View Sample PDF - Clinical Publishing

Therapeutic Strategies in

SCHIZOPHRENIAA. Mortimer · P. McKenna

CLINICAL PUBLISHING

TherapeuticStrategies

inSCHIZO

PHRENIA

Mortim

erMcKenna

CLIN

ICALPUBLIS

HIN

G

This new volume updates the reader on the therapeutic optionsavailable for the management of schizophrenia, aiding the clinician totranslate scientific evidence into improved outcomes. This book alsopresents a thorough discussion of the new generation of ‘atypical’antipsychotic drugs – their mode of action and their clinical efficacy in arange of applications. These new agents are compared with existingmedications, guiding the reader on their use in combination with othertreatments as part of an integrated programme of patient management.Additional special topics covered include metabolic side-effects, earlypsychosis, cognitive behavioural therapy, comorbid substance abuseand emergencies.

RELATED TITLES

Therapeutic Strategies in DementiaC. W. Ritchie, D. Ames, C. L. Masters, J. CummingsISBN 978 1 904392 58 3

The Year in Schizophrenia · Volume 2G.K. Thaker, W.T. CarpenterISBN 978 1 84692 049 3

www.clinicalpublishing.co.uk

Therapeutic Strategies in

SCHIZOPHRENIA

TS Schizophrenia COVER A/W revised :TS Schizophrenia 13/5/10 17:00

Therapeutic Strategies

SCHIZOPHRENIA

Edited by

Ann M. MortimerPeter J. McKenna

CLINICAL PUBLISHING

OXFORD

Clinical Publishingan imprint of Atlas Medical Publishing Ltd

Oxford Centre for InnovationMill Street, Oxford OX2 0JX, UKTel: +44 1865 811116Fax: +44 1865 251550Email: [email protected]: www.clinicalpublishing.co.uk

Distributed in USA and Canada by:Clinical Publishing30 Amberwood ParkwayAshland OH 44805, USA

Tel: 800-247-6553 (toll free within U.S. and Canada)Fax: 419-281-6883Email: [email protected]

Distributed in UK and Rest of World by:Marston Book Services LtdPO Box 269AbingdonOxon OX14 4YN, UK

Tel: +44 1235 465500Fax: +44 1235 465555Email: [email protected]

© Atlas Medical Publishing Ltd 2010

First published 2010

All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing or Atlas Medical Publishing Ltd

Although every effort has been made to ensure that all owners of copyright material have been acknowledged in this publication, we would be glad to acknowledge in subsequent reprints or editions any omissions brought to our attention

Clinical Publishing and Atlas Medical Publishing Ltd bear no responsibility for the persistence or accuracy of URLs for external or third-party internet websites referred to in this publication, and does not guarantee that any content on such websites is, or will remain, accurate or appropriate.

A catalogue record for this book is available from the British Library

ISBN-13 978 1 84692 035 6ISBN e-book 978 1 84692 612 9

The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regula-tions. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work

Typeset by Prepress Projects Ltd, Perth, UKPrinted by Marston Book Services, Abingdon, Oxfordshire, UK

Contents

Editors vii

Contributors vii

Preface ix

1 Medical side-effects of antipsychotic agents: hyperprolactinaemia and metabolic disorders 1V. Frighi

2 Dual diagnosis treatment strategies 21N. Seivewright, R. Rele, F. Kamal

3 Long-acting antipsychotic injections 33O. S. Niaz, P. M. Haddad

4 Novel antipsychotic drugs: the current climate 55A. M. Mortimer

5 Cognitive therapy for schizophrenia: does it work? 75P. J. McKenna

6 Treatment strategies in early psychosis 87R. J. Drake, S. Lewis

7 Structural and functional brain imaging in schizophrenia: implications for pathophysiology 99P. Salgado-Pineda, E. Pomarol-Clotet, P. McKenna

8 Functional imaging with ligands in schizophrenia: therapeutic inferences 123O. D. Howes, S. Kapur

9 When monotherapy is insufficient: the role and effectiveness of additional drugs in schizophrenia 139A. M. Mortimer

10 The current status of clozapine in and beyond treatment-resistant schizophrenia 157D. L. Kelly, R. W. Buchanan

vi Contents

11 Neurochemical theories of schizophrenia 173P. J. McKenna

12 Second-generation atypical versus first-generation conventional antipsychotic drug treatment in schizophrenia: another triumph of hope over experience? 193F. Cheng, P. B. Jones

13 Second-generation antipsychotic drugs: mechanistically distinct or minor variants? 207J. L. Waddington, C. M. P. O’Tuathaigh, G. J. Remington

14 Disturbed behaviour and its management 217S. Dye

Abbreviations 233

Index 237

EditorsAnn M. MortiMer, MD BSc MMedSc FRCPsych, Head, Department of Psychiatry, University of Hull, Hull, UK

Peter J. McKennA, MB ChB MRCPsych, Research Psychiatrist, Benito Menni CASM, Barcelona, and CIBERSAM, Spain

Contributorsrobert W. buchAnAn, Professor of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Balitimore, USA

FrAnces cheng, Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

richArd J. drAKe, PhD, Senior Lecturer, University of Manchester, Manchester, UK

stePhen dye, MRCPsych, Consultant Psychiatrist (In-patients), Suffolk Mental Health Partnership NHS Trust, Ipswich, UK

VAleriA Frighi, MD, Department of Psychiatry, University of Oxford, Oxford, UK

Peter M. hAddAd, BSc MD FRCPsych, Consultant Psychiatrist, Greater Manchester West Mental Health NHS Foundation Trust, Salford, UK

oliVer hoWes, MRCPsych PhD DM, Group Head and Senior Clinical Lecturer, Clinical Sciences Centre, Hammersmith Hospital, and Institute of Psychiatry, King’s College London, London, UK

Peter b. Jones, Department of Psychiatry, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK

FArihA KAMAl, MBBS DCP DPM MRCPsych, Consultant Psychiatrist in Substance Misuse, Derbyshire Mental Health Services NHS Trust, UK

shitiJ KAPur, MD PhD FRCPC, Dean and Professor, Institute of Psychiatry, King’s College London, London, UK

deAnnA l. Kelly, PharmD BCPP, Associate Professor, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, USA

shôn leWis, MD FRCPsych, University of Manchester, Manchester, UK

viii Contributors

Peter J. McKennA, MB ChB MRCPsych, Research Psychiatrist, Benito Menni CASM, Barcelona, and CIBERSAM, Spain

Ann M. MortiMer, MD BSc MMedSc FRCPsych, Head, Department of Psychiatry, University of Hull, Hull, UK

oMAir s. niAz, MBChB MRCPsych, Consultant Psychiatrist, NHS Barnsley, Barnsley, UK

colM M. P. o’tuAthAigh, PhD, Research Fellow, Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland

edith PoMArol-clotet, MD PhD, Co-ordinator, the Research Unit, Benito Menni CASM, Barcelona, and CIBERSAM, Spain

rutA rele, MBBS DPM MD (Psych) MRCPsych, Consultant Psychiatrist in Substance Misuse, Sheffield Health and Social Care NHS Foundation Trust, Sheffield, UK

gAry J. reMington, MD PhD FRCPC, Professor of Psychiatry, Schizophrenia Division, Centre for Addiction and Mental Health, Toronto, Canada

PilAr sAlgAdo-PinedA, PhD, Research Scientist, Benito Menni CASM, Barcelona, and CIBERSAM, Spain

nicholAs seiVeWright, MBChB FRCPsych DM, Consultant Psychiatrist in Substance Misuse, North Nottinghamshire Community Drug Team, Mansfield, UK

John WAddington, PhD DSc MRIA, Professor of Neuroscience, Molecular and Cellular Therapeutics and RCSI Research Institute, Royal College of Surgeons in Ireland, Dublin, Ireland

Preface

Schizophrenia is one of medicine’s most daunting therapeutic challenges. After a century of research, we do not know its cause. More than 50 years after treatment first became available it is still a leading source of morbidity, excess mortality and lost opportunity. Nevertheless, understanding of the biological basis of the disorder slowly advances, and there have been a number of important developments in its treatment and management. This book aims to bring together some of the progress being made on both these fronts.

The best way to attack a disease is by knowing its cause. Salgado-Pineda et al. review brain-imaging findings in schizophrenia and conclude that the evidence for structural brain abnormality is reliable, but has not told us much about the localization of the disease process. However, this may be set to change with the development of methods such as voxel-based morphometry and diffusion tensor imaging. With respect to functional imaging, the authors quote Calhoun, who recently summarized the field as suffering from large variability and low robustness. Nevertheless, there seems no doubt about the reality of prefrontal cortex dysfunction in schizophrenia, even if it is becoming increasingly clear that this is far more complex than the traditional concept of hypofrontality.

The dopamine hypothesis has cast a long shadow over schizophrenia research. After several years in the doldrums, Howes and Kapur argue that this is now undergoing some-thing of a renaissance, with a slow but steady trickle of positive findings. The evidence they review further suggests that antidopaminergic antipsychotic drugs act ‘downstream’ from the pathophysiology of the disorder, and do not point to its source. Could this source be abnormal glutamate function? Or has the glutamate hypothesis of schizophrenia, which has absorbed vast amounts of research funds over the last 20 years, been, as McKenna suggests, a billion-dollar red herring?

The most important recent development in the treatment of schizophrenia has undoubt-edly been the introduction of clozapine, which is now of proven superior efficacy (Kelly and Buchanan). The development of other atypical antipsychotic drugs in the 1990s was heralded as a further major therapeutic advance. Unfortunately, as Frighi notes, many of these drugs fail to avoid the endocrinological side-effects of their predecessors, and most if not all of them have the capacity to cause the metabolic syndrome. Cheng and Jones bring more bad news, that pragmatic trials compel the conclusion that atypical antipsychotic drugs other than clozapine have been a false dawn.

