam NJ, Hirschfeld RM (2004). Intravenous

antidepressants : a review. Depression and Anxiety 19,

1–9.

Muhlbacher M, Konstantinidis A, Kasper S, Eichberger G,

Hinterhuber H, Hofmann P, Nimmerrichter A,

Schubert H, Egger C, Nickel M, Stuppaeck C (2006).

Intravenous mirtazapine is safe and effective in the

treatment of depressed inpatients. Neuropsychobiology 53,

83–87.

Mulder H, Herder A, Wilmink FW, Tamminga WJ,

Belitser SV, Egberts AC (2006). The impact of cytochrome

P450-2D6 genotype on the use and interpretation of

therapeutic drug monitoring in long-stay patients treated

with antidepressant and antipsychotic drugs in daily

psychiatric practice. Pharmacoepidemiology and Drug Safety

15, 107–114.

Muller-Oerlinghausen B, Ahrens B, Felber W (2006). The

suicide-preventive and mortality reducing effect of

lithium. In : Bauer M, Grof P, Muller-Oerlinghausen B

(Eds.), Lithium in Neuropsychiatry : The Comprehensive Guide

(pp. 179–192). Oxfordshire, UK: Informa Healthcare.

Mulsant BH, Sweet RA, Rosen J, Pollock BG, Zubenko GS,

Flynn T, Begley AE, Mazumdar S, Reynolds CF, III

(2001). A double-blind randomized comparison of

nortriptyline plus perphenazine versus nortriptyline

plus placebo in the treatment of psychotic depression

in late life. Journal of Clinical Psychiatry 62, 597–604.

Mundo E, Bareggi SR, Pirola R, Bellodi L (1999). Effect of

acute intravenous clomipramine and antiobsessional

response to proserotonergic drugs : is gender a predictive

variable? Biological Psychiatry 45, 290–294.

Murphy BEP (1991). Treatment of major depression with

steroid suppressive drugs. Journal of Steroid Biochemistry

and Molecular Biology 39, 239–244.

Murphy BEP, Dhar V, Ghadirian AM, Chouinard G,

Keller R (1991). Response to steroid suppression in

major depression resistant to antidepressant therapy.


Murphy BEP, Filipini D, Ghadirian AM (1993). Possible

use of glucocorticoid receptor antagonists in the treatment

of major depression: preliminary results using RU 486.

Journal of Psychiatry and Neuroscience 18, 209–213.

Murphy PA, Kern SE, Stanczyk FZ, Westhoff CL (2005).

Interaction of St. John’s Wort with oral contraceptives :

effects on the pharmacokinetics of norethindrone and

ethinyl estradiol, ovarian activity and breakthrough

bleeding. Contraception 71, 402–408.

Musselman DL, Evans DL, Nemeroff CB (1998). The

relationship of depression to cardiovascular disease :

epidemiology, biology, and treatment. Archives of General


Myint AM, Kim YK, Verkerk R, Scharpe S, Steinbusch H,

Leonard B (2007). Kynurenine pathway in major

depression : evidence of impaired neuroprotection.


Mynors-Wallis L, Davies I, Gray A, Barbour F, Gath D

(1997). A randomised controlled trial and cost analysis of

problem-solving treatment for emotional disorders given

by community nurses in primary care. British Journal of


Naguib M, Koorn R (2002). Interactions between

psychotropics, anaesthetics and electroconvulsive therapy:

implications for drug choice and patient management.

CNS Drugs 16, 229–247.

Nahas Z, Kozel FA, Li X, Anderson B, George MS (2003).

Left prefrontal transcranial magnetic stimulation (TMS)

treatment of depression in bipolar affective disorder : a


pilot study of acute safety and efficacy. Bipolar Disorders 5,

40–47.

Nahas Z, Marangell LB, Husain MM, Rush AJ, Sackeim

HA, Lisanby SH, Martinez JM, George MS (2005).

Two-year outcome of vagus nerve stimulation (VNS) for

treatment of major depressive episodes. Journal of Clinical


Nahunek K, Svestka J, Ceskova E (1983). [Comparison

of the onset of the therapeutic effect of clomipramine

and desipramine after oral and intravenous administration

in patients with endogenous depression]. Ceskoslovenska

Psychiatrie 79, 164–168.

Narushima K, Chan KL, Kosier JT, Robinson RG (2003).

Does cognitive recovery after treatment of poststroke

depression last? A 2-year follow-up of cognitive function

associated with poststroke depression. American Journal of

Psychiatry 160, 1157–1162.

Narushima K, Paradiso S, Moser DJ, Jorge R, Robinson RG

(2007). Effect of antidepressant therapy on executive

function after stroke. British Journal of Psychiatry 190,

260–265.

Narushima K, Robinson RG (2003). The effect of early

versus late antidepressant treatment on physical

impairment associated with poststroke depression:

is there a time-related therapeutic window? Journal of

Nervous and Mental Diseases 191, 645–652.

National Institute for Health and Clinical Excellence (2004).

CG23 Depression: NICE Guideline (http://www.nice.

org.uk/page.aspx?o=cg023niceguideline). Accessed 26

October 2006.

National Institute of Mental Health (1976). CGI :

Clinical Global Impressions. In : Guy WBRR (Ed.),

Manual for the ECDEU Assessment Battery (pp. 12-1–12-6).

Chevy Chase, MD: National Institute of Mental Health.

Navarro V, Gasto C, Torres X, Marcos T, Pintor L (2001).

Citalopram versus nortriptyline in late-life depression : a

12-week randomized single-blind study. Acta Psychiatrica


Nease DE, Maloin JM (2003). Depression screening :

a practical strategy. Journal of Family Practice 52, 118–124.

Nelson JC (2000). Augmentation strategies in

depression 2000. Journal of Clinical Psychiatry 61 (Suppl. 2),

13–19.

Nelson JC (2006). The STAR*D study: a four-course meal

that leaves us wanting more. American Journal of Psychiatry

163, 1864–1866.

Nelson JP, Benjamin L (1989). Efficacy and safety of

combined ECT and tricyclic antidepressant drugs in the

treatment of depressed geriatric patients. Convulsive

Therapy 5, 321–329.

Nemeroff CB (1994). Evolutionary trends in the

pharmacotherapeutic management of depression. Journal

of Clinical Psychiatry 55 (Suppl.), 3–15.

Nemeroff CB (1996). The corticotropin-releasing factor (CRF)

hypothesis of depression : new findings and new

directions. Molecular Psychiatry 1, 336–342.

Nemeroff CB, Gharabawi GM, Canuso CM (2004).

Augmentation with risperidone in chronic resistant

depression : a double-blind placebo-controlled

maintenance trial. Neuropsychopharmacology 29, 5159.

Nemeroff CB, Widerlov E, Bisette G, Walleus H, Karlsson I,

Eklund K, Kilts CD, Loosen PT, Vale W (1984). Elevated

concentrations of CSF corticotropin-releasing factor-like

immunoreactivity in depressed patients. Science 226,

1342–1343.

Nemets B, Stahl Z, Belmaker RH (2002). Addition of

omega-3 fatty acid to maintenance medication treatment

for recurrent unipolar depressive disorder. American


Nemets H, Nemets B, Apter A, Bracha Z, Belmaker RH

(2006). Omega-3 treatment of childhood depression: a

controlled, double-blind pilot study. American Journal of

Psychiatry 163, 1098–1100.

Nestler EJ (1998). Antidepressant treatments in the 21st

century. Biological Psychiatry 44, 526–533.

Neumeister A, Goessler R, Lucht M, Kapitany T, Bamas C,

Kasper S (1996). Bright light therapy stabilizes the

antidepressant effect of partial sleep deprivation. Biological


Newhouse PA, Krishnan KR, Doraiswamy PM, Richter EM,

Batzar ED, Clary CM (2000). A double-blind comparison

of sertraline and fluoxetine in depressed elderly


Niedermaier N, Bohrer E, Schulte K, Schlattmann P,

Heuser I (2004). Prevention and treatment of poststroke

depression with mirtazapine in patients with acute stroke.


Nierenberg AA (2001). Do some antidepressants work

faster than others? Journal of Clinical Psychiatry 62

(Suppl. 15), 22–25.

Nierenberg AA, Amsterdam JD (1990). Treatment-resistant

depression : definition and treatment approaches. Journal of

Clinical Psychiatry 51 (Suppl.), 39–47.

Nierenberg AA, Farabaugh AH, Alpert JE, Gordon J,

Worthington JJ, Rosenbaum JF, Fava M (2000).

Timing of onset of antidepressant response with

fluoxetine treatment. American Journal of Psychiatry 157,

1423–1428.

Nierenberg AA, Fava M, Trivedi MH, Wisniewski SR,

Thase ME, McGrath PJ, Alpert JE, Warden D, Luther JF,

Niederehe G, Lebowitz B, Shores-Wilson K, Rush AJ

(2006a). A comparison of lithium and T(3) augmentation

following two failedmedication treatments for depression :

a STAR*D report. American Journal of Psychiatry 163,

1519–1530.

Nierenberg AA, Petersen TJ, Alpert JE (2003). Prevention of

relapse and recurrence in depression: the role of long-term

pharmacotherapy and psychotherapy. Journal of Clinical


Nierenberg AA, Trivedi MH, Fava M, Biggs MM,

Shores-Wilson K, Wisniewski SR, Balasubramani GK,

Rush AJ (2007). Family history of mood disorder

and characteristics of major depressive disorder : A

STAR(*)D (sequenced treatment alternatives to relieve

depression) study. Journal of Psychiatric Research 41,

214–221.


Nijhuis IJ, Kok-Van Rooij GW, Bosschaart AN (2001).

Withdrawal reactions of a premature neonate after

maternal use of paroxetine. Archives of Disease in Childhood.

Fetal and Neonatal Edition 84, F77.

Nilsson FM, Kessing LV (2004). Increased risk of developing

stroke for patients with major affective disorder : a registry

study. European Archives of Psychiatry and Clinical


Nishizawa S, Benkelfat C, Young SN, Leyton M, Mzengeza

S, de Montigny C, Blier P, Diksic M (1997). Differences

between males and females in rates of serotonin synthesis

in human brain. Proceedings of the National Academy of

Sciences USA 94, 5308–5313.

Nonacs R, Cohen LS (2003). Assessment and treatment of

depression during pregnancy : an update. Psychiatric

Clinics of North America 26, 547–562.

Norman TR, Leonard BE (1994). Fast-acting antidepressants :

can the need be met? CNS Drugs 2, 120–131.

Norman TR, Olver JS (2004). New formulations of existing

antidepressants : advantages in the management of

depression. CNS Drugs 18, 505–520.

Normann C, Hummel B, Scharer LO, Horn M, Grunze H,

Walden J (2002). Lamotrigine as adjunct to paroxetine in

acute depression: a placebo-controlled, double-blind

study. Journal of Clinical Psychiatry 63, 337–344.

North TC,McCullagh P, Tran ZV (1990). Effect of exercise on

depression. Exercise and Sport Sciences Reviews 18, 379–415.

Novick JS, Stewart JW, Wisniewski SR, Cook IA, Manev R,

Nierenberg AA, Rosenbaum JF, Shores-Wilson K,

Balasubramani GK, Biggs MM, Zisook S, Rush AJ (2005).

Clinical and demographic features of atypical depression

in outpatients with major depressive disorder : preliminary

findings from STAR*D. Journal of Clinical Psychiatry 66,

1002–1011.

Nuijten M, Hadjadjeba L, Evans C, van den Berg J (1998).

Cost effectiveness of fluvoxamine in the treatment of

recurrent depression in France. Pharmacoeconomics 14,

433–445.

NuijtenMJ, HardensM, Souetre E (1995). A Markov process

analysis comparing the cost effectiveness of maintenance

therapy with citalopram versus standard therapy in major

depression. Pharmacoeconomics 8, 159–168.

Nutt DJ (2002). The neuropharmacology of serotonin and

noradrenaline in depression. International Clinical

Psychopharmacology 17 (Suppl. 1), S1–12.

Nutt DJ (2003). Death and dependence: current controversies

over the selective serotonin reuptake inhibitors. Journal of


Nuttall GA, Bowersox MR, Douglass SB, McDonald J,

Rasmussen LJ, Decker PA, Oliver WC, Rasmussen KG

(2004). Morbidity and mortality in the use of

electroconvulsive therapy. Journal of ECT 20, 237–241.

O’Brien CP, Volkow N, Li TK (2006). What’s in a word?

Addiction versus dependence in DSM-V. American Journal


O’ConnorMK, Knapp R, HusainM, Rummans TA, Petrides

G, Smith G, Mueller M, Snyder K, Bernstein H, Rush AJ,

Fink M, Kellner C (2001). The influence of age on

the response of major depression to electroconvulsive

therapy : a C.O.R.E. Report. American Journal of Geriatric


O’Dwyer A-M, Lightman SL, Marks MN, Checkley SA

(1995). Treatment of major depression with metyrapone

and hydrocortisone. Journal of Affective Disorders 33,

123–128.

O’Hanlon JF, Robbe HW, Vermeeren A, van LC, Danjou PE

(1998). Venlafaxine’s effects on healthy volunteers’ driving,

psychomotor, and vigilance performance during 15-day

fixed and incremental dosing regimens. Journal of Clinical


Obuchowicz E, Kowalski J, Labuzek K, Krysiak R,

Pendzich J, Herman ZS (2006). Amitriptyline and

nortriptyline inhibit interleukin-1 release by rat mixed glial

and microglial cell cultures. International Journal of


Ohberg A, Vuori E, Klaukka T, Lonnqvist J (1998).

Antidepressants and suicide mortality. Journal of Affective


Olesen J, Leonardi M (2003). The burden of brain diseases in

Europe. European Journal of Neurology 10, 471–477.

Olfson M, Shaffer D, Marcus SC, Greenberg T (2003).

Relationship between antidepressant medication treatment

and suicide in adolescents. Archives of General Psychiatry 60,

978–982.

Olfson M, Marcus SC, Shaffer D (2006). Antidepressant

drug therapy and suicide in severely depressed children

and adults : A case-control study. Archives of General


Olie JP, Kasper S (2007). Efficacy of agomelatine, a MT1/MT2

receptor agonist with 5-HT2C antagonistic properties, in

major depressive disorder. International Journal of


Olver JS, Burrows GD, Norman TR (2001). Third-generation

antidepressants : do they offer advantages over the SSRIs?

CNS Drugs 15, 941–954.

Olver JS, Burrows GD, Norman TR (2004). The treatment

of depression with different formulations of venlafaxine : a

comparative analysis. Human Psychopharmacology 19, 9–16.

Oren DA, Wisner KL, Spinelli M, Epperson CN, Peindl KS,

Terman JS, Terman M (2002). An open trial of morning

light therapy for treatment of antepartum depression.


Osby U, Brandt L, Correia N, Ekbom A, Sparen P (2001).

Excess mortality in bipolar and unipolar disorder in

Sweden. Archives of General Psychiatry 58, 844–850.

Oshima A, Higuchi T (1999). Treatment guidelines for

geriatric mood disorders. Psychiatry and Clinical

Neurosciences 53 (Suppl.), S55–S59.

Ostacher MJ, Huffman J, Perlis R, Nierenberg AA (2005).

Evidence-based pharmacotherapy of major depressive

disorder. In : Stein DJ, Lerer B, Stahl SM (Eds.),

Evidence-Based Psychopharmacology (pp. 1–21). Cambridge :

Cambridge University Press.

Ostenfeld I (1973). [Treatment of endogenous depression

by deprivation of sleep]. Ugeskrift for Laeger 135,

2632–2633.


Ottoson JO, Fink M (2004). The Ethics in Electroconvulsive

Therapy. New York : Brunner/Routledge.

Ownby RL, Crocco E, Acevedo A, John V, Loewenstein D

(2006). Depression and risk for Alzheimer disease :

systematic review, meta-analysis, and metaregression

analysis. Archives of General Psychiatry 63, 530–538.

Ozcanli T, Unsalver B, Ozdemir S, Ozmen M (2005).

Sertraline- and mirtazapine-induced severe neutropenia.

American Journal of Psychiatry 162, 1386.

Pacher P, Kohegyi E, Kecskemeti V, Furst S (2001). Current

trends in the development of new antidepressants. Current

Medicinal Chemistry 8, 89–100.

Padberg F, Moller HJ (2003). Repetitive transcranial

magnetic stimulation: does it have potential in the

treatment of depression? CNS Drugs 17, 383–403.

Padberg F, Zwanzger P, Keck ME, Kathmann N, Mikhaiel

P, Ella R, Rupprecht P, Thoma H, Hampel H, Toschi N,

Moller HJ (2002). Repetitive transcranial magnetic

stimulation (rTMS) in major depression: relation between

efficacy and stimulation intensity.


Padberg F, Zwanzger P, Thoma H, Kathmann N, Haag C,

Greenberg BD, Hampel H, Moller HJ (1999). Repetitive

transcranial magnetic stimulation (rTMS) in

pharmacotherapy-refractory major depression :

comparative study of fast, slow and sham rTMS. Psychiatry

Research 88, 163–171.

Pallanti S, Quercioli L, Koran LM (2002). Citalopram

intravenous infusion in resistant obsessive-compulsive

disorder : an open trial. Journal of Clinical Psychiatry 63,

796–801.

Pampallona S, Bollini P, Tibaldi G, Kupelnick B, Munizza

C (2004). Combined pharmacotherapy and psychological

treatment for depression: a systematic review. Archives of


Papakostas GI (2005). Augmentation of standard

antidepressants with atypical antipsychotic agents for

treatment-resistant major depressive disorder. Essential


Papakostas GI (2006). Dopaminergic-based

pharmacotherapies for depression. Eur.

Neuropsychopharmacol. 16, 391–402.

Papakostas GI, Petersen TJ, Kinrys G, Burns AM,

Worthington JJ, Alpert JE, Fava M, Nierenberg AA

(2005). Aripiprazole augmentation of selective serotonin

reuptake inhibitors for treatment-resistant major


1326–1330.

Papakostas GI, Petersen TJ, Nierenberg AA, Murakami JL,

Alpert JE, Rosenbaum JF, Fava M (2004). Ziprasidone

augmentation of selective serotonin reuptake inhibitors

(SSRIs) for SSRI-resistant major depressive disorder.


Park RJ, Goodyer IM (2000). Clinical guidelines for

depressive disorders in childhood and adolescence.

European Child and Adolescent Psychiatry 9, 147–161.

Parker G (2002). Differential effectiveness of newer and older

antidepressants appears mediated by an age effect on the

phenotypic expression of depression. Acta Psychiatrica


Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM,

Hadzi-Pavlovic D (2006). Omega-3 fatty acids and

mood disorders. American Journal of Psychiatry 163,

969–978.

Parker G, Parker K, Austin MP, Mitchell P, Brotchie H

(2003). Gender differences in response to differing

antidepressant drug classes : two negative studies.


Parry BL, Curran ML, Stuenkel CA, Yokimozo M, Tam L,

Powell KA, Gillin JC (2000). Can critically timed sleep

deprivation be useful in pregnancy and postpartum

depressions? Journal of Affective Disorders 60, 201–212.

Pascual-Leone A, Rubio B, Pallardo F, Catala MD (1996).

Rapid-rate transcranial magnetic stimulation of left

dorsolateral prefrontal cortex in drug-resistant depression.

Lancet 347, 233–237.

Patel V, Chisholm D, Rabe-Hesketh S, Dias-Saxena F,

Andrew G, Mann A (2003). Efficacy and cost-effectiveness

of drug and psychological treatments for common mental

disorders in general health care in Goa, India : a

randomised, controlled trial. Lancet 361, 33–39.

Pathak S, Kratochvil CJ, Rogers GM, Silva S, Vitiello B,

Weller EB, March JS (2005). Comparative efficacy of

cognitive behavioral therapy, fluoxetine, and their

combination in depressed adolescents : initial lessons from

the treatment for adolescents with depression study.

Current Psychiatry Reports 7, 429–434.

Patten S, Cipriani A, Brambilla P, Nose M, Barbui C (2005).

International dosage differences in fluoxetine clinical trials.

Canadian Journal of Psychiatry 50, 31–38.

Patten SB (2006). Does almost everybody suffer from a

bipolar disorder? Canadian Journal of Psychiatry 51, 6–8.

Patten SB, Barbui C (2004). Drug-induced depression : a

systematic review to inform clinical practice. Psychotherapy

and Psychosomatics 73, 207–215.

Patten SB, Metz LM (1997). Depression in multiple sclerosis.


Patten SB, Sedmak B, Russell ML (2001). Major depression :

prevalence, treatment utilization and age in Canada.

Canadian Journal of Clinical Pharmacology 8, 133–138.

Paul IA, Nowak G, Layer RT, Popik P, Skolnick P (1994).

Adaptation of the N-methyl-D-aspartate receptor complex

following chronic antidepressant treatments. Journal of

Pharmacology and Experimental Therapeutics 269, 95–102.

Pauwels PJ (2000). Diverse signalling by 5-

hydroxytryptamine (5-HT) receptors. Biochemical


Pavlovic DM, Milovic AM (1999). [Clinical characteristics

and therapy of neurosyphilis in patients who are negative

for human immunodeficiency virus]. Srpski Arhiv Za

Celokupno Lekarstvo 127, 236–240.

Paykel ES (2001). Continuation and maintenance therapy in

depression. British Medical Bulletin 57, 145–159.

Paykel ES, Brugha T, Fryers T (2005). Size and burden of

depressive disorders in Europe. European



Paykel ES, Priest RG (1992). Recognition andmanagement of

depression in general practice : consensus statement.

British Medical Journal 305, 1198–1202.

Pearlman C, Obedian E (1995). ECT-valproic acid

interaction. General Hospital Psychiatry 17, 456–457.

Pedersen AG (2005). Escitalopram and suicidality in adult

depression and anxiety. International Clinical


Peet M (1994). Induction of mania with selective serotonin

re-uptake inhibitors and tricyclic antidepressants. British


Peet M, Horrobin DF (2002). A dose-ranging study of

the effects of ethyl-eicosapentaenoate in patients with

ongoing depression despite apparently adequate treatment

with standard drugs. Archives of General Psychiatry 59,

913–919.

Penninx BW, Beekman AT, Honig A, Deeg DJ, Schoevers

RA, van Eijk JT, van Tilburg W (2001). Depression and

cardiac mortality : results from a community-based

longitudinal study. Archives of General Psychiatry 58,

221–227.

Peretti S, Judge R, Hindmarch I (2000). Safety and

tolerability considerations : tricyclic antidepressants vs.

selective serotonin reuptake inhibitors. Acta Psychiatrica


Perez V, Soler J, Puigdemont D, Alvarez E, Artigas F (1999).

A double-blind, randomized, placebo-controlled trial of

pindolol augmentation in depressive patients resistant to

serotonin reuptake inhibitors. Grup de Recerca en

Trastorns Afectius. Archives of General Psychiatry 56,

375–379.

Perlick DA, Hohenstein JM, Clarkin JF, Kaczynski R,

Rosenheck RA (2005). Use of mental health and primary

care services by caregivers of patients with bipolar

disorder : a preliminary study. Bipolar Disorders 7, 126–135.

Perlis RH, Perlis CS, Wu Y, Hwang C, Joseph M,

Nierenberg AA (2005). Industry sponsorship and financial

conflict of interest in the reporting of clinical trials

in psychiatry. American Journal of Psychiatry 162, 1957–1960.

Pesola GR, Avasarala J (2002). Bupropion seizure proportion

among new-onset generalized seizures and drug related

seizures presenting to an emergency department. Journal of

Emergency Medicine 22, 235–239.

Petrides G, Fink M, Husain MM, Knapp RG, Rush AJ,

Mueller M, Rummans TA, O’Connor KM, Rasmussen

KGJ, Bernstein HJ, Biggs M, Bailine SH, Kellner CH

(2001). ECT remission rates in psychotic versus

nonpsychotic depressed patients : a report from CORE.

Journal of ECT 17, 244–253.

Peveler R, Kendrick T, BuxtonM, Longworth L, Baldwin D,

Moore M, Chatwin J, Goddard J, Thornett A, Smith H,

Campbell M, Thompson C (2005). A randomised

controlled trial to compare the cost-effectiveness of

tricyclic antidepressants, selective serotonin reuptake

inhibitors and lofepramine. Health Technology Assessment 9,

1–134, iii.

Pevet P (2002). Melatonin. Dialogues in Clinical Neuroscience 4,

57–72.

Pezawas L, Angst J, Kasper S (2005). Recurrent brief

depression revisited. International Review of Psychiatry 17,

63–70.

Pezawas L, Stamenkovic M, Kasper S (2001). [Recurrent

brief depressive episodes. Epidemiology, clinical aspects,

diagnosis and therapy]. Nervenarzt 72, 169–180.

Pfaff JJ, Almeida OP (2005). Detecting suicidal ideation in

older patients : identifying risk factors within the general

practice setting. British Journal of General Practice 55,

269–273.

Philibert RA, Richards L, Lynch CF, Winokur G (1995).

Effect of ECT on mortality and clinical outcome in geriatric

unipolar depression. Journal of Clinical Psychiatry 56,

390–394.

Philipp M, Kohnen R, Hiller KO (1999). Hypericum

extract versus imipramine or placebo in patients with

moderate depression : randomised multicentre study of

treatment for eight weeks. British Medical Journal 319,

1534–1538.

Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W (2001).

Potential role of pharmacogenomics in reducing adverse

drug reactions : a systematic review. Journal of the American


Phillips SD, Ringo P (1995). Phenelzine and venlafaxine

interaction. American Journal of Psychiatry 152, 1400–1401.

Pilowsky DJ, Wickramaratne PJ, Rush AJ, Hughes CW,

Garber J, Malloy E, King CA, Cerda G, Sood AB, Alpert

JE, Wisniewski SR, Trivedi MH, Talati A, Carlson MM,

Liu HH, Fava M, Weissman MM (2006). Children of

currently depressed mothers : a STAR*D ancillary study.


Pincus HA, Zarin DA, Tanielian TL, Johnson JL, West JC,

Pettit AR, Marcus SC, Kessler RC, McIntyre JS (1999).

Psychiatric patients and treatments in 1997 : findings from

the American Psychiatric Practice Research Network.


Pineyro G, Deveault L, Blier P, Dennis T, de Montigny C

(1995a). Effect of acute and prolonged tianeptine

administration on the 5-HT transporter :

electrophysiological, biochemical and radioligand binding

studies in the rat brain. Naunyn-Schmiedeberg’s Archives of


Pineyro G, Deveault L, de Montigny C, Blier P (1995b).

Effect of prolonged administration of tianeptine on 5-HT

neurotransmission : an electrophysiological study in the rat

hippocampus and dorsal raphe. Naunyn-Schmiedeberg’s

Archives of Pharmacology 351, 119–125.

Pinto-Meza A, Usall J, Serrano-Blanco A, Suarez D, Haro

JM (2006). Gender differences in response to

antidepressant treatment prescribed in primary care. Does

menopause make a difference? Journal of Affective Disorders

93, 53–60.

Pisani F, Spina E, Oteri G (1999). Antidepressant drugs and

seizure susceptibility : from in vitro data to clinical

practice. Epilepsia 40 (Suppl. 10), S48–S56.

Pogosova GV, Zhidko NI, Krasnitskii VB, Tikhomirova EA,

Odintsova AS, Akhmedzhanov NM, Baichorov IK (2004).

[Clinical efficacy of tianeptine in patients with ischemic


heart disease and comorbid depression]. Kardiologiia 44,

20–24.

Porche DJ, Willis DG (2006). Depression in HIV-infected

men. Issues in Mental Health Nursing 27, 391–401.

Post RM, Altshuler LL, Leverich GS, Frye MA, Nolen WA,

Kupka RW, Suppes T, McElroy S, Keck PE, Denicoff KD,

Grunze H, Walden J, Kitchen CM, Mintz J (2006). Mood

switch in bipolar depression: comparison of adjunctive

venlafaxine, bupropion and sertraline. British Journal of


Post RM, Calabrese JR (2004). Bipolar depression : the role of

atypical antipsychotics. Expert Review of Neurotherapeutics

4, S27–S33.

Post RM, Uhde TW, Roy-Byrne PP, Joffe RT (1986).

Antidepressant effects of carbamazepine. American Journal


Praschak-Rieder N, Neumeister A, Hesselmann B, Willeit

M, Barnas C, Kasper S (1997). Suicidal tendencies as a

complication of light therapy for seasonal affective

disorder : a report of three cases. Journal of Clinical


Prasko J, Horacek J, Klaschka J, Kosova J, Ondrackova I,

Sipek J (2002). Bright light therapy and/or imipramine for

inpatients with recurrent non-seasonal depression.

Neuroendocrinology Letters 23, 109–113.

Preskorn SH (1995). Comparison of the tolerability of

bupropion, fluoxetine, imipramine, nefazodone,

paroxetine, sertraline, and venlafaxine. Journal of Clinical


Price LH, Conwell Y, Nelson JC (1983). Lithium

augmentation of combined neuroleptic-tricyclic treatment

in delusional depression.American Journal of Psychiatry 140,

318–322.

Pridmore S, Bruno R, Turnier-Shea Y, Reid P, Rybak M

(2000). Comparison of unlimited numbers of rapid

transcranial magnetic stimulation (rTMS) and ECT

treatment sessions in major depressive episode.

International Journal of Neuropsychopharmacology 3,

Prien RF (1990). Efficacy of continuation drug therapy of

depression and anxiety : issues and methodologies. Journal

of Clinical Psychopharmacology 10, 86S–90S.

Prien RF, Kupfer DJ (1986). Continuation drug therapy for

major depressive episodes : how long should it be

maintained? American Journal of Psychiatry 143, 18–23.

Prien RF, Kupfer DJ, Mansky PA, Small JG, Tuason VB,

Voss CB, Johnson WE (1984). Drug therapy in the

prevention of recurrences in unipolar and bipolar affective

disorders. Report of the NIMH Collaborative Study Group

comparing lithium carbonate, imipramine, and a lithium

carbonate-imipramine combination. Archives of General


Procyshyn RM, Chau A, Fortin P, Jenkins W (2004).

