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Current approaches to treatments for schizophrenia spectrum disorders, part i: an overview and medical treatments

wai Tong ChienAnnie LK YipSchool of Nursing, Faculty of Health and Social Sciences, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong

Correspondence: wai Tong Chien School of Nursing, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong Tel +852 2766 5648 Fax +852 2334 1124 email wai.tong.chien@polyu.edu.hk

Abstract: During the last three decades, an increasing understanding of the etiology,

psychopathology, and clinical manifestations of schizophrenia spectrum disorders, in addition to

the introduction of second-generation antipsychotics, has optimized the potential for recovery from

the illness. Continued development of various models of psychosocial intervention promotes the

goal of schizophrenia treatment from one of symptom control and social adaptation to an optimal

restoration of functioning and/or recovery. However, it is still questionable whether these new

treatment approaches can address the patients’ needs for treatment and services and contribute

to better patient outcomes. This article provides an overview of different treatment approaches

currently used in schizophrenia spectrum disorders to address complex health problems and a wide

range of abnormalities and impairments resulting from the illness. There are different treatment

strategies and targets for patients at different stages of the illness, ranging from prophylactic

antipsychotics and cognitive–behavioral therapy in the premorbid stage to various psychosocial

interventions in addition to antipsychotics for relapse prevention and rehabilitation in the later

stages of the illness. The use of antipsychotics alone as the main treatment modality may be

limited not only in being unable to tackle the frequently occurring negative symptoms and

cognitive impairments but also in producing a wide variety of adverse effects to the body or organ

functioning. Because of varied pharmacokinetics and treatment responsiveness across agents,

the medication regimen should be determined on an individual basis to ensure an optimal effect

in its long-term use. This review also highlights that the recent practice guidelines and standards

have recommended that a combination of treatment modalities be adopted to meet the complex

health needs of people with schizophrenia spectrum disorders. In view of the heterogeneity of

the risk factors and the illness progression of individual patients, the use of multifaceted illness

management programs consisting of different combinations of physical, psychological, and social

interventions might be efficient and effective in improving recovery.

Keywords: schizophrenia, schizophrenia spectrum disorders, treatment, psychosocial interven-

tion, pharmacology, antipsychotics

IntroductionSchizophrenia and its spectrum disorders (all falling under the term “schizophrenia” in

this article) are chronic remitting and disruptive disorders associated with significant

abnormalities and the progressive deterioration of a wide variety of cognitive, psycho-

social, vocational, and behavioral functioning. The fourth edition of the Diagnostic

and Statistical Manual of Mental Disorders (DSM-IV) defines schizophrenia as a

syndrome characterized by long duration, high relapse rate (.70%), bizarre delusions

and behaviors, negative symptoms, and sometimes a few mood problems.1 The onset

of symptoms typically occurs in adolescence and young adulthood, with a worldwide

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1312

Chien and Yip

estimate of its lifetime prevalence and incidence of 1.4–4.6

and 0.16–0.42 per 1,000 persons annually, respectively.2,3

A recent systematic review indicated that patients diagnosed

with this disorder have a shorter lifespan than the average

general population and are particularly at risk for suicide,

increased physical risk (eg, limited exercise, poor diet,

and obesity), and reduced access to medical treatment and

healthcare services.4 In addition, 5%–8% of healthy people

indicate an attenuated form of schizoid personality and

schizophrenia-like symptoms, such as paranoid delusional

thinking and auditory hallucination.5

Because of the complex health problems and wide range

of abnormalities and impairments concerning schizophrenia,

comprehensive and multimodal treatment approaches are

considered and tested in different combinations, with the

goal of reducing patients’ illness episodes and symptoms,

as well as improving their functioning and quality of life

in the longer term. Antipsychotic medications have been

recommended consistently and continuously as the main-

stream and standard treatment for nearly all patients with

schizophrenia, to provide them with a safe and therapeutic

environment and effective symptom control since the intro-

duction of chlorpromazine (the first antipsychotic) in the

1960s. In the last three to four decades, physical treatments

such as electroconvulsive therapy (ECT; in the 1930s) and

different approaches to psychosocial interventions such as

psychoanalysis (in the 1950s), family therapy (in the 1960s),

psychoeducation (in the 1980s), cognitive–behavioral ther-

apy (in the 1990s), and cognitive remediation (in the 2000s)

have been introduced successively,7–14 and their comparative

or combined efficacies for schizophrenia treatment have

been increasingly evaluated in various clinical trials.8,10,12,13

Recent systematic reviews and practice guidelines have

recommended that as an adjunct to psychopharmacological

treatment, psychosocial interventions designed to support

both people with schizophrenia and their families should

also be used to improve their rehabilitation, reintegration into

the community, and recovery from the illness.6,15 Different

modalities and combinations of psychosocial programs are

recommended to address the complex individualized needs

of these patients for multimodal care, particularly regarding

relapse prevention, management of negative symptoms and

cognitive dysfunction, and medication adherence.14,16 Despite

increased recognition and demands for an individualized

treatment plan and the integration of different intervention

approaches to optimize patient outcomes, current psychiat-

ric treatments and services still involve practicing the same

set of treatment approaches for each patient group in the

course of illness. More clinical trials are recommended to

examine the active ingredients of unimodal or integrated

psychosocial interventions for schizophrenia that can be

effective in enhancing recovery and other patient outcomes.

There has also been increasing attention and demand for

cost-effectiveness analyses of these interventions.

To gain a more in-depth and focused understanding of

the effects and benefits of recent approaches to treatments

for schizophrenia, we performed a comparative review, sum-

marized here, of the efficacy, safety, and tolerability of the

current pharmacological and other medical treatments for

these patients. In another article, we also performed a com-

parative review of the efficacy of approaches to psychosocial

interventions for schizophrenia and a critical discussion about

patient-focused perspectives of acceptance, benefits, and

satisfaction in psychiatric care. Recommendations for best

practices for continuity of schizophrenia care are also made.

This article also provides an overview of the approaches to

treatments across different stages of schizophrenia and the

future direction of treatments for this illness.

Review of current approaches to medical treatments for schizophreniaDuring the last two decades, the mainstream of medical treat-

ment for schizophrenia has remained the use of antipsychotics

and/or other psychotropic medications. With increasing

initiatives and evidence of the effectiveness of psychosocial

interventions for schizophrenia, the highly structured or

manualized (eg, cognitive–behavioral and psychoeducation

programs) and a few integrated programs (eg, the Schizo-

phrenia Patient Outcomes Research Team Programs and the

Recovery After an Initial Schizophrenia Episode Early Treat-

ment Program in the United States),17,18 used as an adjunct to

antipsychotics, have indicated positive patient outcomes. On

the basis of several large-scale randomized controlled trials,

single and multiple types of antipsychotics, or polypharmacy

in combination with other psychotropic drugs, are consid-

ered useful in schizophrenia treatment. The introduction of

second-generation antipsychotics has further improved the

desired effects of these medications for schizophrenia care

and, more important, reduced their undesirable effects such

as extrapyramidal adverse effects, mortality, and metabolic

disorder. Before exploring the recent changes or improve-

ments needed in schizophrenia treatment and rehabilitation, it

is important to review and understand the current knowledge

about pharmacological and other medical treatments for

schizophrenia sufferers.