New antipsychotic drugs are in the pipeline and polypharmacy is a rational option with an increasing degree of reasonable evidence for suitable patients (Waddington, Tuathaigh, Remington; Mortimer). But, with drug treatment remaining unsatisfactory, academic leaders look increasingly towards other ways of lessening the impact of schizophrenia. There are now well-developed strategies for early detection and intervention in prodromal psychotic states and first-episode schizophrenia. Drake and Lewis review the evidence that these lead to better outcomes. In the UK, much attention is currently lavished on cognitive behavioural therapy (CBT), and this therapeutic model has colonized the treatment of numerous mental disorders. According to NICE, it is also effective in schizophrenia. McKenna begs to differ.

There are other issues in the management of patients with schizophrenia. Partial and complete non-compliance (Niaz and Haddad) and substance abuse, particularly of cannabis and stimulants (Seivewright, Rele and Kamal), are major challenges. Nor should we ignore

x Preface

the rise of managerial governance, consumerism, the recession and the ‘capacitous lifestyle choices’ of patients who act in anyone’s interests but their own. Dye ponders the necessity to develop treatment strategies for aggressive and violent patients, and Haddad discusses the inception of legislation which may order treatment in the community.

We hope that this volume will arm the practising psychiatrist with enough balanced information to confront the currently important issues surrounding the treatment of schizo-phrenia and its underlying science.

Ann Mortimer and Peter McKenna

1Medical side-effects of antipsychotic agents: hyperprolactinaemia and metabolic disordersV. Frighi

AntiPsyChotiC-induCEd hyPErProlACtinAEMiA: A thEorEtiCAl And PrACtiCAl APProACh

Regulation of pRolactin secRetion and causes of hypeRpRolactinaemia

Prolactin (PRL) is a 198 amino acid peptide hormone secreted by the lactotroph cells of the anterior pituitary. Its major actions are the induction and maintenance of lactation in the oestrogen-primed breast. The hypersecretion of PRL achieved during breastfeeding inhibits the pulsatility of hypothalamic gonadotrophin-releasing hormone and therefore phasic gonadotrophin secretion, thus suppressing fertility as long as regular breastfeeding is maintained.

PRL secretion is under tonic inhibition by dopamine, which is released by the tubero-infundibular neurons and activates the lactotroph D2 receptors, thus inhibiting PRL gene expression [1]. Hence, any conditions reducing dopamine delivery to the anterior pituitary increase prolactin release. These can be structural, such as lesions in the hypothalamic area, interrupting dopamine pathways by pituitary stalk compression or dissection (‘dysconnec-tion hyperprolactinaemia’); functional causes include dopamine D2 receptor blockade from antipsychotic drugs and antidepressants. Purely peripheral D2 antagonists are also active as the pituitary is situated outside the blood–brain barrier.

Although antipsychotic drugs are by far the most frequent cause of hyperprolactinaemia in the psychiatric population, there is a wide variety of physiological and pathological condi-tions, as well as many other drugs, that should be considered in the differential diagnosis in individual patients (Table 1.1).

pathophysiology and pRevalence of antipsychotic-induced hypeRpRolactinaemia

Antipsychotic drugs have the potential to increase prolactin secretion, something that was firmly established for the phenothiazines in the early 1970s, when the crucial development of radioimmunoassays allowed widespread availability of reliable measurements of human PRL [2]. The most visible complication of hyperprolactinaemia, galactorrhoea, was described soon after the introduction of chlorpromazine [3] and, in the same years, amenorrhoea was interpreted as a result of chlorpromazine’s action on the pituitary [4]. Hyperprolactinaemia,

Valeria Frighi, MD, Department of Psychiatry, University of Oxford, Oxford, UK

2 Therapeutic Strategies in Schizophrenia

together with its clinical and hormonal correlates including galactorrhoea, amenorrhoea, and male and female hypogonadism, was extensively investigated in two seminal studies in 1974 [5, 6].

After the introduction of clozapine in 1975 and the subsequent availability of other atypi-cal antipsychotic drugs, marked differences were noticed between individual drugs, with conventional antipsychotic drugs having a stronger hyperprolactinaemic potential than most of the atypical antipsychotic drugs, with the exception of amisulpride and risperidone [7, 8]. Several observations underpin the view that antipsychotic-induced hyperprolacti-naemia is a peripheral rather than a central effect. These include the fact that drugs with a purely peripheral antidopaminergic action (such as metoclopramide and domperidone) induce large PRL elevations [9, 10], that the anatomical position of the pituitary gland is outside the blood–brain barrier, and that antipsychotic drugs such as amisulpride and ris-peridone, which have high affinity for peripheral dopamine D2 receptors [11], also have a high potential for causing hyperprolactinaemia. This explains why antipsychotic drugs with a high central-to-peripheral binding have a lower potential for causing hyperprolac-tinaemia [11]. Moreover, fast dissociation from dopamine D2 receptors explains the only

table 1.1 Causes of hyperprolactinaemia

Physiological

Pregnancy, nipple stimulation, physical or psychological stress

Pathological

Prolactinoma, mixed growth hormone-/prolactin-secreting tumour

Empty sella syndrome

Hypothalamic/pituitary infiltration (sarcoidosis, histiocytocis, tuberculosis)

‘Disconnection hyperprolactinaemia’ due to pituitary stalk compression (from pituitary macroadenoma or hypothalamic masses such as craniopharyngioma, meningioma, neurofibromatosis, cyst) or stalk section (head injury)

Primary hypothyroidism

Polycystic ovary syndrome

Chronic renal or liver failure

Chest wall lesions (herpes zoster, trauma)

Pharmacological

Dopamine receptor antagonists with purely peripheral action (metoclopramide, domperidone)

Dopamine receptor antagonists with central and peripheral action (antipsychotic drugs*)

Antidepressants (most selective serotonin reuptake inhibitors, tricyclics, moclobemide)

Opiates

Cocaine

Oestrogens

Protease inhibitors (e.g. ritonavir, zidovudine)

H2 antagonists (e.g. ranitidine)

Proton pump inhibitors (e.g. omeprazole)

Cardiovascular drugs (verapamil, methyldopa)

*See text for discussion.

Medical side-effects of antipsychotic agents 3

transient (up to 6 h) PRL elevation after clozapine administration [12]. Fast dissociation and transient hyperprolactinaemia also characterize olanzapine and quetiapine [12] and both these drugs have been shown not to induce hyperprolactinaemia [13, 14] and to normalize PRL in patients with hyperprolactinaemia induced by other antipsychotic drugs [15, 16]. Nevertheless, cases of hyperprolactinaemia, amenorrhoea and galactorrhoea on olanzapine [17–19] and a case of galactorrhoea on quetiapine have been published [20], and a recent study showed a prevalence of hyperprolactinaemia of 8% and 29% in a small number of patients on long-term olanzapine and quetiapine respectively [21].

Hence, the only antipsychotic drugs that do not stimulate PRL secretion and consistently normalize the hyperprolactinaemia induced by other antipsychotic drugs are clozapine [7, 13] and the partial dopamine D2 agonist aripiprazole [22–24]. Importantly, the novel glu-tamate receptor agonists currently under investigation decrease PRL levels, probably by a concomitant partial dopamine D2 agonist activity [25, 26], one of them doing so even in the presence of the potent peripheral D2 antagonist domperidone [25].

Because of the profound differences between individual atypical antipsychotic drugs, the prevalence of hyperprolactinaemia found in a large number of studies varies between zero for clozapine and aripiprazole and 70–100% for risperidone and amisulpride. Conventional antipsychotic drugs also demonstrate high rates, while olanzapine and quetiapine are consistently associated with low figures [8, 27–32]. Moreover, prevalence rates of hyperp-rolactinaemia and, even more so, the degree of PRL elevation vary according to the gender composition of the patient sample, women being consistently more severely affected than men [21, 32–35]. In fact, PRL elevations above two or three times the upper limit of normal are rare in antipsychotic-treated men, whereas this degree of hyperprolactinaemia is com-mon in women [21, 34], in whom PRL levels can reach 8–10 times the upper limit of normal, even on doses of risperidone of 1–3 mg [32].

complications of chRonic dopamine blockade

Chronic dopamine receptor blockade may induce lactotroph hyperplasia and increased pitu-itary volume as shown by animal and human studies [36–38]. Clinical cases of prolactinoma or growth of pre-existing prolactinoma have been reported in the literature in both adults and children on risperidone or amisulpride, and by two UK mental health trusts [39–45].

A pharmacovigilance study based on Food and Drug Administration (FDA) adverse drug reaction (ADR) reports showed an up to 19-fold increase in prolactinoma risk in patients on risperidone [46]. However, the annual incidence of clinically significant pituitary tumours is 3.3 per 100 000 in the US population [47]. Although prolactinomas are the most frequent of these lesions, with the exception of asymptomatic lesions in autopsy series, they are a rare entity. Hence, even on the assumption that two-thirds of pituitary tumours might be prolactinomas, and that ADR reports are generally an underestimate of the true number of adverse reactions, even a gross increase compared with that in the general population still may not signify that, in absolute terms, prolactinoma prevalence in risperidone-treated patients is substantially high. This was confirmed by a study on pituitary tumours in patients on antipsychotic drugs reported in the ADR WHO database. This showed a total of 42 cases on risperidone and eight on amisulpride, which are not large numbers, given the size of the database [48].