Prevalence and outcomes of pharmaceutical industry-

sponsored clinical trials involving clozapine, risperidone,

or olanzapine. Canadian Journal of Psychiatry 49, 601–606.

Prudic J, Haskett RF, Mulsant B, Malone KM, Pettinati HM,

Stephens S, Greenberg R, Rifas SL, Sackeim HA (1996).

Resistance to antidepressant medications and short-term

clinical response to ECT. American Journal of Psychiatry 153,

985–992.

Prudic J, Sackeim HA, Devanand DP (1990). Medication

resistance and clinical response to electroconvulsive

therapy. Psychiatry Research 31, 287–296.

Puech A, Montgomery SA, Prost JF, Solles A, Briley M

(1997). Milnacipran, a new serotonin and noradrenaline

reuptake inhibitor : an overview of its antidepressant

activity and clinical tolerability. International Clinical


Puozzo C, Albin H, Vincon G, Deprez D, Raymond JM,

Amouretti M (1998). Pharmacokinetics of milnacipran in

liver impairment. European Journal of Drug Metabolism and

Pharmacokinetics 23, 273–279.

Purebl G, Birkas E, Csoboth C, Szumska I, KoppMS (2006).

The relationship of biological and psychological risk

factors of cardiovascular disorders in a large-scale national

representative community survey. Behavioral Medicine 31,

133–139.

Quitkin FM, McGrath PJ, Stewart JW, Deliyannides D,

Taylor BP, Davies CA, Klein DF (2005). Remission rates

with 3 consecutive antidepressant trials : effectiveness for

depressed outpatients. Journal of Clinical Psychiatry 66,

670–676.

Quitkin FM, Taylor BP, Kremer C (2001). Does mirtazapine

have a more rapid onset than SSRIs? Journal of Clinical


Rabheru K (2001). The use of electroconvulsive therapy in

special patient populations. Canadian Journal of Psychiatry

46, 710–719.

Rabheru K, Persad E (1997). A review of continuation and

maintenance electroconvulsive therapy. Canadian Journal of


Rabiner EA, Bhagwagar Z, Gunn RN, Sargent PA, Bench CJ,

Cowen PJ, Grasby PM (2001). Pindolol augmentation of

selective serotonin reuptake inhibitors : PET evidence

that the dose used in clinical trials is too low. American


Rajagopalan M, Little J (1999). Discontinuation symptoms

with nefazodone. Australian & New Zealand Journal of


Ramaekers JG (2003). Antidepressants and driver

impairment : empirical evidence from a standard

on-the-road test. Journal of Clinical Psychiatry 64, 20–29.

Ramaekers JG, Muntjewerff ND, O’Hanlon JF (1995).

A comparative study of acute and subchronic effects of

dothiepin, fluoxetine and placebo on psychomotor and

actual driving performance. British Journal of Clinical


Ramaekers JG, Muntjewerff ND, van Veggel LM,

Uiterwijk MMC, O’Hanlon JF (1998). Effects of Nocturnal

Doses of Mirtazapine and Mianserin on Sleep and on

Daytime Psychomotor and Driving Performance in Young,

Healthy Volunteers. Human Psychopharmacology : Clinical

and Experimental 13, S87–S97.

Ramaekers JG, Swijgman HF, O’Hanlon JF (1992). Effects of

moclobemide and mianserin on highway driving,

psychometric performance and subjective parameters,


relative to placebo. Psychopharmacology (Berlin) 106

(Suppl.), S62–S67.

Ramana R, Paykel ES, Cooper Z, Hayhurst H, Saxty M,

Surtees PG (1995). Remission and relapse in major

depression : a two-year prospective follow-up study.


Rampello L, Chiechio S, Nicoletti G, Alvano A, Vecchio I,

Raffaele R, Malaguarnera M (2004). Prediction of the

response to citalopram and reboxetine in post-stroke

depressed patients. Psychopharmacology 173, 73–78.

Rampono J, Kristensen JH, Hackett LP, Paech M, Kohan R,

Ilett KF (2000). Citalopram and demethylcitalopram in

human milk ; distribution, excretion and effects in breast

fed infants. British Journal of Clinical Pharmacology 50,

263–268.

Rao KM, Gangadhar BN, Janakiramaiah N (1993).

Nonconvulsive status epilepticus after the ninth

electroconvulsive therapy. Convulsive Therapy 9, 128–129.

Rapaport MH, Schneider LS, Dunner DL, Davies JT, Pitts

CD (2003). Efficacy of controlled-release paroxetine in the

treatment of late-life depression. Journal of Clinical


Rapp MA, Schnaider-Beeri M, Grossman HT, Sano M, Perl

DP, Purohit DP, Gorman JM, Haroutunian V (2006).

Increased hippocampal plaques and tangles in patients

with Alzheimer disease with a lifetime history of major


Rasgon NL, Altshuler LL, Fairbanks LA, Dunkin JJ,

Davtyan C, Elman S, Rapkin AJ (2002). Estrogen

replacement therapy in the treatment of major depressive

disorder in perimenopausal women. Journal of Clinical


Rasmussen KG, Sampson SM, Rummans TA (2002).

Electroconvulsive therapy and newer modalities for the

treatment of medication-refractory mental illness. Mayo

Clinic Proceedings 77, 552–556.

Rasmussen NA, Schroder P, Olsen LR, Brodsgaard M,

Unden M, Bech P (2005). Modafinil augmentation in

depressed patients with partial response to

antidepressants : a pilot study on self-reported symptoms

covered by the Major Depression Inventory (MDI) and the

Symptom Checklist (SCL-92). Nordic Journal of Psychiatry

59, 173–178.

Rau A, Grossheinrich N, Palm U, Pogarell O, Padberg F

(2007). Transcranial and deep brain stimulation

approaches as treatment for depression. Clinical EEG and


Raue PJ, Meyers BS, Rowe JL, Heo M, Bruce ML (2007).

Suicidal ideation among elderly homecare patients.

International Journal of Geriatric Psychiatry 22, 32–37.

Ravaris CL, Robinson DS, Ives JO, Nies A, Bartlett D (1980).

Phenelzine and amitriptyline in the treatment of

depression. A comparison of present and past studies.


Raven PW, O’Dwyer A-M, Taylor NF, Checkley SA (1996).

The relationship between the effects of metyrapone

treatment on depressed mood and urinary steroid profiles.

Psychoneuroendocrinology 21, 277–286.

Ravindran AV, Anisman H, Merali Z, Charbonneau Y,

Telner J, Bialik RJ, Wiens A, Ellis J, Griffiths J (1999).

Treatment of primary dysthymia with group cognitive

therapy and pharmacotherapy: clinical symptoms and

functional impairments. American Journal of Psychiatry 156,

1608–1617.

Ravizza L (1979). [Clinical and biochemical contributions on

the effect of maprotiline and clomipramine in depressive

states (preliminary observation)]. Psychiatria Clinica 12,

164–172.

Ray WA, Fought RL, Decker MD (1992). Psychoactive

drugs and the risk of injurious motor vehicle crashes in

elderly drivers. American Journal of Epidemiology 136,

873–883.

Reagan LP, Rosell DR, Wood GE, Spedding M, Munoz C,

Rothstein J, McEwen BS (2004). Chronic restraint stress

up-regulates GLT-1 mRNA and protein expression in the

rat hippocampus : reversal by tianeptine. Proceedings of the

National Academy of Sciences USA 101, 2179–2184.

Rees AM, Austin MP, Parker G (2005). Role of omega-3 fatty

acids as a treatment for depression in the perinatal period.

Australian and New Zealand Journal of Psychiatry 39, 274–280.

Reimherr FW, Hodges MR, Hill GE, Wong KC (1977).

Prolongation of muscle relaxant effects by lithium

carbonate. American Journal of Psychiatry 134, 205–206.

Reme CE, Grimm C, Hafezi F, Wenzel A (2001). Lamp

standards and ocular safety. In : Partonen T, Magnosson A

(Eds.), Seasonal Affective Disorder (pp. 79–83). New York :


Remick RA, Campos PE, Misri S, Miles JE, Van Wyck FJ

(1982). A comparison of the safety and efficacy of

bupropion HCL and amitriptyline hcl in depressed

outpatients. Progress in Neuro-Psychopharmacology and


Revicki DA, Brown RE, Keller MB, Gonzales J, Culpepper

L, Hales RE (1997). Cost-effectiveness of newer

antidepressants compared with tricyclic antidepressants in

managed care settings. Journal of Clinical Psychiatry 58,

47–58.

Reynolds CF, III, DewMA, Pollock BG, Mulsant BH, Frank

E, Miller MD, Houck PR, Mazumdar S, Butters MA,

Stack JA, Schlernitzauer MA, Whyte EM, Gildengers A,

Karp J, Lenze E, Szanto K, Bensasi S, Kupfer DJ

(2006). Maintenance treatment of major depression

in old age. New England Journal of Medicine 354,

1130–1138.

Reynolds CF, III, Frank E, Perel JM, Imber SD, Cornes C,

Miller MD, Mazumdar S, Houck PR, Dew MA, Stack JA,

Pollock BG, Kupfer DJ (1999). Nortriptyline and

interpersonal psychotherapy as maintenance therapies

for recurrent major depression: a randomized controlled

trial in patients older than 59 years. Journal of the American


Richards A, Barkham M, Cahill J, Richards D, Williams C,

Heywood P (2003). PHASE: a randomised, controlled trial

of supervised self-help cognitive behavioural therapy in

primary care. British Journal of General Practice 53,

764–770.


Richelson E (2001). Pharmacology of antidepressants. Mayo

Clinic Proceedings 76, 511–527.

Rickards H (2005). Depression in neurological disorders :

Parkinson’s disease, multiple sclerosis, and stroke. Journal

of Neurology, Neurosurgery and Psychiatry 76 (Suppl. 1),

i48–i52.

Ridout F, Meadows R, Johnsen S, Hindmarch I (2003). A

placebo controlled investigation into the effects of

paroxetine and mirtazapine on measures related to car

driving performance. Human Psychopharmacology 18,

261–269.

Riecher-Rossler A (2000). [Mental diseases in women – some

arguments for a gender-sensitive psychiatry and

psychotherapy]. Zeitschrift Fur Psychosomatische Medizin

Und Psychotherapie 46, 129–139.

Riecher-Rossler A, Kuhl H, Bitzer J (In Press). Psychische

Storungen in Zeiten hormoneller Umstellung – eine

selektive Uebersicht. Neuropsychiatrie.

Riemann D, Schnitzler M, Hohagen F, Berger M (1994).

[Depression and sleep: the status of current research].

Fortschritte Der Neurologie-Psychiatrie 62, 458–478.

Rihmer Z, Akiskal H (2006). Do antidepressants t(h)reat(en)

depressives? Toward a clinically judicious formulation of

the antidepressant-suicidality FDA advisory in light of

declining national suicide statistics from many countries.


Rihmer Z, Appleby L, Rihmer A, Belso N (2000). Decreasing

suicide in Hungary. British Journal of Psychiatry 177, 84.

Rihmer Z, Rutz W, Pihlgren H (1995). Depression and

suicide on Gotland. An intensive study of all suicides

before and after a depression-training programme for

general practitioners. Journal of Affective Disorders 35,

147–152.

Risch NJ (2000). Searching for genetic determinants in the

new millennium. Nature 405, 847–856.

Robbe HW, O’Hanlon JF (1995). Acute and subchronic

effects of paroxetine 20 and 40 mg on actual driving,

psychomotor performance and subjective assessments in

healthy volunteers. European Neuropsychopharmacology 5,

35–42.

Robins LN, Wing J, Wittchen HU, Helzer JE, Babor TF,

Burke J, Farmer A, Jablenski A, Pickens R, Regier DA

(1988). The Composite International Diagnostic Interview:

an epidemiologic Instrument suitable for use in

conjunction with different diagnostic systems and in

different cultures. Archives of General Psychiatry 45,

1069–1077.

Robinson DS, Lerfald SC, Bennett B, Laux D, Devereaux E,

Kayser A, Corcella J, Albright D (1991). Continuation and

maintenance treatment of major depression with the

monoamine oxidase inhibitor phenelzine : a double-blind

placebo-controlled discontinuation study.


Robinson WS (1950). Ecological correlations and the

behavior of individuals. American Sociological Review 15,

351–357.

Rocca P, Fonzo V, Ravizza L, Rocca G, Scotta M, Zanalda E,

Bogetto F (2002). A comparison of paroxetine and

amisulpride in the treatment of dysthymic disorder.


Rodin G, Katz M, Lloyd N, Green E, Mackay JA, Wong RK

(2007). Treatment of depression in cancer patients.

Currrnt Oncology 14, 180–188.

Rodriguez C, Puerta G (1997). Prevalencia de dintomas

de depresion y ansiedad en los pacientes de consulta

no psiquiatrica. Revista Colombiana De Psiquiatrıa XXVI,

273–288.

Rohland BM, Carroll BT, Jacoby RG (1993). ECT in the

treatment of the catatonic syndrome. Journal of Affective


Rojo JE, Ros S, Aguera L, de la Gandara J, de Pedro JM

(2005). Combined antidepressants : clinical experience.

Acta Psychiatrica Scandinavica. Supplementum 25–31, 36.

Roman FJ, Pascaud X, Martin B, Vauche D, Junien JL (1990).

JO 1784, a potent and selective ligand for rat and mouse

brain sigma-sites. Journal of Pharmacy and Pharmacology 42,

439–440.

Romeo R, Patel A, Knapp M, Thomas C (2004). The

cost-effectiveness of mirtazapine versus paroxetine in

treating people with depression in primary care.


Roose SP, Sackeim HA, Krishnan KR, Pollock BG,

Alexopoulos G, Lavretsky H, Katz IR, Hakkarainen H

(2004). Antidepressant pharmacotherapy in the

treatment of depression in the very old : a randomized,

placebo-controlled trial. American Journal of Psychiatry 161,

2050–2059.

Roose SP, Schatzberg AF (2005). The efficacy of

antidepressants in the treatment of late-life depression.

Journal of Clinical Psychopharmacology 25, S1–S7.

Roschke J, Wolf C, Muller MJ, Wagner P, Mann K,

Grozinger M, Bech S (2000). The benefit from whole

body acupuncture in major depression. Journal of Affective


Rosenbaum JF, Fava M, Hoog SL, Ascroft RC, Krebs WB

(1998). Selective serotonin reuptake inhibitor

discontinuation syndrome: a randomized clinical trial.


Rosenbaum JF, Zajecka J (1997). Clinical management of

antidepressant discontinuation. Journal of Clinical


Rosenthal NE, Sack DA, Carpenter CJ, Parry BL,

MendelsonWB,Wehr TA (1985). Antidepressant effects of

light in seasonal affective disorder. American Journal of


Rosenthal NE, Sack DA, Gillin JC, Lewy AJ, Goodwin FK,

Davenport Y, Mueller PS, Newsome DA, Wehr TA

(1984). Seasonal affective disorder : a description of the

syndrome and preliminary findings with light therapy.


Ross S, Williams D (2005). Bupropion : risks and benefits.

Expert Opinion on Drug Safety 4, 995–1003.

Rossello J, Bernal G (1999). The efficacy of cognitive-

behavioral and interpersonal treatments for depression in

Puerto Rican adolescents. Journal of Consulting and Clinical



Rossini D, Lucca A, Zanardi R, Magri L, Smeraldi E (2005).

Transcranial magnetic stimulation in treatment-resistant

depressed patients : a double-blind, placebo-controlled

trial. Psychiatry Research 137, 1–10.

Roth A, Fonagy P (2004). What Works for Whom? New York :

Guilford Press.

Rothschild AJ (1996). Management of psychotic,

treatment-resistant depression. Psychiatric Clinics of

North America 19, 237–252.

Rothschild AJ, Samson JA, Bessette MP, Carter-Campbell

JT (1993). Efficacy of the combination of fluoxetine and

perphenazine in the treatment of psychotic depression.


Rothschild AJ, Williamson DJ, Tohen MF, Schatzberg A,

Andersen SW, Van Campen LE, Sanger TM, Tollefson

GD (2004). A double-blind, randomized study of

olanzapine and olanzapine/fluoxetine combination for

major depression with psychotic features. Journal of


Rouillon F, Warner B, Pezous N, Bisserbe JC (2000).

Milnacipran efficacy in the prevention of recurrent

depression : a 12-month placebo-controlled study.

Milnacipran recurrence prevention study group.


Roxanas MG, Machado JF (1998). Serotonin syndrome in

combined moclobemide and venlafaxine ingestion.

Medical Journal of Australia 168, 523–524.

Roy-Byrne PP, Uhde TW, Post RM (1986). Effects of one

night’s sleep deprivation on mood and behavior in

panic disorder. Patients with panic disorder compared

with depressed patients and normal controls. Archives of


Rudorfer MV, Potter WZ (1997). The role of metabolites of

antidepressants in the treatment of depression [review].

CNS Drugs 7, 273–312.

Ruhe HG, Huyser J, Swinkels JA, Schene AH (2006a).

Dose escalation for insufficient response to standard-dose

selective serotonin reuptake inhibitors in major depressive

disorder : systematic review. British Journal of Psychiatry

189, 309–316.

Ruhe HG, Huyser J, Swinkels JA, Schene AH (2006b).

Switching antidepressants after a first selective serotonin

reuptake inhibitor in major depressive disorder : a

systematic review. Journal of Clinical Psychiatry 67,

1836–1855.

Ruhrmann S, Kasper S, Hawellek B, Martinez B, Hoflich G,

Nickelsen T, Moller HJ (1998). Effects of fluoxetine versus

bright light in the treatment of seasonal affective disorder.


Rumi DO, Gattaz WF, Rigonatti SP, Rosa MA, Fregni F,

Rosa MO, Mansur C, Myczkowski ML, Moreno RA,

Marcolin MA (2005). Transcranial magnetic stimulation

accelerates the antidepressant effect of amitriptyline in

severe depression : a double-blind placebo-controlled

study. Biological Psychiatry 57, 162–166.

Rupprecht R (1997). The neuropsychopharmacological

potential of neuroactive steroids. Journal of Psychiatric

Research 31, 297–314.

Rupprecht R, Baghai TC, Moller HJ (2004). [New

developments in pharmacotherapy of depression].

Nervenarzt 75, 273–280.

Rupprecht R, Holsboer F (1999). Neuroactive steroids :

mechanisms of action and neuropsychopharmacological

perspectives. Trends in Neurosciences 22, 410–416.

Ruschitzka F, Meier PJ, Turina M, Luscher TF, Noll G

(2000). Acute heart transplant rejection due to Saint John’s

wort. Lancet 355, 548–549.

Rush AJ (1999). Strategies and tactics in the management

of maintenance treatment for depressed patients. Journal

of Clinical Psychiatry 60 (Suppl. 14), 21–26 ; discussion

31–35.

Rush AJ, Crismon ML, Kashner TM, Toprac MG,

Carmody TJ, Trivedi MH, Suppes T, Miller AL,

Biggs MM, Shores-Wilson K, Witte BP, Shon SP, Rago

WV, Altshuler KZ (2003a). Texas Medication Algorithm

Project, phase 3 (TMAP-3) : rationale and study design.


Rush AJ, Fava M, Wisniewski SR, Lavori PW, Trivedi MH,

Sackeim HA, Thase ME, Nierenberg AA, Quitkin FM,

Kashner TM, Kupfer DJ, Rosenbaum JF, Alpert J,

Stewart JW, McGrath PJ, Biggs MM, Shores-Wilson K,

Lebowitz BD, Ritz L, Niederehe G (2004). Sequenced

treatment alternatives to relieve depression (STAR*D) :

rationale and design. Controlled Clinical Trials 25, 119–142.

Rush AJ, George MS, Sackeim HA, Marangell LB, Husain

MM, Giller C, Nahas Z, Haines S, Simpson RKJ,

Goodman R (2000). Vagus nerve stimulation (VNS) for

treatment-resistant depressions : a multicenter study.


Rush AJ, Kraemer HC, Sackeim HA, Fava M, Trivedi MH,

Frank E, Ninan PT, Thase ME, Gelenberg AJ, Kupfer DJ,

Regier DA, Rosenbaum JF, Ray O, Schatzberg AF

(2006a). Report by the ACNP Task Force on response and

remission in major depressive disorder.


Rush AJ, Marangell LB, Sackeim HA, George MS, Brannan

SK, Davis SM, Howland R, Kling MA, Rittberg BR,

Burke WJ, Rapaport MH, Zajecka J, Nierenberg AA,

HusainMM, Ginsberg D, Cooke RG (2005a). Vagus nerve

stimulation for treatment-resistant depression : a

randomized, controlled acute phase trial. Biological


Rush AJ, Sackeim HA, Marangell LB, George MS,

Brannan SK, Davis SM, Lavori P, Howland R, Kling MA,

Rittberg B, Carpenter L, Ninan P, Moreno F, Schwartz T,

Conway C, BurkeM, Barry JJ (2005b). Effects of 12 months

of vagus nerve stimulation in treatment-resistant

depression : a naturalistic study. Biological Psychiatry 58,

355–363.

Rush AJ, Thase ME, Dube S (2003b). Research issues in the

study of difficult-to-treat depression. Biological Psychiatry

53, 743–753.

Rush AJ, Thase ME (1999). Psychotherapies for depressive

disorders : a review. In : Maj M, Sartorius N (Eds.),

Depressive Disorders : WPA Series Evidence and Experience

in Psychiatry (pp. 161–206). Chichester : John Wiley & Sons.


Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA,

Stewart JW, Warden D, Niederehe G, Thase ME,

Lavori PW, Lebowitz BD, McGrath PJ, Rosenbaum JF,

Sackeim HA, Kupfer DJ, Luther J, Fava M (2006b).

Acute and longer-term outcomes in depressed outpatients

requiring one or several treatment steps : a STAR*D

report. American Journal of Psychiatry 163, 1905–1917.

Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW,

Nierenberg AA, Thase ME, Ritz L, Biggs MM,Warden D,

Luther JF, Shores-Wilson K, Niederehe G, Fava M

(2006c). Bupropion-SR, sertraline, or venlafaxine-XR after

failure of SSRIs for depression. New England Journal of

Medicine 354, 1231–1242.

Rush AJ, Zimmerman M, Wisniewski SR, Fava M,

Hollon SD, Warden D, Biggs MM, Shores-Wilson K,

Shelton RC, Luther JF, Thomas B, Trivedi MH (2005c).

Comorbid psychiatric disorders in depressed outpatients :

demographic and clinical features. Journal of Affective


Rutz W, von Knorring L, Walinder J (1989). Frequency of

suicide on Gotland after systematic postgraduate

education of general practitioners. Acta Psychiatrica


Rybakowski JK, Suwalska A, Chlopocka-Wozniak M

(1999). Potentiation of antidepressants with lithium or

carbamazepine in treatment-resistant depression.

Neuropsychobiology 40, 134–139.

Saarto T, Wiffen PJ (2005, 2007). Antidepressants for

neuropathic pain. Cochrane Database of Systematic Reviews.

CD005454.

SaatciogluO, Erim R, CakmakD (2006). [A case of tianeptine

abuse]. Turk Psikiyatri Dergisi 17, 72–75.

Sachdev PS, Sachdev J (2005). Long-term outcome of

neurosurgery for the treatment of resistant depression.


478–485.

Sachs GS, Lafer B, Stoll AL, Banov M, Thibault AB, Tohen

M, Rosenbaum JF (1994). A double-blind trial of

bupropion versus desipramine for bipolar depression.


Sachs GS, Nierenberg AA, Calabrese JR, Marangell LB,

Wisniewski SR, Gyulai L, Friedman ES, Bowden CL,

Fossey MD, Ostacher MJ, Ketter TA, Patel J, Hauser P,

Rapport D, Martinez JM, Allen MH, Miklowitz DJ,

Otto MW, Dennehy EB, Thase ME (2007). Effectiveness

of adjunctive antidepressant treatment for bipolar

depression.New England Journal of Medicine 356, 1711–1722.

Sackeim HA (2001). The definition and meaning of

treatment-resistant depression. Journal of Clinical Psychiatry

62 (Suppl. 16), 10–17.

Sackeim HA, Decina P, Kanzler M, Kerr B, Malitz S (1987).

Effects of electrode placement on the efficacy of titrated,

low-dose ECT. American Journal of Psychiatry 144,

1449–1455.

Sackeim HA, Haskett RF, Mulsant BH, Thase ME, Mann JJ,

Pettinati HM, Greenberg RM, Crowe RR, Cooper TB,

Prudic J (2001a). Continuation pharmacotherapy in

the prevention of relapse following electroconvulsive

therapy : a randomized controlled trial. Journal of the


Sackeim HA, Prudic J, Devanand DP, Kiersky JE,

Fitzsimons L, Moody BJ, McElhiney MC, Coleman EA,

Settembrino JM (1993). Effects of stimulus intensity and

electrode placement on the efficacy and cognitive effects of

electroconvulsive therapy. New England Journal of Medicine

328, 839–846.

Sackeim HA, Prudic J, Devanand DP, Nobler MS, Lisanby

SH, Peyser S, Fitzsimons L, Moody BJ, Clark J (2000). A

prospective, randomized, double-blind comparison of

bilateral and right unilateral electroconvulsive therapy at

different stimulus intensities. Archives of General Psychiatry

57, 425–434.

Sackeim HA, Rush AJ, George MS, Marangell LB, Husain

MM, Nahas Z, Johnson CR, Seidman S, Giller C, Haines

S, Simpson RKJ, Goodman RR (2001b). Vagus nerve

stimulation (VNS) for treatment-resistant depression:

efficacy, side effects, and predictors of outcome.


Sairanen M, Lucas G, Ernfors P, Castren M, Castren E

(2005). Brain-derived neurotrophic factor and

antidepressant drugs have different but coordinated

effects on neuronal turnover, proliferation, and survival in

the adult dentate gyrus. Journal of Neuroscience 25,

1089–1094.

Sallee FR, Koran LM, Pallanti S, Carson SW, Sethuraman G

(1998). Intravenous clomipramine challenge in obsessive-

compulsive disorder : predicting response to oral therapy

at eight weeks. Biological Psychiatry 44, 220–227.

Sallee FR, Vrindavanam NS, Deas-Nesmith D, Carson SW,

Sethuraman G (1997). Pulse intravenous clomipramine

for depressed adolescents : double-blind, controlled trial.


Samuelian JC, Hackett D (1998). A randomized,

double-blind, parallel-group comparison of venlafaxine

and clomipramine in outpatients with major depression.

Journal of Psychopharmacology 12, 273–278.

Sanacora G, Mason GF, Krystal JH (2000). Impairment of

GABAergic transmission in depression : new insights from

neuroimaging studies. Critical Reviews in Neurobiology 14,

23–45.

Sanchez C, Bogeso KP, Ebert B, Reines EH, Braestrup C

(2004). Escitalopram versus citalopram: the surprising

role of the R-enantiomer. Psychopharmacology 174, 163–176.

Sanchez C, Hyttel J (1999). Comparison of the effects of

antidepressants and their metabolites on reuptake of

biogenic amines and on receptor binding. Cellular and

Molecular Neurobiology 19, 467–489.

Santarelli L, Gobbi G, Debs PC, Sibille ET, Blier P, Hen R,

Heath MJ (2001). Genetic and pharmacological disruption

of neurokinin 1 receptor function decreases anxiety-

related behaviors and increases serotonergic function.

Proceedings of the National Academy of Sciences USA 98,

1912–1917.

Santarelli L, SaxeM, Gross C, Surget A, Battaglia F, Dulawa

S, Weisstaub N, Lee J, Duman R, Arancio O, Belzung C,

Hen R (2003). Requirement of hippocampal neurogenesis


for the behavioral effects of antidepressants. Science 301,

805–809.

Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R

(2005b). Selective serotonin reuptake inhibitors in pregnant

women and neonatal withdrawal syndrome: a database

analysis. Lancet 365, 482–487.

Sanz EJ, De-las-Cuevas C, Kiuru A, Bate A, Edwards R

(2005a). Selective serotonin reuptake inhibitors in pregnant

women and neonatal withdrawal syndrome: a database

analysis. Lancet 365, 482–487.

Sapolsky RM (2000). Glucocorticoids and hippocampal

atrophy in neuropsychiatric disorders. Archives of General


Sartorius A, Henn FA (2005a). [Continuation ECT].

Psychiatrische Praxis 32, 408–411.

Sartorius A, Henn FA (2005b). Treating depressive disorders

with continuation electroconvulsive therapy. Nervenarzt

76, 1363–1369.

Sartorius A, Wolf J, Henn FA (2005). Lithium and ECT:

concurrent use still demands attention : three case reports.

World Journal of Biological Psychiatry 6, 121–124.

Sartorius N (1974). Description and classification of

depressive disorders. Contributions for the definition of

the therapy-resistance and of therapy resistant

depressions. Pharmakopsychiatrie, Neuro-

Psychopharmakologie 7, 76–79.

Sartorius N (1986). Cross-cultural research on depression.

Psychopathology 19 (Suppl. 2), 6–11.

Sartorius N (1993). WHO’s work on the epidemiology of

mental disorders. Social Psychiatry and Psychiatric


Sartorius N (1995). Recent changes in suicide rates in selected

eastern European and other European countries.

International Psychogeriatrics 7, 301–308.

Sartorius N (2001). The economic and social burden of


8–11.

Sartorius N, Ustun TB, Costa e Silva JA, Goldberg D,

Lecrubier Y, Ormel J, Von Korff M, Wittchen HU (1993).

An international study of psychological problems in

primary care. Preliminary report from the World Health

Organization Collaborative Project on ‘Psychological

Problems in General Health Care’. Archives of General


Saxena S, Paraje G, Sharan P, Karam G, Sadana R (2006).

The 10/90 divide in mental health research : trends over

a 10-year period. British Journal of Psychiatry 188, 81–82.

Schachter SC (2006). Therapeutic effects of vagus nerve

stimulation in epilepsy and implications for sudden

unexpected death in epilepsy. Clinical Autonomic Research

16, 29–32.

Schaefer M, Engelbrecht MA, Gut O, Fiebich BL, Bauer J,

Schmidt F, Grunze H, Lieb K (2002). Interferon alpha

(IFNalpha) and psychiatric syndromes : a review. Progress

in Neuro-Psychopharmacology and Biological Psychiatry 26,

731–746.