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Current treatments for schizophrenia spectrum disorders

Pharmacological treatmentFirst- and second-generation antipsychoticsMore than 70 antipsychotics have been introduced. They are

mainly categorized into first- and second-generation agents

and share a similar pharmacological mechanism in blocking

the dopamine D-2 receptors.19 Their blocking mechanisms

or actions are linked to their efficacy against positive and

disorganization symptoms of schizophrenia.11–13

The first-generation antipsychotics (FGAs), or typi-

cal antipsychotics (eg, chlorpromazine, fluphenazine, and

haloperidol, included in the World Health Organization’s

list of Essential Medications in 2009),20 were first intro-

duced for the treatment of schizophrenia in the 1950s. The

second- generation (atypical) antipsychotics (eg, clozapine,

olanzapine, and risperidone) introduced in the last three

decades were believed to be more efficacious and toler-

able than the FGAs, and a few have progressively replaced

the older FGAs to become the first-line prescription or the

standard of care. To capture the research evidence or drug

trials on antipsychotics, full-text articles published in English

between 1966 and 2010 were searched for in CINAHL,

MEDLINE, EMBASE, The Cochrane Library, Cochrane

Schizophrenia Group’s Register, Biological Abstracts,

Sociological Abstracts, Sociofile, and PsycLIT. Participants

included people with schizophrenia, schizophrenia-like

psychoses such as schizophreniform and schizoaffective dis-

orders, and psychotic disorders such as delusional disorder,

nonaffective psychosis, or dual diagnosis. The main out-

comes identified from the reviewed articles mainly involved

mental state, global functioning, and adverse events.

Thirteen systematic reviews on the efficacy of FGAs

using a randomized controlled trial design were found

(Table 1). With similar intended outcomes, several outcome

measurement tools were commonly used, including the

Clinical Global Impression, Global Assessment Scale, and

Global Assessment of Functioning scale for patients’ global

functioning; the Brief Psychiatric Rating Scale, Positive

and Negative Syndrome Scale, Scale for the Assessment

of Negative Symptoms, and Scale for the Assessment of

Positive Symptoms for their mental state or symptom sever-

ity; and the Involuntary Movement Scale, Extrapyramidal

Symptom Rating Scale, Extrapyramidal Rating Scale, and

Simpson and Angus Scale for the adverse effects of medi-

cation used. Most of the clinical trials (.70%) evaluated

the medication effects over a short period of time (eg, up

to 12 weeks), whereas a few (,10%) involved a long-term

follow-up (eg, .1 year).

The first FGA invented – chlorpromazine, has become

the well-established and benchmark treatment for people

with schizophrenia to facilitate their deinstitutionalization21

and has been used for more than 40 years. Nevertheless,

the reviewed literature showed that the incidence and

average dose of chlorpromazine prescribed to people with

schizophrenia has been decreasing.22 Other commonly

used FGAs such as trifluoperazine, thioridazine, sulpiride,

pimozide, perphenazine, and fluphenazine were tested

and confirmed to have similar and satisfactory efficacy in

symptom reduction – mainly for positive symptoms (eg,

delusions and hallucinations).23–28 However, there was

limited evidence to support their efficacy at lower doses or

in short-term treatment.28–31 Major adverse events induced

by FGAs generally include sedation, movement disorders,

endocrine disturbance, and metabolic and electrocardiogram

changes.24,25,28,32

Most of all, FGAs are a relatively low-cost treatment and

commonly used medication; however, there is little evidence

to support their efficacy in reducing negative symptoms

(eg, anhedonia, loss of volition, and social withdrawal) and

cognitive functioning, which may contribute much to the

functional disability of people with schizophrenia.26,29,33 It is

generally concluded that there is similar satisfactory clini-

cal efficacy in terms of mental state and global functioning

across the FGAs and second-generation antipsychotics.34–37

However, a few trials indicate the superiority of individual

second-generation agents over the FGAs in specific illness

condition or patient outcomes.29,33,37,38 In two meta-analyses

of placebo-controlled trials,39,40 haloperidol was reported

to be less effective in reducing symptoms and/or relapse

than certain second-generation agents (eg, clozapine and

olanzapine).

Second-generation (or atypical) antipsychotics were

believed to have good antipsychotic properties and minimal

adverse effects compared with those noted with the use of

FGAs. Some of them have been shown to be more efficacious

and less problematic in terms of sedative and neurologi-

cal effects than FGAs.41,42 Using the same databases and a

similar procedure as the literature search on FGAs presented

earlier, 12 systematic reviews (between 1966 and 2010)

have been conducted to compare the effects among second-

generation antipsychotics and the effects between these

second-generation agents and FGAs or a placebo (Table 2). In

addition to the main patient outcomes used (ie, mental state,

global functioning, and relapse), several other psychosocial

outcomes were usually compared across studies, including

level of depression, acceptability of treatment (eg, dropout

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1314

Chien and Yip

Tab

le 1

Sum

mar

y of

rev

iew

s on

firs

t-ge

nera

tion

antip

sych

otic

s fo

r sc

hizo

phre

nia

Aut

hors

Clin

ical

tri

als

revi

ewed

, NIn

terv

enti

ons

Sam

ple

size

and

st

udy

sett

ing

Leng

th o

f stu

dy

or fo

llow

-upa

Sum

mar

y of

mai

n fin

ding

sC

oncl

usio

n

Ada

ms

et a

l2150

Chl

orpr

omaz

ine

(o

ral o

r by

inje

ctio

n)

vs p

lace

bo

N =

1,3

95; m

ainl

y

hosp

ital-b

ased

; a

few

con

duct

ed

in t

he c

omm

unity

24 h

ours

to

5

year

s; fo

llow

-up

in

onl

y 22

sho

rt-

term

stu

dies

, 20

med

ium

-ter

m

stud

ies,

and

eig

ht

long

-ter

m s

tudi

es

• Si

x of

50

cont

rolle

d tr

ials

foun

d th

at

chlo

rpro

maz

ine

coul

d re

duce

rel

apse

in a

sh

ort-

to m

ediu

m-t

erm

follo

w-u

p; th

ree

wer

e in

a

long

-ter

m fo

llow

-up

(6 m

onth

s to

2 y

ears

); an

d

two

in a

muc

h lo

nger

-ter

m fo

llow

-up

(2–5

yea

rs).