Nevertheless, clinicians must be vigilant and include prolactinoma in the differential diagnosis of severe hyperprolactinaemia, particularly if associated with visual symptoms and if dechallenge by substitution with a PRL-neutral drug cannot be attempted.

complications of hypeRpRolactinaemia

Some patients with hyperprolactinemia remain asymptomatic, many may not report symp-toms but others exhibit a wide range of clinical problems resulting from either the direct


effect of prolactin on the breast (galactorrhoea) or endocrine-related secondary effects, namely hypogonadism leading to sexual and reproductive dysfunction in the short term, and osteoporosis in the longer term (Table 1.2). Short-term side-effects may reduce adher-ence to medication, and long-term effects may cause serious health consequences.

galactorrhoea

Galactorrhoea is the most specific symptom of hyperprolactinaemia and normally affects women, although it can also be seen in a small proportion of men [49]. Galactorrhoea was reported as a chlorpromazine side-effect a few years after the introduction of the drug [3]. Its prevalence has been examined in two studies of 50 and 150 patients on antipsychotic drugs, in which it was reported as affecting 31% and 19% of female patients respectively [50, 51].

breast cancer

Concerns about an increased breast cancer risk have recently been expressed in the psy-chiatric literature [52], partly based on studies of co-carcinogenesis in rodents [53] and an epidemiological study showing a slightly increased risk between the highest and the lowest quartile of the normal PRL distribution in a large cohort of women from the general popula-tion [54, 55]. However, a recent study, which included 2000 women with schizophrenia, showed a slightly lower rather than higher prevalence of breast cancer compared with the general population [56] and another previous large study also failed to show an excess of breast cancer in women with schizophrenia [57]. Furthermore, no increased prevalence of breast cancer in long-term hyperprolactinaemic women from the general population has been reported. Hence, the association between breast cancer and hyperprolactinaemia remains unproven and a more intensive screening policy than that recommended for women in the general population is not currently warranted. Nevertheless, clinicians should try to ensure that women with severe mental illness, whether hyperprolactinaemic or not, adhere to the national breast cancer screening programme, namely a 3-yearly mammogram between the ages of 50 and 70 years [58].

hypogonadism

Hyperprolactinaemia reduces the pulsatility of hypothalamic gonadotrophin-releasing factor [59], causing suppression of cyclical gonadotrophin secretion and, ultimately, of sex steroids, probably also as a direct action on the gonads. Secondary hypogonadism is the most serious complication of hyperprolactinaemia. The prevalence of this complication in patients on antipsychotic drugs has been investigated in various studies [60]. The largest

table 1.2 Complications of hyperprolactinaemia

Galactorrhoea

hypogonadismAmenorrhoea/oligomenorrhoea

Infertility

Sexual dysfunction (erectile, ejaculatory, orgasmic dysfunction ± low libido)

Low testosterone, low oestradiol

Gynaecomastia

osteoporosis and fractures (complication of hypogonadism)


of these, on 402 patients, showed that almost half of hyperprolactinaemic premenopausal women had menstrual irregularities, and that over 30% had oestradiol levels in the post-menopausal range [30]. Hypogonadism manifests itself clinically with impaired sexual func-tion (erectile, ejaculatory and orgasmic dysfunction, with or without low libido), infertility, amenorrhoea or oligomenorrhoea, and biochemically with low plasma oestradiol in women and testosterone in men. These symptoms have also been observed in psychotic patients with hyperprolactinaemia [61]. Occasionally, men can manifest gynaecomastia, which is not a direct effect of hyperprolactinaemia per se but a result of the decreased testosterone/oestradiol ratio induced by hypogonadism [62, 63].

osteoporosis

Hyperprolactinaemic hypogonadism, like any other type of hypogonadism, induces bone demineralization in men and women [64, 65], but bone mass increases, although it may not normalize, on treatment of hyperprolactinaemia and restoration of normal menses [66, 67]. Osteoporosis and an increased fracture risk have been observed in patients with schizophrenia [68, 69] and antipsychotic-induced hyperprolactinaemic hypogonadism has been shown to be associated with decreased bone mineral density in this population [60]. However, treatment with bone-preserving agents including hormone replacement therapy over a year has not been associated with improvement in bone parameters in women with persistent hyperprolactinaemia [70]. Whether this finding may implicate a direct negative action, independent of hypogonadism, of hyperprolactinaemia on bone, as suggested by animal studies [71], is unknown.

management of hypeRpRolactinaemia

Hyperprolactinaemia is not an illness per se but becomes a serious health problem when complications develop. However, management is complex because the diagnosis and clini-cal significance of such complications is too specialized to be within the sole reach of psy-chiatrists or of general practitioners. Hence, advice from endocrinologists should be sought. Should long-term management be required, it is essential that a joint approach with a clear definition of individual roles be agreed between the psychiatrist, the endocrinologist and the general practitioner (GP). This is particularly important in view of the numerous other risk factors for hypogonadism and sexual dysfunction (additional medications, alcohol and substance abuse) and for bone loss and fractures (smoking, alcohol excess), which are com-mon in the psychiatric population.

Over the past few years, several guidelines for the monitoring of patients on antipsychotic drugs and the physical health of patients with schizophrenia have been published, and some of these include recommendations for screening for hyperprolactinaemia [72]. However, there is no generalized agreement on how, when and in which patients this should be done. Moreover, there is some evidence that PRL is hardly ever measured in psychiatric practice and that there is no consensus on how to manage antipsychotic-induced hyperprolactinae-mia once a diagnosis has been reached [73, 74].

Recent clinical recommendations represent a substantial improvement [75] but it is essential that the wider endocrinology community be involved in their refinement and the formation of a solid evidence base, before widespread dissemination.

What follows is a brief outline of a practical management approach that might be use-ful to clinicians until more structured, evidence-based, interdisciplinary guidelines become available.


prevention

Prevention could obviously be achieved by the use as first-line treatment of antipsychotic drugs with no or a lower potential for hyperprolactinaemia. However, owing to its other serious side-effects, clozapine is reserved for treatment-resistant schizophrenia and therefore not an option for the majority of patients. Olanzapine and quetiapine can induce metabolic side-effects [76], aripiprazole is not commonly used as a first-line treatment in clinical prac-tice given that it is the most recent of the atypical drugs, and new classes of antipsychotic drugs that do not increase PRL are not yet available.

screening

Screening for hyperprolactinaemia is aimed at detecting not a biochemical abnormality, but its potential clinical complication of hypogonadism. Ideally, patients about to start an antipsychotic drug should have a baseline measurement before the drug is started and a clinical assessment and follow-up measurement that should lead to measurement of sex ste-roids, gonadotrophin and thyroid-stimulating hormone (TSH), in case of an abnormal result. Further management, if necessary, would be determined on an individual basis and would require the involvement of an endocrinologist. Suggested PRL measurements and initial management of hyperprolactinaemia in patients starting antipsychotic drugs are outlined in Table 1.3.

For patients on long-term antipsychotic drugs who have never had a PRL measurement, this would be useful for those in whom hyperprolactinaemic hypogonadism is likely, namely premenopausal women with amenorrhoea or oligomenorrhoea. A PRL measurement would also be useful in men as hypogonadism may be clinically silent or patients may not report symptoms of sexual dysfunction. A raised PRL in these patients should be initially managed as suggested in Table 1.3.

Screening for hyperprolactinaemia in postmenopausal women may not be useful because obviously gonadal function cannot be recovered. However, it should be done in those who had a history of amenorrhoea before the age of the menopause. These women are likely to have had long-term hyperprolactinaemic hypogonadism. This may have induced osteopo-rosis, which would require further investigation and management.

table 1.3 Suggested PRL measurements and management of patients starting antipsychotic drugs

basal* 6 months follow-up

Menstrual history X X According to 6-month results and planned management

Sexual symptoms X XGalactorrhoea XProlactin X XOestradiol, testosterone,

FSH, LH, TSHIf PRL raised†

Involve endocrinologist If PRL raisedConsider switching to or

adding aripiprazoleIf PRL significantly

raised‡

Time of sampling: before antipsychotic dose.

*Baseline: before starting antipsychotic or as soon as the mental state allows.

†Normal ranges: women 60–620 mU/L (3–31 ng/ml); men 45–375 mU/l (2.2–19 ng/ml). Conversion factor SI/conventional units: 20. NB: Normal ranges and conversion factor may have small variations between laboratories.

‡Patient symptomatic (galactorrhoea) and/or hypogonadal.

FSH, follicle-stimulating hormone; LH, luteinizing hormone; TSH, thyroid-stimulating hormone.


treatment

Treatment should be offered only when hyperprolactinaemia is clinically significant, namely if the patient is symptomatic and/or biochemically hypogonadal. A very successful strategy seems to be switching to or adding aripiprazole. This agent has been shown to normalize prolactin and restore ovarian function both as monotherapy and as combination therapy [77–79] and to induce tumour shrinkage in a case of risperidone-associated prolactinoma [45]. Additionally, contrary to other atypical antipsychotic drugs, it has no deleterious effect on glucose and lipids [80, 81]. Clinical trials and cases in which adjunctive aripiprazole was used for treatment of severe hyperprolactinaemia, or for amelioration of metabolic parameters, have shown this strategy to be devoid of serious side-effects and generally well tolerated [78, 79, 82–86]. Nevertheless, a case of worsening of psychosis on addition of aripiprazole to amisulpride treatment has been reported and caution should be adopted when using combination therapy [87]. Dopaminergic agents used to treat hyperprolactinaemia in the general population, such as bromocriptine and cabergoline, should be avoided given their potential to aggravate or precipitate psychosis [88, 89].

Treatment of hyperprolactinaemia should generally be used only in patients whose gonadal function can be restored, namely men and premenopausal women. PRL-lowering treatment would not be appropriate in postmenopausal women, as their ovarian function cannot be recovered.