Schaefer M, Schmidt F, Folwaczny C, Lorenz R, Martin G,

Schindlbeck N, Heldwein W, Soyka M, Grunze H,

Koenig A, Loeschke K (2003). Adherence and mental side

effects during hepatitis C treatment with interferon alfa

and ribavirin in psychiatric risk groups. Hepatology 37,

443–451.

Schatzberg AF (2004). Pharmacologic treatments of major

depression : are two mechanisms really better than one?


Schatzberg AF, Blier P, Delgado PL, Fava M, Haddad PM,

Shelton RC (2006). Antidepressant discontinuation

syndrome: consensus panel recommendations for

clinical management and additional research. Journal of


Schatzberg AF, Haddad P, Kaplan EM, Lejoyeux M,

Rosenbaum JF, Young AH, Zajecka J (1997). Serotonin

reuptake inhibitor discontinuation syndrome: a

hypothetical definition. Discontinuation Consensus panel.

J Clin. Psychiatry 58 (Suppl. 7), 5–10.

Schatzberg AF, Kremer C, Rodrigues HE, Murphy GM

(2002). Double-blind, randomized comparison of

mirtazapine and paroxetine in elderly depressed

patients. American Journal of Geriatric Psychiatry 10,

541–550.

Scheibe S, Preuschhof C, Cristi C, Bagby RM (2003). Are

there gender differences in major depression and its

response to antidepressants? Journal of Affective Disorders

75, 223–235.

Schilgen B, Tolle R (1980). Partial sleep deprivation as

therapy for depression. Archives of General Psychiatry 37,

267–271.

Schillevoort I, van Puijenbroek EP, de Boer A, Roos RA,

Jansen PA, Leufkens HG (2002). Extrapyramidal

syndromes associated with selective serotonin reuptake

inhibitors : a case-control study using spontaneous reports.


Schirren CA, Baretton G (2000). Nefazodone-induced acute

liver failure. American Journal of Gastroenterology 95,

1596–1597.

Schlaepfer TE, Lieb K (2005). Deep brain stimulation

for treatment of refractory depression. Lancet 366,

1420–1422.

Schmauss M, Kapfhammer HP, Meyr P, Hoff P (1988).

Combined MAO-inhibitor and tri- (tetra) cyclic

antidepressant treatment in therapy resistant depression.

Progress in Neuro-Psychopharmacology and Biological


Schneider LS, Nelson JC, Clary CM, Newhouse P,

Krishnan KR, Shiovitz T, Weihs K (2003). An 8-week

multicenter, parallel-group, double-blind, placebo-

controlled study of sertraline in elderly outpatients with

major depression. American Journal of Psychiatry 160,

1277–1285.

Schneider LS, Small GW, Clary CM (2001). Estrogen

replacement therapy and antidepressant response to

sertraline in older depressed women. American Journal of

Geriatric Psychiatry 9, 393–399.

Schneider LS, Small GW, Hamilton SH, Bystritsky A,

Nemeroff CB, Meyers BS (1997). Estrogen replacement

and response to fluoxetine in a multicenter geriatric


depression trial. Fluoxetine Collaborative Study Group.

American Journal of Geriatric Psychiatry 5, 97–106.

Schoenmakers EAJM, Robbe HW, O’Hanlon JF (1989).

Acute and Subchronic Effects of the Antidepressants

Levoprotiline and Doxepin on the Performance of Healthy

Volunteers in Psychometric and Actual Driving Tests.

Maastricht, The Netherlands : University of Maastricht,

Institute for Human Psychopharmacology.

Schou M (1995). Prophylactic lithium treatment of unipolar

and bipolar manic-depressive illness. Psychopathology 28

(Suppl. 1), 81–85.

Schrader E (2000). Equivalence of St John’s wort extract (Ze

117) and fluoxetine : a randomized, controlled study in

mild-moderate depression. International Clinical


Schule C, Zwanzger P, Baghai T, Mikhaiel P, Thoma H,

Moller HJ, Rupprecht R, Padberg F (2003). Effects of

antidepressant pharmacotherapy after repetitive

transcranial magnetic stimulation in major depression : an

open follow-up study. Journal of Psychiatric Research 37,

145–153.

Schulz R, Beach SR, Ives DG, Martire LM, Ariyo AA, Kop

WJ (2000). Association between depression and mortality

in older adults : the Cardiovascular Health Study. Archives

of Internal Medicine 160, 1761–1768.

Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S,

Syagailo YV, Windemuth C, Neidt H, Grassle M,

Papassotiropoulos A, Heun R, Nothen MM, Maier W,

Lesch KP, Rietschel M (2000). Association between a

functional polymorphism in the monoamine oxidase A

gene promoter and major depressive disorder. American

Journal of Medical Genetics 96, 801–803.

Schulze-Rauschenbach SC, Harms U, Schlaepfer TE,

Maier W, Falkai P, Wagner M (2005). Distinctive

neurocognitive effects of repetitive transcranial magnetic

stimulation and electroconvulsive therapy in major

depression. British Journal of Psychiatry 186,

Schuurman AG, Van den AM, Ensinck KT, Metsemakers

JF, Knottnerus JA, Leentjens AF, Buntinx F (2002).

Increased risk of Parkinson’s disease after depression : a

retrospective cohort study. Neurology 58, 1501–1504.

Schwarz MJ, Ackenheil M (2002). The role of substance P in

depression : therapeutic indications. Dialogues in Clinical


Scott AI, Freeman CP (1992). Edinburgh primary care

depression study: treatment outcome, patient

satisfaction, and cost after 16 weeks. British Medical

Journal 304, 883–887.

Scott AI, Perini AF, Shering PA, Whalley LJ (1991).

In-patient major depression : is rolipram as effective as

amitriptyline? European Journal of Clinical Pharmacology 40,

127–129.

Scott J, Palmer S, Paykel E, Teasdale J, Hayhurst H (2003).

Use of cognitive therapy for relapse prevention in

chronic depression. Cost-effectiveness study.

British Journal of Psychiatry 182, 221–227.

Segal ZV, Kennedy SH, Cohen NL (2001a). Clinical

guidelines for the treatment of depressive disorders. V.

Combining psychotherapy and pharmacotherapy.

Canadian Journal of Psychiatry 46 (Suppl. 1), 59S–62S.

Segal ZV, Whitney DK, Lam RW (2001b). Clinical guidelines

for the treatment of depressive disorders. III.

Psychotherapy. Canadian Journal of Psychiatry 46 (Suppl. 1),

29S–37S.

Segrave R, Nathan PJ (2005). Pindolol augmentation of

selective serotonin reuptake inhibitors : accounting for the

variability of results of placebo-controlled double-blind

studies in patients with major depression. Human


Seguin CA (1986). Psiquiatria Tradicional y Psiquiatria

Folklorica. In : Vidal G, Alarcon RD (Eds.), Psiquiatria

(pp. 630–640). Buenos Aires : Editorial Medica

Panamericana.

Serebruany VL (2006). Selective serotonin reuptake

inhibitors and increased bleeding risk : are we

missing something? American Journal of Medicine 119,

113–116.

Serretti A, Artioli P, Quartesan R (2005). Pharmacogenetics

in the treatment of depression: pharmacodynamic studies.

Pharmacogenetics and Genomics 15, 61–67.

Serretti A, Cusin C, Lattuada E, di Bella D, Catalano M,

Smeraldi E (1999). Serotonin transporter gene (5-HTTLPR)

is not associated with depressive symptomatology in

mood disorders. Molecular Psychiatry 4, 280–283.

Sharan P, Saxena S (1998). Treatment-resistant depression:

clinical significance, concept and management. National

Medical Journal of India 11, 69–79.

Shea MT, Widiger TA, Klein MH (1992). Comorbidity of

personality disorders and depression: implications for

treatment. Journal of Consulting and Clinical Psychology 60,

857–868.

Sheehan JD, Shelley RK (1990). Leucopenia secondary to

carbamazepine despite concurrent lithium treatment.

British Journal of Psychiatry 157, 911–912.

Sheline YI, Gado MH, Kraemer HC (2003). Untreated

depression and hippocampal volume loss.American Journal


Shelton RC (2001). Steps Following Attainment of

Remission : Discontinuation of Antidepressant Therapy.

Prim. Care Companion. J Clin. Psychiatry 3, 168–174.

Shelton RC, Keller MB, Gelenberg A, Dunner DL,

Hirschfeld R, Thase ME, Russell J, Lydiard RB,

Crits-Cristoph P, Gallop R, Todd L, Hellerstein D,

Goodnick P, Keitner G, Stahl SM, Halbreich U (2001a).

Effectiveness of St John’s wort in major depression: a

randomized controlled trial. Journal of the American Medical


Shelton RC, Tollefson GD, Tohen M, Stahl S, Gannon KS,

Jacobs TG, Buras WR, Bymaster FP, Zhang W,

Spencer KA, Feldman PD, Meltzer HY (2001b). A novel

augmentation strategy for treating resistant major

depression. American Journal of Psychiatry 158, 131–134.

Shelton RC, Williamson DJ, Corya SA, Sanger TM, Van

Campen LE, Case M, Briggs SD, Tollefson GD (2005).

Olanzapine/Fluoxetine Combination for Treatment-

Resistant Depression : A Controlled Study of SSRI and


Nortriptyline Resistance. Journal of Clinical Psychiatry 66,

1289–1297.

Shen ZM, Zhu ML, Zhao AQ (2004). [Comparative

observation on efficacy of jieyu pill and maprotiline in

treating depression]. Zhongguo Zhong Xi Yi Jie He Za Zhi 24,

415–417.

Shepherd G, Velez LI, Keyes DC (2004). Intentional

bupropion overdoses. Journal of Emergency Medicine 27,

147–151.

Shepherd M, Sartorius N (1989). Non-Specific Aspects of

Treatment. Toronto : Hans Huber.

Shim YS, Yang DW (2006). Depression as prognostic factor : 6

months follow-up in a geriatric institution. Archives of

Gerontology and Geriatrics 43, 277–283.

Shimbo D, Davidson KW, Haas DC, Fuster V, Badimon JJ

(2005). Negative impact of depression on outcomes in

patients with coronary artery disease : mechanisms,

treatment considerations, and future directions. Journal of

Thrombosis and Haemostasis 3, 897–908.

Shiwach RS, Reid WH, Carmody TJ (2001). An

analysis of reported deaths following electroconvulsive

therapy in Texas, 1993–1998. Psychiatric Services 52,

1095–1097.

Silva RC, Brandao ML (2000). Acute and chronic effects

of gepirone and fluoxetine in rats tested in the elevated

plus-maze : an ethological analysis. Pharmacology,

Biochemistry and Behavior 65, 209–216.

Silvers KM, Woolley CC, Hamilton FC, Watts PM, Watson

RA (2005). Randomised double-blind placebo-controlled

trial of fish oil in the treatment of depression.

Prostaglandins, Leukotrienes, and Essential Fatty Acids 72,

211–218.

Silverstone T (2001). Moclobemide vs. imipramine in bipolar

depression : a multicentre double-blind clinical trial. Acta


Sim K, Lee NB, Chua HC, Mahendran R, Fujii S, Yang SY,

Chong MY, Si T, He YL, Lee MS, Sung KM, Chung EK,

Chan YH, Shinfuku N, Tan CH, Sartorius N, Baldessarini

RJ (2006). Newer antidepressant drug use in East Asian

psychiatric treatment settings : REAP (Research on East

Asia Psychotropic Prescriptions) Study. British Journal of

Clinical Pharmacology. Published Online : 36 October 2006.

DOI : 10.1111/j.1365-2125.2006.02780.x.

Simeon JG, Dinicola VF, Ferguson HB, Copping W

(1990). Adolescent depression : a placebo-controlled

fluoxetine treatment study and follow-up. Progress

in Neuro-Psychopharmacology and Biological Psychiatry 14,

791–795.

Simon GE, Heiligenstein J, Revicki D, Von Korff M, Katon

WJ, Ludman E, Grothaus L, Wagner E (1999a). Long-term

outcomes of initial antidepressant drug choice in a ‘real

world’ randomized trial. Archives of Family Medicine 8,

319–325.

Simon GE, Revicki D, Heiligenstein J, Grothaus L, Von

Korff M, Katon WJ, Hylan TR (2000a). Recovery from

depression, work productivity, and health care costs

among primary care patients. General Hospital Psychiatry

22, 153–162.

Simon GE, Savarino J, Operskalski B, Wang PS (2006).

Suicide risk during antidepressant treatment. American


Simon GE, Von Korff M (1998). Suicide mortality among

patients treated for depression in an insured population.

American Journal of Epidemiology 147, 155–160.

Simon GE, Von Korff M, Heiligenstein JH, Revicki DA,

Grothaus L, Katon W, Wagner EH (1996). Initial

antidepressant choice in primary care. Effectiveness and

cost of fluoxetine vs tricyclic antidepressants. Journal of the


Simon GE, Von Korff M, Ludman EJ, Katon WJ, Rutter C,

Unutzer J, Lin EH, Bush T, Walker E (2002). Cost-

effectiveness of a program to prevent depression relapse in

primary care. Medical Care 40, 941–950.

Simon GE, Von Korff M, Piccinelli M, Fullerton C, Ormel J

(1999b). An international study of the relation between

somatic symptoms and depression. New England Journal of

Medicine 341, 1329–1335.

Simon GE, Von Korff M, Rutter C, Wagner E (2000b).

Randomised trial of monitoring, feedback, and

management of care by telephone to improve treatment of

depression in primary care. British Medical Journal 320,

550–554.

Simon JS, Nemeroff CB (2005). Aripiprazole augmentation

of antidepressants for the treatment of partially

responding and nonresponding patients with major


1216–1220.

Simpson HB, Liebowitz MR, Foa EB, Kozak MJ, Schmidt

AB, Rowan V, Petkova E, Kjernisted K, Huppert JD,

Franklin ME, Davies SO, Campeas R (2004). Post-

treatment effects of exposure therapy and clomipramine in

obsessive-compulsive disorder. Depression and Anxiety 19,

225–233.

Simpson S, Corney R, Fitzgerald P, Beecham J (2003). A

randomized controlled trial to evaluate the effectiveness

and cost-effectiveness of psychodynamic counselling for

general practice patients with chronic depression.


Sinclair JM, Harriss L, Baldwin DS, King EA (2005). Suicide

in depressive disorders : a retrospective case-control study

of 127 suicides. Journal of Affective Disorders 87, 107–113.

Sindrup SH, Otto M, Finnerup NB, Jensen TS (2005).

Antidepressants in the treatment of neuropathic pain. Basic

and Clinical Pharmacology and Toxicology 96, 399–409.

Singh NA, Clements KM, Singh MA (2001). The efficacy of

exercise as a long-term antidepressant in elderly subjects : a

randomized, controlled trial. Journals of Gerontology. Series

A, Biological Sciences and Medical Sciences 56, M497–M504.

Sir A, D’Souza RF, Uguz S, George T, Vahip S, Hopwood

M, Martin AJ, Lam W, Burt T (2005). Randomized trial of

sertraline versus venlafaxine XR in major depression :

efficacy and discontinuation symptoms. Journal of Clinical


Slattery DA, Hudson AL, Nutt DJ (2004). Invited review: the

evolution of antidepressant mechanisms. Fundamental and

Clinical Pharmacology 18, 1–21.


Smeraldi E, Benedetti F, Barbini B, Campori E, Colombo C

(1999). Sustained antidepressant effect of sleep deprivation

combined with pindolol in bipolar depression. A

placebo-controlled trial. Neuropsychopharmacology 20,

380–385.

Smith CA, Hay PP (2005). Acupuncture for depression.

Cochrane Database of Systematic Reviews CD004046.

SmithD,Dempster C,Glanville J, FreemantleN,Anderson I

(2002). Efficacy and tolerability of venlafaxine compared

with selective serotonin reuptake inhibitors and other

antidepressants : a meta-analysis. British Journal of


Smith KA, Fairburn CG, Cowen PJ (1997). Relapse of

depression after rapid depletion of tryptophan. Lancet 349,

915–919.

Smith RS (1991). The macrophage theory of depression.

Medical Hypotheses 35, 298–306.

Sogaard J, Lane R, Latimer P, Behnke K, Christiansen PE,

Nielsen B, Ravindran AV, Reesal RT, Goodwin DP

(1999). A 12-week study comparing moclobemide and

sertraline in the treatment of outpatients with atypical

depression. Journal of Psychopharmacology 13, 406–414.

Sokolski KN, Conney JC, Brown BJ, DeMet EM (2004).

Once-daily high-dose pindolol for SSRI-refractory

depression. Psychiatry Research 125, 81–86.

Solomon DA, Keller MB, Leon AC, Mueller TI, Lavori PW,

Shea MT, Coryell W, Warshaw M, Turvey C, Maser JD,

Endicott J (2000). Multiple recurrences of major depressive

disorder. American Journal of Psychiatry 157, 229–233.

Sondergaard MP, Jarden JO, Martiny K, Andersen G,

Bech P (2006). Dose response to adjunctive light therapy

in citalopram-treated patients with post-stroke depression.

A randomised, double-blind pilot study. Psychotherapy

and Psychosomatics 75, 244–248.

Sondergard L, Kvist K, Andersen PK, Kessing LV (2006). Do

antidepressants precipitate youth suicide? A nationwide

pharmacoepidemiological study. European Child and

Adolescent Psychiatry

Sontrop J, Campbell MK (2006). omega-3 polyunsaturated

fatty acids and depression: a review of the evidence and a

methodological critique. Preventive Medicine 42, 4–13.

Sotsky SM, Glass DR, Shea MT, Pilkonis PA, Collins JF,

Elkin I, Watkins JT, Imber SD, Leber WR,Moyer J (1991).

Patient predictors of response to psychotherapy and

pharmacotherapy : findings in the NIMH Treatment of

Depression Collaborative Research Program. American


Souery D, Amsterdam J, de Montigny C, Lecrubier Y,

Montgomery S, Lipp O, Racagni G, Zohar J, Mendlewicz

J (1999). Treatment resistant depression: methodological

overview and operational criteria. European


Souza FG, Goodwin GM (1991). Lithium treatment and

prophylaxis in unipolar depression : a meta-analysis.

British Journal of Psychiatry 158, 666–75., 666–675.

Sovner R, Fogelman S (2002). Ketoconazole therapy for

atypical depression. Journal of Clinical Psychiatry 57,

227–228.

Spencer SS, Berg AT, Vickrey BG, Sperling MR, Bazil CW,

Shinnar S, Langfitt JT, Walczak TS, Pacia SV, Ebrahimi

N, Frobish D (2003). Initial outcomes in the Multicenter

Study of Epilepsy Surgery. Neurology 61, 1680–1685.

Spoont MR (1992). Modulatory role of serotonin in neural

information processing : implications for human

psychopathology. Psychol. Bull. 112, 330–350.

Stahl SM (1997). Psychopharmacology of Antidepressants.

London : Martin Dunitz.

Stahl SM (1998a). Mechanism of action of serotonin selective

reuptake inhibitors. Serotonin receptors and pathways

mediate therapeutic effects and side effects. Journal of


Stahl SM (1998b). Selecting an antidepressant by using

mechanism of action to enhance efficacy and avoid side

effects. Journal of Clinical Psychiatry 59, 23–29.

Stahl SM (2001). Effects of estrogen on the central nervous

system. Journal of Clinical Psychiatry 62, 317–318.

Stahl SM (2006). Essential Psychopharmacology : The Prescriber’s

Guide. Cambridge : Cambridge University Press.

Stahl SM, Grady MM, Moret C, Briley M (2005). SNRIs :

their pharmacology, clinical efficacy, and tolerability in

comparison with other classes of antidepressants. CNS

Spectrums 10, 732–747.

Starkstein SE, Petracca G, Teson A, Chemerinski E, Merello

M, Migliorelli R, Leiguarda R (1996). Catatonia in

depression : prevalence, clinical correlates, and validation

of a scale. Journal of Neurology, Neurosurgery and Psychiatry

60, 326–332.

Stassen HH, Angst J (1998). Delayed onset of action of

antidepressants : fact or fiction? CNS Drugs 9, 177–184.

Stassen HH, Angst J, Delini-Stula A (1996). Delayed

onset of action of antidepressant drugs? Survey of

results of Zurich meta-analyses. Pharmacopsychiatry 29(3),

87–96.

Stassen HH, Angst J, Delini-Stula A (1997). Onset of action

under antidepressant treatment. European Psychiatry 12(4),

163–165.

Stassen HH, Angst J, Delini-Stula A (1999). Fluoxetine

versus moclobemide : cross-comparison between the

time courses of improvement. Pharmacopsychiatry 32,

56–60.

Steffens DC, Plassman BL, Helms MJ, Welsh-Bohmer KA,

Saunders AM, Breitner JC (1997). A twin study of

late-onset depression and apolipoprotein E epsilon 4 as

risk factors for Alzheimer’s disease. Biological Psychiatry 41,

851–856.

Steffens DC, Skoog I, Norton MC, Hart AD, Tschanz JT,

Plassman BL, Wyse BW, Welsh-Bohmer KA, Breitner JC

(2000). Prevalence of depression and its treatment in an

elderly population: the Cache County study. Archives of


Steimer W, Muller B, Leucht S, Kissling W (2001).

Pharmacogenetics : a new diagnostic tool in the

management of antidepressive drug therapy. Clinica

Chimica Acta 308, 33–41.

Stein DJ, Kupfer D, Schatzberg A (2006). Textbook of Mood

Disorders. Washington : American Psychiatric Press.


Stein DJ, Zungu-Dirwayi N, Der Linden GJ, Seedat S

(2000). Pharmacotherapy for posttraumatic stress disorder.

Cochrane Database of Systematic Reviews. CD002795.

Steinacher L, Vandel P, Zullino DF, Eap CB, Brawand-

Amey M, Baumann P (2002). Carbamazepine

augmentation in depressive patients non-responding to

citalopram: a pharmacokinetic and clinical pilot study.


Sterne JA, Gavaghan D, Egger M (2000). Publication and

related bias in meta-analysis : power of statistical tests and

prevalence in the literature. Journal of Clinical Epidemiology

53, 1119–1129.

Stotz G, Woggon B, Angst J (1999). Psychostimulants in the

therapy of treatment-resistant depression. Review of the

literature and findings from a retrospective study in 65

depressed patients. Dialogues in Clinical Neuroscience 1,

165–174.

Stout SC, Owens MJ, Nemeroff CB (2001). Neurokinin(1)

receptor antagonists as potential antidepressants.

Annual Review of Pharmacology and Toxicology 41, 877–906.

Sturm R, Wells KB (1995). How can care for depression

become more cost-effective? Journal of the American Medical


Sugahara H, Tokunaga S, Kondo T, Akamine M,

Yoshimasu K, Fujisawa K, Fukudome K, Kanemitsu Y,

Kubo C (2005). Comparative adherence to antidepressant

drugs in a non-psychiatric outpatient clinic setting in

Japan. Primary Care and Community Psychiatry 10, 57–62.

Sulser F, Vetulani J, Mobley PL (1978). Mode of action of

antidepressant drugs. Biochemical Pharmacology 27,

257–261.

Suri A, Reddy S, Gonzales C, Knadler MP, Branch RA,

Skinner MH (2005). Duloxetine pharmacokinetics in

cirrhotics compared with healthy subjects. International

Journal of Clinical Pharmacology and Therapeutics 43, 78–84.

Suri RA, Altshuler LL, Burt VK, Hendrick VC (1998).

Managing psychiatric medications in the breast-feeding

woman. Medscape Women’s Health 3, 1.

Sussman N, Ginsberg DL, Bikoff J (2001). Effects of

nefazodone on body weight : a pooled analysis of selective

serotonin reuptake inhibitor- and imipramine-controlled

trials. Journal of Clinical Psychiatry 62, 256–260.

Svenningsson P, Chergui K, Rachleff I, FlajoletM, Zhang X,

El YM, Vaugeois JM, Nomikos GG, Greengard P (2006).

Alterations in 5-HT1B receptor function by p11 in

depression-like states. Science 311, 77–80.

Svestka J, Rysanek R, Ceskova E (1990). Sodium valproate in

the treatment of endogenous depression. Activitas Nervosa

Superior 32, 231–232.

Szanto K,Mulsant BH, Houck P, DewMA, Reynolds CF, III

(2003). Occurrence and course of suicidality during short-

term treatment of late-life depression. Archives of General


Szegedi A, Kohnen R, Dienel A, Kieser M (2005). Acute

treatment of moderate to severe depression with

hypericum extract WS 5570 (St John’s wort) : randomised

controlled double blind non-inferiority trial versus

paroxetine. British Medical Journal 330, 503.

Szegedi A, Muller MJ, Anghelescu I, Klawe C, Kohnen R,

Benkert O (2003). Early improvement under mirtazapine

and paroxetine predicts later stable response and

remission with high sensitivity in patients with major

depression. Journal of Clinical Psychiatry 64, 413–420.

Szegedi A, Schwertfeger N (2005). Mirtazapine : a review of

its clinical efficacy and tolerability. Expert Opinion on


Szuba MP, Baxter LR, Altshuler LL, Allen EM, Guze BH,

Schwartz JM, Liston EH (1994). Lithium sustains the acute

antidepressant effects of sleep deprivation : preliminary

findings from a controlled study. Psychiatry Research 51,

283–295.

TADS study group (2003). The Treatment for Adolescents

With Depression Study (TADS) : rationale, design, and

methods. Journal of the American Academy of Child and

Adolescent Psychiatry 42, 531–542.

TADS study group (2005). The Treatment for Adolescents

With Depression Study (TADS) : demographic and clinical

characteristics. Journal of the American Academy of Child

and Adolescent Psychiatry 44, 28–40.

Taleb M, Rouillon F, Hegerl U, Hamdani N, Gorwood P

(2006). Programmes against depression. Encephale 32, 9–15.

Tamminga CA, Nemeroff CB, Blakely RD, Brady L, Carter

CS, Davis KL, Dingledine R, Gorman JM, Grigoriadis

DE, Henderson DC, Innis RB, Killen J, Laughren TP,

McDonald WM, Murphy GMJ, Paul SM, Rudorfer MV,

Sausville E, Schatzberg AF, Scolnick EM, Suppes T

(2002). Developing novel treatments for mood disorders :

accelerating discovery. Biological Psychiatry 52, 589–609.

Tardiff K, Marzuk PM, Leon AC (2002). Role of

antidepressants in murder and suicide. American Journal of

Psychiatry 159, 1248–1249.

Tatsumi M, Groshan K, Blakely RD, Richelson E (1997).

Pharmacological profile of antidepressants and related

compounds at human monoamine transporters. Eur. J.

Pharmacol. 340, 249–258.

Taylor CB, Youngblood ME, Catellier D, Veith RC, Carney

RM, Burg MM, Kaufmann PG, Shuster J, Mellman T,

Blumenthal JA, Krishnan R, Jaffe AS (2005). Effects of

antidepressant medication on morbidity and mortality in

depressed patients after myocardial infarction. Archives of


Taylor DP, Carter RB, Eison AS, Mullins UL, Smith HL,

Torrente JR, Wright RN, Yocca FD (1995). Pharmacology

and neurochemistry of nefazodone, a novel antidepressant

drug. Journal of Clinical Psychiatry 56 (Suppl. 6), 3–11.

Taylor MA, Fink M (2003). Catatonia in psychiatric

classification : a home of its own. American Journal of

Psychiatry 160, 1233–1241.

Tayor MA, Fink M (2006). Melancholia : The Diagnosis,

Pathophysiology and Treatment of Depressive Illness.

Cambridge : Cambridge University Press.

Taylor MJ, Freemantle N, Geddes JR, Bhagwagar Z

(2006). Early onset of selective serotonin reuptake

inhibitor antidepressant action : systematic review

and meta-analysis. Archives of General Psychiatry 63,

1217–1223.


Teicher MH, Glod C, Cole JO (1990). Emergence of intense

suicidal preoccupation during fluoxetine treatment.


Terman M, Terman JS (1999). Bright light therapy: side

effects and benefits across the symptom spectrum. Journal


Terman M, Terman JS (2005). Light therapy for seasonal and

nonseasonal depression: efficacy, protocol, safety, and side

effects. CNS Spectrums 10, 647–663.

Terman M, Terman JS, Rafferty B (1990). Experimental

design and measures of success in the treatment of winter

depression by bright light. Psychopharmacology Bulletin 26,

505–510.

Terra JL, Montgomery SA (1998) Fluvoxamine prevents

recurrence of depression: results of a long-term, double-

blind, placebo-controlled study. International Clinical


Thakore JH, Dinan TG (1995). Cortisol synthesis inhibition :

a new treatment strategy for the clinical and endocrine

manifestations of depression. Biological Psychiatry 37,

364–368.

Tharyan P (2000). Electroconvulsive therapy for

schizophrenia. Cochrane Database of Systematic Reviews.

CD000076.

Tharyan P, Adams CE (2005). Electroconvulsive therapy for

schizophrenia. Cochrane Database of Systematic Reviews.

CD000076.

Thase ME (1999a). Antidepressant treatment of the

depressed patient with insomnia. Journal of Clinical


Thase ME (1999b). Redefining antidepressant efficacy

toward long-term recovery. Journal of Clinical Psychiatry

60 (Suppl. 6), 15–19.

Thase ME (2003). Evaluating antidepressant therapies :

remission as the optimal outcome. Journal of Clinical


Thase ME (2004). Comparing the efficacy of the newer

antidepressants. In : Gilaberte I (Ed.), Nuevas Perspectivas

En La Depresion (pp. 253–284). Madrid : Aula Medica

Endiciones.

Thase ME (2005). Bipolar depression : issues in diagnosis and

treatment. Harvard Review of Psychiatry 13, 257–271.

Thase ME (2006). Managing depressive and anxiety

disorders with escitalopram. Expert Opinion on


Thase ME, Baker RA, Simmons JH, Van Willigenburg AP,

Schutte AJ (2006a). Effects of mirtazapine versus SSRIs

on core symptoms of depression. Journal of Affective

Disorders 91, S83.

Thase ME, Entsuah AR, Rudolph RL (2001). Remission rates

during treatment with venlafaxine or selective serotonin

reuptake inhibitors. British Journal of Psychiatry 178,

234–241.