• T

wen

ty-fo

ur o

f the

tri

als

foun

d th

at

antip

sych

otic

s co

uld

indu

ce g

loba

l im

prov

emen

ts in

pos

itive

sym

ptom

s an

d

func

tioni

ng in

a s

hort

- to

med

ium

-ter

m

(up

to 6

mon

ths)

follo

w-u

p.•

Not

sur

pris

ingl

y, a

ran

ge o

f adv

erse

effe

cts

such

as

extr

apyr

amid

al s

ympt

oms,

sed

atio

n,

dizz

ines

s, a

nd w

eigh

t ga

in w

as fo

und.

• FG

As

such

as

chlo

rpro

maz

ine

ca

n be

the

ben

chm

ark

of

trea

tmen

t fo

r sc

hizo

phre

nia.

• it

is w

ell-e

stab

lishe

d bu

t

impe

rfec

t tr

eatm

ent.

Mos

t

evid

ence

on

thei

r si

gnifi

cant

ef

fect

s ha

s be

en fo

und

in

hosp

itals

, and

rel

ativ

ely

little

w

as a

pplic

able

to

patie

nts

in

com

mun

ity c

are.

Fent

on e

t al

2442

Thi

orid

azin

e vs

FG

As,

se

cond

-gen

erat

ion

an

tipsy

chot

ics,

an

d/or

pla

cebo

N =

3,4

98; m

ainl

y

hosp

ital-b

ased

; thr

ee

tria

ls c

ondu

cted

in

outp

atie

nt s

ettin

gs

Follo

w-u

p:

30 s

hort

- te

rm, t

en m

ediu

m-

term

, and

tw

o

long

-ter

m t

rial

s

• A

s co

mpa

red

with

the

pla

cebo

con

trol

s, t

hree

R

CT

s fa

vore

d th

iori

dazi

ne in

ter

ms

of g

loba

l fu

nctio

ning

afte

r lo

nger

-ter

m fo

llow

-up

(ie, u

p

to 6

mon

ths)

, and

ano

ther

thr

ee R

CT

s fo

und

it

seda

ting,

but

it w

as n

ot g

ener

ally

foun

d to

ca

use

mov

emen

t di

sord

ers.

• C

ompa

red

with

FG

As,

11

smal

l and

thr

ee

med

ium

RC

Ts

foun

d no

diff

eren

ce in

glo

bal

func

tioni

ng; 1

9 sm

all R

CT

s fo

und

no

diffe

renc

e in

ear

ly a

ttri

tion

or d

efau

lts; a

nd

seve

n R

CT

s fo

und

thio

rida

zine

to

have

few

er

extr

apyr

amid

al a

dver

se e

vent

s, b

ut t

hree

R

CT

s re

port

ed it

was

ass

ocia

ted

with

ca

rdia

c ad

vers

e ef

fect

s.

• T

hior

idaz

ine

indi

cate

d no

si

gnifi

cant

diff

eren

ce in

clin

ical

ef

ficac

y w

hen

com

pare

d

with

oth

er c

omm

only

use

d

antip

sych

otic

s in

ter

ms

of g

loba

l fu

nctio

ning

.•

The

res

earc

hers

sug

gest

ed

cons

ider

ing

othe

r al

tern

ativ

es

whe

n pa

tient

s di

d no

t re

spon

d

wel

l to

thio

rida

zine

.

Har

tung

et

al26

25Pe

rphe

nazi

ne v

s

plac

ebo

and

othe

r

antip

sych

otic

s

N =

2,4

78

(2,2

85 r

ando

miz

ed);

al

l con

duct

ed in

ho

spita

ls o

r

outp

atie

nt s

ettin

gs

Tw

o sh

ort-

term

, tw

o m

ediu

m-t

erm

tr

ials

• T

wen

ty R

CT

s fo

und

perp

hena

zine

as

effe

ctiv

e

as o

ther

ant

ipsy

chot

ics

in t

erm

s of

saf

ety,

ill

ness

beh

avio

r, a

nd t

oler

abili

ty.

• Po

or d

ata

repo

rtin

g an

d th

e us

e of

var

ious

co

mpa

rato

rs li

mite

d th

e va

lidity

of t

he r

evie

w.

• it

was

not

pos

sibl

e to

dra

w

clea

r co

nclu

sion

s; p

erph

enaz

ine

in

dica

ted

sim

ilar

desi

rabl

e an

d

adve

rse

even

ts t

o ot

her

drug

s.•

How

ever

, it

is r

elat

ivel

y

low

-cos

t, an

d th

us m

ore

fr

eque

ntly

use

d.ir

ving

et

al31

21H

alop

erid

ol (

oral

)

vs p

lace

boN

= 1

,519

; all

co

nduc

ted

in

hosp

ital o

r ou

tpat

ient

se

ttin

gs; u

sual

ly

mul

ticen

ter

desi

gn

elev

en s

hort

-ter

m

and

ten

med

ium

- te

rm tr

ials

• T

hree

RC

Ts

foun

d th

at h

alop

erid

ol p

rodu

ced

im

prov

emen

t in

glo

bal f

unct

ioni

ng d

urin

g th

e

first

6 w

eeks

of f

ollo

w-u

p; e

ight

RC

Ts

favo

red

th

e dr

ug a

t 6–

24 w

eeks

.

• it

was

sug

gest

ed t

hat

pres

crib

ing

alte

rnat

ive

drug

s an

d ha

lope

rido

l sh

ould

not

be

an o

ptio

n fo

r

a ra

ndom

ized

con

trol

led

tria

l.

it is

, how

ever

, stil

l sur

pris

ingl

y

wid

ely

used

.

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1315

Current treatments for schizophrenia spectrum disorders

• A

bout

hal

f fai

led

to c

ompl

ete

the

shor

t-te

rm

follo

w-u

p (0

–6 w

eeks

), an

d el

even

stu

dies

foun

d

that

the

out

com

e di

ffere

nce

only

mar

gina

lly

favo

red

halo

peri

dol.

• H

alop

erid

ol is

a p

oten

t cau

se o

f mov

emen

t di

sord

ers

in th

e sh

ort-

term

; a s

igni

fican

t num

ber

of

peo

ple

suffe

red

from

sle

epin

ess,

and

a fe

w

adve

rse

effe

cts

such

as

park

inso

nism

, aka

thisi

a

and

acut

e dy

ston

ia w

ere

foun

d in

ele

ven

RCTs

.K

umar

and

St

rech

30

18Z

uclo

pent

hixo

l di

hydr

ochl

orid

e vs

pl

aceb

o, F

GA

s, a

nd/

or s

econ

d-ge

nera

tion

an

tipsy

chot

ics

N =

1,5

78; m

ainl

y

cond

ucte

d in

inpa

tient

or

out

patie

nt s

ettin

gs;

a fe

w s

ettin

gs w

ere

no

t ab

le t

o be

id

entifi

ed

18 s

hort

-ter

m

stud

ies

• T

wo

RC

Ts

did

not

repo

rt t

he fi

ndin

gs o

f glo

bal

or m

enta

l sta

te o

utco

mes

, but

an

incr

ease

d

risk

of e

xper

ienc

ing

extr

apyr

amid

al a

dver

se

effe

cts

was

foun

d.•

Com

pare

d w

ith F

GA

s, se

ven

RCTs

sho

wed

th

at z

uclo

pent

hixo

l dec

reas

ed th

e ris

k of

no

ch

ange

or

a w

orse

ning

of t

he il

lnes

s; ni

ne R

CTs

sh

owed

no

diffe

renc

e in

term

s of

adv

erse

effe

cts.