For patients who are known or suspected to have had long-term hyperprolactinaemic hypogonadism, a bone mineral density scan should be performed, as they may have devel-oped osteoporosis. If evidence of demineralization is found, then appropriate bone protec-tive treatment should be considered.

time of sampling

PRL secretion is pulsatile and follows a circadian rhythm with a night-time peak. However, the variations over the 24 h remain within the normal range, hence abnormal measurements cannot be attributed to time of sampling. Nevertheless, this is important in relation to the timing of the antipsychotic dose, given the transient rise PRL can have even with drugs that rarely give chronic elevations. Hence, PRL should be measured before the patient has taken the daily dose.

baseline measurement in patients starting on an antipsychotic

Ideally, this should be done before the first dose of antipsychotic. In patients in whom a blood sample is impossible before this is administered, the baseline measurement could be taken according to the suggestions above, although this is not an ideal solution.

first follow-up measurement

Prolactin measurements should not follow too soon after the introduction of an antipsy-chotic. In fact, after an initial steep rise, PRL levels decrease and stabilize approximately after 4 months’ treatment at the level that will be maintained [90]. Hence, for practical purposes, the first follow-up measurement could be made at 6 months, namely at a time when a stable value will have been reached and patients may require other measurements (e.g. glucose and lipids).

subsequent measurements

None will be required if the 6 months’ measurement is normal, unless the antipsychotic dose is increased or the drug changed. If the measurement is abnormal, subsequent assessments


will be required according to the 6 months’ results, and based on the type of management required.

influence of stress on prolactin secretion

It is known that stress, including venepuncture, can induce minor PRL elevations. However, these were seen in only 2 out of 170 learning-disabled patients in whom PRL was measured, without particular precautions, as part of a study [32]. In clinical practice, these elevations are also rare and do not cause problems in the differential diagnosis of hyperprolactinaemia (V. Frighi, personal observations).

summaRy

Hyperprolactinaemia has been considered traditionally as an inevitable and relatively benign side-effect of antipsychotic treatment, for which management was not often offered. In fact, although the recognition of the problem and of its complications dates back for decades, the realization of its severity and the impetus towards management are recent. This novel approach, made possible by the recent availability of effective treatments, should lead to rapid improvements in the care of psychiatric patients.

MEtAboliC sidE-EFFECts oF AntiPsyChotiC AGEnts

Antipsychotic drugs have a profound effect on metabolism, being able to cause hyperglycae-mia, dyslipidaemia and obesity [81, 91]. These side-effects, which can be grouped together as the metabolic syndrome [92], contribute substantially, in synergism with lifestyle factors and difficult access to health care, to the very high cardiovascular risk and reduced life expectancy of patients with severe mental illness [93–96]. Moreover, antipsychotic-related metabolic disorders occur in psychiatric patients of any age [97–99], being particularly severe in children and adolescents [99, 100].

The hyperglycaemic potential of chlorpromazine was recognized soon after its introduc-tion in the early 1950s [101, 102]. Subsequently, it was recognized that the other pheno-thiazines shared the same side-effect, which was attributed to inhibition of catecholamine uptake [103]. Furthermore, the term ‘phenothiazine diabetes’ was used in a seminal paper in 1968 [104]. However, it took almost 50 years and the advent of the atypical antipsychotic drugs, given the particularly high metabolic risk induced by some of them, before diabetes, dyslipidaemia and obesity started to be widely recognized as serious side-effects of antipsy-chotic drugs [105–109] and sufficiently common to require screening [110].

epidemiology

The prevalence of the metabolic syndrome as a constellation of cardiovascular risk factors such as hyperglycaemia, dyslipidaemia, abdominal obesity and hypertension, and of its single components, particularly diabetes, has been investigated in various studies. These have consistently shown a two to three times higher prevalence of the metabolic syndrome in schizophrenia patients than in the general population, estimated at 36–58%, according to the individual studies and the definition adopted [111–113].

Also the prevalence rates of diabetes per se are two to three times higher than in the general population and incidence rates are also disproportionately high [94, 98, 114, 115]. Moreover, changes in glucose tolerance, including new-onset diabetes, can occur very early after initiation of atypical antipsychotic treatment [76], which justifies the intensive glucose monitoring that has been recommended at the beginning of antipsychotic therapy [110]. The occurrence of diabetes generally follows the development of obesity but in as many as 25% of the patients it can occur without any increase in weight [116]. Antipsychotic-induced


diabetes commonly presents phenotypically as type 2, non-insulin-dependent diabetes, occasionally with its most severe complication of hyperosmolar non-ketotic coma. However, a presentation similar to type 1, insulin-dependent diabetes, including with diabetic ketoaci-dosis, can also occur, and fatalities have been reported. Most case reports and studies based on adverse drug reaction reports have shown diabetes to present generally within the first 6 months of treatment and to be reversible on drug withdrawal in approximately 70% of the cases. However, presentations after many years, followed by resolution of diabetes on drug withdrawal, have also been reported. Antipsychotic drugs can also induce deterioration of pre-existing diabetes [105–109, 117–126].

The impact of antipsychotic drugs on metabolic parameters varies widely according to individual drugs. It is considered higher overall for atypical than conventional antipsychotic drugs, but within these two large groups marked individual variations exist. Among the atypical antipsychotic drugs, the potential for glucose elevation, which accompanies that for weight increase and hyperlipidaemia, is the highest for clozapine and olanzapine, inter-mediate for risperidone and quetiapine, and virtually non-existent for amisulpride [97, 110, 127, 128].

Regarding aripiprazole, a large body of experimental and clinical evidence has shown this drug to be glucose and lipid neutral [81]. However, four cases of diabetic ketoacidosis and one of hyperosmolar coma in aripiprazole-treated patients have been published [129–133]. These cases, despite the very small numbers, the limitations of anecdotal evidence, and the contradiction to the rest of the published evidence, call for the need for safety checks also in patients on aripiprazole. Moreover, although most evidence points to a lack of or minimal weight gain in patients on aripiprazole [81], a few studies have also shown clinically signifi-cant weight gain in 7–20% of patients [134–137].

pathophysiology

The cause of antipsychotic-related hyperglycaemia is uncertain but studies in human pan-creatic islets have identified dopamine receptors in the β-cells: dopamine and dopaminergic agents modulate glucose-stimulated insulin secretion as well as having a putative role in hypothalamic regulation of metabolism. Whether dopamine has a predominantly stimu-latory or inhibitory role is unclear, and may partly depend on the ambient concentration of glucose, catecholamines and dopamine itself, and on the type of receptor stimulated [138–141]. Several studies, including a recent trial in over 3000 patients, have shown that bromocriptine, a dopamine D2 agonist, decreases blood glucose and glycated haemoglo-bin in diabetic patients, probably by improving insulin sensitivity or secretion [142–146]. Bromocriptine also reduces hyperphagia, hyperglycaemia, hypertriglyceridaemia and the fatty infiltration of non-alcoholic hepatic steatosis in a rat model of obesity [147]. Hence, both direct and indirect evidence point to the possibility that dopamine D2 receptor antagonism is involved in the adverse metabolic effects of antipsychotic drugs. This is further supported by the fact that aripiprazole, a partial D2 agonist [148], has been shown in clinical trials and observational studies not to increase blood glucose or lipids [80–83, 149–152].

Another important modulator of insulin secretion is serotonin. Antagonist activity at the 5-HT1A and 5-HT2C serotonin receptors and polymorphisms of the 5-HT2C serotonin receptor gene have been shown to be associated with weight gain and glucose intolerance [153–156]. Moreover, an experimental study has shown that 5-HT2C knockout mice develop insulin resistance, hyperglycaemia and obesity [157]. This is consistent with a major role of serotonin in glucose regulation: it helps to explain why drugs with antiserotoninergic activ-ity, like most atypical antipsychotic drugs, can induce metabolic side-effects. Last, histamine receptor antagonist activity, which is the highest for clozapine and olanzapine, seems to be crucial in the development of weight gain, probably through a disruption of the appetite control mechanism [154, 158].


management of tReatment-emeRgent metabolic complications

prevention

This could be attempted by choosing, as first-line therapy, an antipsychotic drug with mini-mal metabolic impact. Obviously this has to be balanced with the patient’s psychiatric needs and with the probability of other side-effects. Among the atypical antipsychotic drugs, ami-sulpride could be a suitable choice [159]. However, this drug’s ability to increase prolactin in virtually the totality of patients [8, 32] may limit its use, particularly in women, in whom hypogonadism is a frequent complication of hyperprolactinaemia [30, 32], and in children and adolescents, who are at greater risk than adults from antipsychotic side-effects [160]. Aripiprazole might be a better choice, as it generally has no deleterious effects on metabolic parameters or prolactin levels [81], is mostly well tolerated and, in a large randomized study, has been shown to be preferred by patients over standard care with olanzapine, quetiapine or risperidone [134]. Furthermore, in patients with antipsychotic-induced diabetes, switch-ing to aripiprazole maintains the normalization or improvement of metabolic parameters achieved on withdrawal of the initial agent [80]. Three studies and a few case reports have also demonstrated that adjunctive aripiprazole can induce weight loss and improvements in plasma lipids in clozapine- or olanzapine-treated patients [82–86]. As to other antipsychotic drugs that seem not to induce weight gain or hyperprolactinaemia, asenapine [161] is not yet licensed and the glutamate receptor agonist LY2140023 [162] is still in an early phase of development.

Hence, prevention of metabolic side-effects simply by using the currently available agents with little metabolic impact would leave psychiatrists in the impossible situation of having to choose between only two drugs, namely amisulpride and aripiprazole. There is thus a com-pelling need to develop other strategies to prevent weight gain, diabetes and dyslipidaemia.

The most logical preventative measure would be the introduction of a lifestyle interven-tion programme, based on diet and physical exercise, for all patients starting antipsychotic treatment. An intensive intervention based on regular physical activity and a diet promoting a modest weight loss has proven highly effective in the prevention of diabetes in high-risk patients, as shown by a risk reduction of almost 60% in a large 3-year trial by the US National Institute of Health in the general population [163]. A pharmacological approach to the pre-vention of diabetes in high-risk groups from the general population with a variety of drugs such as metformin, acarbose, glitazones and orlistat has been tested in 3- to 5-year clinical tri-als. These have shown reductions in the incidence of diabetes of 31% with metformin to 60% with rosiglitazone [164]. However, of these drugs, acarbose and orlistat are poorly tolerated, and rosiglitazone may have detrimental effects on cardiovascular events, increase the risk of heart failure and promote weight gain [165]. Only metformin, because of its safety, efficacy and tolerability, has been recommended, at a dose of 850 mg twice daily, and in conjunc-tion with lifestyle intervention, by the American Diabetes Association (ADA) for prevention of diabetes in very high-risk patients, such as those with both fasting hyperglycaemia and impaired glucose tolerance [166]. It would be reasonable to extend these recommendations to antipsychotic-treated patients with the same clinical characteristics. This management approach would obviously require the involvement of a diabetologist, being too specialized to be within the sole reach of the psychiatrist or the GP.