Thase ME, Greenhouse JB, Frank E, Reynolds CF, III,

Pilkonis PA, Hurley K, Grochocinski V, Kupfer DJ

(1997). Treatment of major depression with psychotherapy

or psychotherapy-pharmacotherapy combinations.


Thase ME, Mallinger AG, McKnight D, Himmelhoch JM

(1992). Treatment of imipramine-resistant recurrent

depression, IV : A double-blind crossover study of

tranylcypromine for anergic bipolar depression. American


Thase ME, Ninan PT (2002). New goals in the treatment

of depression : moving toward recovery.

Psychopharmacology Bulletin 36 (Suppl. 2), 24–35.

Thase ME, Rush AJ (1997). When at first you don’t succeed:

sequential strategies for antidepressant nonresponders.


Thase ME, Shelton RC, Khan A (2006b). Treatment with

venlafaxine extended release after SSRI nonresponse or

intolerance : a randomized comparison of standard- and

higher-dosing strategies. Journal of Clinical


Thase ME, Trivedi MH, Rush AJ (1995). MAOIs in the

contemporary treatment of depression.


The European Agency for the Evaluation of Medicinal

Products (2002). Evaluation of Medicines for Human Use

(http://www.emea.europa.eu/pdfs/human/ewp/

051897en.pdf). Accessed 2 November 2007.

Thiels C, Linden M, Grieger F, Leonard J (2005). Gender

differences in routine treatment of depressed outpatients

with the selective serotonin reuptake inhibitor sertraline.


Thomas CM, Morris S (2003). Cost of depression among

adults in England in 2000. British Journal of Psychiatry 183,

514–519.

Thomas CS, ReadDA (1990). Mianserin, agranulocytosis and

suicide. Lancet 336, 1511.

Thompson C, Kinmonth AL, Stevens L, Peveler RC,

Stevens A, Ostler KJ, Pickering RM, Baker NG,

Henson A, Preece J, Cooper D, Campbell MJ (2000).

Effects of a clinical-practice guideline and practice-based

education on detection and outcome of depression in

primary care : Hampshire Depression Project randomised

controlled trial. Lancet 355, 185–191.

Thompson SG (1994). Why sources of heterogeneity in

meta-analysis should be investigated. British Medical

Journal 309, 1351–1355.

Tollefson GD, Bosomworth JC, Heiligenstein JH, Potvin

JH, Holman S (1995). A double-blind, placebo-controlled

clinical trial of fluoxetine in geriatric patients with major

depression. The Fluoxetine Collaborative Study Group.

International Psychogeriatrics 7, 89–104.

Tossani E, Cassano P, Fava M (2005). Depression and renal

disease. Seminars in Dialysis 18, 73–81.

Tran PV, Bymaster FP, McNamara RK, Potter WZ (2003).

Dual monoamine modulation for improved treatment of

major depressive disorder. Journal of Clinical


Trautmann-Sponsel RD, Dienel A (2004). Safety of

Hypericum extract in mildly to moderately depressed

outpatients : a review based on data from three

randomized, placebo-controlled trials. Journal of Affective



Trenque T, Piednoir D, Frances C, Millart H, Germain ML

(2002). Reports of withdrawal syndrome with the use of

SSRIs : a case/non-case study in the French

Pharmacovigilance database. Pharmacoepidemiology and


Trescoli-Serrano C, Smith NK (1996). Sertraline-induced

agranulocytosis. Postgraduate Medical Journal 72, 446.

Trindade E, MenonD, Topfer LA, Coloma C (1998). Adverse

effects associated with selective serotonin reuptake

inhibitors and tricyclic antidepressants : a meta-analysis.

CMAJ. 159, 1245–1252.

Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F,

Warden D, Ritz L, Nierenberg AA, Lebowitz BD, Biggs

MM, Luther JF, Shores-Wilson K, Rush AJ (2006a).

Medication augmentation after the failure of SSRIs

for depression. New England Journal of Medicine 354,

1243–1252.

Trivedi MH, Greer TL, Grannemann BD, Chambliss HO,

Jordan AN (2006b). Exercise as an augmentation strategy

for treatment of major depression. Journal of Psychiatric

Practice 12, 205–213.

Trivedi MH, Greer TL, Grannemann BD, Church TS,

Galper DI, Sunderajan P, Wisniewski SR, Chambliss

HO, Jordan AN, Finley C, Carmody TI (2006c). TREAD:

TReatment with Exercise Augmentation for Depression:

study rationale and design. Clinical Trials 3, 291–305.

Trivedi MH, Rush AJ, Crismon ML, Kashner TM, Toprac

MG, Carmody TJ, Key T, Biggs MM, Shores-Wilson K,

Witte B, Suppes T, Miller AL, Altshuler KZ, Shon SP

(2004). Clinical results for patients with major depressive

disorder in the Texas Medication Algorithm Project.


Tuma S, Strubbe JJ, Mocaer E, Koolhaas JM (2002). S20098

affects the free-running rhythms of body temperature and

activity and decreases light-induced phase delay of

circadian rhythms of the rat. Chronobiology International 18,

781–799.

Tuunainen A, Kripke DF, Endo T (2004). Light therapy for

non-seasonal depression. Cochrane Database of Systematic

Reviews. CD004050.

Tylee A (2006). Identifying and managing depression in

primary care in the United kingdom. Journal of Clinical


Tzimas GN, Dion B, Deschenes M (2003). Early onset,

nefazodone-induced fulminant hepatic failure. American

Journal of Gastroenterology 98, 1663–1664.

Uchida H, Takeuchi H, Suzuki T, Nomura K, Watanabe K,

Kashima H (2005). Combined treatment with sulpiride

and paroxetine for accelerated response in patients with

major depressive disorder. Journal of Clinical


Uebelhack R, Gruenwald J, Graubaum HJ, Busch R (2004).

Efficacy and tolerability of Hypericum extract STW 3-VI in

patients with moderate depression: a double-blind,

randomized, placebo-controlled clinical trial. Advances in

Therapy 21, 265–275.

Uhr M, Grauer MT (2003). abcb1ab P-glycoprotein is

involved in the uptake of citalopram and trimipramine

into the brain of mice. Journal of Psychiatric Research 37,

179–185.

Uhr M, Steckler T, Yassouridis A, Holsboer F (2000).

Penetration of amitriptyline, but not of fluoxetine, into

brain is enhanced in mice with blood-brain barrier

deficiency due to Mdr1a P-glycoprotein gene disruption.


Ural AU, Avcu F, Gokcil Z, Nevruz O, Cetin T (2005).

Leucopenia and thrombocytopenia possibly associated

with lamotrigine use in a patient. Epileptic Disorders 7,

33–35.

US Food and Drug Administration (2006). Applications for

FDA Approval to Market a new Drug (http://

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/

CFRSearch.cfm?fr=314.126). Accessed 2 November 2007.

US Food and Drug Administration (2007). FDA Proposes

New Warnings About Suicidal Thinking, Behavior in

Young Adults Who Take Antidepressant Medications

(http://www.fda.gov/bbs/topics/NEWS/2007/

NEW01624.html). Accessed 9 June 2007.

US Food and Drug Administration (2005). Templates for

Antidepressant Black Box Warning and Medication Guide

Posted on FDA Website, February 3, 2005.

US Preventive Services Task Force AfHRaQ (2002).

Screening for depression : recommendations and rationale.

Annals of Internal Medicine 136, 760–764.

Ustun TB, Sartorius N (1995). Mental Illness in General Health

Care : An International Study. Chichester, United Kingdom:

John Wiley.

Vaidya VA, Siuciak JA, Du F, Duman RS (1999).

Hippocampal mossy fiber sprouting induced by

chronic electroconvulsive seizures. Neuroscience 89,

157–166.

Valenstein M, Taylor KK, Austin K, Kales HC, McCarthy

JF, Blow FC (2004). Benzodiazepine use among depressed

patients treated in mental health settings. American Journal


Valuck RJ, Libby AM, Sills MR, Giese AA, Allen RR (2004).

Antidepressant treatment and risk of suicide attempt

by adolescents with major depressive disorder : a

propensity-adjusted retrospective cohort study. CNSDrugs

18, 1119–1132.

van Amerongen AP, Ferrey G, Tournoux A (2002). A

randomised, double-blind comparison of milnacipran and

imipramine in the treatment of depression. Journal of


van Baardewijk M, Vis PM, Einarson TR (2005). Cost

effectiveness of duloxetine compared with venlafaxine-XR

in the treatment of major depressive disorder. Current

Medical Research and Opinion 21, 1271–1279.

van Balkom AJ, Bakker A, Spinhoven P, Blaauw BM,

Smeenk S, Ruesink B (1997). A meta-analysis of the

treatment of panic disorder with or without agoraphobia : a

comparison of psychopharmacological, cognitive-

behavioral, and combination treatments. Journal of Nervous

and Mental Disease 185, 510–516.

van Calker D, Berger M (2000). Affektive Erkrankungen.

Richtlinienentwurf Der DGPPN. Darmstadt : Steinkopff.


van den Broek WW (2005). [The practice guideline

‘Depressive disorder’ (first revision) from the Dutch

College of General Practitioners ; a response from the

perspective of psychiatry]. Nederlands Tijdschrift Voor

Geneeskunde 149, 509–510.

van Heeringen K, Zivkov M (1996). Pharmacological

treatment of depression in cancer patients. A placebo-

controlled study of mianserin. British Journal of Psychiatry

169, 440–443.

van Laar MW, Volkerts ER, Van Willigenburg AP (1992).

Therapeutic effects and effects on actual driving

performance of chronically administered buspirone and

diazepam in anxious outpatients. Journal of Clinical


van Laar MW, van Willigenburg AP, Volkerts ER (1995).

Acute and subchronic effects of nefazodone and

imipramine on highway driving, cognitive functions,

and daytime sleepiness in healthy adult and

elderly subjects. Journal of Clinical Psychopharmacology 15,

30–40.

van Laar MW, Volkerts ER (1998). Driving and

benzodiazepine use – Evidence that they do not mix. CNS

Drugs 10, 383–396.

van Moffaert M, de Wilde J, Vereecken A, Dierick M,

Evrard JL, Wilmotte J, Mendlewicz J (1995). Mirtazapine

is more effective than trazodone : a double-blind controlled

study in hospitalized patients with major depression.


van Os TW, Ormel J, Van den Brink RH, Jenner JA, Van der

Meer K, Tiemens BG, van der Doorn W, Smit A, van den

Brink W (1999). Training primary care physicians

improves the management of depression. General Hospital


van Os TW, Van den Brink RH, Van der Meer K, Ormel J

(2006). The care provided by general practitioners for

persistent depression. European Psychiatry 21, 87–92.

van Reeth O, Olivares E, Zhang Y, Tripathi B, Turek FW

(1999). Chronobiotic effects of gepirone, a potential

antidepressant with 5HT1A receptor partial agonist

properties. Behavioural Pharmacology 10, 119–130.

van Waarde JA, Stek ML (2001). [Electroconvulsive

therapy effective and safe in 55 patients aged 56 years

and older with mood disorders and physical comorbidity].

Nederlands Tijdschrift Voor Geneeskunde 145, 1693–1697.

Vandel P, Regina W, Bonin B, Sechter D, Bizouard P

(1999). [Abuse of tianeptine. A case report]. Encephale 25,

672–673.

Varney NR, GarveyMJ, Cook BL, Campbell DA, Roberts RJ

(1993). Identification of treatment-resistant depressives

who respond favorably to carbamazepine. Annals of


Veldhuijzen DS, van Wijck AJ, Verster JC, Kalkman CJ,

Kenemans JL, Olivier B, Volkerts ER (2006). The impact

of chronic pain patients’ psychotropic drug knowledge

and warning labels on the decision whether to drive a car

or not. Traffic Injury Prevention 7, 360–364.

Versiani M, Mehilane L, Gaszner P, Arnaud-Castiglioni R

(1999). Reboxetine, a unique selective NRI, prevents

relapse and recurrence in long-term treatment of major


400–406.

Vesta KS, Medina PJ (2003). Valproic acid-induced

neutropenia. Annals of Pharmacotherapy 37, 819–821.

Vis PM, van Baardewijk M, Einarson TR (2005). Duloxetine

and venlafaxine-XR in the treatment of major depressive

disorder : a meta-analysis of randomized clinical trials.

Annals of Pharmacotherapy 39, 1798–1807.

Visser PJ, Verhey FR, Ponds RW, Kester A, Jolles J (2000).

Distinction between preclinical Alzheimer’s disease and

depression. Journal of the American Geriatrics Society 48,

479–484.

Voderholzer U, Valerius G, Schaerer L, Riemann D, Giedke

H, Schwarzler F, Berger M, Wiegand M (2003). Is the

antidepressive effect of sleep deprivation stabilized by a

three day phase advance of the sleep period? A pilot

study. European Archives of Psychiatry and Clinical


Voellinger R, Berney A, Baumann P, Annoni JM, Bryois C,

Buclin T, Bula C, Camus V, Christin L, Cornuz J, de

Goumoens P, Lamy O, Strnad J, Burnand B, Stiefel F

(2003). Major depressive disorder in the general hospital :

adaptation of clinical practice guidelines. General Hospital


Vohra J, Burrows G, Hunt D, Sloman G (1975). The effect of

toxic and therapeutic doses of tricyclic antidepressant

drugs on intracardiac conduction. European Journal of

Cardiology 3, 219–227.

Vohra J, Burrows GD (1974). Cardiovascular complications

of tricyclic antidepressant overdosage. Drugs 8, 432–437.

Volz HP, Laux P (2000). Potential treatment for subthreshold

and mild depression : a comparison of St. John’s wort

extracts and fluoxetine. Comprehensive Psychiatry 41,

133–137.

Volz HP, Stoll KD (2004). Clinical trials with sigma ligands.

Pharmacopsychiatry 37 (Suppl. 3), S214–S220.

von Knorring AL, Olsson GI, Thomsen PH, Lemming OM,

Hulten A (2006). A randomized, double-blind, placebo-

controlled study of citalopram in adolescents with major

depressive disorder. Journal of Clinical Psychopharmacology

26, 311–315.

von Korff M, Katon W, Bush T, Lin EH, Simon GE,

Saunders K, Ludman E, Walker E, Unutzer J (1998).

Treatment costs, cost offset, and cost-effectiveness of

collaborative management of depression. Psychosomatic

Medicine 60, 143–149.

Vovin RI, Fakturovich AI (1985). [Sleep deprivation as a

method of treating endogenous depression]. Zhurnal

Nevropatologii i Psikhiatrii Imeni S. S. Korsakova 85, 560–565.

Wade AG (2006). Closing the antidepressant efficacy gap

between clinical trials and real patient populations.

International Journal of Psychiatry in Clinical Practice 10,

25–31.

Wade AG, Toumi I, Hemels ME (2005a). A

pharmacoeconomic evaluation of escitalopram versus

citalopram in the treatment of severe depression in the

United Kingdom. Clinical Therapeutics 27, 486–496.


Wade AG, Toumi I, HemelsME (2005b). A probabilistic cost-

effectiveness analysis of escitalopram, generic citalopram

and venlafaxine as a first-line treatment of major

depressive disorder in the UK. Current Medical Research and

Opinion 21, 631–642.

Wagner KD, Ambrosini P, Rynn M, Wohlberg C, Yang R,

GreenbaumMS, Childress A, Donnelly C, Deas D (2003).

Efficacy of sertraline in the treatment of children and

adolescents with major depressive disorder : two

randomized controlled trials. Journal of the American


Wagner KD, Jonas J, Findling RL, Ventura D, Saikali K

(2006). A double-blind, randomized, placebo-controlled

trial of escitalopram in the treatment of pediatric

depression. Journal of the American Academy of Child and

Adolescent Psychiatry 45, 280–288.

Wagner KD, Robb AS, Findling RL, Jin J, Gutierrez MM,

Heydorn WE (2004). A randomized, placebo-controlled

trial of citalopram for the treatment of major depression in

children and adolescents. American Journal of Psychiatry

161, 1079–1083.

Waldinger MD, Hengeveld MW, Zwinderman AH, Olivier

B (1998). Effect of SSRI antidepressants on ejaculation: a

double-blind, randomized, placebo-controlled study with

fluoxetine, fluvoxamine, paroxetine, and sertraline. Journal

of Clinical Psychopharmacology 18, 274–281.

Walker R, Swartz CM (1994). Electroconvulsive therapy

during high-risk pregnancy. General Hospital Psychiatry 16,

348–353.

Wallace AE, Neily J, Weeks WB, Friedman MJ (2006). A

cumulative meta-analysis of selective serotonin reuptake

inhibitors in pediatric depression: did unpublished studies

influence the efficacy/safety debate? Journal of Child and

Adolescent Psychopharmacology 16, 37–58.

Wang PS, Schneeweiss S, Brookhart MA, Glynn RJ, Mogun

H, Patrick AR, Avorn J (2005). Suboptimal antidepressant

use in the elderly. Journal of Clinical Psychopharmacology 25,

118–126.

Ware MR (1997). Fluvoxamine : a review of the controlled

trials in depression. Journal of Clinical Psychiatry 58

(Suppl. 5), 15–23.

Warneke L (1993). Managing resistant depression. When

patients do not respond to therapy. Canadian Family

Physician 39, 843–850.

Warner CH, Bobo W, Warner C, Reid S, Rachal J (2006).

Antidepressant discontinuation syndrome. American

Family Physician 74, 449–456.

Warrington SJ (1991). Clinical implications of the

pharmacology of sertraline. International Clinical

Psychopharmacology 6 (Suppl. 2), 11–21.

Wassermann EM (1998). Risk and safety of repetitive

transcranial magnetic stimulation: report and suggested

guidelines from the International Workshop on the Safety

of Repetitive Transcranial Magnetic Stimulation, June 5–7,

1996. Electroencephalography and Clinical Neurophysiology

108, 1–16.

Watanabe A, Hasegawa S, Nishi K, Nguyen KQ, Diksic M

(2006). Chronic buspirone treatment normalizes regional

serotonin synthesis in the olfactory bulbectomized rat

brain : an autoradiographic study. Brain Research Bulletin

69, 101–108.

Wedding U, Koch A, Rohrig B, Pientka L, Sauer H, Hoffken

K, Maurer I (2007). Requestioning depression in patients

with cancer : contribution of somatic and affective

symptoms to Beck’s Depression Inventory. Annals of

Oncology. 5 September 2007 [epub ahead of print].

Ween JE (2005). Prophylactic mirtazapine may help to

prevent post-stroke depression in people with good

cognitive function. Evidence-Based Mental Health 8, 74.

Weihs KL, Settle EC, Batey SR, Houser TL, Donahue RM,

Ascher JA (2000). Bupropion sustained release versus

paroxetine for the treatment of depression in the elderly.


Weinrieb RM, Auriacombe M, Lynch KG, Lewis JD

(2005). Selective serotonin re-uptake inhibitors and

the risk of bleeding. Expert Opinion on Drug Safety 4,

337–344.

Weinstock M (2007). Gender differences in the effects of

prenatal stress on brain development and behaviour.

Neurochemical Research 32, 1730–1740.

Weintraub D, Morales KH, Moberg PJ, Bilker WB,

Balderston C, Duda JE, Katz IR, Stern MB (2005).

Antidepressant studies in Parkinson’s disease : a review

and meta-analysis. Movement Disorders 20, 1161–1169.

Weissman MM, Markowitz JC, Klerman GL (2000).

Comprehensive Guide to Interpersonal Psychotherapy. New

York : Basic Books.

Wells KB, Sherbourne C, Schoenbaum M, Duan N,

Meredith L, Unutzer J, Miranda J, Carney MF,

Rubenstein LV (2000). Impact of disseminating quality

improvement programs for depression in managed

primary care : a randomized controlled trial. Journal of the


Wen SW, Yang Q, Garner P, Fraser W, Olatunbosun O,

Nimrod C, Walker M (2006). Selective serotonin reuptake

inhibitors and adverse pregnancy outcomes. American

Journal of Obstetrics and Gynecology 194, 961–966.

Westermeyer J (1989). Addiction to tranylcypromine

(Parnate) : a case report. American Journal of Drug and

Alcohol Abuse 15, 345–350.

Wharton RN, Perel JM, Dayton PG, Malitz S (1971). A

potential clinical use for methylphenidate with tricyclic

antidepressants. American Journal of Psychiatry 127,

1619–1625.

Wheatley DP, van Moffaert M, Timmerman L, Kremer CM

(1998). Mirtazapine : efficacy and tolerability in comparison

with fluoxetine in patients with moderate to severe major

depressive disorder. Mirtazapine-Fluoxetine Study Group.


White AD, Andrews EB (1999). The Pregnancy Registry

program at Glaxo Wellcome Company. Journal of Allergy

and Clinical Immunology 103, S362–S363.

Whittington CJ, Kendall T, Fonagy P, Cottrell D, Cotgrove

A, Boddington E (2004). Selective serotonin reuptake

inhibitors in childhood depression: systematic review of

published versus unpublished data. Lancet 363, 1341–1345.


Wichers M, Maes M (2002). The psychoneuroimmuno-

pathophysiology of cytokine-induced depression in

humans. International Journal of Neuropsychopharmacology 5,

375–388.

Wilcox CS, Ferguson JM, Dale JL, Heiser JF (1996). A

double-blind trial of low- and high-dose ranges of

gepirone-ER compared with placebo in the treatment of

depressed outpatients. Psychopharmacology Bulletin 32,

335–342.

Wilde MI, Benfield P (1995). Tianeptine. A review of its

pharmacodynamic and pharmacokinetic properties, and

therapeutic efficacy in depression and coexisting anxiety

and depression. Drugs 49, 411–439.

Wilkinson GR (2005). Drug metabolism and variability

among patients in drug response. New England Journal of

Medicine 352, 2211–2221.

Willner P (1990). Animal models of depression: an overview.

Pharmacology & Therapeutics 45, 425–455.

Wilson K, Mottram P (2004). A comparison of side effects

of selective serotonin reuptake inhibitors and tricyclic

antidepressants in older depressed patients : a

meta-analysis. International Journal of Geriatric Psychiatry 19,

754–762.

Wilson KC, Mottram PG, Ashworth L, Abou-Saleh MT

(2003). Older community residents with depression :

long-term treatment with sertraline. Randomised,

double-blind, placebo-controlled study. British Journal of


Wilson K, Mottram P, Sivanranthan A, Nightingale A

(2001). Antidepressant versus placebo for depressed

elderly. Cochrane Database of Systematic Reviews.

CD000561.

Wingen M, Bothmer J, Langer S, Ramaekers JG (2005).

Actual driving performance and psychomotor function in

healthy subjects after acute and subchronic treatment with

escitalopram, mirtazapine, and placebo : a crossover trial.


Wingen M, Ramaekers JG, Schmitt JA (2006). Driving

impairment in depressed patients receiving long-term

antidepressant treatment. Psychopharmacology 188, 84–91.

Winkler D, Pjrek E, Kasper S (2005a). Anger attacks in

depression – evidence for a male depressive syndrome.


Winkler D, Pjrek E, Praschak-Rieder N, Willeit M, Pezawas

L, Konstantinidis A, Stastny J, Kasper S (2005b).

Actigraphy in patients with seasonal affective disorder and

healthy control subjects treated with light therapy.


Wirz-Justice A, Benedetti F, Berger M, Lam RW, Martiny K,

Terman M, Wu JC (2005). Chronotherapeutics (light and

wake therapy) in affective disorders. Psychological Medicine

35, 939–944.

Wirz-Justice A, Graw P, Krauchi K, Sarrafzadeh A, English

J, Arendt J, Sand L (1996). ‘Natural’ light treatment of

seasonal affective disorder. Journal of Affective Disorders 37,

109–120.

Wisner KL, Gelenberg AJ, Leonard H, Zarin D, Frank E

(1999). Pharmacologic treatment of depression during

pregnancy. Journal of the American Medical Association 282,

1264–1269.

Wisner KL, Zarin DA, Holmboe ES, Appelbaum PS,

Gelenberg AJ, Leonard HL, Frank E (2000). Risk-benefit

decision making for treatment of depression during

pregnancy. American Journal of Psychiatry 157, 1933–1940.

Witkin JM, Marek GJ, Johnson BG, Schoepp DD (2007).

Metabotropic glutamate receptors in the control of mood

disorders. CNS & Neurological Disorders – Drug Targets 6,

87–100.

Wittchen HU (1994). Reliability and validity studies of the

WHO – Composite International Diagnostic Interview

(CIDI) : a critical review. Journal of Psychiatric Research 28,

57–84.

Wittchen HU, Knauper B, Kessler RC (1994). Lifetime risk of

depression. British Journal of Psychiatry (Suppl.) 16–22.

Wittchen HU, Pittrow D (2002). Prevalence, recognition and

management of depression in primary care in Germany:

the Depression 2000 study. Human Psychopharmacology 17

(Suppl. 1), S1–11.

Woelk H (2000). Comparison of St John’s wort and

imipramine for treating depression: randomised

controlled trial. British Medical Journal 321, 536–539.

Wohlfarth T, Storosum JG, Elferink AJ, van Zwieten BJ,

Fouwels A, van den Brink W (2004). Response to tricyclic

antidepressants : independent of gender? American Journal


Wohlfarth TD, van Zwieten BJ, Lekkerkerker FJ, Gispen-de

Wied CC, Ruis JR, Elferink AJ, Storosum JG (2006).

Antidepressants use in children and adolescents and the

risk of suicide. European Neuropsychopharmacology 16,

79–83.

Wohlreich MM, Mallinckrodt CH, Watkin JG, Wilson MG,

Greist JH, Delgado PL, Fava M (2005a). Immediate

switching of antidepressant therapy: results from a

clinical trial of duloxetine. Annals of Clinical Psychiatry 17,

259–268.

Wohlreich MM,Martinez JM, Mallinckrodt CH, Prakash A,

Watkin JG, Fava M (2005b). An open-label study of

duloxetine for the treatment of major depressive disorder :

comparison of switching versus initiating treatment

approaches. Journal of Clinical Psychopharmacology 25,

552–560.

Wolfe SM, Sasich LD, Lurie P, Hope RE, Barbehenn E,

Knapp DE, Ardati A, Shubin S, Ku DB (2005).Worst Pills,

Best Pills. A Consumer’s Guide to Avoiding Drug-Induced

Death or Illness. New York, London, Toronto, Sydney :

Public Citizen Foundation and Public Citizen’s Health

Research Group.

Wolkowitz OM, Reus VI, Chan T, Manfredi F, Raum W,

Johnson R, Canick J (1999a). Antiglucocorticoid treatment

of depression : double-blind ketoconazole. Biological


Wolkowitz OM, Reus VI, Keebler A, Nelson N, Friedland

M, Brizendine L, Roberts E (1999b). Double-blind

treatment of major depression with

dehydroepiandrosterone. American Journal of Psychiatry

156, 646–649.


Wolkowitz OM, Reus VI, Manfredi F, Ingbar J, Brizendine

L, Weingartner H (1993). Ketoconazole administration in

hypercortisolemic depression. American Journal of


Wolkowitz OM, Reus VI, Roberts E, Manfredi F, Chan T,

Raum WJ, Ormiston S, Johnson R, Canick J, Brizendine

L, Weingartner H (1997). Dehydroepiandrosterone

(DHEA) treatment of depression. Biological Psychiatry 41,

311–318.

Wong AH, Smith M, Boon HS (1998). Herbal remedies in

psychiatric practice. Archives of General Psychiatry 55,

1033–1044.

Wong ML, Licinio J (2004). From monoamines to genomic

targets : a paradigm shift for drug discovery in depression.

Nature Reviews. Drug Discovery 3, 136–151.

Woods SW, Rizzo JA (1997). Cost-effectiveness of

antidepressant treatment reassessed. British Journal of


Workman EA, Short DD (1993). Atypical antidepressants

versus imipramine in the treatment of major depression: a

meta-analysis. Journal of Clinical Psychiatry 54, 5–12.

World Health Organization (1992). The ICD-10 Classification

of Mental and Behavioural Disorders : Clinical Descriptions and

Diagnostic Guidelines. Geneva, Switzerland.

World Health Organization (2001). Conquering Depression.

(http://www.searo.who.int/en/Section1174/

Section1199/Section1567/Section1826_8096.htm).

Accessed 1 November 2006.

World Health Organization (2002). The Global Burden of

Disease Project (www.who.int). Accessed 30 January 2007.

World Health Organization (2005a). WHO Model List of

Essential Medicines (http://www.who.int/medicines/

publications/essentialmedicines/en.). Accessed 14

November 2006.

World Health Organization (2005b). WHO Report on Mental

Health : Depression (http://www.who.int/mental_health/

management/depression/definition/en/). Accessed 14

November 2006.

World Health Organization (2005c). WHO Resource Book on

Mental Health, Human Rights and Legislation. Geneva :

WHO.

World Psychiatric Association (2006). WPA Educational

Program on Depressive Disorder – Module 2 (Depressive

Disorders in Physical Illness) (http://www.wpanet.org/

sectorial/edu4a.html). Accessed 30 July 2006.

Wu JC, Bunney WE (1990). The biological basis of an

antidepressant response to sleep deprivation and relapse :

review and hypothesis. American Journal of Psychiatry 147,

14–21.

Wulsin LR, Singal BM (2003). Do depressive symptoms

increase the risk for the onset of coronary disease? A

systematic quantitative review. Psychosomatic Medicine 65,

201–210.

Xia Z, DePierre JW, Nassberger L (1996). Tricyclic

antidepressants inhibit IL-6, IL-1 beta and TNF-alpha

release in human blood monocytes and IL-2 and

interferon-gamma in T cells. Immunopharmacology 34,

27–37.

Yamada K, Kanba S (2002). Herbal medicine

(kami-shoyo-san) in the treatment of premenstrual

dysphoric disorder. Journal of Clinical Psychopharmacology

22, 442.

Yamada K, Yagi G, Kanba S (2003a). Clinical efficacy of

tandospirone augmentation in patients with major

depressive disorder : a randomized controlled trial.

Psychiatry and Clinical Neurosciences 57, 183–187.