• A

s co

mpa

red

with

sec

ond-

gene

ratio

n

antip

sych

otic

s, t

wo

RC

Ts

show

ed n

o di

ffere

nce

in

ter

ms

of g

loba

l sta

te a

nd w

eigh

t ga

in w

ith

risp

erid

one,

but

one

foun

d th

at m

ore

an

ti-Pa

rkin

soni

an m

edic

atio

ns w

ere

pres

crib

ed

in p

eopl

e ta

king

zuc

lope

nthi

xol.

• So

me

clin

ical

adv

anta

ges

of

zucl

open

thix

ol d

ihyd

roch

lori

de

in t

he s

hort

-ter

m, s

uch

as

sign

ifica

nt im

prov

emen

ts

in g

loba

l sta

te.

• M

ore

mov

emen

t di

sord

ers

w

ere

foun

d th

an w

ith t

he

new

er g

ener

atio

n of

dru

gs.

• T

here

is n

o cl

ear

and

adeq

uate

in

form

atio

n ab

out

serv

ice

us

e, fu

nctio

nal a

nd b

ehav

iora

l ou

tcom

es, a

nd r

elap

se

prev

entio

n.

Leuc

ht e

t al

3214

Hal

oper

idol

vs

ch

lorp

rom

azin

e

(ora

l and

intr

amus

cula

r

rout

e)

N =

794

; ten

stu

dies

co

nduc

ted

in in

patie

nt

sett

ings

and

four

in

noni

dent

ified

set

tings

Follo

w-u

p:

48 h

ours

to

3 y

ears

, mos

tly

shor

t-te

rm

• N

ine

RC

Ts

favo

red

halo

peri

dol,

even

tho

ugh

th

e di

ffere

nce

was

not

sta

tistic

ally

sig

nific

ant.

• Si

x R

CT

s re

port

ed t

hat

mov

emen

t di

sord

ers

w

ith h

alop

erid

ol w

ere

mor

e fr

eque

nt, a

nd

five

foun

d th

at h

ypot

ensi

on w

as a

ssoc

iate

d

with

chl

orpr

omaz

ine.

• N

o di

ffere

nce

was

foun

d be

twee

n in

tram

uscu

lar

an

d or

al a

dmin

istr

atio

n.

• Fe

wer

tha

n 80

0 pe

ople

wer

e

rand

omiz

ed, a

nd r

epor

ting

on

the

mai

n re

sults

was

inco

mpl

ete.

• H

alop

erid

ol in

dica

ted

stat

istic

ally

no

nsig

nific

ant

effic

acy

in t

erm

s

of v

ario

us p

atie

nt o

utco

mes

, th

us m

akin

g it

diffi

cult

to d

raw

co

nclu

sion

s.Le

ucht

and

H

artu

ng28

Six

Pera

zine

vs

othe

r

FGA

s an

d/or

pla

cebo

N =

288

; five

co

nduc

ted

in in

patie

nt s

ettin

gs

and

one

in a

no

nide

ntifi

ed s

ettin

g

Six

shor

t-te

rm

tria

ls•

One

RC

T w

ith a

5-w

eek

follo

w-u

p fo

und

th

at p

eraz

ine

was

sup

erio

r to

the

pla

cebo

on

impr

ovem

ent

in g

loba

l fun

ctio

ning

but

m

ade

no s

igni

fican

t di

ffere

nce

to m

enta

l sta

te.

• Si

mila

r ad

vers

e ef

fect

s w

ere

foun

d am

ong

th

e m

edic

atio

ns u

sed

and

com

pare

d; m

ost

pa

rtic

ipan

ts r

ecei

ved

at le

ast

one

dose

of

ant

i-Par

kins

onia

n m

edic

atio

n.•

Five

RC

Ts p

rovi

ded

insu

ffici

ent i

nfor

mat

ion

of

out

com

es to

dra

w c

oncl

usio

n, a

nd th

ree

RC

Ts s

how

ed th

e dr

ug in

dica

ted

simila

r ris

ks

of e

xtra

pyra

mid

al a

dver

se e

ffect

s to

oth

er d

rugs

.

• T

here

was

no

stat

istic

ally

si

gnifi

cant

diff

eren

ce in

mos

t

clin

ical

out

com

es, a

nd li

mite

d

evid

ence

to

draw

con

clus

ions

.

(Con

tinue

d )

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1316

Chien and Yip

Tab

le 1

(Con

tinue

d)

Aut

hors

Clin

ical

tri

als

revi

ewed

, NIn

terv

enti

ons

Sam

ple

size

and

st

udy

sett

ing

Leng

th o

f stu

dy

or fo

llow

-up

Sum

mar

y of

mai

n fin

ding

sC

oncl

usio

n

Liu

and

De

H

aan22

Four

Chl

orpr

omaz

ine

vs

pla

cebo

N =

1,0

12; m

ainl

y

cond

ucte

d in

hos

pita

l se

ttin

gs

Four

sho

rt-t

erm

tr

ials

• Tw

o RC

Ts fo

und

few

er e

xtra

pyra

mid

al a

dver

se

effe

cts

in a

low

-dos

e gr

oup

of c

hlor

prom

azin

e,

faci

litat

ing

a be

tter

qua

lity

of li

fe.

• O

ne R

CT

favo

red

the

high

-dos

e gr

oup

w

ith m

uch

bett

er fu

nctio

ning

, eve

n th

ough

th

ey in

dica

ted

mor

e ad

vers

e ef

fect

s.

Both

gro

ups

expe

rien

ced

akat

hisi

a.

• Th

e do

se o

f chl

orpr

omaz

ine

gi

ven

decl

ined

acr

oss

time,

th

us c

ontr

ibut

ing

to fa

vora

ble

ou

tcom

es a

nd le

ss a

dver

se e

ffect

s.•

it is

ext

ensi

vely

use

d in

de

velo

ping

cou

ntri

es.