Metformin could also be useful in the prevention of weight increase, as the results of a recent trial showed attenuation of weight gain in drug-naive schizophrenia patients start-ing olanzapine [167]. However, lifestyle intervention should always accompany pharma-cological treatment. This is supported by the results of a trial by the same authors, which showed that lifestyle intervention plus metformin induced greater weight loss in long-term antipsychotic-treated patients than either intervention alone [168].


screening

A joint statement by the ADA and the American Psychiatric Association (APA) in 2004 [110] suggested a strategy that should be applied to all patients starting on atypical antipsychotic drugs. However, despite the American and numerous other guidelines, the rate of screening for metabolic complications in antipsychotic-treated patients remains very low [73, 74, 111, 169, 170]. No formal strategy has yet been suggested for patients who have been on long-term antipsychotic treatment but have never been screened for metabolic complications. A reasonable approach could be to carry out a full screening as advised for first-time users and, if no abnormalities are detected, repeat it at yearly intervals. An important modifica-tion to the ADA/APA screening schedule would be the addition of glycated haemoglobin (HbA1c) measurements to the fasting plasma glucose. This is both because HbA1c provides additional biochemical information, and because its results are not altered by food intake. Hence, HbA1c would be particularly valuable for patients in whom it is too difficult to obtain a fasting blood sample. Finally, attention should be paid to other risk factors for diabetes in these patients, namely a positive family history, South Asian or black ethnicity, age over 40 years, obesity, hypertension and dyslipidaemia. Table 1.4 shows a suggested protocol for screening and initial management of patients starting an antipsychotic drug. Further man-agement would obviously need to be individualized and would require a multidisciplinary approach with the involvement of the psychiatrist, the GP, a dietician and a diabetologist for the most complicated cases.

treatment

The first logical approach for patients with treatment-emergent metabolic complications would obviously be an attempt at switching to a medication with no or fewer side-effects.

table 1.4 Suggested management protocol for diabetes, dyslipidaemia and obesity in patients starting antipsychotic drugs

baseline every visit 3 months 6 monthsannually or 6-monthly*

Medical/family history XAssess risk factors XSymptom enquiry X XEducation on symptoms of

diabetesX

Weight (body mass index) X XWaist X X X XBlood pressure X X XFasting plasma glucose X X X XHbA1c X X X XTotal/HDL-/LDL-cholesterol,

triglyceridesX X X X

Refer for lifestyle advice and long-term support

X

Consider metformin† X XInvolve diabetologist‡ X

*Six-monthly for patients on clozapine or olanzapine.

†With drugs with high metabolic impact and/or in patients with rapid weight gain.

‡If starting metformin or if management problems arise.

HDL, high-density lipoprotein; LDL, low-density lipoprotein.


When switching is either impossible or unsuccessful in reversing the metabolic problem, or in the case of acute presentation such as diabetic ketoacidosis or hyperosmolar coma, this will have to be treated on its own merit. Diabetes and dyslipidaemia should be treated in the same fashion as in the general population. Management should always be shared with the GP and with a diabetologist in particularly difficult cases.

Regarding interventions to reduce weight gain, a 2007 Cochrane review showed a modest effect with selective pharmacological and non-pharmacological interventions in antipsy-chotic-treated patients. However, published trials were few, small and of short duration, and the interventions were highly variable, so that firm conclusions could not be drawn [171]. However, more recent studies showed beneficial effects of metformin, alone or in combination with lifestyle intervention, in decreasing or stabilizing weight in antipsychotic-treated adults and children [168, 172, 173]. Hence, despite some controversial evidence [174], metformin, particularly in combination with a diet and exercise programme, may be a clini-cally useful treatment.

conclusions

Metabolic side-effects such as weight gain, diabetes and dyslipidaemia are common in antipsychotic-treated patients; there is a clear differential effect between individual drugs. These complications can explain in part the high cardiovascular morbidity and mortality of psychiatric patients. Despite numerous published guidelines, most metabolic side-effects remain undiagnosed and untreated. Potentially effective prevention and treatment strate-gies are available, together with a simple screening protocol. Further research in this area, and the implementation of currently available clinical evidence, could help to improve the health of patients with severe mental illness.

ACknowlEdGEMEnt

The author wishes to thank the Trustees of the Baily Thomas Charitable Fund for their gen-erous support of the Oxford Learning Disabilities Study.

rEFErEnCEs 1. Enjalbert A, Bockaert J. Pharmacological characterization of the D2 dopamine receptor negatively

coupled with adenylate cyclase in rat anterior pituitary. Mol Pharmacol 1983; 23:576–84. 2. Clemens JA, Smalstig EB, Sawyer BD. Antipsychotic drugs stimulate prolactin release.

Psychopharmacologia 1974; 40:123–7. 3. Winnik HZ, Tennenbaum L. [Appearance of galactorrhea during largactil therapy.]. Presse Med 1955;

63:1092. 4. Polishuk WZ, Kulcsar S. Effects of chlorpromazine on pituitary function. J Clin Endocrinol Metab 1956;

16:292–3. 5. Beumont PJ, Gelder MG, Friesen GH, Harris GW, MacKinnon PC, Mandelbrote BM, et al. The effects of

phenothiazines on endocrine function: I. Patients with inappropriate lactation and amenorrhoea. Br J Psychiatry 1974; 124:413–19.

6. Beumont PJ, Corker CS, Friesen HG, Kolakowska T, Mandelbrote M, Marshall J, et al. The effects of phenothiazines on endocrine function: II. Effects in men and post-menopausal women. Br J Psychiatry 1974; 124:420–30.

7. Meltzer HY, Goode DJ, Schyve PM, Young M, Fang VS. Effect of clozapine on human serum prolactin levels. Am J Psychiatry 1979; 136:1550–5.

8. Bushe C, Shaw M, Peveler RC. A review of the association between antipsychotic use and hyperprolac-tinaemia. J Psychopharmacol 2008; 22(2 Suppl):46–55.

9. Judd SJ, Lazarus L, Smythe G. Prolactin secretion by metoclopramide in man. J Clin Endocrinol Metab 1976; 43:313–17.

10. Brown GM, Verhaegan H, Van Wimersma Greidanus TB, Brugmans J. Endocrine effects of domperi-done: a peripheral dopamine blocking agent. Clin Endocrinol (Oxf) 1981; 15:275–82.


11. Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS. The differential effects of atypi-cal antipsychotics on prolactin elevation are explained by their differential blood–brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther 2002; 302:1129–34.

12. Kapur S, Seeman P. Does fast dissociation from the dopamine d(2) receptor explain the action of atypical antipsychotics?: A new hypothesis. Am J Psychiatry 2001; 158:360–9.

13. Volavka J, Czobor P, Cooper TB, Sheitman B, Lindenmayer JP, Citrome L, et al. Prolactin levels in schizophrenia and schizoaffective disorder patients treated with clozapine, olanzapine, risperidone, or haloperidol. J Clin Psychiatry 2004; 65:57–61.

14. Bushe C, Sniadecki J, Bradley A, Poole Hoffmann V. Comparison of metabolic and prolactin variables from a six-month randomised trial of olanzapine and quetiapine in schizophrenia. J Psychopharmacol 2009. doi:10.1177/0269881108101783.

15. Kim KS, Pae CU, Chae JH, Bahk WM, Jun TY, Kim DJ, et al. Effects of olanzapine on prolactin levels of female patients with schizophrenia treated with risperidone. J Clin Psychiatry 2002; 63:408–13.

16. Keller R, Mongini F. Switch to quetiapine in antipsychotic agent-related hyperprolactinemia. Neurol Sci 2002; 23:233–5.

17. Miller DE, Sebastian CS. Olanzapine-induced hyperprolactinemia and galactorrhea reversed with addition of bromocriptine: a case report. J Clin Psychiatry 2005; 66:269–70.

18. Wolf J, Fiedler U. Hyperprolactinemia and amenorrhea associated with olanzapine normalized after addition of aripiprazole. J Clin Pharm Ther 2007; 32:197–8.

19. Licht RW, Arngrim T, Cristensen H. Olanzapine-induced galactorrhea. Psychopharmacology (Berl) 2002; 162:94–5.

20. Gupta M. Low dose quetiapine induced galactorrhoea: a case report. Clin Pract Epidemol Ment Health 2007; 3:12.

21. Bushe C, Yeomans D, Floyd T, Smith SM. Categorical prevalence and severity of hyperprolactinaemia in two UK cohorts of patients with severe mental illness during treatment with antipsychotics. J Psychopharmacol 2008; 22(2 Suppl):56–62.

22. Inoue A, Seto M, Sugita S, Hide I, Hirose T, Koga N, et al. Differential effects on D2 dopamine receptor and prolactin gene expression by haloperidol and aripiprazole in the rat pituitary. Brain Res Mol Brain Res 1998; 55:285–92.

23. Hirose T, Uwahodo Y, Yamada S, Miwa T, Kikuchi T, Kitagawa H, et al. Mechanism of action of aripip-razole predicts clinical efficacy and a favourable side-effect profile. J Psychopharmacol 2004; 18:375–83.

24. Lieberman JA. Dopamine partial agonists: a new class of antipsychotic. CNS Drugs 2004; 18:251–67. 25. Seeman P, Caruso C, Lasaga M. Dopamine partial agonist actions of the glutamate receptor agonists LY

354,740 and LY 379,268. Synapse 2008; 62:154–8. 26. Seeman P, Guan HC. Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High

receptors: D2 basis for schizophrenia. Synapse 2008; 62:819–28. 27. Lee HS, Kim CH, Song DH, Choi NK, Yoo KJ. Clozapine does not elevate serum prolactin levels in

healthy men. Biol Psychiatry 1995; 38:762–4. 28. Bushe C, Shaw M. Prevalence of hyperprolactinaemia in a naturalistic cohort of schizophrenia and

bipolar outpatients during treatment with typical and atypical antipsychotics. J Psychopharmacol 2007; 21:768–73.

29. Jung DU, Seo YS, Park JH, Jeong CY, Conley RR, Kelly DL, et al. The prevalence of hyperprolactinemia after long-term haloperidol use in patients with chronic schizophrenia. J Clin Psychopharmacol 2005; 25:613–15.

30. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Prevalence of hyperprolactinemia in schizophrenic patients treated with conventional antipsychotic medications or risperidone. Psychoneuroendocrinology 2003; 28(Suppl 2):55–68.

31. Melkersson K. Differences in prolactin elevation and related symptoms of atypical antipsychotics in schizophrenic patients. J Clin Psychiatry 2005; 66:761–7.

32. Frighi V , Goodwin G, Stephenson M, Morovat A, Dudley C, Hammond T, et al. for the Oxford Learning Disabilities Study Group. Manuscript in preparation.

33. Seeman MV. Secondary effects of antipsychotics: women at greater risk than men. Schizophr Bull 2009; 35:937–48.

34. Kuruvilla A, Peedicayil J, Srikrishna G, Kuruvilla K, Kanagasabapathy AS. A study of serum prolactin levels in schizophrenia: comparison of males and females. Clin Exp Pharmacol Physiol 1992; 19:603–6.

35. Kinon BJ, Gilmore JA, Liu H, Halbreich UM. Hyperprolactinemia in response to antipsychotic drugs: characterization across comparative clinical trials. Psychoneuroendocrinology 2003; 28(Suppl 2):69–82.


36. Perez RL, Machiavelli GA, Romano MI, Burdman JA. Prolactin release, oestrogens and proliferation of prolactin-secreting cells in the anterior pituitary gland of adult male rats. J Endocrinol 1986; 108:399–403.

37. Pariante CM, Dazzan P, Danese A, Morgan KD, Brudaglio F, Morgan C, et al. Increased pituitary volume in antipsychotic-free and antipsychotic-treated patients of the AEsop first-onset psychosis study. Neuropsychopharmacology 2005; 30:1923–31.

38. Pariante CM. Pituitary volume in psychosis: the first review of the evidence. J Psychopharmacol 2008; 22(2 Suppl):76–81.

39. Perroud N, Huguelet P. A possible effect of amisulpride on a prolactinoma growth in a woman with borderline personality disorder. Pharmacol Res 2004; 50:377–9.

40. Koves IH, Jarman FC, Cameron FJ. Antipsychotic medication and marked hyperprolactinaemia: iatros or true prolactinoma? Acta Paediatr 2004; 93:1543–7.

41. Mendhekar DN, Jiloha RC, Srivastava PK. Effect of risperidone on prolactinoma – a case report. Pharmacopsychiatry 2004; 37:41–2.

42. Pal JK, Sarino WA. Effect of risperidone on prolactinoma growth in a psychotic woman. Psychosom Med 2000; 62:736–8.

43. Melkersson K, Hulting AL. Prolactin-secreting pituitary adenoma in neuroleptic treated patients with psychotic disorder. Eur Arch Psychiatry Clin Neurosci 2000; 250:6–10.

44. Daradkeh TK, Ajlouni KM. The effect of neuroleptics on prolactinoma growth in a Jordanian schizo-phrenic girl. Acta Psychiatr Scand 1988; 77:228–9.

45. Freeman B, Levy W, Gorman JM. Successful monotherapy treatment with aripiprazole in a patient with schizophrenia and prolactinoma. J Psychiatr Pract 2007; 13:120–4.

46. Szarfman A, Tonning JM, Levine JG, Doraiswamy PM. Atypical antipsychotics and pituitary tumors: a pharmacovigilance study. Pharmacotherapy 2006; 26:748–58.

47. Centers for Disease Control and Prevention. United States Cancer Statistics. Brain cancer statistics by tumor type. http://apps.nccd.cdc.gov/uscs/Table .aspx?Group=1g&Year=2005&Display=n. Accessed 15 June 2009.

48. Doraiswamy PM, Schott G, Star K, Edwards R, Mueller-Oerlinghausen B. Atypical antipsychotics and pituitary neoplasms in the WHO database. Psychopharmacol Bull 2007; 40:74–6.

49. Kleinberg DL, Noel GL, Frantz AG. Galactorrhea: a study of 235 cases, including 48 with pituitary tumors. N Engl J Med 1977; 296:589–600.

50. Thangavelu K, Geetanjali S. Menstrual disturbance and galactorrhea in people taking conventional antipsychotic medications. Exp Clin Psychopharmacol 2006; 14:459–60.

51. Windgassen K, Wesselmann U, Schulze Monking H. Galactorrhea and hyperprolactinemia in schizophrenic patients on neuroleptics: frequency and etiology. Neuropsychobiology 1996; 33:142–6.

52. Harvey PW, Everett DJ, Springall CJ. Adverse effects of prolactin in rodents and humans: breast and prostate cancer. J Psychopharmacol 2008; 22(2 Suppl):20–7.

53. Welsch CW, Louks G, Fox D, Brooks C. Enhancement by prolactin of carcinogen induced mammary cancerigenesis in the male rat. Br J Cancer 1975; 32:427–31.

54. Tworoger SS, Eliassen AH, Rosner B, Sluss P, Hankinson SE. Plasma prolactin concentrations and risk of postmenopausal breast cancer. Cancer Res 2004; 64:6814–19.

55. Tworoger SS, Eliassen AH, Sluss P, Hankinson SE. A prospective study of plasma prolactin concentra-tions and risk of premenopausal and postmenopausal breast cancer. J Clin Oncol 2007; 25:1482–8.

56. Barak Y, Levy T, Achiron A, Aizenberg D. Breast cancer in women suffering from serious mental illness. Schizophr Res 2008; 102:249–53.

57. Goode DJ, Corbett WT, Schey HM, Suh SH, Woodie B, Morris DL, et al. Breast cancer in hospitalized psychiatric patients. Am J Psychiatry 1981; 138:804–6.

58. NHS. Cancer Screening Programme. http://www.cancerscreening.nhs.uk/breastscreen/. Accessed 15 June 2009.

59. Matsuzaki T, Azuma K, Irahara M, Yasui T, Aono T. Mechanism of anovulation in hyperprolactinemic amenorrhea determined by pulsatile gonadotropin-releasing hormone injection combined with human chorionic gonadotropin. Fertil Steril 1994; 62:1143–9.

60. O’Keane V. Antipsychotic-induced hyperprolactinaemia, hypogonadism and osteoporosis in the treatment of schizophrenia. J Psychopharmacol 2008; 22(2 Suppl):70–5.

61. Smith SM. The impact of hyperprolactinaemia on sexual function in patients with psychosis. J Psychopharmacol 2008; 22(2 Suppl):63–9.

62. Mendhekar DN, Andrade CR. Unilateral gynecomastia induced by risperidone in a geriatric male patient. Indian J Med Sci 2005; 59:361–2.


63. Kaneda Y, Fujii A. Gynecomastia with sulpiride. J Clin Pharm Ther 2002; 27:75–7. 64. Klibanski A, Neer RM, Beitins IZ, Ridgway EC, Zervas NT, McArthur JW. Decreased bone density in

hyperprolactinemic women. N Engl J Med 1980; 303:1511–14. 65. Greenspan SL, Neer RM, Ridgway EC, Klibanski A. Osteoporosis in men with hyperprolactinemic

hypogonadism. Ann Intern Med 1986; 104:777–82. 66. Klibanski A, Greenspan SL. Increase in bone mass after treatment of hyperprolactinemic amenorrhea.

N Engl J Med 1986; 315:542–6. 67. Greenspan SL, Oppenheim DS, Klibanski A. Importance of gonadal steroids to bone mass in men with

hyperprolactinemic hypogonadism. Ann Intern Med 1989; 110:526–31. 68. Meyer JM, Lehman D. Bone mineral density in male schizophrenia patients: a review. Ann Clin

Psychiatry 2006; 18:43–8. 69. Howard L, Kirkwood G, Leese M. Risk of hip fracture in patients with a history of schizophrenia. Br J

Psychiatry 2007; 190:129–34. 70. Meaney AM, O’Keane V. Bone mineral density changes over a year in young females with schizophre-

nia: relationship to medication and endocrine variables. Schizophr Res 2007; 93:136–43. 71. Bowman BM, Siska CC, Miller SC. Greatly increased cancellous bone formation with rapid improve-

ments in bone structure in the rat maternal skeleton after lactation. J Bone Miner Res 2002; 17:1954–60. 72. Citrome L. Current guidelines and their recommendations for prolactin monitoring in psychosis. J

Psychopharmacol 2008; 22(2 Suppl):90–7. 73. Frighi V, Marven M. Audit of the monitoring of patients of the Oxfordshire and Buckinghamshire

Mental Health Trust on long term antipsychotic treatment, 2007. 74. Frighi V. Audit of the monitoring of patients of the Oxfordshire Learning Disability Trust on long term

antipsychotic treatment, 2007. 75. Peveler RC, Branford D, Citrome L, Fitzgerald P, Harvey PW, Holt RI, et al. Antipsychotics and

hyperprolactinaemia: clinical recommendations. J Psychopharmacol 2008; 22(2 Suppl):98–103. 76. van Winkel R, De Hert M, Wampers M, Van Eyck D, Hanssens L, Scheen A, et al. Major changes in

glucose metabolism, including new-onset diabetes, within 3 months after initiation of or switch to atypical antipsychotic medication in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2008; 69:472–9.

77. Byerly MJ, Marcus RN, Tran QV, Eudicone JM, Whitehead R, Baker RA. Effects of aripiprazole on prolactin levels in subjects with schizophrenia during cross-titration with risperidone or olanzapine: analysis of a randomized, open-label study. Schizophr Res 2009; 107:218–22.

78. Shim JC, Shin JG, Kelly DL, Jung DU, Seo YS, Liu KH, et al. Adjunctive treatment with a dopamine partial agonist, aripiprazole, for antipsychotic-induced hyperprolactinemia: a placebo-controlled trial. Am J Psychiatry 2007; 16:1404–10.

79. Lu ML, Shen WW, Chen CH. Time course of the changes in antipsychotic-induced hyperprolactinemia following the switch to aripiprazole. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1978–81.