Yamada K, Yagi G, Kanba S (2003b). Effectiveness of Gorei-

san (TJ-17) for treatment of SSRI-induced nausea and

dyspepsia : preliminary observations. Clinical


Yamada K, Yagi G, Kanba S (2005). Effectiveness of herbal

medicine (Rokumigan and Hachimijiogan) for fatigue or

loss of energy in patients with partial remitted major

depressive disorder. Psychiatry and Clinical Neurosciences

59, 610–612.

Yang X, Liu X, Luo H, Jia Y (1994). Clinical observation on

needling extrachannel points in treating mental

depression. Journal of Traditional Chinese Medicine 14, 14–18.

Yatham LN (2005). Atypical antipsychotics for bipolar

disorder. Psychiatric Clinics of North America 28, 325–347.

Yerevanian BI, Koek RJ, Feusner JD, Hwang S, Mintz J

(2004). Antidepressants and suicidal behaviour in unipolar

depression. Acta Psychiatrica Scandinavica 110, 452–458.

Yonkers KA, Brawman-Mintzer O (2002). The

pharmacologic treatment of depression: is gender a critical

factor? Journal of Clinical Psychiatry 63, 610–615.

Yous S, Andrieux J, Howell HE, Morgan PJ, Renard P,

Pfeiffer B, Lesieur D, Guardiola-Lemaitre B (1992). Novel

naphthalenic ligands with high affinity for the melatonin

receptor. Journal of Medicinal Chemistry 35, 1484–1486.

Zanardi R, Franchini L, Gasperini M, Perez J, Smeraldi E

(1996). Double-blind controlled trial of sertraline versus

paroxetine in the treatment of delusional depression.


Zanardi R, Franchini L, Gasperini M, Smeraldi E, Perez J

(1997). Long-term treatment of psychotic (delusional)

depression with fluvoxamine : an open pilot study.


Zanardi R, Serretti A, Rossini D, Franchini L, Cusin C,

Lattuada E, Dotoli D, Smeraldi E (2001). Factors affecting

fluvoxamine antidepressant activity : influence of pindolol

and 5-HTTLPR in delusional and nondelusional

depression. Biological Psychiatry 50, 323–330.

Zanardi R, Smeraldi E (2005). A double-blind, randomised,

controlled clinical trial of acetyl-l-carnitine vs. amisulpride

in the treatment of dysthymia. European


Zapletalek M, Zbytovsky J, Kudrnova K (1982). Clinical

experience with maprotilin and maprotilin/clomipramine

infusions in resistant depression. Activitas Nervosa Superior

24, 73–76.

Zarate CA, Singh JB, Carlson PJ, Brutsche NE, Ameli R,

Luckenbaugh DA, Charney DS, Manji HK (2006). A

randomized trial of an N-methyl-D-aspartate antagonist in

treatment-resistant major depression. Archives of General



Zarate CA, TohenM, Baraibar G (1997). Combined valproate

or carbamazepine and electroconvulsive therapy.

Annals of Clinical Psychiatry 9, 19–25.

Zhang W, Perry KW, Wong DT, Potts BD, Bao J, Tollefson

GD, Bymaster FP (2000). Synergistic effects of olanzapine

and other antipsychotic agents in combination with

fluoxetine on norepinephrine and dopamine release

in rat prefrontal cortex. Neuropsychopharmacology 23,

250–262.

Zhang ZQ, Yuan L, Yang M, Luo ZP, Zhao YM (2002). The

effect of Morinda officinalis How, a Chinese traditional

medicinal plant, on the DRL 72-s schedule in rats and the

forced swimming test in mice. Pharmacology, Biochemistry

and Behavior 72, 39–43.

Zhou D, Grecksch G, Becker A, Frank C, Pilz J, Huether G

(1998). Serotonergic hyperinnervation of the frontal cortex

in an animal model of depression, the bulbectomized rat.

Journal of Neuroscience Research 54, 109–116.

Zimmerman M, McGlinchey JB, Posternak MA,

Friedman M, Attiullah N, Boerescu D (2006). How

should remission from depression be defined? The

depressed patient’s perspective. American Journal of


Zobel AW, Nickel T, Kunzel HE, Ackl N, Sonntag A,

Ising M, Holsboer F (2000). Effects of the high-affinity

corticotropin-releasing hormone receptor 1 antagonist

R121919 in major depression: the first 20 patients treated.

Journal of Psychiatric Research 34, 171–181.

Zobel AW, Yassouridis A, Frieboes R-M, Holsboer F (1999).

Prediction of medium-term outcome by cortisol response

to the combined dexamethasone-CRH test in patients with

remitted depression. American Journal of Psychiatry 156,

949–951.

Zourkova A, Hadasova E (2003). Paroxetine-induced

conversion of cytochrome P450 2D6 phenotype and

occurence of adverse effects. General Physiology &

Biophysics 22, 103–113.

Zullino D, Baumann P (2001). Lithium augmentation in

depressive patients not responding to selective serotonin

reuptake inhibitors. Pharmacopsychiatry 34, 119–127.

19 Annexes

19.1 Annex 1 : Opinions and suggestions that

could not be fully accommodated in the review

The Task Force and the editors have carefully con-

sidered the comments and suggestions made by the

Advisory Group, participants in meetings and by

experts consulted on specific issues. Most of the

comments and suggestions could be accommodated

by changes or additions to the text. There were, how-

ever, some views that could not be fully reflected in

the review. They are listed below, in alphabetical order

by author.

Max Fink suggested not publishing an annex con-

taining information about psychotherapy within the

CINP review because of insufficient scientific evidence

about the effectiveness of several forms of psycho-

therapy in the treatment of depression. The CINP

antidepressants task force agreed not to publish an

extensive review about the use and usefulness of

psychotherapy in depression because this would be

beyond the scope of a technical review about

antidepressants. Nevertheless, there was broad con-

sensus in the task force and the advisory board that

some psychotherapy forms, e.g. IPT (interpersonal

therapy) and CBT (cognitive behavioral therapy),

represent an important therapeutic option for many

patients suffering fromdepression that should be taken

into consideration in treatment plans together with

antidepressant medication. A short chapter and an

annex about the psychotherapy of depression there-

fore have been included.

Because David Healy has concerns about the

review on principle, the CINP antidepressants Task

Force decided to present his views without abridg-

ment :

HEALY : ‘My principal concern with the report that I have

read lies with the interpretation it puts on clinical trial data.

The report adopts one of several possible interpretations, and

ideally it might have considered how the evidence looks from

a number of different points of view. I think the interpretation

adopted is arguably the least supportable one, and this is of

some consequence as the interpretation of these clinical trials

feeds through to the views adopted as regards the possible

economic benefits of antidepressants and their use in co-

morbid conditions etc.

The report adopts the position that a relatively modest

superiority over placebo in a selected number of clinical trials

means that antidepressants work. While most practicing

clinicians have little doubt that antidepressants can be of

benefit, the RCTs that are appealed to here do not demon-

strate that antidepressants work. For the most part they have

employed samples of convenience and it is not clear how

generalizable the results from these studies might be – parti-

cularly to populations with comorbid physical disorders.

Second, the studies are only a selection of those undertaken ; a

great number of studies demonstrating even less or no su-

periority of the antidepressant compared with placebo have

not been published and accordingly have not been factored

into the claims made here.

The response to this point – that these unpublished studies

will often have involved failed assay systems – does not take

care of the issue in this context. It may be reasonable to appeal

to failed assay systems in a regulatory context, which requires


demonstrations of a treatment signal, but these are not failed

studies in a wider clinical context. Any wider assessment of

what antidepressants might do or their utility needs to take

these negative studies into account.

The greater problem, however, in the approach taken lies

with the apparent willingness to adopt an interpretation

which sees five patients out of ten responding to the anti-

depressant compared with four responding to the placebo,

with the assessment of benefits dependant on rating scale

data only, as evidence that the drugs work. One of several

alternate interpretations of the 50% response to anti-

depressants versus 40% response to placebo in terms of the

therapeutic response in the antidepressant group is that 80%

of the response to the antidepressant comes from non-specific

factors. We are unable to quantify the contribution of the

various non-specific factors involved, while in contrast we

can quantify the specific drug contribution. But this specific

drug contribution is only 20% of the therapeutic response.

One can make the argument that if the money and culture in

psychiatry is to follow the evidence, it should follow the evi-

dence of the 80% rather than the 20%.

This can be put another way. Of every ten people entered

into clinical trials one specifically responds to an anti-

depressant and nine either don’t respond specifically to the

antidepressant or fail to respond at all or respond adversely.

Taking the approach that the authors in this report have taken

privileges the response of one individual against the re-

sponses of nine and this is clearly problematic in terms of a

report that may go to policy makers and others purporting to

be a report that if implemented will lead to benefits.

I think it would be preferable to flag up the preliminary

and provisional nature of the results. They point to the fact

that antidepressants have benefits. They do not indicate that

much science has been done in this area but rather that a great

deal of science remains to be done. We should be attempting

to establish for instance who responds to SSRIs versus who

responds to antidepressants active on other systems.

Selecting out responsive patients would be quite likely to lead

to a much greater difference between the response to active

treatment and response to a placebo. This would bring in

areas like pharmacogenetics and questions about the effects

of specific treatments on different constitutional or person-

ality types rather than simply the effects of these agents on

some disease process.

I think there is a signal failure in the field that we have

permitted 800 odd trials or more to be done and published

and perhaps an equal number to be done and left unpub-

lished, since the first trials on Prozac, all of which essentially

repeat the formula of trying to show a small difference be-

tween active treatment and placebo, without even in a small

proportion of trials moving forward to determining who the

treatment responsive groups of patients might be. This is an

issue on which Tom Ban has written cogently. He has argued,

and I would agree, that we have failed both in terms of

the opportunity offered to advance the science of psycho-

pathology and also in terms of the science of clinical thera-

peutics.

The report bases almost everything on minimal rating scale

changes. In terms of any hard outcomes that these clinical

trials offer, one of the few hard outcomes is the data on sui-

cidal act and completed suicide rates. When these are looked

at, as the expert working group report from the MHRA in

Britain, in 2004, reveals, there is a 2.6-fold increased rate of

completed suicides in adults after treatment compared to

placebo and a 2.4-fold increased rate of completed suicides or

other suicidal acts on active treatment compared to placebo.

These figures should raise questions for someone about the

validity of constructing economic models that depend solely

on rating scale results. Adverse responses such as completed

suicides have not to the best of my knowledge been factored

into the economic modes detailed in this report, but the ad-

verse events from nausea to suicide offer the only hard out-

comes we have. If even a proportion of the adverse responses

were factored in it is doubtful that the economic benefits

claimed could be substantiated.

There are a number of further points to note with this issue

of suicides and suicidal acts that are at odds with the in-

terpretation offered in the report on this specific point. The

report covers the issue of pediatric suicidality primarily.

It makes some mistakes. It claims that there were no sui-

cides in the pediatric trials. In fact there were no known

suicides in the set of pediatric trials submitted for registration

purposes, but a very large number of patients dropped

out because of adverse responses and were not followed

up. It would be more correct to say there were no known

suicides rather than there were no suicides. There were of

course several pediatric suicides in controlled trials of recent

antidepressants. But these occurred in trials other than the

pediatric registration trials to which the report refers. There

have also been published clinical reports from reputable

clinical centers on suicides in children and adolescents dating

back 15 years now.

There are a large number of other substantive issues that

the report essentially left in abeyance – such as the issue of

dependence and withdrawal. Aside from specific issues like

this there were the more general issues that have enveloped

the field recently, referred to by Dr Belmaker, such as in-

creasing difficulties with articles being ghost written, with

conflicts of interest etc., with data selection, data suppression

and data from non-existent patients.

In summary, if the object of this exercise or one likely out-

come of the exercise is to put into the hands of planners re-

sults that will bear the weight of policy, then the report that I

have seen is a dangerous structure that I would have thought

is likely to collapse in the not too distant future with only a

few pillars left standing such as the pillar on ECT. If the re-

port is taken seriously by anyone within the pharmaceutical

industry involved with drug development rather than just

marketing, it will hamper innovative drug development.

CINP can stand back and say in the words of the Tom

Lehrer song that it is not their department to consider what

uses the report might be put to, but I can’t believe that CINP

members with their particular backgrounds would be very

happy for the organization to adopt such an ethical position.’


Some of David Healy’s critiques have been integrated

in the review, e.g. additional chapters about suicid-

ality and antidepressants in adult patients (see chapter

11) and dependence and withdrawal (see chapter

9.1.1.3.2). Some of his concerns have been discussed

more extensively, e.g. the problem of unpublished

studies (see chapter 4.4), the new trends in pharma-

cogenetic research to establish methods for an

individualized antidepressant therapy (see chapter

8.3) and the problem of comorbid physical disorders in

depressed patients (see chapter 5.2.4). Because other

difficult issues such as the existing problem of mis-

conduct in clinical science and subjective evaluation of

study results concerning responder rates in clinical

trials cannot be resolved completely, the CINP anti-

depressants task force decided to report David Healy’s

view in full to empower readers to draw their own

conclusions about these issues.

Ulrich Hegerl suggested changing the structure of

the review and discussing antidepressant medications

before the chapters about diagnosis and epidemiology

because medications are already mentioned within the

description of specific manifestations of depression.

The CINP antidepressants task force decided not to

change the structure of the document based on agree-

ment that it is important to establish treatment plans

after the correct diagnosis of depressive disorders and

concomitant or comorbid diseases.

Florence Thibaut suggested including recommen-

dations for clinicians with the level of evidence at the

end of each chapter. The CINP antidepressants task

force decided to leave out recommendations and to

publish only a review about the usefulness of anti-

depressant medications that will constitute the basis

for treatment recommendations formulated at a

national level.

Wayne Katon suggested not including studies

using modeling techniques in the economics chapter.

He suggested adding other studies and references in

the economics chapter, and he did not agree with the

statement that the comparison of psychotherapy and

medication reveals economic advantages for antide-

pressants. The economics experts within the CINP

antidepressants task force agreed to present the results

of modeling studies together with other kinds of

economic studies, including a subchapter about dif-

ferences in methodologies of economic evaluations.

Because the use and usefulness of psychotherapy was

not the main focus of this review, the CINP anti-

depressants task force agreed not to expand the chap-

ter about psychotherapy.

Markus Kosel suggested adding references

about DBS in the treatment of OCD. The CINP

antidepressants task force agreed not to include such

studies because predominantly the pharmacological

and non-pharmacological treatment of depressive

disorders has been evaluated in the present review.

Min-Soo Lee suggested including specific re-

commendations for pharmacotherapy. The CINP an-

tidepressants task force agreed to to include those

recommendations because they represented un-

referenced treatment schedules. Specific treatment

recommendations will be integrated as mentioned at

a later stage of the project, but not in the current re-

view.

Shigenobu Kanba suggested not mentioning ECT

three times in the review. The CINP antidepressants

task force and the advisory board agreed to mention

ECT in the chapter about combination therapies in

treatment-resistant depression, in a short chapter

about ECT, and in an additional and more extensive

annex about this treatment method, because at present

ECT still represents a very effective treatment method

for severe and treatment-resistant depressive dis-

orders.

19.2 Annex 2 : Additional information on the

types of economic evaluation

19.2.1 Cost-offset studies

The simplest of economic studies are concerned only

with costs, not (usually) because they see outcomes as

irrelevant but because, in relation to the treatments or

services under study, the health and quality of life

outcomes have already been established from other

research, or are (currently) not measurable because of

conceptual difficulties or research funding limitations.

One of these cost-only methods is the cost-offset study,

which compares costs incurred with (other) costs

saved. For instance, a new antidepressant may have

a higher acquisition cost (higher price) compared

with an older drug, but may reduce the need for in-

patient admissions and thus lead to cost savings

downstream.

While a cost-offset study is not an economic

evaluation, and therefore cannot answer the ‘Is it

worth it? ’ question, it nevertheless addresses an issue

that is often fundamental to health system decision

making: Within a fixed or even shrinking budget (at

least in the short run), are treatment changes afford-

able?

19.2.2 Cost-effectiveness analysis

Probably the most intuitive and straightforward

modes of economic evaluation are cost-effectiveness


and cost-consequences analyses. Both types of analysis

measure outcomes using instruments and scales fam-

iliar to clinical researchers. Both are employed to help

decision makers choose between alternative interven-

tions available to or aimed at specific patient groups. A

cost-effectiveness analysis (CEA) looks at a single

outcome dimension – such as the number of life years

saved, the number of depression-free days or the

duration of time in remission – and then computes

and compares the ratio of the difference in costs be-

tween the two treatments being evaluated with the

difference in (primary) outcome (the incremental cost-

effectiveness ratio or ICER).

A common finding is that a new treatment is both

more effective (the outcome profiles are better than

for the older or comparator treatment) and simul-

taneously more expensive. Decision makers therefore

face the challenge of weighing up the outcomes

against the higher expenditure necessary to secure

them. The decision is far from straightforward in these

cases. The widely used cost-effectiveness ‘plane’

(Figure 5) illustrates the range of possible CEA results

and the difficult decision-making task in some cir-

cumstances.

The cost-effectiveness plane in Figure 5 shows the

possible combinations of outcomes and costs when

comparing two interventions or treatments. The point

marked B indicates that the new treatment (say a new

antidepressant drug) is both more effective (it has

better outcomes) and less costly than the old treat-

ment. The task for the decision maker looks quite

straightforward in these circumstances : recommend

wider use of the new treatment. However, many eva-

luations find that new treatment modes produce better

outcomes than older interventions but at a higher cost

(illustrated by point A). The choice facing the decision

maker is now more complex : are the better outcomes

worth the higher costs?

To aid such decision making, economists have de-

veloped cost-utility analysis (see below) and more

recently the net benefit approach, linked to the con-

struction of cost-effectiveness acceptability curves

(CEACs). These show the probability that a new in-

tervention will be reviewed by the decision maker as

cost-effective for each prespecified or implicit valu-

ation of an outcome improvement. Comparisons are

then possible across quite disparate clinical areas

(comparing, for example, depression treatment with

dementia treatment ; or psychiatry with oncology).

This kind of decision context is exactly the one faced

by decision makers one or two steps removed from the

patient interface.

An obvious weakness with the strict cost-

effectiveness methodology is the enforced focus on a

single outcome dimension (in order to compute ratios)

when we know that many people with depression

have multiple needs for support and when most clin-

icians might expect to achieve improvements in

meeting more than one need. Carrying multiple out-

comes forward in an analysis is less tractable analyti-

cally, but three options are available, associated with

three other modes of economic evaluation. One op-

tion – which is cost-consequences analysis – is to retain

all or most outcome dimensions (measured using

standard clinical scales). The other two options weight

the outcomes, either in terms of money (cost-benefit)

or in terms of utility (cost-utility).

A weakness noted earlier is that the comparator in a

trial may not be appropriate, not giving decision ma-

kers the evidence base they need (in their local cir-

cumstances, or more generally).

19.2.3 Cost-utility analysis

An increasingly used evaluative mode that seeks to

reduce outcomes to a single dimension is cost-utility

analysis (CUA), which measures and then values the

impact of an intervention in terms of improvements in

preference-weighted, health-related quality of life. The

value of the quality of life improvement is measured in

units of ‘utility ’, usually expressed by a combined in-

dex of the mortality and quality of life effects of an

intervention. The best-known andmost robust index is

the quality-adjusted life year (QALY). CUAs have a

number of distinct advantages, including using a uni-

dimensional measure of impact, a generic measure

which allows comparisons to be made across diag-

nostic or clinical groups (e.g. comparing psychiatry

with oncology or cardiology), and a fully explicit

methodology for weighting preferences and valuing

health states. But these same features are sometimes

New treatment more costly

New treatment less costly

New treatmentless effective

New treatmentmore effective

New treatmentdominates – moreeffective and less costly

Old treatmentdominates

Trade-off needed:compare costdifference andoutcome difference

Trade-off needed:compare costdifference andoutcome difference

X

X

0

A

B

Figure 5.Cost-effectiveness of antidepressant treatment (from

Woods and Rizzo, 1997).


seen as disadvantages : the utility measure may

be too reductionist, the generic quality of life indi-

cator may be insufficiently sensitive to the kinds

of change expected in depression treatment, and a

transparent approach to scale construction para-

doxically opens the approach to criticism from those

who question the values thereby obtained (Chisholm

et al., 1997).

On the other hand, CUAs avoid the potential ambi-

guities with multidimensional outcomes in cost-

consequences studies and are obviously more general

than the single-outcome CEA. The transparency of

approach is also to be welcomed. The result is an in-

cremental cost-utility ratio for each intervention, rela-

tive to some comparator, which can be compared with

similar ratios for other interventions (potentially from

across the widest diagnostic range, i.e. not just from

mental health). These cost-per-QALY ratios can then

inform health-care resource allocation decisions

or priority setting.

19.2.4 Cost-benefit analysis

Cost-benefit analysis (CBA) asks whether a treatment

or policy is socially worthwhile in the broadest

sense : Do the benefits exceed the costs? This kind of

analysis would allow decision makers to consider the

merits not only of allocating resources within health

care, but also to consider whether it would be more

appropriate to invest in other sectors such as housing,

education or even the military. All costs and benefits

are valued in the same (monetary) units. If benefits

exceed costs, the evaluation would recommend pro-

viding the treatment, and vice versa. With two or

more alternatives, the treatment with the greatest

net benefit would be deemed the most efficient.

CBAs are thus intrinsically attractive, but conducting

them is especially problematic because of the diffi-

culties associated with valuing outcomes in monetary

terms.

Recent methodological advances in health econom-

ics offer ways to obtain direct valuations of health

outcomes by patients, relatives or the general public.

These techniques ask individuals to state the amount

they would be prepared to pay (hypothetically) to

achieve a given health state or health gain, or observe

actual behavior and impute the implicit values.

However, they are likely to be quite difficult to apply

in mental health contexts. Another approach used to

value health interventions is ‘conjoint analysis ’. Indi-

viduals are asked to rank different real- world sce-

narios, which may consist of several dimensions

(including, for instance, health outcomes, time inputs,

discomfort, possible externalities and stigma), and by

including cost as one of these dimensions, a monetary

value can be elicited. While complex, this conjoint

analysis approach has the advantage of not specifically

asking individuals to put a monetary value on health

states or health gain, which can make the technique

easier to administer than traditional willingness-to-

pay studies.

19.2.5 Cost-consequences analysis

A cost-consequences analysis has the ability to

evaluate policies and practices in a way that arguably

comes quite close to everyday reality, but it also

has some limitations. For each treatment alternative a

cost-consequences evaluation computes total (and

component) costs and measures change along every

one of the relevant outcome dimensions. The cost

and outcome results are then reviewed by decision

makers ; the different outcomes are weighed up (in-

formally and subjectively) and compared with

costs. For example, the researcher could compute

a series of ICERs (one for each measured outcome)

for presentation to the decision maker. The decision

calculus is therefore certainly much less tidy and

more complicated than when using cost-effectiveness

ratios or monetary or utility measures of impact

(see below), but it could be argued that decision

makers in health-care systems – from strategic

policy-makers at the macro level to individual

psychiatrists at the micro level – face these kinds of

decisions daily.

On the other hand, the process of weighing up the

various outcomes by the decision maker is subjective,

hidden and ‘technocratic ’, whereas the choice of the

single outcome dimension in a CEA and the weighting

algorithms in other evaluative modes (described be-

low) are transparent, less likely to be influenced by

the personal predilections or value positions of a few

individuals, and (potentially) reflective of societal

values.

19.2.6 Cost-minimization analysis

Another ‘cost-only’ approach is cost-minimization

analysis, which seeks to find which of a number

of treatment options has the lowest cost. A cost-

minimization analysis is carried out in one of two

ways. It often proceeds in the knowledge that previous

research has shown outcomes to be identical in the

treatment or policy alternatives being evaluated.

In this sense the approach is really more accurately

described as an ‘interrupted’ cost-effectiveness


analysis (see above). The other way a cost-minimiz-

ation analysis can proceed is to compare costs without

any regard for outcomes. Such an approach is narrow

and potentially misleading and should never be en-

couraged: it is not an economic evaluation.

Well-conducted cost-minimization analysis can

therefore be thought of as a special type of cost-effec-

tiveness analysis, where evidence on effectiveness

demonstrates no difference between two or more in-

terventions. In most instances, however, clinical and

quality of life outcomes will not be equivalent, and

more complex evaluations are required, which can

make them far more informative, but correspondingly

more complex to conduct.

19.3 Annex 3 : Additional information on

electroconvulsive therapy

Electroconvulsive therapy (ECT) is the safe induction

of a series of generalized epileptic seizures for thera-

peutic purposes using brief-pulse stimulation techni-

ques under anesthesia and muscle paralysis. Informed

consent of the patient or the responsible legal guardian

is mandatory. Since the first publication of a placebo

controlled double-blind study indicating the efficacy

of ECT in the treatment of depression (Greenblatt et al.,

1964), the excellent therapeutic effectiveness of this

method has been described in extensive studies

(Abrams, 2002 ; Baghai et al., 2005). These studies are

summarized in a variety of reviews and meta-analyses

(Abrams, 2002 ; Baghai et al., 2005 ; ECT review group,

2003).

19.3.1 ECT as first-line treatment

In the case of refusal of food and drink, and severe

psychomotor retardation, ECT has been shown to be

one of the safest therapeutic options with fast relief of

symptoms (Gangadhar et al., 1982). Therefore, de-

pressive stupor and inanition, as in melancholic, cata-

tonic and/or psychotic depression, can be a first-line

indication for ECT. If, due to other conditions, e.g. se-

vere psychotic symptoms and/or high suicide risk,

rapid improvement is crucial for the patient, ECT

should be considered earlier than other therapeutic

options (American Psychiatric Association Committee

on Electroconvulsive Therapy et al., 2001). In psy-

chotic depression, the remission rate for ECT approx-

imates 90%, with relief experienced within 10–14 days

(Ottoson and Fink, 2004 ; Petrides et al., 2001). The

risks of suicide that mark severe psychiatric illnesses

are quickly relieved by ECT, although attention

to continuation treatment is essential to sustain

the benefit (Kellner et al., 2005). Also other acute

psychiatric syndromes, e.g. malignant catatonia or a

neuroleptic malignant syndrome (NMS) may show

rapid benefit from ECT as a first-line treatment

(Abrams, 2002 ; Baghai et al., 2005). Intensive ECT,

usually administered daily (en bloc), relieves the high

rates of mortality associated with malignant catatonia

and delirious mania (Fink, 1999 ; Fink and Taylor,

2003). In the case of severe and life-threatening ad-

verse events of antidepressants and in psychotic de-

pressed patients ECT monotherapy can be a safe first-

line treatment. This recommendation also holds for

patients suffering from severe somatic diseases, in-

cluding the risk of worsening due to antidepressant

and antipsychotic pharmacotherapy (Beliles and

Stoudemire, 1998 ; Franco-Bronson, 1996 ; Rothschild,

1996).

In addition, long duration and chronic course of

the index episode are negative outcome predictors

in depressive disorders that signal a higher risk for

therapy resistance to medication and ECT (Beliles

and Stoudemire, 1998 ; Prudic et al., 1990). Never-

theless, the primary use of ECT is handicapped

by severe stigma and even legal restrictions against

its use in some jurisdictions (Ottoson and Fink,

2004).

19.3.2 ECT as second-line treatment

Even if patients receive ECT only in rare cases im-

mediately after reaching criteria for pharmacotherapy

resistance, those treatment failures are the most fre-

quent ECT indication (Moller, 1997 ; Prudic et al., 1996;

Sackeim, 2001; Warneke, 1993). Use of ECT signifi-

cantly enhances response rates (Davidson et al., 1978;

Folkerts et al., 1997 ; Kroessler, 1985). This finding is

especially true in patients suffering from psychotic

depression, even if antipsychotic therapies have been

applied adequately (American Psychiatric Association

Committee on Electroconvulsive Therapy et al., 2001;

Folkerts et al., 1997). Intolerable side effects of anti-

depressant medications, somatic comorbidities

emerging during the pharmacological treatment


Electroconvulsive Therapy et al., 2001 ; Rasmussen et

al., 2002) or worsening of depressive symptoms, in-

cluding severe suicidality during an antidepressant

pharmacotherapy, can also be the reason for initiating

an ECT treatment course (American Psychiatric


et al., 2001).

First- and second-line indications and rare last resort

indications are summarized in Table 26.


19.3.3 Efficacy of ECT in depressive syndromes of

differential etiology

19.3.3.1 Unipolar depression

The general efficacy and superiority of ECT compared

with antidepressant pharmacotherapy has been de-

scribed in controlled clinical trials and meta-analyses

(ECT review group, 2003). Response rates between 80

and 90% (Prudic et al., 1990; Prudic et al., 1996) and

even 100% (Sackeim et al., 2000) have been reported.

Also, lower response rates of about 50–60% have been

described in patients after several medication treat-

ment failures receiving unilateral ECT (Sackeim et al.,

2000). Nevertheless, in a recent study sustained re-

sponse rates of 80%, superior to pharmacotherapy re-

sponse rates (up to 70%), and remission rates of 75%

(up to 87% for study completers suffering from psy-

chotic depression) were found in major depressed

patients treated with optimized ECT (Husain et al.,

2004 ; Kellner et al., 2005 ; O’Connor et al., 2001 ;

Petrides et al., 2001).

A 20% better improvement compared with tricyclic

antidepressants and a 45% better improvement com-

pared with monamine-oxidase inhibitors (MAOIs)

(Janicak et al., 1985) as well as a better improvement in

comparison with the selective serotonin reuptake in-

hibitor (SSRI) paroxetine (Folkerts et al., 1997) have

been described. In addition, a more rapid improve-

ment in comparison with pharmacotherapeutic ap-

proaches has been reported (Abrams, 2002 ; Petrides

et al., 2001 ; Prudic et al., 1996 ; Sackeim et al., 1993).

Most patients show a faster treatment response during

ECT in comparison with pharmacotherapy (Sackeim

et al., 1987). But also an advantage in speed of re-

sponse in similarly efficacious pharmacotherapeutic

approaches, such as lithium augmentation (Sackeim

et al., 1993) after tricyclic antidepressant (TCA) treat-

ment failure, has been described. Especially for

patients who receive ECT after pharmacotherapy

treatment has failed, longer treatment intervals until

complete remission are to be expected.