Mar

ques

et

al23

50T

riflu

oper

azin

e vs

pl

aceb

o, o

ther

FG

As,

an

d/or

sec

ond-

gene

ratio

n

antip

sych

otic

s

N =

2,5

83; 4

4 st

udie

s

cond

ucte

d in

hos

pita

l se

ttin

gs

28 s

hort

-ter

m, s

ix

med

ium

-ter

m, a

nd

one

long

-ter

m t

rial

• w

hen

com

pare

d w

ith t

he p

lace

bo, t

hree

sm

all-s

cale

sho

rt-t

erm

RC

Ts

favo

red

tr

ifluo

pera

zine

in t

erm

s of

glo

bal i

mpr

ovem

ents

, fo

ur fo

und

that

mor

e pe

ople

allo

cate

d to

tr

ifluo

pera

zine

use

d an

ti-Pa

rkin

soni

an d

rugs

, an

d se

ven

repo

rted

12%

att

ritio

ns in

bot

h

grou

ps a

t fo

llow

-ups

.•

whe

n co

mpa

red

with

the

FGA

s, 22

RC

Ts fo

und

no

diff

eren

ce in

term

s of

glo

bal i

mpr

ovem

ent

betw

een

grou

ps, 1

4 fo

und

that

sim

ilar

num

ber

of

par

ticip

ants

rep

orte

d at

leas

t one

adv

erse

ef

fect

, and

thre

e fo

und

trifl

uope

razi

ne m

ost l

ikel

y

caus

ed e

xtra

pyra

mid

al a

dver

se e

ffect

s.•

One

sm

all-s

cale

RC

T fo

und

no d

iffer

ence

be

twee

n tr

ifluo

pera

zine

and

sec

ond-

gene

ratio

n

antip

sych

otic

s on

pat

ient

out

com

es.

• Si

mila

r ef

ficac

y an

d ad

vers

e

even

ts a

re fo

und

betw

een

tr

ifluo

pera

zine

and

the

oth

er

com

mon

ly u

sed

antip

sych

otic

s.•

Tri

fluop

eraz

ine

is a

pot

ent

FG

A, i

nexp

ensi

ve a

nd w

idel

y

acce

ssib

le, b

ut it

s su

peri

ority

is

inco

nclu

sive

whe

n co

mpa

red

w

ith s

econ

d-ge

nera

tion

an

tipsy

chot

ics.

Mat

ar, A

lmer

ie

and

Sam

pson

27

Seve

nFl

uphe

nazi

ne (

oral

)

vs p

lace

boN

= 4

39; m

ainl

y in

ho

spita

l or

com

mun

ity

sett

ings

Mos

t sh

ort-

te

rm (

6)•

Tw

o R

CT

s fo

und

no d

iffer

ence

on

glob

al

stat

es b

etw

een

fluph

enaz

ine

and

plac

ebo

gr

oup

in t

he s

hort

-ter

m.

• Fo

ur r

epor

ted

fluph

enaz

ine

grou

p tr

ial

indi

cate

d a

high

er r

isk

of d

evel

opin

g

adve

rse

effe

cts

in t

he s

hort

-ter

m.

• Fl

uphe

nazi

ne is

an

effe

ctiv

e

but

impe

rfec

t tr

eatm

ent;

it is

in

expe

nsiv

e an

d ac

cess

ible

.•

The

res

earc

hers

pre

fer

to u

se

othe

r al

tern

ativ

es w

ith fe

wer

ad

vers

e ef

fect

s.R

athb

one

and

M

cMon

ag25

35 (

27 r

ando

miz

ed;

eigh

t do

uble

-blin

d)Pi

moz

ide

vs p

lace

boN

= 1

,348

; mai

nly

co

nduc

ted

in in

patie

nt

or o

utpa

tient

set

tings

Follo

w-u

p: fr

om

28 d

ays

(sho

rt-

term

) to

3 ye

ars

(lo

ng-t

erm

)

• T

wo

RC

Ts

sugg

este

d pi

moz

ide

coul

d be

tter

pr

even

t re

laps

e w

hen

com

pare

d w

ith p

lace

bo.

• Si

x fo

und

the

drug

had

sim

ilar

effic

acy

and

did

not

have

a h

ighe

r m

orta

lity

rate

than

oth

er F

GA

s, bu

t m

ore

likel

y ca

used

lim

b tr

emor

in th

e sh

ort-

term

.•

How

ever

, five

indi

cate

d th

e dr

ug w

as le

ss li

kely

to

cau

se s

edat

ion

in m

ediu

m-t

erm

.•

Four

indi

cate

d an

ti-Pa

rkin

soni

an m

edic

atio

n

shou

ld b

e ne

eded

.

• M

ost

stud

ies

cann

ot b

e us

eful

to

com

men

t on

effi

cacy

of

pim

ozid

e fo

r pe

ople

with

de

lusi

onal

dis

orde

rs.

• It

show

s si

mila

r ef

ficac

y to

ot

her

FGA

s.

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1317

Current treatments for schizophrenia spectrum disorders

rate and patient dissatisfaction), inability to work, family

burden, and social and cognitive functioning. Therefore,

there are a wider variety of outcome measurements than

used in previous studies, such as depression (eg, the Calgary

Depression Scale, the Hamilton Rating Scale for Depres-

sion, or the Montgomery Asberg Depression Rating Scale),

quality of life (eg, the Quality of Life Scale, the Schizo-

phrenia Quality of Life Scale, the Subjective Well-being

on Neuroleptics [Antipsychotics] Scale, or the Personal and

Social Performance Scale), and patient satisfaction (eg, the

Nurses Observational Scale Inpatients Evaluation) measures.

Similar to those receiving FGAs, most of the clinical trials

evaluated the short-term effects (up to 12 weeks) of the

second-generation antipsychotics, even though a few long-

term evaluations appear promising.39,40

A few systematic reviews also indicated that the con-

trolled trials of second-generation antipsychotics have mainly

tested only a few kinds, including risperidone, olanzapine,

quetiapine, loxapine, sertindole, aripiprazole, and amisul-

pride, and mostly compared them with placebo controls.43–50

The reviews concluded that second-generation antipsychotics

had similar effects to FGAs in terms of reduction of positive

symptoms. The treatment efficacy of both FGAs and second-

generation antipsychotics varies in terms of stages of the

illness, with first-episode schizophrenia responding faster

and better than at later illness stages.35,41,51 Nevertheless, most

of the second-generation antipsychotics had comparatively

fewer and lower levels of adverse effects such as movement

disorders and cardiac and sedative problems than FGAs.

Clozapine, the first second-generation antipsychotic, has

been found to be particularly effective in treating refractory

patients and reducing suicidality.36,41 A recent meta-analysis

comparing nine second-generation antipsychotics with the

FGAs (eg, chlorpromazine, fluphenazine and haloperidol)

for overall efficacy concluded that four second-generation

antipsychotics (namely, amisulpride, clozapine, olanzapine,

and risperidone) were better than the FGAs, with small

to medium effect sizes (ie, 0.13–0.52).37 The four second-

generation antipsychotics have been shown to induce fewer

extrapyramidal adverse effects than the low-potency FGAs.

Although olanzapine can induce more weight gain and pro-

duction of prolactin, it is shown to exert a persistent treatment

effect over other second-generation antipsychotics in chronic

schizophrenia.37,52

A recent Cochrane’s systematic review was published on

nine randomized, placebo-controlled trials of aripiprazole,

which is one of the newer second-generation antipsychotics.

Its main results indicated that aripiprazole can significantly Soar

es e

t al

2918

Sulp

irid

e vs

pla

cebo

, FG

As,

and

/or

se

cond

-gen

erat

ion

an

tipsy

chot

ics

N .