80. De Hert M, Hanssens L, van Winkel R, Wampers M, Van Eyck D, Scheen A, et al. A case series: evalua-tion of the metabolic safety of aripiprazole. Schizophr Bull 2007; 33:823–30.

81. Newcomer JW. Metabolic considerations in the use of antipsychotic medications: a review of recent evidence. J Clin Psychiatry. 2007; 68(Suppl 1):20–7.

82. Henderson DC, Kunkel L, Nguyen DD, Borba CP, Daley TB, Louie PM, et al. An exploratory open-label trial of aripiprazole as an adjuvant to clozapine therapy in chronic schizophrenia. Acta Psychiatr Scand 2006; 113:142–7.

83. Karunakaran K, Tungaraza TE, Harborne GC. Is clozapine–aripiprazole combination a useful regime in the management of treatment-resistant schizophrenia? J Psychopharmacol 2007; 21:453–6.

84. Henderson DC, Fan X, Copeland PM, Sharma B, Borba CP, Boxill R, et al. Aripiprazole added to overweight and obese olanzapine-treated schizophrenia patients. J Clin Psychopharmacol 2009; 29:165–9.

85. Rocha FL, Hara C. Benefits of combining aripiprazole to clozapine: three case reports. Prog Neuropsychopharmacol Biol Psychiatry 2006; 30:1167–9.

86. Masopust J, Tuma I, Libiger J. Adjunctive aripiprazole decreased metabolic side effects of clozapine treatment. Neuro Endocrinol Lett 2008; 29:435–7.

87. Adan-Manes J, Garcia-Parajua P. Aripiprazole in combination with other antipsychotic drugs may worsen psychosis. J Clin Pharm Ther 2009; 34:245–6.

88. Chang SC, Chen CH, Lu ML. Cabergoline-induced psychotic exacerbation in schizophrenic patients. Gen Hosp Psychiatry 2008; 30:378–80.


89. Dorevitch A, Aronzon R, Stark M. Psychotic exacerbation attributed to low-dose bromocriptine treat-ment of galactorrhea and hyperprolactinemia. Acta Obstet Gynecol Scand 1991; 70:375–6.

90. Brown WA, Laughren TP. Tolerance to the prolactin-elevating effect of neuroleptics. Psychiatry Res 1981; 5:317–22.

91. Koro CE, Meyer JM. Atypical antipsychotic therapy and hyperlipidemia: a review. Essent Psychopharmacol 2005; 6:148–57.

92. Alberti KG, Zimmet P, Shaw J. Metabolic syndrome – a new world-wide definition. A Consensus Statement from the International Diabetes Federation. Diabet Med 2006; 23:469–80.

93. Stahl SM, Mignon L, Meyer JM. Which comes first: atypical antipsychotic treatment or cardiometabolic risk? Acta Psychiatr Scand 2009; 119:171–9.

94. Henderson DC, Nguyen DD, Copeland PM, Hayden DL, Borba CP, Louie PM, et al. Clozapine, dia-betes mellitus, hyperlipidemia, and cardiovascular risks and mortality: results of a 10-year naturalistic study. J Clin Psychiatry 2005; 66:1116–21.

95. Hennekens CH, Hennekens AR, Hollar D, Casey DE. Schizophrenia and increased risks of cardiovas-cular disease. Am Heart J 2005; 150:1115–21.

96. Fleischhacker WW, Cetkovich-Bakmas M, De Hert M, Hennekens CH, Lambert M, Leucht S, et al. Comorbid somatic illnesses in patients with severe mental disorders: clinical, policy, and research challenges. J Clin Psychiatry 2008; 69:514–19.

97. De Hert M, Schreurs V, Vancampfort D, Van Winkel R. Metabolic syndrome in people with schizo-phrenia: a review. World Psychiatry 2009; 8:15–22.

98. Mackin P, Watkinson HM, Young AH. Prevalence of obesity, glucose homeostasis disorders and meta-bolic syndrome in psychiatric patients taking typical or atypical antipsychotic drugs: a cross-sectional study. Diabetologia 2005; 48:215–21.

99. McIntyre RS, Jerrell JM. Metabolic and cardiovascular adverse events associated with antipsychotic treatment in children and adolescents. Arch Pediatr Adolesc Med 2008; 162:929–35.

100. Correll CU. Antipsychotic use in children and adolescents: minimizing adverse effects to maximize outcomes. J Am Acad Child Adolesc Psychiatry 2008; 47:9–20.

101. Charatan FB, Bartlett NG. The effect of chlorpromazine (largactil) on glucose tolerance. J Ment Sci 1955; 101:351–3.

102. Courvoisier S, Fournel J, Ducrot R, Kolsky M, Koetschet P. [Pharmacodynamic properties of 3-chloro-10-(3-dimethylaminopropyl)-phenothiazine hydrochloride (R.P. 4560); experimental study of a new substance used in potentialized anesthesia and in artificial hibernation.]. Arch Int Pharmacodyn Ther 1953; 92:305–61.

103. Bonaccorsi A, Garattini S, Jori A. Studies on the hyperglycaemia induced by chlorpromazine in rats. Br J Pharmacol Chemother 1964; 23:93–100.

104. Thonnard-Neumann E. Phenothiazines and diabetes in hospitalized women. Am J Psychiatry 1968; 124:978–82.

105. Koller E, Schneider B, Bennett K, Dubitsky G. Clozapine-associated diabetes. Am J Med 2001; 111:716–23.

106. Koller EA, Doraiswamy PM. Olanzapine-associated diabetes mellitus. Pharmacotherapy 2002; 22:841–52. 107. Koller EA, Cross JT, Doraiswamy PM, Schneider BS. Risperidone-associated diabetes mellitus: a

pharmacovigilance study. Pharmacotherapy 2003; 23:735–44. 108. Koller E, Malozowski S, Doraiswamy PM. Atypical antipsychotic drugs and hyperglycemia in adoles-

cents. JAMA 2001; 286:2547–8. 109. Koller EA, Cross JT, Schneider B. Risperidone-associated diabetes mellitus in children. Pediatrics 2004;

113:421–2. 110. American Diabetes Association, American Psychiatric Association, American Association of Clinical

Endocrinologists and North American Association for the Study of Obesity. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care 2004; 27:596–601.

111. Holt R, Abdelrahman T, Hirsch M, Dhesi Z, George T, Blincoe T, et al. The prevalence of undiagnosed metabolic abnormalities in people with serious mental illness. J Psychopharmacol 2009 Mar 20. doi: 10.1177/0269881109102788

112. Meyer J, Loh C, Leckband SG, Boyd JA, Wirshing WC, Pierre JM, et al. Prevalence of the metabolic syndrome in veterans with schizophrenia. J Psychiatr Pract 2006; 12:5–10.

113. McEvoy JP, Meyer JM, Goff DC, Nasrallah HA, Davis SM, Sullivan L, et al. Prevalence of the metabolic syndrome in patients with schizophrenia: baseline results from the Clinical Antipsychotic Trials of


Intervention Effectiveness (CATIE) schizophrenia trial and comparison with national estimates from NHANES III. Schizophr Res 2005; 80:19–32.

114. Taylor D, Young C, Mohamed R, Paton C, Walwyn R. Undiagnosed impaired fasting glucose and diabetes mellitus amongst inpatients receiving antipsychotic drugs. J Psychopharmacol 2005; 19:182–6.

115. Leslie DL, Rosenheck RA. Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications. Am J Psychiatry 2004; 161:1709–11.

116. Newcomer JW. Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 2005; 19(Suppl 1):1–93.

117. McCall M, Bourgeois JA. Olanzapine-induced hyperglycemic hyperosmolar nonketotic coma: a case report. J Clin Psychopharmacol 2004; 24:670–3.

118. Roefaro J, Mukherjee SM. Olanzapine-induced hyperglycemic nonketonic coma. Ann Pharmacother 2001; 35:300–2.

119. Avella J, Wetli CV, Wilson JC, Katz M, Hahn T. Fatal olanzapine-induced hyperglycemic ketoacidosis. Am J Forensic Med Pathol 2004; 25:172–5.

120. Dibben CR, Kalavalapalli SS, Linnington HE, Hynes FA, Dinneen SF, Adler AI, et al. Diabetes associated with atypical antipsychotic treatment may be severe but reversible: case report. Int J Psychiatry Med 2005; 35:307–11.

121. Sirois F. New-onset diabetic ketoacidosis associated with quetiapine: a case report. Gen Hosp Psychiatry 2008; 30:587–8.

122. Mallya A, Chawla P, Boyer SK, DeRosear L. Resolution of hyperglycemia on risperidone discontinua-tion: a case report. J Clin Psychiatry 2002; 63:453–4.

123. Selva KA, Scott SM. Diabetic ketoacidosis associated with olanzapine in an adolescent patient. J Pediatr 2001; 138:936–8.

124. Courvoisie HE, Cooke DW, Riddle MA. Olanzapine-induced diabetes in a seven-year-old boy. J Child Adolesc Psychopharmacol 2004; 14:612–16.

125. Takahashi M, Ohishi S, Katsumi C, Moriya T, Miyaoka H. Rapid onset of quetiapine-induced diabetic ketoacidosis in an elderly patient: a case report. Pharmacopsychiatry 2005; 38:183–4.

126. Frighi V, Stephenson M. Exacerbation of pre-existing diabetes by low dose quetiapine. In: Gough SC, Manley SE, Stratton IM (eds) HbA1c in Diabetes: Case Studies Using IFCC Units. Oxford: Wiley-Blackwell, 2010.

127. Meyer JM, Koro CE. The effects of antipsychotic therapy on serum lipids: a comprehensive review. Schizophr Res 2004; 70:1–17.

128. Nasrallah HA. Metabolic findings from the CATIE trial and their relation to tolerability. CNS Spectr 2006; 11(7 Suppl 7):32–9.

129. Campanella LM, Lartey R, Shih R. Severe hyperglycemic hyperosmolar nonketotic coma in a nondia-betic patient receiving aripiprazole. Ann Emerg Med 2009; 53:264–6.