Earlier reports showed lower-stimulation-energy

bilateral ECT to be more effective than unilateral

ECT (ECT review group, 2003; Sackeim et al., 1987 ;

Table 26. Indications74 for electroconvulsive therapy (adopted from Baghai et al., 2005)

Category of ECT indications Indication

ECT as a first-line treatment $ Febrile catatonia*$ Malignant neuroleptic syndrome*$ Severe depressive episode**$ Schizoaffective psychosis**$ Schizophrenia**, ***$ In the case of life-threatening or intolerable side effects of

psychopharmacological treatments

ECT as a second-line treatment Medication treatment failures in :

$ Depression$ Schizoaffective psychosis$ Schizophrenia$ Mania$ Depression or psychotic symptoms in case of organic diseases

ECT as a last-resort treatment $ Treatment-resistant obsessive compulsive disorder (OCD)$ Treatment-resistant dyskinesias$ Treatment resistant Gilles de la Tourette syndrome$ Treatment-resistant epilepsy$ Treatment resistant Parkinson’s disease

* Fink and Taylor, 2003.

**With suicidality that cannot be handled even on protected wards, psychotic symptoms, depressive stupor, with positive

symptoms or acute danger of self-harm or harm to others or with severe reduction in oral intake.

*** Fink and Sackeim, 1996.

74 ECT is indicated as a first- or second-line treatment on the basis of

broad clinical consensus on the basis of open label studies, case

series and case reports. Exceptions are the indications depression

and schizophrenia, for whom scientific evidence from RCTs and

meta-analyses have been published (ECT review group, 2003 ;

Tharyan, 2000 ; Tharyan and Adams, 2005).


Sackeim et al., 1993). But unilateral ECT may achieve

efficacy rates equal to bilateral ECT if the dose regime

is 6–8 times above the titrated seizure threshold

(McCall et al., 2000 ; Sackeim et al., 2000).

19.3.3.2 Bipolar depression

ECT is an effective antidepressant therapy whether

depressive episodes occur due to unipolar depression

or bipolar disorder (Abrams, 2002 ; American Psy-

chiatric Association Committee on Electroconvulsive

Therapy et al., 2001). As described in chapter 5.2.2.1 an

enhanced switch risk, including the occurrence of hy-

pomania or mania is associated with every highly ef-

fective antidepressant treatment. Infrequent switches

from depression to mania may also occur during the

course of ECT (American Psychiatric Association

Committee on Electroconvulsive Therapy et al., 2001).

But owing to a lack of randomized controlled trials

and switch rates up to 30%, regardless of the anti-

depressant therapy, this clinical observation has also

been discussed as an artifact (Tayor and Fink, 2006).

In contrast to antidepressant pharmacotherapy, the

electroconvulsive treatment has not to be stopped due

to the anti-manic properties of ECT. Furthermore, ECT

may be combined with lithium treatment to augment

lithium effects and to prevent a switch into mania in

high-risk patients. In this case, an enhanced risk for

cognitive and medical side effects must be taken into

account (Zarate et al., 1997). In the event of urgent in-

dication for mood stabilizers, even combined use of

ECT and anticonvulsants is possible and may yield

clinical advantages in specific circumstances (Aarre

and Bugge, 2002 ; Pearlman and Obedian, 1995 ; Zarate

et al., 1997).

19.3.3.3 Dysthymia and double depression

Chronic depression in the case of dysthymia alone is

not an indication for ECT treatment. Nevertheless, if

the diagnostic criteria for MDD or double depression

are present, dysthymia is not a predictor for a poor

ECT response (Abrams, 2002 ; American Psychiatric


et al., 2001).

19.3.3.4 Depressive syndromes in OCD

Patients suffering from OCD who do not respond to

pharmacotherapy may respond following ECT pre-

dominantly if OCD is accompanied by depressive

symptoms (American Psychiatric Association Com-

mittee on Electroconvulsive Therapy et al., 2001),

which often is the case. Also, the beneficial use of ECT

during OCD continuation therapy has been reported


Electroconvulsive Therapy et al., 2001).

19.3.3.5 Comorbid personality disorder

Comorbid personality disorder is a predictor of poor

response to ECT, and the recommendation for ECT

should be made cautiously in such patients (Abrams,

2002 ; O’Connor et al., 2001). Nevertheless, in the case

of resistance to pharmacotherapy, ECT should not be

withheld from patients suffering from MDD with co-

morbid personality disorder (American Psychiatric


et al., 2001). Rather, the information about lower re-

sponse rates must be included in the patients’ infor-

mation about the estimated treatment outcome.

19.3.3.6 Organic depression due to somatic disorders

Patients suffering from secondary depression asso-

ciated with somatic diseases show lower response

rates to biological therapies such as pharmacotherapy

and ECT (Black et al., 1993; Coryell et al., 1985 ; Krystal

and Coffey, 1997) in comparison with MDD.

Nevertheless, ECT is clinically effective in patients

suffering from depression after cerebral infarction

(‘poststroke depression’) (Krystal and Coffey, 1997;

Sackeim et al., 1987 ; Sackeim et al., 2000). Of course,

for this patient group organic risk factors must be

considered especially carefully during interdisci-

plinary neurological and psychiatric evaluations.

19.3.4 Combination of ECT and antidepressants

The majority of patients referred for ECT have had

multiple trials of medication. Despite this experience,

high remission rates to effective ECT – up to 90% in

psychotic depression – can be expected (Abrams,

2002 ; Husain et al., 2004 ; Petrides et al., 2001). The use

of bilateral or high-dose unilateral stimulation can

enhance the effectiveness of ECT treatment (Husain et

al., 2004 ; Sackeim et al., 2000). A further option for

augmenting an ECT treatment course may be the

concomitant prescription of antidepressants.However,

findings from study of a putative benefit of combining

ECT with TCAs (Lauritzen et al., 1996 ; Nelson and

Benjamin, 1989) and the lack of advantages of other

concomitant medications, like SSRIs, are still contro-

versial (Lauritzen et al., 1996). In particular, the effi-

cacy of modern antidepressants in combination

with ECT, e.g. the dual-action substances mirtazapine,

venlafaxine and duloxetine, has never been in-

vestigated in controlled studies. Nevertheless, some

safety data are available, e.g. venlafaxine at doses


lower than 300 mg/day has been shown to be safe in

combination with ECT. In high-dose treatments above

300 mg/day, side effects of a cardiovascular nature,

such as transient asystolia and bradycardia, were

more frequent if venlafaxine treatment was combined

with propofol anesthesia during ECT (Gonzales-Pinto

et al., 2002).

19.3.5 Continuation ECT75

As described in chapter 9.2, in addition to pharmaco-

logic and psychotherapeutic continuation therapies,

especially after pharmacotherapy treatment failure,

ECT is an also effective continuation treatment (Fink

et al., 1996 ; Kellner et al., 2005 ; Sartorius and Henn,

2005a; Sartorius and Henn, 2005b), even given the

absence of controlled studies. Continuation ECT

should be considered when depressive symptoms

recur despite adequate pharmacological continuation

therapy. Even when the prior history of an individual

patient shows enhanced risk for recurrence of de-

pression during continued pharmacotherapy, includ-

ing both antidepressants and mood stabilizers, C-ECT

should be part of the treatment plan (Frey et al., 2001 ;

McCall, 2001 ; Rabheru and Persad, 1997). The usual

clinical procedure is to prolong the treatment intervals

according to individual clinical requirements. During

acute treatment, a patient usually receives two or three

treatments per week. Afterwards, usually one treat-

ment per week is applied for 4–8 weeks, then one

treatment every 2 weeks and then one treatment every

4 weeks. This frequency should be maintained for at

least 6 months. A frequently used alternative strategy

(the so-called cafeteria style) is the individual decision

whether to administer C-ECT treatment when the first

signs of recurring depressive symptoms are reported

(Abrams, 2002 ; Fink et al., 1996). Regular weekly

evaluations help to judge the necessity to shorten

or prolong treatment-free intervals on an individual

basis.

19.3.6 Safety

In general, ECT is one of the best-tolerated anti-

depressant therapies, with low risk for severe compli-

cations, even lower than TCAs (Abrams, 2002 ;

American Psychiatric Association Committee on Elec-

troconvulsive Therapy et al., 2001). The reported

mortality rate during ECT varies between 1:50000 and

1:25000 treatments (Abrams, 2002 ; American Psychi-

atric Association Committee on Electroconvulsive

Therapy et al., 2001). Severe complications that war-

rant special attention are seen in less than one in 10 000

treatments (American Psychiatric Association Com-

mittee on Electroconvulsive Therapy et al., 2001). ECT

therefore is considered to be one of the safest medical

procedures performed under anesthesia. Clinical con-

ditions requiring special attention before and during

ECT described in (Abrams, 2002 ; Baghai et al., 2005)

are summarized in Table 27.

19.3.7 Side effects

19.3.7.1 Somatic side effects

The most frequent immediate unpleasant effects of

ECT are headache, nausea and vomiting (varying with

the anesthetic). Headache is reported in up to 45% of

patients and can be treated symptomatically using

analgesics such as acetylsalicylic acid or paracetamol

or, if severe, by changing the induction medications.

Patients suffering from regular migraine attacks are

predisposed for postictal headache following ECT. In

this case triptans, e.g. sumatriptan, can be applied

orally or intranasally (Angst et al., 1992). Nausea

occurs rarely following intravenous anesthesia and

can be treated using metoclopramide. Other rare

complications of ECT are cardiovascular events

emerging from anesthesia. On rare occasions, the

seizure is prolonged beyond the anticipated 30–180

seconds (American Psychiatric Association Committee

on Electroconvulsive Therapy et al., 2001). This risk

is considerably enhanced in patients receiving

theophylline (Grogan et al., 1995 ; Rao et al., 1993). The

treating anesthesiologist or psychiatrist will end the

seizure by administering intravenous benzodiaze-

pines (e.g. diazepam, lorazepam), anesthetics or other

anticonvulsants. This event is best managed by ictal

and postictal electroencephalogram monitoring

(Grogan et al., 1995), which can also be of use in

treating non-convulsive seizures, which rarely occur

after ECT (Grogan et al., 1995 ; Rao et al., 1993).

In the case of prolonged effectiveness of muscle re-

laxants due to predisposition or lithium therapy (Hill

et al., 1977 ; Reimherr et al., 1977), longer assisted res-

piration and subsequent measurement of oxygen

saturation using finger or toe pulse oxymetry is

necessary to prevent hypoxia. Aching muscles can be

prevented by adequate muscle relaxation and are re-

ported rarely.

75 The terms ‘continuation treatment ’ and ‘continuation ECT’

(C-ECT) are predominantly used to characterize maintenance

treatment after successful treatment of the index phase. They are

sometimes distinguished from ‘maintenance treatment ’ and

‘maintenance ECT’ (M-ECT) (Sartorius and Henn, 2005a) based on

theoretical considerations regarding switching to prophylactic

treatment to prevent new episodes of depression. Because for

individual patients this time point cannot be precisely defined, in the

following text only the term ‘C-ECT’ is used.


In patients suffering from bipolar depression ECT,

like any other antidepressant agent (Angst et al., 1992),

can induce hypomania or mania (‘switch’) (Angst

et al., 1992). Concomitant lithium therapy (Zarate et al.,

1997) can be used despite the higher risk of side effects

such as prolonged muscle relaxation and confusional

states. The use of mood stabilizers, such as valproate,

lamotrigine or carbamazepine (if required, at lower

doses than usual), is possible despite the anticon-

vulsant properties of these agents (Zarate et al., 1997).

Both methods can significantly reduce the switch risk.

19.3.7.2 Cognitive side effects

All patients are confused on awakening after a seizure.

The duration and severity of the post-seizure delirium

vary with age (older patients have more severe and

more prolonged periods of confusion), dosage and

type of anesthetic, and the characteristics of the medi-

cations, both psychoactive and systemic, that have

been prescribed. Special attention is paid to sedatives

and anxiolytics, antipsychotics and lithium, which

may enhance the confusional syndrome.

Transient cognitive disturbances are typical side

effects that are more prominent in bilateral than in

unilateral and in high-dose than in lower-dose ECT

(ECT review group, 2003). These include short-term

memory disturbances in up to 30% of patients treated

(van Waarde and Stek, 2001). Postictal delirium, in-

cluding a prolonged reorientation period and memory

disturbances such as anterograde and retrograde

amnesia, can be differentiated from rarely occurring

effects on autobiographic long-term memory (Lisanby

et al., 2000). In addition, cognitive deficits that are

not a product of memory disturbances, such as con-

centration or attention deficits can occur. It can be

difficult in an individual patient to differentiate cog-

nitive side effects of an ECT treatment from cognitive

disturbances caused by depression itself (Lisanby

et al., 2003a). A variety of patients report amelioration

of cognitive impairment after a course of ECT treat-

ment (Devanand et al., 1991).

As described, the rate of cognitive disturbances de-

pends on dose and application of electrical stimulation

(Devanand et al., 1991 ; Krystal and Coffey, 1997).

Sometimes patients experience profound and sus-

tained memory loss, sufficient to interfere with their

ability to return to work. Such instances are rare, but

constitute the principal burden of complaints against

the use of ECT (Abrams, 2002 ; Ottoson and Fink,

2004).

Nevertheless, recent improvements in the use of

ECT include methods to maintain good therapeutic

efficacy together with better tolerability concerning

cognitive disturbances. Modified ECT techniques

(Ghaziuddin et al., 2000), including unilateral and

bifrontal pulse wave stimulation, anesthesia with

muscle relaxation and sufficient oxygenation, could

substantially reduce these risks (Ghaziuddin et al.,

2000 ; Sackeim et al., 1993 ; Sackeim et al., 2000).

If cognitive disturbances occur despite these pre-

cautions, rapid improvement within 1 and up to

Table 27. Clinical conditions requiring special attention before and during ECT (adopted from Baghai et al., 2005)

Category Clinical condition

Enhanced intracerebral pressure* At present

Cerebral infarction* Not older than 3 months

Myocardial infarction* Not older than 3 months

Intracerebral tumor* Including intracerebral edema

Any life-threatening anesthesia risk* At present

Cardiovascular disorders Cardiac arrhythmias, instable angina pectoris, myocardial infarction (older

than 3 months), myocardial insufficiency, heart-valve abnormalities,

not sufficiently treated hyper- or hypotonia, aortal aneurysm

Medical disorders Disturbance of blood coagulation, severe liver diseases, severe pulmonary

diseases, pheochromocytoma

Neurological disorders Intracerebral neoplasias, intracranial bleeding, intracerebral vascular

malformations, cerebral ischemia, cerebral inflammations, hydrocephalus,

dementias, diseases of the basal ganglia, craniotomies, severe cerebral traumas

Orthopedic disorders Osteoporosis

Esophageal hernia Increased aspiration risk ; intubation recommended

Concomitant pharmacological treatment If enhancing the ECT risks or reducing ECT efficacy

* In former times considered as absolute contraindications ; today an individual risk/benefit-analysis is necessary.


4 weeks can be observed in most cases (Ghaziuddin

et al., 2000). Follow-up investigations showed a com-

plete reversibility of cognitive side effects following an

ECT course (Ghaziuddin et al., 2000; Krause et al.,

1988) and even improvement in comparison with the

time interval before ECT treatment (Baghai et al., 2005 ;

Krause et al., 1988). A variety of case reports, case

series and controlled studies confirm that ECT does

not cause long-lasting functional impairment (Krause

et al., 1988) or any structural damage of the central

nervous system (Devanand et al., 1991 ; Krause et al.,

1988 ; Lisanby et al., 2003b).

19.3.8 Clinical precautions and special considerations

After many decades of research and clinical experi-

ence, clinicians have developed protocols for the safe

treatment of patients who warrant ECT regardless of

age, medical status or physical condition.

Conditions that carry higher somatic risks include

recent myocardial or cerebral infarction, high intra-

cranial pressure, normal pressure hydrocephalus with

risk for herniation and every other untreated severe

medical and life-threatening anesthesiological risk. If

treated sufficiently, these conditions become relative

contraindications, and a risk-benefit analysis must be

performed for each patient on an individual and in-

terdisciplinary basis. Other conditions associated with

enhanced cardiovascular risk include coronary artery

disease, arrhythmias, insufficiently treated hypertonia

and aneurysms. Other medical conditions, such as se-

vere lung and liver diseases, disturbances of blood

coagulation and untreated pheochromocytoma, also

enhance the risk associated with ECT and anesthesia.

Neurological diseases, including intracranial tumors

and bleeding, vascular malformations, cerebral is-

chemia, acute infections and others enhance treatment

risk. In general, each factor that enhances the risk of

side effects for ECT and anesthesia should be taken

into consideration. In the case of specific risks, inter-

disciplinary counseling may be necessary. Next, the

higher somatic risk must be compared with the risk of

insufficiently treated or prolonged psychiatric illness.

Patients and relatives or responsible legal guardians

need to be informed about risk-benefit ratios so they

can share in the decision making.


transcranial magnetic stimulation

Transcranial magnetic stimulation (TMS) was orig-

inally introduced in 1985 by Barker et al. as a non-

invasive tool to electromagnetically stimulate the

primary motor cortex in humans (Lisanby et al.,

2003b). More recently, repetitive TMS (rTMS) has be-

come a powerful research tool in neurophysiology and

cognitive neuroscience. rTMS is usually targeted to the

dorsolateral prefrontal cortex based on well-replicated

findings that show reversible functional changes in

this region using different neuroimaging techniques.

The majority of studies focus on the left prefrontal

cortex based on the observed asymmetry of prefrontal

function associated with major depression (Lisanby

et al., 2003b). A large number of different stimulation

parameters, e.g. frequency and intensity of stimu-

lation, have been applied in studies, and very few

studies have compared different treatment modalities

(Padberg and Moller, 2003). The usual treatment dur-

ation has been 1–4 weeks of treatment, and in most

studies rTMS has been used as an add-on intervention

with a stable antidepressant medication.

Some 25 randomized placebo-controlled clinical

trials, including about 750 patients suffering from

major depressive episodes, have been conducted to

date investigating the safety and efficacy of rTMS as

an antidepressant intervention (Berman et al., 2000b;

Burt et al., 2002 ; Dolberg et al., 2002 ; Garcia-Toro et al.,

2001a; Garcia-Toro et al., 2001b ; Kauffmann et al.,

2004 ; Loo et al., 2003 ; Miniussi et al., 2005 ; Mosimann

et al., 2004 ; Nahas et al., 2003 ; Padberg et al., 1999 ;

Padberg et al., 2002 ; Padberg and Moller, 2003 ;

Pascual-Leone et al., 1996 ; Rossini et al., 2005). In

the majority of these trials, significant placebo/verum

differences have been observed, with antidepressant

effects ranging from modest to substantial. Due to the

methodological limitations of many of these trials

stemming from rather small sample sizes, the diffi-

culty of controlling sham rTMS used as placebo con-

dition, modified double-blind designs with the person

applying rTMS being aware of the condition and

patient and rating psychiatrist being blinded, and

the short observation periods, the level of evidence

currently provided by the available data still needs

improvement. Several meta-analyses have been con-

ducted that differ largely in the studies selected and

the methodology of analysis used (Burt et al., 2002 ;

Couturier, 2005 ; Ebmeier et al., 2006 ; Martin et al.,

2003 ; Pascual-Leone et al., 1996 ; Schulze-

Rauschenbach et al., 2005). Most of these meta-

analyses support the antidepressant efficacy of rTMS,

but the clinical effects found are not very strong and

the clinical significance may be questionable. rTMS

has also been directly compared with ECT in five

parallel design trials (Grunhaus et al., 2000; Grunhaus

et al., 2003 ; Pridmore et al., 2000 ; Schulze-

Rauschenbach et al., 2005). In these trials rTMS was

found to be as effective as ECT in patients suffering


from major depressive episodes without psychotic

features, but to be inferior for psychotic depression

(Grunhaus et al., 2000). Surprisingly, only one study

compared different rTMS modalities with anti-

depressant pharmacotherapy (clomipramine) ; how-

ever, no meaningful interpretation of the results in

terms of efficacy was possible due to small sizes of

treatment groups (Lisanby et al., 2001b). Four trials

have investigated combined treatment with active

rTMS plus antidepressant compared with sham rTMS

plus antidepressant to answer the question whether

rTMS augments the effect of antidepressant medi-

cation (Lisanby et al., 2001b; Rumi et al., 2005). Only

one study that combined rTMS with amitriptyline

reported significant superiority of combined active

treatment (Rumi et al., 2005), whereas the other trials,

which applied SSRIs and other substances, failed to

show a significant difference between treatment

groups. These results may support the idea of rTMS

being particularly effective combined with distinct

neuropharmacological actions, and this hypothesis

should be systematically addressed by future studies.

Apart from single studies and case reports, little is

known regarding the stability of effects and potential

maintenance treatment strategies (Pascual-Leone et al.,

1996). The largest body evidence points to transient

effects following completion of rTMS treatment

(Pascual-Leone et al., 1996 ; Schule et al., 2003).

rTMS appears to be safe and well tolerated by

patients within a range of parameters defined accord-

ing to a consensus (Wassermann, 1998). Side effects

include the risk of seizure, which increases with

higher intensity and higher frequency of stimulation

as well as shorter intertrain intervals. Since safety

criteria for limiting these stimulation parameters have

been published, no additional seizures have been re-

ported within these limits. Among the side effects that

are frequently observed are slight local painful stimu-

lation artifacts on the scalp, transient headaches fol-

lowing stimulation and single cases of autonomous

arousal reactions, including dizziness and fainting

(personal communications). Clinical contraindications

include implanted devices (pacemakers), intracranial

articles of ferromagnetic material, a history of epileptic

seizures and brain injuries or surgery. Particular at-

tention should also be paid to the psychiatric side ef-

fects of rTMS, including the risk for switching into

hypomania and manic states, particularly in patients

with bipolar disorder, and de novo induction of psy-

chotic symptoms (Padberg and Moller, 2003 ; Rush

et al., 2000).

In conclusion, considerable evidence argues for the

antidepressant efficacy of high-frequency rTMS over

the left dorsolateral prefrontal cortex applied over 2–4

weeks, and rTMS may also be successfully used as an

adjuvant antidepressant intervention. Patients with

psychotic symptoms appear to respond only poorly to

rTMS. There is no evidence that rTMS-associated

antidepressant effects are stable beyond the end of

rTMS treatment. Thus, continuation therapy should be

planned and initiated as recommended by current

clinical guidelines. Since the antidepressant efficacy of

rTMS has still not been sufficiently proven owing to

the methodological limitations of previous clinical

trials, the results of several ongoing placebo-controlled

multicenter trials in the US and Germany are expected

to clarify the role of rTMS within the range of anti-

depressant interventions.

19.5 Annex 5: Additional information on vagus

nerve stimulation

In the 1980s and 1990s vagus nerve stimulation (VNS)

was developed in animal models for its putative anti-

convulsant action. It was approved by the FDA and

introduced into the routine treatment of therapy-

resistant focal epilepsies about a decade ago.

Theoretical considerations regarding the functional

anatomy of the vagus nerve also projecting to areas of

the brain relevant for generation and control of mood

and emotions, but also observations of mood changes

in epilepsy patients undergoing VNS, have triggered

the application of VNS in depressive disorders

(George et al., 2003). A NeuroCybernetic Prosthesis

(NCP) System is used for VNS that consists of a pulse

generator implanted into the thoracic wall and sub-

cutaneously implanted bipolar leads linked to the left

vagal nerve. This system has been investigated in a

series of open and controlled clinical trials as part of an

industrial development program, and the data of the

complete trial set have been published (George et al.,

2005 ; Nahas et al., 2005 ; Rush et al., 2000 ; Rush et al.,

2005b; Rush et al., 2005a; Sackeim et al., 2001b).

The first open study (D-01) showed clinically

meaningful effects over a period of 2 years, with re-

sponse rates between 42 and 45% (defined as at least

50% reduction of baseline HAMD scores) and re-

mission rates between 21 and 22% (Rush et al., 2000;

Sackeim et al., 2001b). However, all patients included

in the first open study received additional anti-

depressant medication, which also was changed over

time. The promising results of this open pilot study

led to a double-blind randomized placebo-controlled

multicenter trial (D-02 study) that included 235

patients who received either active or placebo stimu-

lation during a 10-week period (Rush et al., 2005a).


After completion of the acute treatment period, all

patients received continuous treatment, and long-term

data on 205 patients following 12 months of stimu-

lation were recently published (Rush et al., 2005b).

Patients of the placebo group also received active

treatment during the long-term period, and changes in

the concomitant treatment (medication and psycho-

therapy) were allowed according to clinical require-

ments (‘ treatment as usual ’, TAU). The primary

efficacy criteria of the acute study were the number of

responders in the treatment groups. No difference be-

tween those groups was found in the acute study (15%

response in the active vs. 10% response in the placebo

group), nor were significant differences among the

secondary efficacy criteria (self- and observer ratings)

observed (Rush et al., 2005a). The negative finding in

the acute study was discussed as being due to the low

stimulation intensity applied in the active group (0.67

mA vs. 0.96 mA in the D-01 study). To make sense of

the clinical meaning of the long-term data in terms of

efficacy, a comparison study was initiated (D-04) that

included 124 patients receiving only TAU (George

et al., 2005). This study had the same inclusion criteria

as the D-02 study: chronic depressive episode (dur-

ation longer than 2 years) or recurrent depression

(more than four episodes, including the current

episode), an HAMD baseline score >20 and non-

response after two to four appropriate antidepressant

medication trials. After 12 months, a clinical response

was found in 29.8% of the patients included in

the D-02 study, whereas only 12.5% responded in the

D-04 study; remission was achieved in 17.1% of the

D-02 study compared with 6.7% of the D-04 study

(George et al., 2005).

Concerning the safety of VNS, the results of the

studies in epilepsy were essentially confirmed.

Following the acute period, the D-02 study found

voice alterations, increased cough, dyspnea, neck pain,

dysphagia, laryngismus, paraesthesia and pharyngitis

(Rush et al., 2005a). During long-term treatment over 1

year most of these adverse events showed a clear de-

cline (Rush et al., 2005b).

Based on the efficacy and safety data, the VNS

therapy system was recently approved by the FDA for

the adjuvant, long-term treatment of chronic or recur-

rent depression for patients 18 years of age or older

who are experiencing a major depressive episode and

have not had an adequate response to four or more

adequate antidepressant treatments.

Despite the recent FDA approval, the body of evi-

dence testifying that VNS exerts antidepressant effects

superior to placebo is still limited andmainly based on

long-term data compared with naturalistic treatment.

A placebo-controlled trial is urgently needed to clarify

the issues arising from the D-02 acute study, and to

provide more data for the efficacy of VNS in de-

pression. Because of its invasive nature, VNS should

be reserved for special clinical cases where the

patient’s demand for this treatment is high, several

other interventions have failed and a clinical benefit

is likely. VNS should only be used where thorough

medical follow-up can be guaranteed.


acupuncture

19.6.1 Efficacy

Due to the fact that the use of complementary and

alternative therapies is overrepresented in patients

suffering from depressive syndromes (Kessler et al.,

2001), the actual knowledge about the main thera-

peutic options in this field need to be evaluated. The

history of acupuncture in Eastern culture goes back

more than 4000 years, and traditional Chinese medi-

cine describes its influence on the balance of health

and energy in the human body. The original practice

involves inserting needles into specific trigger points

at different parts of the body. Electro-acupuncture

(EA) includes electrical stimulation of classical trigger

points using sine wave and undulatory wave stimu-

lation of different frequencies. An influence on b-

receptor function (Fan, 1992) and central serotonergic

(Fan, 1992) and noradrenergic (Meng et al., 1994)

functions in depressed patients responding to EA has

been suggested.

Despite a variety of published studies in this field, a

recent review describes insufficient evidence to deter-

mine the efficacy of acupuncture in comparison with

pharmacological antidepressant treatment (Smith and

Hay, 2005). The cause for this uncertainty is the

methodological quality of the investigations published

up to now. Nevertheless, some of these controlled

studies are presented below to describe the present

state of information.

In a comparative randomized controlled trial 20

patients suffering from depression were treated with

traditional acupuncture or the TCA amitriptyline. No

significant differences between the treatment groups

could be seen, but due to the relatively small number

of patients, the study seems to be underpowered

(Yang et al., 1994). Further studies investigated EA in

comparison with amitriptyline and placebo in an ana-

lysis of two separate study parts. Again, therapeutic

effects in the treatment groups showed no significant

differences. A better therapeutic effect on anxiety and

cognitive symptoms following acupuncture has been


described (Allen and Schnyer, 1998). Similarly, a

variety of Chinese RCTs found no significant differ-

ences between EA or computerized EA and ami-

triptyline treatment (Luo et al., 1985 ; Luo et al., 1988;

Luo et al., 1990b; Luo et al., 1990a; Luo et al., 1998) (see

(Luo et al., 1995 ; Meng et al., 2002) for review).

A further study compared acupuncture for de-

pression with acupuncture for other complaints and a

group of patients waiting for treatment (n=35).

Patients receiving depression-specific acupuncture

showed significantly more improvement than the

group receiving non-specific acupuncture, but no sig-

nificant difference from the placebo condition in

waiting-list patients could be seen (Allen and Schnyer,

1998). A single blind study also compared depression-

specific and non-specific acupuncture with mianserin

monotherapy in a total of 70 patients. Additionally,

acupuncture improved depression more than treat-

ment with mianserin. No differences between either

forms of acupuncture could be seen (Roschke et al.,

2000). Moreover, specific acupuncture showed a

greater and lasting amelioration of symptoms in

women suffering from depression during pregnancy

(Manber et al., 2004). Other authors describe some

evidence for the clinical effectiveness of acupuncture,

but mention that further studies are needed before

recommendations can be made (Gallagher et al., 2001;

Manber et al., 2002). Note also that to be able to com-

pare different investigations will require not only

randomized controlled trials of adequate power but

also a detailed description of standardized procedures

in acupuncture. Finally, adequate blinding of physi-

cians and patients together with standardized out-

come measures are also needed before clinical and

scientific recommendations can be made (Smith and

Hay, 2005).