900

; 14

stud

ies

co

nduc

ted

in h

ospi

tal

sett

ings

and

one

in t

he

com

mun

ity; t

hree

in

noni

dent

ified

set

tings

Mos

t fol

low

-up

ov

er 8

wee

ks

(sho

rt-t

erm

).

• Su

lpir

ide

indi

cate

d fe

wer

adv

erse

effe

cts,

an

d lit

tle d

iffer

ence

was

foun

d be

twee

n th

e

drug

and

oth

er a

ntip

sych

otic

s.•

No

findi

ngs

of n

egat

ive

sym

ptom

s w

ere

show

n.

• in

gen

eral

, sm

all-s

cale

and

poo

r-

qual

ity s

tudi

es w

ere

foun

d.•

it m

ay b

e ef

fect

ive

and

have

fe

wer

adv

erse

effe

cts

at lo

w

dose

s, b

ut t

here

was

insu

ffici

ent

evid

ence

.•

The

re w

ere

limite

d re

sults

on

neg

ativ

e sy

mpt

oms.

Soar

es a

nd

Silv

a de

Lim

a33

27 (

elev

en s

tudi

es

rand

omiz

ed)

Penfl

urid

ol v

s FG

As,

de

pot

inje

ctio

ns,

and/

or p

lace

bo

N =

1,0

24; m

ainl

y

cond

ucte

d in

hos

pita

l or

out

patie

nt s

ettin

gs;

four

with

non

iden

tified

se

ttin

gs

Five

sho

rt-t

erm

an

d 22

med

ium

- te

rm tr

ials

• Fo

ur m

ediu

m-t

erm

RC

Ts

foun

d pe

nflur

idol

su

peri

or t

o pl

aceb

o in

ter

ms

of g

loba

l fu

nctio

ning

, whe

reas

ano

ther

five

RC

Ts

sh

owed

tha

t a

com

bina

tion

of a

ntip

sych

otic

s

was

con

side

red

nece

ssar

y.•

Ten

sho

wed

no

diffe

renc

e be

twee

n pe

nflur

idol

an

d ot

her

FGA

s in

ter

ms

of g

loba

l sta

te

over

3–6

mon

ths.

• Fi

ve fo

und

that

the

dru

g w

as s

uper

ior

in

kee

ping

pat

ient

s in

tre

atm

ent.

• Ef

ficac

y an

d ad

vers

e ef

fect

pr

ofile

s ar

e si

mila

r am

ong

FG

As,

no

mat

ter

whe

ther

by

ora

l or

depo

t ro

ute.

• Pe

nflur

idol

is a

n op

tion

for

ch

roni

c ill

ness

with

res

idua

l ps

ycho

tic s

ympt

oms

and

is

con

side

red

a lo

w-c

ost

in

terv

entio

n.

Not

es: a D

urat

ion

of s

tudy

or

follo

w-u

p, w

ith t

rial

s ra

ngin

g fr

om s

hort

-ter

m, u

p to

12

wee

ks, t

o m

ediu

m-t

erm

, 13–

24 w

eeks

, to

long

-ter

m, m

ore

than

24

wee

ks.

Abb

revi

atio

ns: F

GA

s, fi

rst-

gene

ratio

n an

tipsy

chot

ics;

RC

Ts,

ran

dom

ized

con

trol

led

tria

ls; v

s, v

ersu

s.

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1318

Chien and Yip

Tab

le 2

Sum

mar

y of

rev

iew

s on

sec

ond-

gene

ratio

n an

tipsy

chot

ics

for

schi

zoph

reni

a

Aut

hors

Clin

ical

tri

als

revi

ewed

, NIn

terv

enti

ons

Sam

ple

size

and

st

udy

sett

ing

Leng

th o

f stu

dy

or fo

llow

-upa

Sum

mar

y of

mai

n fin

ding

sC

oncl

usio

n

Alp

teki

n et

al34

One

RC

T a

nd

a fe

w w

ith

nonr

ando

miz

ed

com

pari

son

gr

oups

des

ign

Ola

nzap

ine,

ri

sper

idon

e or

ha

lope

rido

l vs

zipr

asid

one

N =

287

; mul

ticen

ter

tr

ials

in a

hos

pita

l or

out

patie

nt s

ettin

g

Follo

w-u

p: u

p

to 1

2 w

eeks

(s

hort

-ter

m)

• Z

ipra

sido

ne s

how

ed s

igni

fican

t ef

fect

s on

impr

ovem

ent

in

men

tal s

tate

and

cog

nitiv

e fu

nctio

ning

.•

It ha

s a

com

para

tivel

y ne

utra

l met

abol

ic p

rofil

e an

d

is c

linic

ally

val

uabl

e w

hen

take

n w

ith fo

od.

• T

he fi

ndin

gs c

onfir

m t

he

effe

ctiv

enes

s of

zip

rasi

done

as

an

appr

opri

ate

choi

ce fo

r

switc

hing

of d

rugs

whe

neve

r

need

ed.

Belg

amw

ar a

nd

el-S

ayeh

48

Nin

eA

ripi

praz

ole

vs

plac

ebo

N =

2,5

85; m

ainl

y

cond

ucte

d in

a

hosp

ital o

r

outp

atie

nt s

ettin

g

eigh

t sh

ort-

term

an

d tw

o m

ediu

m-

term

tri

als

• O

ne R

CT

with

less

tha

n 3

mon

ths

follo

w-u

p fo

und

th

at a

ripi

praz

ole

sign

ifica

ntly

red

uced

rel

apse

.•

eigh

t R

CT

s sh

owed

bet

ter

med

icat

ion

com

plia

nce,

an

d tw

o sh

owed

low

er r

isks

of r

aise

d pr

olac

tin

and

prol

onga

tion

of t

he c

orre

cted

QT

inte

rval

of e

CG

(r

epre

sent

s th

e de

pola

riza

tion

and

repo

lari

zatio

n of

the

le

ft an

d ri

ght

vent

ricl

es o

r ve

ntri

cula

r ar

rhyt

hmia

s).

• M

ost

wer

e un

able

to

extr

act

any

usab

le d

ata

on

mor

talit

y, s

ervi

ce u

tiliz

atio

n an

d sa

tisfa

ctio

n,

and

cogn

itive

func

tioni

ng.

• A

ripi

praz

ole

can

be e

ffect

ive

in

the

sho

rt-

to m

ediu

m-t

erm

of

tre

atm

ent.

• T

here

was

hig

h at

triti

on in

al

l stu

dies

(.

30%

).