130. Makhzoumi ZH, McLean LP, Lee JH, Ibe AI. Diabetic ketoacidosis associated with aripiprazole. Pharmacotherapy 2008; 28:1198–202.

131. Logue DD, Gonzalez N, Heligman SD, McLaughlin JV, Belcher HM. Hyperglycemia in a 7-year-old child treated with aripiprazole. Am J Psychiatry 2007; 164:173.

132. Reddymasu S, Bahta E, Levine S, Manas K, Slay LE. Elevated lipase and diabetic ketoacidosis associ-ated with aripiprazole. J Pancreas 2006; 7:303–5.

133. Church CO, Stevens DL, Fugate SE. Diabetic ketoacidosis associated with aripiprazole. Diabet Med 2005; 22:1440–3.

134. Kerwin R, Millet B, Herman E, Banki CM, Lublin H, Pans M, et al. A multicentre, randomized, natural-istic, open-label study between aripiprazole and standard of care in the management of community-treated schizophrenic patients. Schizophrenia Trial of Aripiprazole: (STAR) study. Eur Psychiatry 2007; 22:433–43.

135. Kane JM, Osuntokun O, Kryzhanovskaya LA, Xu W, Stauffer VL, Watson SB, et al. A 28-week, random-ized, double-blind study of olanzapine versus aripiprazole in the treatment of schizophrenia. J Clin Psychiatry 2009; 70:572–81.

136. Fleischhacker WW, McQuade RD, Marcus RN, Archibald D, Swanink R, Carson WH. A double-blind, randomized comparative study of aripiprazole and olanzapine in patients with schizophrenia. Biol Psychiatry 2009; 65:510–17.

137. Budman C, Coffey BJ, Shechter R, Schrock M, Wieland N, Spirgel A, et al. Aripiprazole in children and adolescents with Tourette disorder with and without explosive outbursts. J Child Adolesc Psychopharmacol 2008; 18:509–15.


138. Ahren B, Lundquist I. Effects of L-dopa-induced dopamine accumulation on 45Ca2+ efflux and insulin secretion in isolated rat islets. Pharmacology 1985; 30:71–82.

139. Bina KG, Cincotta AH. Dopaminergic agonists normalize elevated hypothalamic neuropeptide Y and corticotropin-releasing hormone, body weight gain, and hyperglycemia in ob/ob mice. Neuroendocrinology 2000; 71:68–78.

140. Rubi B, Ljubicic S, Pournourmohammadi S, Carobbio S, Armanet M, Bartley C, et al. Dopamine D2-like receptors are expressed in pancreatic beta cells and mediate inhibition of insulin secretion. J Biol Chem 2005; 280:36824–32.

141. Shankar E, Santhosh KT, Paulose CS. Dopaminergic regulation of glucose-induced insulin secretion through dopamine D2 receptors in the pancreatic islets in vitro. IUBMB Life 2006; 58:157–63.

142. Aminorroaya A, Janghorbani M, Ramezani M, Haghighi S, Amini M. Does bromocriptine improve glycemic control of obese type-2 diabetics? Horm Res 2004; 62:55–9.

143. Barnett AH, Chapman C, Gailer K, Hayter CJ. Effect of bromocriptine on maturity onset diabetes. Postgrad Med J 1980; 56:11–14.

144. Cincotta AH, Meier AH, Cincotta Jr M. Bromocriptine improves glycaemic control and serum lipid profile in obese type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert Opin Investig Drugs 1999; 8:1683–707.

145. Scranton RE, Gaziano JM, Rutty D, Ezrokhi M, Cincotta A. A randomized, double-blind, placebo-controlled trial to assess safety and tolerability during treatment of type 2 diabetes with usual diabetes therapy and either Cycloset or placebo. BMC Endocr Disord 2007; 7:3.

146. Pijl H, Ohashi S, Matsuda M, Miyazaki Y, Mahankali A, Kumar V, et al. Bromocriptine: a novel approach to the treatment of type 2 diabetes. Diabetes Care 2000; 23:1154–61.

147. Davis LM, Pei Z, Trush MA, Cheskin LJ, Contoreggi C, McCullough K, et al. Bromocriptine reduces steatosis in obese rodent models. J Hepatol 2006; 45:439–44.

148. Shapiro DA, Renock S, Arrington E, Chiodo LA, Liu LX, Sibley DR, et al. Aripiprazole, a novel atypical antipsychotic drug with a unique and robust pharmacology. Neuropsychopharmacology 2003; 28:1400–11.

149. Blonde L, Kan HJ, Gutterman EM, L’Italien GJ, Kim MS, Hanssens L, et al. Predicted risk of diabetes and coronary heart disease in patients with schizophrenia: aripiprazole versus standard of care. J Clin Psychiatry 2008; 69:741–8.

150. Chang JS, Ahn YM, Park HJ, Lee KY, Kim SH, Kang UG, et al. Aripiprazole augmentation in clozapine-treated patients with refractory schizophrenia: an 8-week, randomized, double-blind, placebo-controlled trial. J Clin Psychiatry 2008; 69:720–31.

151. Christensen AF, Poulsen J, Nielsen CT, Bork B, Christensen A, Christensen M. Patients with schizophrenia treated with aripiprazole, a multicentre naturalistic study. Acta Psychiatr Scand 2006; 113:148–53.

152. Muzina DJ, Momah C, Eudicone JM, Pikalov A, McQuade RD, Marcus RN, et al. Aripiprazole mono-therapy in patients with rapid-cycling bipolar I disorder: an analysis from a long-term, double-blind, placebo-controlled study. Int J Clin Pract 2008; 62:679–87.

153. Assie MB, Carilla-Durand E, Bardin L, Maraval M, Aliaga M, Malfetes N, et al. The antipsychotics clozapine and olanzapine increase plasma glucose and corticosterone levels in rats: comparison with aripiprazole, ziprasidone, bifeprunox and F15063. Eur J Pharmacol 2008; 592:160–6.

154. Nasrallah HA. Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles. Mol Psychiatry 2008; 13:27–35.

155. Yuan X, Yamada K, Ishiyama-Shigemoto S, Koyama W, Nonaka K. Identification of polymorphic loci in the promoter region of the serotonin 5-HT2C receptor gene and their association with obesity and type II diabetes. Diabetologia 2000; 43:373–6.

156. Zhang JY, Kowal DM, Nawoschik SP, Lou Z, Dunlop J. Distinct functional profiles of aripiprazole and olanzapine at RNA edited human 5-HT2C receptor isoforms. Biochem Pharmacol 2006; 71:521–9.

157. Nonogaki K, Strack AM, Dallman MF, Tecott LH. Leptin-independent hyperphagia and type 2 diabetes in mice with a mutated serotonin 5-HT2C receptor gene. Nat Med 1998; 4:1152–6.

158. Starrenburg FC, Bogers JP. How can antipsychotics cause diabetes mellitus? Insights based on receptor-binding profiles, humoral factors and transporter proteins. Eur Psychiatry 2009; 24:164–70.

159. Peuskens J, De Hert M, Mortimer A. Metabolic control in patients with schizophrenia treated with amisulpride or olanzapine. Int Clin Psychopharmacol 2007; 22:145–52.

160. Correll CU, Carlson HE. Endocrine and metabolic adverse effects of psychotropic medications in children and adolescents. J Am Acad Child Adolesc Psychiatry 2006; 45:771–91.


161. Potkin SG, Cohen M, Panagides J. Efficacy and tolerability of asenapine in acute schizophrenia: a placebo- and risperidone-controlled trial. J Clin Psychiatry 2007; 68:1492–500.

162. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med 2007; 13:1102–7.

163. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346:393–403.

164. Chiasson JL. Prevention of type 2 diabetes: fact or fiction? Expert Opin Pharmacother 2007; 8:3147–58. 165. Krentz AJ, Patel MB, Bailey CJ. New drugs for type 2 diabetes mellitus: what is their place in therapy?

Drugs 2008; 68:2131–62. 166. Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR, Pratley R, et al. Impaired fasting

glucose and impaired glucose tolerance: implications for care. Diabetes Care 2007; 30:753–9. 167. Wu RR, Zhao JP, Guo XF, He YQ, Fang MS, Guo WB, et al. Metformin addition attenuates olanzapine-

induced weight gain in drug-naive first-episode schizophrenia patients: a double-blind, placebo-controlled study. Am J Psychiatry 2008; 165:352–8.

168. Wu RR, Zhao JP, Jin H, Shao P, Fang MS, Guo XF, et al. Lifestyle intervention and metformin for treatment of antipsychotic-induced weight gain: a randomized controlled trial. JAMA 2008; 299:185–93.

169. Barnes TR, Paton C, Hancock E, Cavanagh MR, Taylor D, Lelliott P. Screening for the metabolic syndrome in community psychiatric patients prescribed antipsychotics: a quality improvement programme. Acta Psychiatr Scand 2008; 118:26–33.

170. Morrato EH, Newcomer JW, Kamat S, Baser O, Harnett J, Cuffel B. Metabolic screening after the American Diabetes Association’s consensus statement on antipsychotic drugs and diabetes. Diabetes Care 2009; 32:1037–42.

171. Faulkner G, Cohn T, Remington G. Interventions to reduce weight gain in schizophrenia. Cochrane Database Syst Rev 2007; 1:CD005148.

172. Shin L, Bregman H, Breeze JL, Noyes N, Frazier JA. Metformin for weight control in pediatric patients on atypical antipsychotic medication. J Child Adolesc Psychopharmacol 2009; 19:275–9.

173. Klein DJ, Cottingham EM, Sorter M, Barton BA, Morrison JA. A randomized, double-blind, placebo-controlled trial of metformin treatment of weight gain associated with initiation of atypical antipsy-chotic therapy in children and adolescents. Am J Psychiatry 2006; 163:2072–9.

174. Miller LJ. Management of atypical antipsychotic drug-induced weight gain: focus on metformin. Pharmacotherapy 2009; 29:725–35.

View Sample PDF - Clinical Publishing

Documents

Transcript of View Sample PDF - Clinical Publishing