19.6.2 Safety and tolerability

An overall good safety and tolerability of acupuncture

has been described. Especially in trials comparing

TCA with acupuncture, typical side effects were much

less in the acupuncture groups (American Psychiatric

Association, 1994). Studies comparing modern and

better-tolerated antidepressants have not been pub-

lished up to now.


chronotherapeutics : light and wake therapy

Chronotherapeutics refers to treatments that modulate

the circadian and seasonal rhythms of mood and sleep

regulation. These manipulations include wake therapy

(sleep deprivation), sleep-phase advance therapy and

light therapy (Wirz-Justice et al., 2005).

19.7.1 Wake therapy

Numerous studies have confirmed that the majority of

patients with depression who abstain from a night’s

sleep obtain immediate relief from depression (Kuhs

and Tolle, 1991 ; Ostenfeld, 1973 ; Wu and Bunney,

1990), often with full, although temporary remission.

This effect appears to be most pronounced in patients

with bipolar illness and in those with diurnal or day-

to-day mood variation (Kuhs and Tolle, 1991). The

mechanism of action is unknown but may rest on the

reduction of REM sleep, which is believed to be de-

pressogenic (Riemann et al., 1994). Wake therapy has

been – and remains in many countries – a standard

method for treating depression, most often as an aug-

mentation strategy with drug treatment. Wake

therapy is used either in the form of a whole night’s

waking (total sleep deprivation) or staying awake in

the latter part of the night (partial sleep deprivation).

A procedural elaboration, which sustains the first-day

benefit, is to use sleep deprivation followed by a sleep

phase advance in which the habitual sleep time is

gradually approached over several nights (Berger

et al., 2003 ; Voderholzer et al., 2003). Used on its own,

a substantial number of patients will relapse into de-

pression when resuming normal sleep (Wu and

Bunney, 1990). However, new methods have been de-

veloped over the last decade that are designed to

maintain the antidepressant response of wake therapy

(Neumeister et al., 1996; Wirz-Justice et al., 2005). The

simplest form simply repeats wake therapy for a

number of nights, with recovery nights interspersed.

A simple and well-tested protocol repeats wake

therapy three times over a period of 5 days (Colombo

et al., 2000). Other methods to sustain the anti-

depressant effect of sleep deprivation include combi-

nation with antidepressant drugs, pindolol, lithium

and the use of bright light therapy, all of which have

been shown to effectively reduce the relapse into de-

pression after wake therapy (Benedetti et al., 1999;

Colombo et al., 2000 ; Smeraldi et al., 1999 ; Szuba et al.,

1994). Even though wake therapy is almost exclusively

used in an inpatient setting for both inpatients and

visiting outpatients, one study has been carried out

using home wake treatment (Loving et al., 2002). The

switch rate into mania for bipolar patients is no higher

than with the use of antidepressant drugs (Colombo

et al., 1999), and the suicide risk does not appear to

be increased (Kuhs and Tolle, 1991 ; Vovin and

Fakturovich, 1985). Caution is, however, warranted in


the course of wake therapy due to occasional steep

mood swings experienced in the course of the proto-

col. There is some evidence to suggest that patients

with high levels of anxiety and panic attacks improve

less from wake therapy and that they may develop

panic attacks on the day after sleep deprivation (Roy-

Byrne et al., 1986). The research field needs larger trials

with suitable control groups to assess the absolute

magnitude of the wake therapy effect and trials of

longer duration to assess the relapse pattern in differ-

ent patient groups. A treatment manual (Benedetti

et al., 2006) and guidelines are in preparation.

19.7.2 Light therapy

The modern and systematic use of light treatment in

psychiatry stems from the observation by Rosenthal

and colleagues in the early 1980s of recurrent winter

depression and the subsequent evidence that light

treatment alleviated the depressive symptoms

(Rosenthal et al., 1984). Seasonal affective disorder

(SAD) is now incorporated in the DSM-IV diagnostic

system as a subtype of major depression (‘with sea-

sonal pattern’) (American Psychiatric Association,

1994). Light therapy has seen an extensive research

effort, and its antidepressant effect and chrono-

biological effects have now been established in sev-

eral systematic reviews and in many clinical studies

(Golden et al., 2005 ; Kripke, 1998 ; Terman and

Terman, 2005 ; Tuunainen et al., 2004 ; Winkler et al.,

2005b). Light treatment has been used in SAD as a

monotherapy and and in non-seasonal depression

(chronic and recurrent) both as a monotherapy and

as augmentation with drugs. Light treatment is per-

formed by the use of a light box that produces 10000

lux, wide-screen, ultraviolet-filtered diffuse white flu-

orescent light. Narrow-band spectra with blue or

green appearance have been investigated, but the data

are insufficient to recommend their use. Additionally,

there is a suspected retinal hazard of blue-light ex-

posure, which may damage retinal structures and ex-

acerbate age-related macular degeneration (Reme

et al., 2001). Light boxes come in many designs, but

larger screens that emit diffuse light are best tolerated

and maximize desired stimulation of the peripheral

retina.

Light treatment from ambulatory, battery-powered

light visors is available, but controlled data have not

shown a benefit relative to placebo dim light. Another

variant is gradually incremental dawn simulation that

mimics outdoor sunrise in the bedroom, where the

signal is often absent or deficient. This method uses far

lower light intensity than in post-awakening bright

light therapy, yet has shown efficacy in several trials of

SAD, where a simulated springtime sunrise is pre-

sented in winter (Avery and Norden, 1998). Finally,

going outdoors into natural sunlight can be effective,

assuming good weather conditions and seasonal

availability of early morning sunlight (Wirz-Justice

et al., 1996).

Treatment duration is in the range of 30 minutes to 1

hour, preferably in the morning upon awakening. A

dose-response effect has been confirmed, thus en-

abling treatment regimens with shorter exposure

duration at higher intensity (Sondergaard et al., 2006 ;

Terman et al., 1990). For SAD, the duration of

treatment extends throughout the dark season in order

to forestall relapse (Lam et al., 1999). For non-seasonal

depression, light therapy presumably works as an ac-

celerating agent in combination with drugs, although

recent evidence indicates only a short-lived positive

effect when the lights are discontinued (Martiny, 2004 ;

Martiny et al., 2006). Light treatment in non-seasonal

depression should thus optimally be used until

remission is reached and sustained for at least 8–12

weeks of daily treatment ; it can easily be resumed if

there is subsequent relapse. The use of light treatment

thus far has not shown any long-term damage to the

visual system (Reme et al., 2001). Acute side effects are

limited to milder degrees of headache and blurring of

vision, and nausea and irritability, which can be alle-

viated by decreasing light intensity or increasing the

distance from the screen. Hypomania can occur but is

often of milder degree and short-lived when light is

discontinued. Patients with bipolar disorder should

use light therapy only in conjunction with mood-

stabilizing medication (Terman and Terman, 1999).


psychotherapy

Empirically supported psychotherapies are potent

alternatives to and augmenters in combination with

antidepressant medications. Although psycho-

therapies have received less study than pharmaco-

therapies, randomized controlled studies have

demonstrated the efficacy of some psychosocial inter-

ventions, acutely and as maintenance treatments, both

as monotherapies and in combination with medication

as antidepressant treatments. The empirically based

psychotherapies, principally cognitive behavioral

therapy (CBT) (Beck et al., 1979), interpersonal

psychotherapy (IPT) (Weissman et al., 2000) and

behavioral therapy (e.g. Martell et al., 2001), have ad-

vantages and disadvantages relative to pharmaco-

therapy, and differential benefits may exist among


these psychotherapies for depressed patients with

particular moderating factors.

Most psychotherapy outcome research has involved

individual psychotherapy, although group and family

therapies have received some study. Empirically vali-

dated treatments are time-limited, diagnosis-focused

and address current life problems rather than the

past. Of the many forms of extant psychotherapy,

only a few have received empirical assessment ;

the antidepressant benefits of the remainder remain

unclear.

19.8.1 Psychotherapies as primary treatment for

mood disorders

After decades of psychotherapists avoiding structured

research, researchers in the 1970s began to conduct

randomized controlled trials (RCTs) of psycho-

therapies for non-delusional outpatients with depres-

sive disorders. In addition to incorporating research

paradigms from pharmacotherapy trials (e.g. random

assignment, blinded independent assessment), re-

searchers wrote manuals to define particular treat-

ment approaches, such as CBT and IPT. Treatment

sessions were recorded to ensure therapist adherence

to the treatment approach, which was reinforced by

frequent supervision. Psychotherapies were initially

compared with waiting lists or low-contact conditions,

but increasingly also to active treatments, including

antidepressant medication (e.g. Elkin et al., 1989).

These trials yielded repeated evidence of the efficacy

of CBT and IPT as treatments for depressive disorders

(Hollon et al., 2005), leading to their incorporation into

national and professional treatment guidelines

(American Psychiatric Association, 2000 ; Depression

Guideline Panel, 1993 ; Karasu et al., 1993 ; Roth

and Fonagy, 2004). Lacking funding from an industry,

psychotherapy researchers have conducted fewer

trials than pharmacotherapy researchers. In general,

empirically supported psychotherapies have demon-

strated similar response and remission rates to

pharmacotherapy for outpatients with depressive

disorders. They treat mood and demoralization more

quickly than neurovegetative symptoms of depression,

the reverse of the pattern seen for antidepressant

medications. Beyond acute efficacy, IPT and CBT have

been shown to provide prophylaxis against relapse

and recurrence when prescribed as less frequently

scheduled (e.g. monthly) maintenance treatments

(Frank et al., 1990 ; Hollon et al., 2005). Studies of CBT

suggest an enduring effect even for acute psycho-

therapy, a lasting protective benefit not seen when

pharmacotherapy is discontinued (Hollon et al., 2005).

This presumably indicates that psychotherapy pro-

vides patients with methods for handling new psy-

chosocial problems, potential triggers of depressive

episodes that arise in their lives after acute treatment

ends.

The empirical evidence for psychotherapy as

monotherapy for chronic depression is sparser and

less strong. The Cognitive Behavioral Analysis System

of Psychotherapy (CPASP) (McCullough, 2003) was as

efficacious as nefazodone both acutely and as main-

tenance treatment in one large (n=681) study of

chronic depressive disorders ; the combination of

nefazodone and CBASP was superior to either mono-

therapy (Keller et al., 2000). This impressive finding

requires replication, as it is the only CBASP trial

published to date. IPT and CBT have shown less ben-

efit than pharmacotherapy for dysthymic patients

(Markowitz et al., 2005 ; Ravindran et al., 1999), albeit

combined IPT and sertraline was cost-effective relative

to pharmacotherapy alone in one study (Browne et al.,

2002).

19.8.2 Combination treatment with antidepressant

medication and psychotherapy

Combined treatment studies often have been con-

founded by inadequate power, differential attrition

and other methodological difficulties. Large sample

sizes are required to find differences between active

monotherapies and combined treatment. Nonetheless,

no research trial has shown combined treatment to be

less efficacious than antidepressant monotherapy

(Manning et al., 1992). Given health economics con-

siderations, combined treatment may best be reserved

for patients with chronic, highly comorbid, severe de-

pressions, or those at high suicide risk (Hollon et al.,

2005 ; Rush, 1999). In an open trial in menopausal de-

pressed women cognitive therapies have been shown

to enhance the efficacy of the SSRI fluoxetine especially

in combination treatments. As a possible mechanism

of action a better normalization of serotonin and nor-

adrenaline levels has been suggested (Gaszner, 2005).

19.8.3 Psychotherapy as adjunct to pharmacotherapy

Some depressed patients remit on antidepressant

medication and require no additional treatment.

Others, particularly chronically depressed patients,

may improve symptomatically yet still function less

than optimally, or feel unsure about social risks or

career decisions. Such patients may benefit from ad-

junctive psychotherapy (Markowitz, 1993) to expand

their social confidence or behavioral repertoire. In ad-

dition, so-called sequential therapy, the use of CBT


after remission achieved with antidepressants for

acute treatment, may be of use (see (Fava and Ruini,

2002) for review).

19.8.4 Differential therapeutics

Behavioral therapy helps patients to schedule

pleasurable activities while avoiding painful ones.

Cognitive therapy, usually combined with behavioral

techniques, helps patients to identify cognitive distor-

tions with depressive biases, thoughts that are un-

necessarily painful, pessimistic and which inhibit

potentially valuable activity. IPT defines depression as

a medical disorder and focuses on the connection be-

tween mood and social situations or life circum-

stances ; it has been shown to build social skills.

Understandably, these therapies may have differing

appeals and benefits for different depressed in-

dividuals.

A few RCTs have directly compared IPT and CBT

(Elkin et al., 1989 ; Rossello and Bernal, 1999) or cog-

nitive therapy and behavioral therapy (Jacobson et al.,

1996). While showing non-significant differences in

outcome, these trials allowed evaluation of mod-

erators of treatment outcome. For example, patients

with poor concentration may respond better to IPT

than CBT, whereas those with a paucity of social skills

may fare better in CBT than IPT (Sotsky et al., 1991).

Far more research of differential therapeutics

is needed.

19.8.5 Comparing medications and psychotherapies

Medications work faster than psychotherapies and

are easier to administer to large populations, although

the therapeutic alliance is equally important for

both antidepressant modalities (Krupnick et al., 1996).

Empirically validated psychotherapies lack medi-

cation interactions, and have low adverse effects and

little risk of inducing mania in depressed bipolar

patients. They may address social stressors, such as

marital pressures, that could potentially trigger future

episodes. Psychotherapies have potential advantages

for depressed women during pregnancy and nursing;

may be better accepted by adolescents, particularly

given recent concerns about serotonin reuptake in-

hibitors in this population; and although not well

tested for depressed children, may be indicated in-

asmuch as medication has not shown benefit. In non-

industrialized countries, such psychotherapies may be

the only feasible, affordable treatments for depression

(Bolton et al., 2003). Psychotherapies adapted to dif-

ferent cultures must address the specific needs and

sensitivities of individuals in those cultures.

Psychotherapies are not intended to treat de-

pression with psychotic features, nor as monotherapy

for bipolar I disorder (Frank et al., 2005 ; Miklowitz

et al., 2003). Some severely depressed patients may

be too depleted to engage in psychotherapy effec-

tively. Patient preference is a predictor of treatment

outcome and hence deserves consideration in treat-

ment selection.

On the basis of their performance in controlled

efficacy trials, IPT and CBT should be included in

algorithms of standard treatment for depressive dis-

orders.

19.8.6 The attitude to CBT and IPT in Korea

Evidence-based medicine has begun to influence the

field of mental health in response to demands for ac-

countability and to address the well-documented dis-

parity between scientific evidence and actual practice

(Chatterjee et al., 2006). Psychotherapy is widely

practiced but has been less intensively studied than

pharmacotherapy because it has no industry to fund

it. Nevertheless, several prominent studies have

demonstrated the effectiveness of psychological ap-

proaches in patients with depression.

Practice guidelines published by several countries,

including the UK (National Institute for Health

and Clinical Excellence, 2004), US (Beutler et al., 2000)

and Canada (Segal et al., 2001b; Segal et al., 2001a)

suggest that psychotherapies for depression such

as CBT and IPT are equivalent to drugs in terms

of efficacy (DeRubeis et al., 1999; DeRubeis et al., 2005;

Hollon et al., 2002).

In Korea, pharmacotherapy for depression is widely

used. CBT was introduced, but few RCTs of CBT in

patients with depression have been published.

Moreover, little is known about IPT among mental

health professionals. Probably the most serious prob-

lems are the lack of IPT therapists (or supervisors) and

a lack of systematic training programs. Our task is to

resolve these problems.

Efficacious psychotherapies such as CBT and IPT

are both primary treatments and alternatives to

pharmacotherapy for depression. The issue of com-

bined psychotherapy and pharmacotherapy deserves

consideration. Many clinicians recommend combined

treatment for patients with depression, based simply

on the belief that combined treatment is more effective

than either pharmacotherapy alone or psychotherapy

alone. However, a meta-analysis showed that com-

bined therapy is superior to psychotherapy alone for

treatment of more severe, recurrent depression (Thase

et al., 1997). Combined treatment and antidepressant


alone, however, have similar efficacy and acceptability

(de Mello et al., 2005 ; Markowitz et al., 2005). This

absence of an adjunctive effect for psychotherapy

seems counterintuitive.

Note that several characteristics of patients and

disorders have been related to differential treatment

response. Some studies show that psychotherapy helps

to keep patients in pharmacotherapy (Pampallona

et al., 2004) and to discontinue medication without

increasing the risk for subsequent relapse or recur-

rence (Hollon et al., 2005). Combined treatment is

likely to be recommended for patients with more

complex or chronic disorders, or with a clinically un-

satisfactory response to either monotherapy (Hollon

et al., 2005). Yet whether combined treatment is more

effective than either monotherapy is controversial.

Further studies are required.


antidepressant drugs in the treatment of anxiety

disorders

The proven efficacy of antidepressant drugs

in relieving anxiety symptoms in patients with de-

pressive disorders naturally led to investigations of

their potential to relieve symptoms and reduce as-

sociated disability in patients with anxiety disorders,

including generalized anxiety disorder (GAD), panic

disorder, social phobia (also known as social anxiety

disorder), post-traumatic stress disorder (PTSD) and

obsessive-compulsive disorder (OCD). In clinical

practice, the need for treatment should be determined

by the severity and persistence of symptoms, and the

level of disability and impact on social functioning;

choice of treatment is influenced by patient character-

istics (such as previous response, concomitant medi-

cation and contraindications), the evidence base

supporting its use, patient and physician preference,

and the local availability of the proposed intervention

(Baldwin and Polkinghorn, 2005). In general, in com-

parison with mood disorders higher doses and longer

time of treatment are required to achieve response in

anxiety disorders.

19.9.1 Generalized anxiety disorder

In GAD, systematic reviews and placebo-

controlled randomized controlled trials (RCTs) indi-

cate that some SSRIs (escitalopram, paroxetine and

sertraline), the SNRI venlafaxine, and the TCA imi-

pramine are all efficacious in acute treatment (Baldwin

and Polkinghorn, 2005 ; Mitte et al., 2005). The small

number of comparator-controlled studies reveals

no consistent differences in efficacy between active

compounds (Mitte et al., 2005). Psychological symp-

toms of anxiety may respond better to antidepressant

drugs than to benzodiazepines (Baldwin and

Polkinghorn, 2005). Double-blind studies in patients

who have undergone acute treatment indicate that

continuing with an SSRI or SNRI is associated with a

further increase in overall response rates. Relapse-

prevention studies in patients who have responded

to previous acute treatment reveal a significant ad-

vantage for staying on active medication (escitalopram

or paroxetine), compared with switching to placebo,

for up to 6 months (Baldwin and Polkinghorn,

2005). When delivered singly, pharmacological and

psychological treatments have broadly similar efficacy

in acute treatment, but the comparative efficacy of

drug and psychological approaches over the long term

is not established. It is uncertain whether combining

drug and psychological treatments is associated with

greater efficacy than with either treatment given alone

(Baldwin and Polkinghorn, 2005).

19.9.2 Panic disorder

Randomized double-blind placebo-controlled trials of

antidepressants indicate that all SSRIs, some TCAs

(clomipramine, imipramine), and the SNRIs venlafax-

ine and the NARI reboxetine are efficacious in acute

treatment. Comparator-controlled studies provide

some evidence for the efficacy of mirtazapine and

moclobemide. The side-effect burden associated with

SSRI treatment in panic disorder is somewhat less than

with other classes of psychotropic drugs (Baldwin and

Birtwistle, 1998). Following acute treatment, continu-

ing with SSRIs or clomipramine is associated with

an increase in overall response rates, and placebo-

controlled and other relapse-prevention studies in

patients who have responded to acute treatment

reveal a significant advantage for staying on active

medication (fluoxetine, paroxetine, sertraline, imi-

pramine) compared with switching to placebo, for

up to 6 months (Baldwin and Polkinghorn, 2005).

Pooled analyses and RCTs indicate that drug and

psychological treatments, delivered singly, have simi-

lar efficacy in acute treatment, but suggest that CBT

may be superior to TCAs in preventing symptomatic

relapse (van Balkom et al., 1997). It has been

mentioned that there is some uncertainty whether

combining drug and psychological treatments is as-

sociated with greater overall efficacy than with either

treatment given alone (Barlow et al., 2000 ; van Balkom

et al., 1997), but a recently published meta-analysis

showed that combined therapy was more effective


than pharmacotherapy alone and was as effective as

psychotherapy (Furukawa et al., 2006). Therefore,

either combined therapy or psychotherapy alone has

been recommended as a first-line treatment for panic

disorder.

19.9.3 Social phobia

Systematic reviews and placebo-controlled RCTs in-

dicate that a range of antidepressants are efficacious,

including most SSRIs (escitalopram, fluoxetine, flu-

voxamine, paroxetine and sertraline), the SNRI venla-

faxine, the MAOI phenelzine, and the RIMA

moclobemide. Double-blind studies indicate that con-

tinuing SSRI or SNRI treatment from 12 weeks to

24 weeks is associated with an increase in overall

treatment response rates. Placebo-controlled relapse-

prevention studies in patients who have responded to

previous acute treatment reveal a significant advan-

tage for staying on antidepressant medication (escita-

lopram, paroxetine and sertraline), compared with

switching to placebo for up to 6 months (Baldwin and

Polkinghorn, 2005 ; Blanco et al., 2003). When de-

livered singly, pharmacological and psychological

treatments have broadly similar efficacy in acute

treatment, but acute treatment with cognitive therapy

may be associated with reduced risk of symptomatic

relapse at follow-up. It is uncertain whether com-

bining drug and psychological treatments is as-

sociated with greater overall efficacy than with either

treatment given alone (Baldwin and Polkinghorn,

2005 ; Blanco et al., 2003).

19.9.4 Post-traumatic stress disorder

Randomized, placebo-controlled trials provide

evidence for the efficacy of some SSRIs (fluoxetine,

paroxetine and sertraline), the SNRI venlafaxine,

the TCAs amitriptyline and imipramine, the MAOI

phenelzine and mirtazapine on some outcome

measures (Baldwin and Polkinghorn, 2005 ; Stein

et al., 2000). Following response to acute treatment,

continuing with venlafaxine or sertraline treatment

over 6 months is associated with a gradual increase

in overall treatment response. Placebo-controlled re-

lapse-prevention studies in patients who have re-

sponded to previous acute treatment reveal a

significant advantage for staying on active medication,

for fluoxetine (Davidson et al., 2005; Martenyi

et al., 2002) and sertraline (Davidson et al., 2001).

The comparative efficacy of psychological and phar-

macological treatments, in either acute or long-term

treatment, is uncertain (Baldwin and Polkinghorn,

2005).

19.9.5 Obsessive-compulsive disorder

Systematic reviews and meta-analyses of randomized

placebo-controlled trials indicate that the TCA clomi-

pramine and the SSRIs (citalopram, escitalopram,

fluoxetine, fluvoxamine, paroxetine and sertraline) are

efficacious in acute treatment. The efficacy of clomi-

pramine appears marginally superior to that of SSRIs

in meta-analysis (Ackerman and Greenland, 2002), but

the tolerability of SSRIs is generally superior (Fineberg

and Gale, 2005). Fixed-dose comparator studies pro-

vide inconsistent evidence for a dose-response re-

lationship with SSRIs, higher doses being associated

with greater efficacy in some, but not all evaluations

(Fineberg and Gale, 2005). Long-term (up to 12

months) double-blind studies show an advantage for

continuing with medication in patients responding to

acute treatment. Most relapse-prevention studies in

patients who have responded to acute treatment re-

veal a significant advantage for staying on active

medication (clomipramine, paroxetine, sertraline and

fluoxetine, at higher dose), compared with switching

to placebo (Fineberg and Gale, 2005). Combining

treatment approaches may be superior to psychologi-

cal approaches or serotonergic antidepressant treat-

ment given alone. The evidence for enhanced efficacy

of exposure therapy with clomipramine compared

with exposure alone is inconsistent, but fluvoxamine

has been shown to enhance the efficacy of exposure

therapy and CBT. Relapse rates may be greater after

initial treatment with a pharmacological rather than a

psychological intervention (Simpson et al., 2004).

19.10 Annex 10 : List of regional meetings and

countries represented

Regional meeting Participating countries

St. Petersburg,

Russia

Armenia, Azerbaijan, Belarus,

Georgia, Kazakhstan, Kyrgyz

Republic, Russia, Ukraine, Uzbekistan

Munich,

Germany

Austria, Denmark, Germany, Greece,

Croatia, Czech Republic, Hungary,

Poland, Serbia, Slovakia, Switzerland

Shanghai, China Australia, China, Hong Kong, Indonesia,

Japan, Korea, Pakistan, Philippines,

Singapore, Taiwan, Thailand

Caracas,

Venezuela

Argentina, Bolivia, Brazil, Chile,

Colombia, Costa Rica, Dominican

Republic, Ecuador, El Salvador,

Honduras, Mexico, Nicaragua, Panama,

Peru, Uruguay, Venezuela

Paris, France France, Egypt, Luxembourg, Morocco,

Spain, Sweden, Tunisia, Turkey


19.11 Annex 11 : Suggestions concerning the

organization of national review meetings

Aims of the meeting

The national meetings should help to bring together

the experience and evidence about the use of anti-

depressant medications in the treatment of depressive

disorders obtained in the countries where the meet-

ings are taking place.

Participants

Participants in national meetings should be experts

representing the fields of psychiatry, pharmacology,

internal medicine and general practice, government

officials dealing with mental health and with questions

of medications, representatives of family or patient

organizations, and persons representing insurance

and the pharmaceutical industry. In all, it is expected

that 12–15 participants will take part in the national

meetings. Subsequently, it would be useful to bring

the results of the review to the knowledge of larger

audiences, both professional and non-professional,

representing the stakeholders involved in the care for

people with depressive disorders.

The agenda and method of work

All the participants should receive the CINP Technical

Review in the language that they can easily use. The

CINP Technical Review has been translated into

Chinese, English, French, Russian and Spanish. It is

also probable that an Arabic version will be prepared

shortly. In some instances, a translation into the

national language will be necessary. The meetings

should take place after the participants have had a

chance to examine the review and prepare their notes

and proposals about additions, comments and changes

that would reflect the national experience and evi-

dence obtained locally and which has not been in-

cluded in the review. The agenda should include a

detailed examination of the CINP Technical Review

and a discussion that will lead to the formulation of a

national report to be added to and considered in con-

junction with the review.

Administrative steps

The convener of the national meeting should prepare a

list of participants, a detailed agenda and a timetable

for the meeting indicating its location and proposed

dates. The proposal should also list the members of the

CINP Task Force or other experts that the convener

would like to invite as resource persons to the meeting.

A budget for the meeting should be prepared, includ-

ing expenditures for travel and accommodation of the

participants, the cost of translation into the national

language and the cost of hiring the meeting location if

necessary. No honoraria should be requested.

Proposals should be sent to Prof. N. Sartorius as soon

as possible so that they can be included in the sum-

mary of work and proposals that will be submitted to

the CINP.

Publication of findings

It is expected that each of the national meetings will

produce a local publication in the national language or

in English. The publication should assemble the points

that will be relevant for the use of antidepressant

medications in the country. Should the group decide

to also publish the Technical Review in the national

language the convener should inform the CINP ac-

cordingly. The national reports will be brought to-

gether, and their findings will be published in an

international journal together with an update of the

Technical Review (should an update prove to be

necessary). The publications will be posted on the

CINP website, together with the review.

19.12 Annex 12: Additional information on the

European Federation of Associations of Families

of People with Mental Illness (EUFAMI)

EUFAMI, the European Federation of Associations

of Families of People with Mental Illness, is the

representative body for voluntary organizations

throughout Europe, promoting the interests and well-

being of people with mental illness and their carers.

Founded in 1992, EUFAMI is a democratic, member-

led organization, registered in Brussels, under Belgian

law. EUFAMI was formed by members of carer

organizations who, overwhelmed by the trauma of

severe mental illness in the family, and finding their

ability to cope undermined, shared their experience

of helplessness and frustration, and resolved to work

together to help themselves and the people that they

care for. Today, EUFAMI has 48 member organiz-

ations from 1 non-European and 26 European

countries.

EUFAMI’s aims are to ensure the continuous im-

provement throughout Europe – and by association

around the world – of the quality of care and welfare

for people with mental illness and their families.

To meet this need, EUFAMI lobbies governments to

provide appropriate financial support for families

and carers as an integral part of their budget. EUFAMI

also works to establish a charter of rights of families


of carers and offers its services in teaching health

professions and planning services for the men-

tally ill.

19.12.1 EUFAMI’s aims

$ To achieve continuous improvement throughout

Europe in mental health generally, in the quality of

care and welfare for mentally ill people, and in the

level of support for their caring relatives and

friends.$ To enable member associations to combine their ef-

forts and act jointly at the European level to achieve

those aims.$ To strengthen and assist member associations in

their effort to improve mental health conditions in

their own territories, while fully respecting their

national or regional autonomy.

19.12.2 EUFAMI’s principles

$ Carers must be acknowledged as equal partners

with professionals in the care team supporting the

person with mental illness.$ Carers need support in their own right and have

independent needs which must be recognized and

respected.$ All people with mental illness should be cared for in

an appropriate environment and provided with a

comprehensive range of health-care and social care

services.$ All people with mental illness should have the right

to share in the opportunities, enjoyments, challenges

and responsibilities of everyday life.

19.12.3 EUFAMI’s mission

$ Contribute to removing the stigma surrounding

mental illness by promoting positive images to

counteract ignorance and misinformation.$ Highlight examples of good practice in the field of

mental illness in order to promote good practice

throughout Europe; identify examples of bad prac-

tice in the field of mental illness and campaign for

positive change.$ Lobby for greater equality of legislation throughout

Europe in order to bring about improvements in the

health and social care of people with mental illness,

and in the well-being of their carers.$ Promote and support further research into the

causes and treatment of mental illness.$ Campaign for adequate resources for the health and

social care of people with mental illness and their

carers.