Cha

krab

arti

et

al47

41Lo

xapi

ne v

s pl

aceb

o,

seco

nd-g

ener

atio

n

antip

sych

otic

s,

and/

or F

GA

s

N =

2,3

81; a

ll

cond

ucte

d in

ho

spita

ls

Follo

w-u

p: fr

om

72 h

ours

(sh

ort-

te

rm)

to 6

mon

ths

(lo

ng-t

erm

)

• T

hirt

een

shor

t-te

rm R

CT

s fo

und

loxa

pine

as

effe

ctiv

e

as o

ther

FG

As,

whe

reas

six

long

er-t

erm

RC

Ts

repo

rted

it

was

as

effe

ctiv

e as

sec

ond-

gene

ratio

n an

tipsy

chot

ics

in

ter

ms

of r

elap

se a

nd a

few

pat

ient

out

com

es.

• Fo

ur fo

und

the

drug

had

sim

ilar

adve

rse

effe

cts

to

oth

er F

GA

s an

d th

at t

hey

wer

e m

ore

seve

re

than

tho

se o

f sec

ond-

gene

ratio

n an

tipsy

chot

ics.

• Lo

xapi

ne c

an b

e ef

fect

ive

from

sh

ort-

to

long

-ter

m t

reat

men

t

in s

chiz

ophr

enia

, but

with

sim

ilar

ef

ficac

y to

a fe

w o

ther

FG

As

and

se

cond

-gen

erat

ion

antip

sych

otic

s.•

it m

ay c

ause

mor

e ex

trap

yram

idal

ad

vers

e ef

fect

s w

hen

com

pare

d

with

oth

er s

econ

d-ge

nera

tion

an

tipsy

chot

ics.

Citr

ome35

32Lu

rasi

done

vs

pl

aceb

oN

= 8

,071

; mos

t

sett

ings

not

sp

ecifi

ed

Follo

w-u

p: fr

om

7 da

ys (

shor

t-te

rm)

to

18

mon

ths

(lo

ng-t

erm

)

• Lu

rasi

done

was

sho

wn

to b

e ef

ficac

ious

and

tol

erab

le

with

food

and

had

a h

ighl

y fa

vora

ble

met

abol

ic p

rofil

e.•

Aka

this

ia o

r Pa

rkin

soni

sm w

as r

epor

ted

in m

ost

RC

Ts.

• A

dditi

onal

dat

a w

ere

nece

ssar

y

to s

uppo

rt it

s lo

ng-t

erm

effi

cacy

as

a m

aint

enan

ce t

reat

men

t.

Dug

gan

et a

l4656

Ola

nzap

ine

vs F

GA

s,

seco

nd-g

ener

atio

n

antip

sych

otic

s,

and/

or p

lace

bo

N .

10,

000;

m

ainl

y co

nduc

ted

in

the

hos

pita

l or

ou

tpat

ient

set

ting;

el

even

con

duct

ed

in n

onid

entifi

ed

sett

ings

31 s

hort

-ter

m,

23 m

ediu

m-t

erm

, an

d tw

o lo

ng-t

erm

tr

ials

• Si

xtee

n R

CT

s sh

owed

hig

h at

triti

on b

y 6

wee

ks

in b

oth

olan

zapi

ne a

nd p

lace

bo/F

GA

s; fo

ur fo

und

th

e dr

ug a

s ef

fect

ive

as F

GA

s.•

Four

foun

d ol

anza

pine

to

caus

e fe

wer

mov

emen

t

diso

rder

s bu

t m

ore

wei

ght

gain

from

3 t

o 12

mon

ths

of

tre

atm

ent.

• el

even

rec

orde

d th

at 2

3% o

f peo

ple

in t

rial

s of

ol

anza

pine

and

oth

er s

econ

d-ge

nera

tion

antip

sych

otic

s

left

by 8

wee

ks, a

nd 4

8% b

y 3

to 1

2 m

onth

s.

• M

ost

stud

ies

repo

rted

ver

y hi

gh

attr

ition

in b

oth

olan

zapi

ne

and

plac

ebo/

FGA

/oth

er s

econ

d-

gene

ratio

n an

tipsy

chot

ic g

roup

s,

rang

ing

from

.30

% b

y 6

wee

ks

to 5

0% b

y 12

mon

ths.

• T

here

was

sim

ilar

effic

acy

to

oth

er s

econ

d-ge

nera

tion

an

tipsy

chot

ics

in r

elap

se

prev

entio

n an

d re

duct

ion

of

pos

itive

sym

ptom

s, b

ut

no n

otab

le b

enefi

t in

neg

ativ

e

sym

ptom

s.

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1319

Current treatments for schizophrenia spectrum disorders

el-S

ayeh

and

M

orga

nti49

15A

ripi

praz

ole

vs F

GA

s,

seco

nd-g

ener

atio

n

antip

sych

otic

s,

and/

or p

lace

bo

N =

7,1

10; e

ight

co

nduc

ted

in

hosp

ital s

ettin

g an

d

two

in o

utpa

tient

se

ttin

g; fi

ve w

ith

noni

dent

ified

se

ttin

gs

Ten

sho

rt-t

erm

, th

ree

med

ium

-ter

m,

and

two

long

-ter

m

tria

ls

• O

ne R

CT

sho

wed

tha

t ar

ipip

razo

le c

ould

sig

nific

antly

de

crea

se r

elap

se in

sho

rt-

and

med

ium

-ter

m fo

llow

-up.

• ei

ght

RC

Ts

foun

d th

at t

he d

rug

prod

uced

bet

ter

co

mpl

ianc

e; s

even

rep

orte

d th

at it

pro

duce

d a

low

er

risk

of a

kath

isia

whe

n co

mpa

red

with

FG

As

and

less

ri

sk o

f met

abol

ic a

nd c

ardi

ac e

vent

s w

hen

com

pare

d

with

oth

er s

econ

d ge

nera

tion

antip

sych

otic

s.•

it w

as n

ot p

ossi

ble

to e

xtra

ct a

ny u

sabl

e da

ta

on m

orta

lity,

ser

vice

use

and

sat

isfa

ctio

n, a

nd g

ener

al

and

cogn

itive

func

tioni

ng.

• M

ost

RC

Ts

repo

rted

hig

h

attr

ition

rat

es (

30%

–50%

).•

Ari

pipr

azol

e ca

n be

effe

ctiv

e

in m

ediu

m-t

erm

tre

atm

ent,

w

ith s

imila

r ef

ficac

y to

oth

er

seco

nd-g

ener

atio

n an

tipsy

chot

ics

and

mos

t FG

As

in r

elap

se

prev

entio

n an

d re

duct

ion

of

pos

itive

sym

ptom

s.•

its p

resc

ript

ion

as r

outin

e

or u

sual

pra

ctic

e ca

nnot

be

co

nfirm

ed.

Kar

ayal

et

al54

An

open

-labe

l,

flexi

ble-

dose

tr

ial

Switc

hing

from

qu

etia

pine

to

zi

pras

idon

e

N =

241

; con

duct

ed

in a

n ou

tpat

ient

se

ttin

g

All

part

icip

ants

w

ere

follo

wed

-up

ov

er 3

mon

ths

(m

ediu

m-t

erm

)

• T

he R

CT

sho

wed

tha

t sw

itchi

ng t

o zi

pras

idon

e

coul

d pr

oduc

e a

sign

ifica

nt d

ecre

ase

in w

eigh

t

and

impr

ovem

ents

in m

enta

l sta

te a

nd c

ogni

tive

fu

nctio

ning

, with

a n

eutr

al m

etab

olic

pro

file.