19.13 Annex 13 : List of Advisors

AGUILAR Mario, Vice-President, Honduran

Society of Psychiatry

[email protected]

ALEMAN Luis Enrique, Secretary of the

Nicaraguan Society of Psychiatry, Masaya

[email protected] ; [email protected]

ALLAIN Herve, Laboratoire de Pharmacologie,

Universite de Rennes I – Faculte de Medecine, 35043

Rennes Cedex, France

[email protected]

ALLILAIRE Jean-Francois, Chef du Service de

Psychiatrie (Adultes), Consultation Chaslin, Hopital

de la Salpetriere, 47, Bd de l’Hopital, 75651 Paris

Cedex 13, France

[email protected]

ALVAREZ M. Carmen, General Secretary,

Venezuelan Society

[email protected]

ANSSEAU Marc, Chairman of the, Department of

Psychiatry, University of Liege, B-4000 Liege, Belgium

[email protected]

AVEDISOVA Alla, Head of New Drugs Division,

Serbsky Centre for Social and Forensic Psychiatry,

Moscow, 123367, Russia

[email protected]

AZORIN Jean-Michel, SHU Psychiatrie Adultes,

Hopital de Sainte-Marguerite, 13274 Marseille Cedex

09, France

[email protected]

BAUER Michael, Head of the Department

of Psychiatry and Psychotherapy,

Universitatsklinikum Carl Gustav Carus, D-01307

Dresden, Germany

[email protected]

BAUMANN Pierre, University Department of

Psychiatry, Site de Cery, CH-1008 Prilly-Lausanne,

Switzerland

[email protected]

BECH Per, Psychiatric Research Unit, Frederiksborg

General Hospital, 3400 Hillerød, Denmark

[email protected]

BELFORT Edgard, WPA Zonal Representative,

WFMH Board of Directors, Caracas 1010, Venezuela


BELMAKER R.H., Beersheva Mental Health Center,

Beersheva, Israel

[email protected]

BERK Michael, Barwon Health and Geelong Clinic,

Swanston Centre, The University of Melbourne,

Geelong, Victoria 3220, Australia

[email protected]


BLIER Pierre, University of Ottawa, Institute of

Mental Health Research, Ottawa ONK1Z 7K4, Canada

[email protected]

BOBROV Alexander, Head of the Department of

Psychiatry, Irkutsk State Institute of Postgraduate

Education for Physicians, Irkutsk, 664079, Russia

[email protected]

BOULENGER Jean-Philippe, Service Universitaire

de Psychiatrie Adulte, INSERM Equipe E-361, Hopital

La Colombiere, CHU de Montpellier : 39 Avenue

Charles Flahault, F-34295-Montpellier Cedex 5

[email protected]

BRASIL Marco Antonio, Past-President, Brazilian

Association of Psychiatry, Rio de Janeiro

[email protected]

BURROWS Graham D., The University of

Melbourne, Department of Psychiatry, Austin

Hospital, Heidelberg, Victoria 3084, Australia

[email protected]

CAI Zhuoji, President, Chinese Mental Health

Association, Beijing

[email protected]

CALDERON Jose, President, Panama Society of

Psychiatry

[email protected]

CALDERON Minerva, Forensic Psychiatry,

Forensic Medical Institute

[email protected]

CALIL Helena Maria, Department of

Psychobiology, Paulista Faculty of Medicine, Federal

University of Sao Paulo, Sao Paulo, Brazil

[email protected]

CANNEVA Jean, President of UNAFAM, France

[email protected]

CASTRO Rojas Rigoberto, President, Costa Rican

Psychiatric Association, San Jose

[email protected]

CARROLL Bernard, Pacific Behavioral Research

Foundation, P.O. Box 223040, Carmel, CA 93922-3040,

USA

[email protected]

CHENG Nengneng, Pharmacology School, Fudan

University, P. R. China

[email protected]

CHONG Mian-Yoon, Chairman, Department of

Psychiatry, Chang Gung Memorial Hospital,

Niao-Sung Hsiang, Kaohsiung County 83342,

Taiwan

[email protected]

CORDOBA Rodrigo, General Director, CISNE

[email protected]

CORREA Eduardo, Professor, Chile University

[email protected]

CORRUBLE Emmanuelle, Service de Psychiatrie,

CHU de Bicetre, 94270 Le Kremlin Bicetre,

France

[email protected]

COWEN PJ, Neurosciences Building, Warneford

Hospital, Oxford OX3 7JX, UK

[email protected]

DANIELYAN Konstantin, Head of the Psychiatry,

Psychotherapy & Medical Psychology Department,

National Institute of Health of RA Armenia

[email protected]

DANION Anne, Child Psychiatrist, Strasbourg,

France

[email protected]

DELGADO Fabrizio, President of the Ecuadorian

Association of Psychiatry

[email protected]

DE VANE C. Lindsay, Department of Psychiatry &

Behavioral Sciences, Director, Laboratory of Drug

Disposition and Pharmacogenetics, Medical

University of South Carolina, USA

[email protected]

DOUKI Saıda, Chef de Service de

Psychiatrie, Hopital Razi, 2010 La Manouba,

Tunis, Tunisia

[email protected]

EVSEGNEEV Roman, Head, Department of

Psychiatry, Byelorussian Medical Academy for

Postgraduate Education, President, Byelorussian

Psychiatric Association, Belarus

[email protected]

FALISSARD Bruno, Epidemiologist and

Psychiatrist, Paris, France

[email protected]

FERNANDEZ Alberto, Researcher, Neuroscience

Institute

[email protected]

FINK Max, M.D., Psychiatry and Neurology

Emeritus at Stony Brook University, Long Island,

St. James, NY 11780-0457, USA

[email protected]

FLORES Julio, Adviser Psychiatrist, Central

Nervous System, Venezuela

[email protected]

FRITZE Jurgen, Leitender Arzt,Verband der

privaten Krankenversicherung e.V. (German

Association of Private Health Insurers), 50968 Koln,

Germany


FOUNTOULAKIS K.N., 3rd Department of

Psychiatry, Arisotle University of Thessaloniki,

55132 Aretsou Thessaloniki, Greece

[email protected]


FURUKAWA Toshiaki, Chair of the Department

of Psychiatry and Cognitive-Behavioral

Medicine, Nagoya City University Graduate

School of Medical Sciences, Nagoya 467-8601

Japan

[email protected]

GALLEGOS Rogelio, Mexican Health National

Service Representative, Mexico

[email protected]

GASTELUMENDI Eduardo, Director,

Neurosciences Institute ; Past-President of the

Peruvian Society of Psychiatry

[email protected]

GASZNER Peter, Orszagos Pszichiatriai Es

Neurologiai Intezet, 1021 Budapest, Hungary

[email protected]

GAVIRIA Silvia

[email protected]

GERARD Alain, Psychiatrist, Paris, France

[email protected]

GINNARI ANTICH Guillermo, President,

Venezuelan Society of Psychiatry, Caracas

[email protected]

GODARD Nathalie, Child Psychiatrist, Director

of a private institution, Garches, France

GONZALEZ Celso, Psychiatrist Researcher,

University General Hospital

[email protected]

GOODWIN Frederick, 5712 Warwick Place,

Chevy Chase, MD 20815, USA

[email protected]

GORWOOD Philip, Paris, France

[email protected]

GRIGORIEVA Elena A, Head of the Department of

Psychiatry, Yaroslavl Medical Academy, Yaroslavl,

150000, Russia

[email protected]

GU Niufan, Shanghai Mental Health Center,

Shanghai, 200030

[email protected]

GUREJE Oye, Head of the Department of

Psychiatry, University College Hospital, Ibadan,

Nigeria

[email protected]

HAEN Ekkehard, Psychiatrische Universitatsklinik,

Medizinische Einrichtungen des Bezirks Oberpfalz,

93053 Regensburg, Germany

[email protected]

HEALY David, North Wales Department of

Psychological Medicine, Cardiff University,

Hergest Unit, Ysbyty Gwynedd, Bangor, Wales

LL57 2PW, UK

[email protected]

HE Yanling, Shanghai Mental Health Center,

Shanghai, 200030


HEGERL Ulrich, Klinik und Poliklinik fur

Psychiatrie und Psychotherapie, Universitatsklinikum

Leipzig, Johannisallee 20, D-04317 Leipzig, Germany

[email protected]

HINDMARCH Ian, HPRU Medical Research

Centre, University of Surrey, Guildford, Surrey

GU2 7XP, UK

[email protected]

HOSCHL Cyril, Director, Prague Psychiatric

Center, 181 03 Praha 8, Czech Republic

hoschl@ pcp.lf3.cuni.cz

HU Teh-Wei, Professor of Health Economics,

University of California, School of Public Health,

Berkeley, CA 94720, USA.

[email protected]

HWANG Tae-Yeon, Director, WHO Collaborating

Center for Psychosocial Rehabilitation and

Community Mental Health, Yongin Mental Hospital,

Korea

[email protected]; [email protected]

IRMANSYAH, Psychiatrist, Department of

Psychiatry, Faculty of Medicine, University of

Indonesia, Jakarta 10430, Indonesia

[email protected]

ISACSSON Goran, Karolinska Institute, Huddinge

University Hospital, S-141 86 Stockholm, Sweden

[email protected]

ISMAYILOV Nadir, Azerbaijan Medical University,

Baku

[email protected]

IVANOV Michail, Head of the Department

of Psychopharmacotherapy of the Bekhterev Psycho-

neurological Institute, St-Petersburg 192019, Russia

[email protected]

IVONOVIC Fernando, Head of Bipolar Disorders

Unit, Chile University

[email protected]

JAKOVLEVIC Miro, Department of Psychiatry,

School of Medicine, University of Zagreb,

Zagreb – Rebro, Croatia

[email protected]

JIANG Kaida, Shanghai Mental Health Center,

Shanghai, 200030

[email protected]

KANBA Shigenobu, Department of

Neuropsychiatry, Kyushu University, Fukuoka,

812-8582, Japan

[email protected]

KASAKOVTSEV Boris, Deputy Head of the section

of legislative regulation of specialized medical care,


Ministry of Public Health and Social Development,

Moscow, Russia

[email protected]

KASPER Siegfried, Department of General

Psychiatry, University of Vienna,

A-1090 Vienna, Austria

[email protected]

KATON Wayne J., M.D., Vice Chair of the

Department of Psychiatry and Behavioral Sciences,

University of Washington, WA 98195, USA

[email protected]

KECK Paul E., Jr., Department of Psychiatry,

University of Cincinnati College of Medicine,

Cincinnati, OH 45267-0559, USA

[email protected]

KENNEDY Sidney H, University Health Network,

Toronto, Ontario M5G 2C4, Canada.

[email protected]

Christian KLESSE, Uniklinik fur Psychiatrie und

Psychosomatik, 79104 Freiburg, Germany

[email protected]

KOSEL Markus, Klinik fur Psychiatrie,

Uniklinikum, 53105 Bonn, Germany

[email protected]

KRAMMLING Franz-Georg, BKK LV Bayern, 81476

Munchen, Germany

[email protected]

KRASNOVValery, Director of theMoscowResearch

Institute of Psychiatry 107076 Moscow, Russia

[email protected], [email protected]

KUPFER David J., University of Pittsburgh Western

Psychiatric Institute and Clinic, Pittsburgh,

Pennsylvania 15261, USA

[email protected]

KUTCHER, Stan Dalhousie University

Department of Psychiatry 5909 Veterans Memorial

Lane 9th Floor, AJLB Halifax, Nova Scotia B3H 2E2,

Canada

[email protected]

LAM Raymond W., Division of Clinical

Neuroscience, Department of Psychiatry, University

of BC, Vancouver, BC, Canada

[email protected]

LANDER Hugo, President, Argentinean Society of

Psychiatrists

[email protected]

LANDOWSKI Jerzy, Chief, Clinic of Psychiatric

and Neurotic Disorders, Department of Psychiatry,

Medical University of Gdansk, 80-211 Gdansk, Poland

[email protected]

LAPREA Isabel, Child and Adolescent Psychiatrist,

UCV

[email protected]

LEE Min-Soo, Department of Psychiatry, Korea

University College of Medicine, Seoul, 136-705 Korea

[email protected]

LEPINE Jean-Pierre, Hopital Fernand Widal,

Assistance Publique, Hopitaux de Paris, INSERM U

705, 75475 Paris, France

[email protected]

LEVINA Nelly, Chief of the All-Russian Society of

disabled mentally ill and their relatives ‘New

Choices’, Moscow 107076, Russia

[email protected]

LI Lingjiang, Director of the Mental Health Institute,

Xiangya Medical School, Central South University,

Changsha, Hunan 410011

[email protected]

LOPEZ-IBOR Juan Jose, Clinica Lopez Ibor, E-28035

Madrid, Spain

[email protected]

MA Hong, Institute of Mental Health, Peking

University, Beijing 100083

[email protected]

MACIAS Nestor, Board Member, Venezuelan


[email protected], [email protected]

MAGZUMOVA Shakhnoza, Uzbekistan

[email protected]

MAJ Mario, Director of the Institute of Psychiatry,

University of Naples, 80138 Napoli, Italy

[email protected]

MALYAROV Sergiy, Head of the Liaison and

Research Department Kiev City Psychiatric Hospital

#2, Kiev 02660, Ukraine

[email protected] or [email protected]

MANJI Husseini K., Director, Mood and Anxiety

Disorders Program, Chief, Laboratory of Molecular

Pathophysiology, NIMH, Porter Neuroscience

Research Center, Bethesda, MD 20892, USA

[email protected]

MARTINEZ Danilo, Coordinator, Postgraduate

Psychiatry Training Program, Military Hospital


MARTINY Klaus, Psychiatric Research Unit,

Hilleroed Hospital, Hilleroed, 3400, Denmark

[email protected]

MAZZARELLA Xiorela, Caracas Psychiatric

Hospital, Head Unit No. 3, Caracas, Venezuela

[email protected];

[email protected]

MELLA Cesar, Vice-President, Latin American

Psychiatric Association

[email protected]

MILLET Bruno, Adult Psychiatry of Rennes

Centre Hospitalier Guillaume Regnier


108, avenue du General Leclerc BP 226,

35011 Rennes Cedex, France

[email protected]

MINHAS Fareed, Head, Institute of Psychiatry,

Rawalpindi General Hospital, Rawalpindi, Pakistan

[email protected]

MOLLER Hans-Jurgen, Chairman of the Psychiatric

Hospital of the University Munich, 80336 Munchen,

Germany

[email protected]

MONTANO Everth, President, Bolivian Society of

Psychiatry

[email protected]

MOSOLOV Sergey, Head of the Department of

Therapy of Mental Disorders, Moscow Research

Institute of Psychiatry, Moscow 107076, Russia

[email protected]

MOUSSAOUI Driss, Faculte de Medecine de

Casablanca, Centre Psychiatrique Universitaire Ibn

Rushd, Casablanca, Moprocco

[email protected]

NETTER Petra, Department of Psychology,

University of Giessen, 35394 Giessen, Germany

[email protected]

NEZNANOV Nikolay, Director of the Bekhterev

Psychoneurological Institute, St-Petersburg 192019,

Russia


NURMAGAMBETOVA Saltanat, Almaty,

Kazakhstan 480012

[email protected]

OKASHA Ahmed, Director of WHO Collaborating

Center, Institute of Psychiatry, Ain Shams University,

Kasr El Nil, Cairo – Egypt

[email protected]

ORAL Timucin, Bakirkoy Ruh ve Sinir Hastaliklari

Hastanesi, Bakirkoy Istanbul, Turkey

[email protected]

PADILLA Franklin, Vice-President, Venezuelan

Society ; Director, Postgraduate Psychiatry Training

Programme, Caracas Psychiatric Hospital, Caracas,

Venezuela

[email protected]

PALOVA Eva, Department of Psychiatry,

University of P.J. Safarik, 040 6 Kosice, Slovakia

[email protected]

PARKER Gordon, School of Psychiatry, University

ofNew SouthWales, Northwood,NSW2066, Australia

[email protected]

PAUNOVIC Vladimir R., Institute of Psychiatry,

Clinical Center of Serbia, 11000 Belgrade, Serbia &

Montenegro

[email protected]

PIDKORYTOV Valeriy, Chief, Department of

Clinical, Social and Child Psychiatry Institute of

Neurology, Psychiatry and Narcology AMS of

Ukraine, 61068 Kharkiv, Ukraine

[email protected]

POIRIERMarie-France, Hopital Sainte-Anne, SHU/

U796, Paris, France

[email protected]

POUY Artigas, General Secretary, Latin American


[email protected]

PULL Charles, Service de Neuropsychiatrie, Centre

Hospitalier de Luxembourg, 1210 Luxembourg

[email protected]

QUIRION Remi, Douglas Hospital Research

Centre, McGill University, Verdun, Quebec H4H 1R3,

Canada

[email protected]

REMSCHMIDT Helmuth, Philipp Universitat,

Head, Klinik fur Kinder- und Jugend Psychiatrie,

35033 Marburg, Germany

[email protected] ;

[email protected]

REQUENA Alvaro, Head, Department of

Psychiatry, Venezuelan Red Cross

[email protected]

RIECHER Anita, Psychiatrische Poliklinik,

Universitatsspital Basel, 4031 Basel, Switzerland

[email protected]

RIHMER Zoltan, Magyar Jakob, Tere, 6. 1/1, 1122

Budapest, Hungary

[email protected]

RIVERA TREJO Gerardo, President, El Salvador


[email protected]

ROBERT Philippe, CHU – Hopital Pasteur, 06002

Nice Cedex, France

[email protected]

RODRIGUEZ Miguel Angel, Publication,

Venezuelan Society of Psychiatry

[email protected]

RODRIGUEZ Olga, Child and Adolescent Training

Postgraduate Program, Tachira Hospital

[email protected]

ROBERT Philippe, Nice, France

[email protected]

RUBIN Robert, Los Angeles, CA 90025-7821, USA

[email protected]

RUIZ Pedro, Vice Chair for Clinical Affairs,

Department of Psychiatry and Behavioral Sciences,

University of Texas-Houston Mental Sciences

Institute, Houston, TX 77030, USA

[email protected]


RUSH John A., Jr., M.D., Vice-Chair, Department of

Clinical Sciences, Department of Psychiatry,

University of Texas SW Medical Center, Dallas, TX

75390-7208, USA

[email protected]

SALAZAR Gerardo Carmelo B, Department of

Neurosciences, Lucena United Doctors Hospital,

Manila, The Philippines

[email protected]

SALAZAR Ismael, Director of the Mental Health

Hospital Social Security


SALETU Bernd, Section of Sleep Research

and Pharmacopsychiatry, Department of Psychiatry,

Medical University of Vienna, 1090 Vienna, Austria

[email protected]

SANCHEZ Carlos, Assistant, Latin American


[email protected]

SCHLAEPFER Thomas E., Psychiatry & Mental

Hygiene, Department of Psychiatry, University

Hospital, Bonn 53105, Germany

[email protected]

SECHTER Daniel, Besancon, France

[email protected]

SEMKE Valentin, Director of the Institute of

Psychiatry of the Tomsk Scientific Centre, Siberian

Division of the Russian Academy of Medical Science,

Tomsk, Russia

[email protected]

SIMON Gregory, Group Health Cooperative of

Puget Sound, Centre for Health Studies. Seattle, WA

98101, USA

[email protected]

STEFFEN Sigrid, Vice-President, European

Federation of Associations of Families of Mentally Ill

People (EUFAMI), 5020 Salzburg, Austria

[email protected]

STUPPACK Christoph, Universitatsklinik fur

Psychiatrie 1, Christian-Doppler-Klinik, Salzburg,

5020 Salzburg, Austria

[email protected]

SULTANOV Agabek A., Gashumbekoglu, Manager

of the chair of Psychiatry Medical University, Baku,

Azerbaijan

[email protected]

SUN Xueli, 7# Xiao Xue Road, Chengdu, Sichuan

610041


TAN Chay-Hoon, Department of Psychological

Medicine, National University Hospital, Singapore

119074

[email protected]

TANG Siu-Wa, Chair of the Department of

Psychiatry University of Hong Kong

[email protected]

TEN Vladimir, Head, Department of Clinical

Psychology and Psychiatry Kyrgyz State Medical

Academy, Bishkek 720023, Kyrgyz Republic

[email protected]

THASE Michael E., University of Pittsburgh

Medical Center, Pittsburgh PA 15213-2593, USA

[email protected]

THIBAUT Florence, University Hospital Ch.

Nicolle, INSERM, Rouen, France

[email protected]

UDOMRATN Pichet, President, The Psychiatric

Association of Thailand (PAT), Department of

Psychiatry, Faculty of Medicine, Prince of

Songkla University, Hat Yai, Songkhla 90110,

Thailand

[email protected]

VAHIP Simavi, Affective Disorders Unit, Ege

University Department of Psychiatry Bornova-Izmir

TR-35100, Turkey

[email protected]

VAN PRAAG Herman M., Huize Berghorst, 7315

HD Apeldoorn, The Netherlands

[email protected]

VIETA PASCUAL Eduard, Director of Research,

Clinical Institute of Neuroscience, Director of

Bipolar Disorders Program, Hospital Clinic,

University of Barcelona, IDIBAPS, 08036 Barcelona,

Spain

[email protected]

WANG Liwei, Shanghai Mental Health Center,

Shanghai, 200030, P. R. China

[email protected]

WATANABE Yasuo, Department of

Pharmacology/Pharmacotherapy, Nihon

Pharmaceutical University, Saitama 362-0806,

Japan


WIED Viktor D., Deputy Director of the Bekhterev

Psychoneurological Institute, St. Petersburg 192019,

Russia

[email protected]

WOOLEY Stephanie, Presidente, Association

France Depression, 4, rue Vigee Lebrun, 75 015

Paris, France

YAN Heqin, Director, Shanghai Mental Health

Centre, Shanghai


YI Chengdong, Director General, Shanghai

Food and Drug Administration Bureau, Shanghai

[email protected]


YOUDIM Moussa B.H., Director of Eve Topf and

National Parkinson Foundation (US), Centers

of Excellence for Neurodegenerative

Diseases, Technion-Faculty of Medicine, Haifa,

Israel.

[email protected]

YOUNG Allan Hunter, LEEF Chair in Depression

Research ; Associate Director, Institute of Mental

Health ; Department of Psychiatry, University of

British Columbia, Vancouver, BC Canada V6T 2A1,

Canada

[email protected]

XIAO Zeping, Shanghai Mental Health Center,

Shanghai, 200030, P. R. China

[email protected]

XIE Bin, Shanghai Mental Health Center, Shanghai,

200030, P. R. China

[email protected]

XU Yifeng, Shanghai Mental Health Center,

Shanghai, 200030, P.R. China

[email protected]

YU, Xin, Director of the Institute of Mental Health,

Peking University 100083, Beijing, P.R. China

[email protected]

ZHANG Li, Director, CDC on Mental Health,

Ministry of Health, Beijing, P.R. China

[email protected]

ZHANG Mingyuan, Shanghai Mental Health

Center, Shanghai, 200030, P.R. China

[email protected]

ZHOU Dongfeng, President, Chinese Psychiatry

Association

[email protected]

ZVARTAU Edvin, Vice-rector, St.-Petersburg State

Medical University, St. Petersburg, Russia

[email protected]

20 Abbreviations

+5-HT1=serotonin 1 receptor stimulation

5-HT2=serotonin 2 receptor antagonism

5-HT2c=5-HT2c receptor antagonist

5-HT3=serotonin 3 receptor antagonism

a1=a1 receptor antagonism

a2=a2-receptor antagonism

all. 5HTT=binding to the allosteric site of the

serotonin transporter

ACTH=adrenocorticotropic hormone,

corticotropin

ACNP=American College of

Neuropsychopharmacology

AD=Alzheimer’s disease

ADH=antidiuretic hormone

ADHD=attention-deficit hyperactivity disorder

AHCPR=Agency for Health Care Policy and

Research

AIDS=acquired immune deficiency syndrome

APA=American Psychiatric Association

APD=amphetamine prodrug

APOE=apolipoprotein E

BAC=blood alcohol concentration

Bcl-2=B-cell lymphoma 2 (anti-apoptotic protein)

BDI=Beck Depression Inventory

BDNF=brain-derived neurotrophic factor

BPRS=Brief Psychiatric Rating Scale

CANMAT=Canadian Network for Mood and

Anxiety Treatments

CBA=Cost-benefit analysis

CBASP=Cognitive Behavioral Analysis System of

Psychotherapy

CBT=cognitive behavioral psychotherapy

CD=combined depression (MDD and RBD)

CGI-I=Clinical Global Impressions-Improvement

Score

CDRS-R=Children’s Depression Rating

Scale-Revised

CEA=cost-effectiveness analysis

CEAC=cost-effectiveness acceptability curve

CIDI=Composite International Diagnostic

Interview

CINP=Collegium Internationale

Neuro-Psychopharmacologicum

CNS=central nervous system

COX=cyclo-oxygenase

CRF=corticotropin releasing factor (=CRH)

CRH=corticotropin releasing hormone (=CRF)

CSF=cerebrospinal fluid

CSM=Committee on Safety of Medicine (UK)

CUA=cost-utility analysis

DA=dopamine (D2) receptor antagonist

DALY=disability-adjusted life years

DBS=deep brain stimulation

DCS=d-cycloserine

DEPRES=Depression Research in European

Society

DGPPN=Deutsche Gesellschaft fur Psychiatrie,

Psychotherapie und Nervenheilkunde

DHEA=dehydroepiandrosterone

DLPFC=dorsolateral prefrontal cortex

DNRI=dopamine and noradrenaline reuptake

inhibitor


DRI=dopamine reuptake inhibition

DSM=diagnostic and statistical manual of mental

disorders

EA=electro-acupuncture

ECT=electroconvulsive therapy

EMEA=European Medicines Agency

ENRICHD=Enhancing Recovery in Coronary

Heart Disease Patients Randomized Trial

ER=extended release

ES=effect size

EUFAMI=European Federation of Association of

Families of People with Mental Illness

ESEMeD=European Study of the Epidemiology of

Mental Diseases

FDA=Food and Drug Administration

GABA=c-amino butyric acid

GAD=generalized anxiety disorder

GM=glutamatergic modulator

GP=general practitioner

H1=blockade of histamine 1 receptors

HAMA=Hamilton rating scale for anxiety

HAMD=Hamilton rating scale for depression

HIV=human immunodeficiency virus

HPA=hypothalamic pituitary adrenal

ICD=international classification of diseases

ICER=incremental cost-effectiveness ratio

ICPE=International Consortium of Psychiatric

Epidemiology

IL=interleukin

IPC=interpersonal counseling

IPT=interpersonal psychotherapy

IR=immediate release

K-SADS=Childhood Version of the Schedule for

Affective Disorders and Schizophrenia

LIDO=Longitudinal Investigation of Depression

Outcomes

M1=blockade of cholinergic muscarinic receptors

MAI=monoamine oxidase A inhibition

MADRS=Montgomery–Asberg depression rating

scale

MAOI=irreversible inhibitor of monoamine

oxidase A and B

MAOBI=irreversible inhibitor of monoamine

oxidase B

MAP=mitogen-activated protein

MBI=monoamine oxidase B inhibition

MCC=Medical Control Council of South Africa

MDD=major depressive disorder

MHID=Mantel-Haenszel incidence difference

MHRA=Medicines and Healthcare products

Regulatory Agency

MHRD=Mantel–Haenszel exposure time-adjusted

rate difference

MINI=Mini International Neuropsychiatric

Interview

MRI=magnetic resonance imaging

MST=magnetoconvulsive therapy

MT1/MT2=melatonin 1 and melatonin 2 receptor

agonist

MT=melatonergic antidepressant

M-TCA=modified tricyclic antidepressant

NA=noradrenaline (=norepinephrine)

NAR=noradrenaline-releasing properties

NARI=selective noradrenaline (norepinephrine)

reuptake inhibitor

NaSSA=noradrenergic and selective serotonergic

antidepressant

NCP=NeuroCybernetic Prosthesis (System)

NGF=nerve growth factor

NIMH=National Institute of Mental Health

NK1=neurokinin 1

NMDA=N-methyl-D-aspartate

NMS=neuroleptic malignant syndrome

NN=nomen nescio (unknown author)

NRI=noradrenaline (norepinephrine) reuptake

inhibition/inhibitor

N-TCA=tricyclic antidepressant with primary

noradrenergic effects

N-TetraCA=tetracyclic antidepressant with

primary noradrenergic effects

OCD=obsessive compulsive disorder

OR=odds ratio

PD=Parkinson’s disease

PET=positron emission tomography

PHQ=Patient Health Questionnaire

PKC=protein kinase C

PMDD=premenstrual dysphoric disorder

PSD=partial sleep deprivation

PTSD=post-traumatic stress disorder

QALY=quality-adjusted life year

RCT=randomized controlled trial

RBD=recurrent brief depression

RIMA=reversible inhibitor of monoamine

oxidase A

rTMS=repetitive transcranial magnetic

stimulation

SCID=Structured Clinical Interview for Diagnostic

and Statistical Manual of Mental Disorders

SMA=serotonin-modulating antidepressant

SMR=standard mortality ratio

SNRI=selective serotonin and noradrenaline

reuptake inhibitor

S/N-TCA=tricyclic antidepressant with similar

serotonergic and noradrenergic effects

SP=substance P

SRI=serotonin reuptake inhibition


SRS=serotonin reuptake stimulation

SSRI=selective serotonin reuptake inhibitor

TADS=Treatment for Adolescents with

Depression Study

SAD=seasonal affective disorders

SD=sleep deprivation

SDLP=standard deviation of lateral position

STAR*D=Sequenced Treatment Alternatives to

Relieve Depression

S-TCA=tricyclic antidepressant with primary

serotonergic effects

S-TetraCA=tetracyclic antidepressant with

primary serotonergic effects

TAU=treatment as usual

tDCS=transcranial direct current stimulation

TDM=therapeutic drug monitoring

TNF=tumor necrosis factor

TRD=treatment resistant depression

TSD=total sleep deprivation

UK=United Kingdom

US=United States of America

VNS=vagus nerve stimulation

WFSBP=World Federation of Societies of

Biological Psychiatry

WHO=World Health Organization

WPA=World Psychiatric Association

XR=extended release

YLD=years lived with disability


CINP - Antidepressant Medications

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