• it

was

rec

omm

ende

d to

be

take

n w

ith fo

od.

• Z

ipra

sido

ne s

how

s si

gnifi

cant

be

nefit

s in

ove

rall

men

tal

stat

e an

d fu

nctio

ning

in t

he

med

ium

-ter

m.

• Pa

tient

s ta

king

thi

s dr

ug s

how

ed

satis

fact

ory

tole

rabi

lity

and

sa

fety

; the

refo

re, i

t is

a g

ood

ch

oice

for

the

switc

hing

of

seco

nd-g

ener

atio

n an

tipsy

chot

ics.

Lew

is e

t al

69T

hree

Sert

indo

le v

s

plac

ebo

or

halo

peri

dol

N =

1,1

04; m

ainl

y

cond

ucte

d in

th

e ho

spita

l or

ou

tpat

ient

set

ting

One

sho

rt-t

erm

, on

e m

ediu

m-t

erm

, an

d on

e lo

ng-t

erm

tr

ial

• W

hen

com

pare

d w

ith t

he p

lace

bo, n

o si

gnifi

cant

di

ffere

nce

was

foun

d w

ith a

dos

e of

mor

e th

an

12 m

g da

ily, b

ut a

mar

gina

lly s

igni

fican

t di

ffere

nce

w

as fo

und

whe

n ta

king

20

mg

daily

.•

The

re w

as n

o si

gnifi

cant

diff

eren

ce b

etw

een

low

and

hi

gh d

oses

of s

ertin

dole

in t

erm

s of

mos

t ad

vers

e

even

ts; c

ardi

ovas

cula

r ad

vers

e ef

fect

s sh

owed

si

gnifi

cant

diff

eren

ce b

etw

een

grou

ps a

t al

l dos

es

by 8

wee

ks, w

here

as w

eigh

t ga

in w

as s

igni

fican

tly

high

er w

ith a

hig

h do

se o

f ser

tindo

le.

• w

hen

com

pare

d w

ith h

alop

erid

ol, s

ertin

dole

indu

ced

m

ore

card

iac

prob

lem

s, r

hini

tis, a

nd w

eigh

t ga

in,

but

few

er m

ovem

ent

diso

rder

s an

d le

ss s

exua

l dy

sfun

ctio

n an

d se

datio

n th

an h

alop

erid

ol.

• Se

rtin

dole

app

ears

to

have

sim

ilar

effic

acy

but

to b

e m

ore

tole

rabl

e

than

hal

oper

idol

.•

Sert

indo

le 1

6 m

g/da

y is

sug

gest

ed

to b

e th

e m

ost

optim

al d

ose.

Nus

sbau

m a

nd

Stro

up45

eigh

tPa

liper

idon

e (o

ral

and

intr

amus

cula

r)

vs p

lace

bo o

r

seco

nd-g

ener

atio

n

antip

sych

otic

s

N =

2,5

62; m

ainl

y

cond

ucte

d in

a

hosp

ital o

r

outp

atie

nt s

ettin

g;

a fe

w n

ot s

peci

fied

All

follo

wed

up

in

shor

t-te

rm•

whe

n co

mpa

red

with

pla

cebo

s, s

even

RC

Ts

in

dica

ted

that

few

er p

eopl

e ra

ndom

ly a

ssig

ned

to t

he

palip

erid

one

grou

p le

ft th

e st

udie

s an

d th

at le

ss r

elap

se

was

rep

orte

d; fo

ur fo

und

that

the

dru

g pr

oduc

ed

sign

ifica

nt im

prov

emen

t in

glo

bal f

unct

ioni

ng, b

ut m

ost

R

CT

s in

dica

ted

that

thi

s dr

ug c

ause

d ad

vers

e ev

ents

su

ch a

s ta

chyc

ardi

a an

d ex

trap

yram

idal

syn

drom

e.

• Pa

liper

idon

e ap

pear

s to

be

ef

fect

ive

in r

elap

se p

reve

ntio

n,

alth

ough

no

firm

con

clus

ions

wer

e dr

awn

as to

its

long

-ter

m e

ffect

s.•

The

re a

re s

imila

r le

vels

of

adve

rse

effe

cts

whe

n it

is

com

pare

d w

ith o

ther

sec

ond-

ge

nera

tion

antip

sych

otic

s.

(Con

tinue

d )

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Dovepress

Dovepress

1320

Chien and Yip

Tab

le 2

(Co

ntin

ued)

Aut

hors

Clin

ical

tri

als

revi

ewed

, NIn

terv

enti

ons

Sam

ple

size

and

st

udy

sett

ing

Leng

th o

f stu

dy

or fo

llow

-upa

Sum

mar

y of

mai

n fin

ding

sC

oncl

usio

n

• w

hen

com

pare

d w

ith o

ther

sec

ond-

gene

ratio

n

antip

sych

otic

s, t

hree

RC

Ts

indi

cate

d no

diff

eren

ce

in e

ffica

cy b

etw

een

palip

erid

one

and

olan

zapi

ne

in t

he s

hort

ter

m; a

noth

er t

hree

favo

red

the

drug

in

ter

ms

of r

elap

se p

reve

ntio

n an

d w

eigh

t ch

ange

, an

d al

l res

ults

favo

red

the

drug

for

caus

ing

few

er

mov

emen

t di

sord

ers.

• N

o da

ta w

ere

foun

d on

ser

vice

use

, qua

lity

of li

fe,

beha

vior

cha

nges

, sat

isfa

ctio

n w

ith t

reat

men

t re

ceiv

ed,

cogn

itive

func

tioni

ng, a

nd c

ost-

bene

fit.

Rat

teha

lli

Jaya

ram

and

Sm

ith43

Ten

Ris

peri

done

vs

pla

cebo

N =

24–

303;

m

ainl

y co

nduc

ted

in

a h

ospi

tal o

r

outp

atie

nt s

ettin

g;

four

stu

dies

with

no

nide

ntifi

ed

sett

ings

All

follo

wed

-up

in

sho

rt-t

erm

• T

en R

CT

s sh

owed

hig

h at

triti

on (

60%

) in

pla

cebo

gr

oups

by

6 w

eeks

.•

Thr

ee R

CT

s fo

und

no d

iffer

ence

bet

wee

n ri

sper

idon

e

and

a pl

aceb

o in

ter

ms

of g

loba

l fun

ctio

ning

, whe

reas

se

ven

show

ed t

hat

risp

erid

one

prod

uced

sig

nific

ant

im

prov

emen

ts in

men

tal s

tate

.•

Five

tri

als

repo

rted

a fe

w a

dver

se e

ffect

s in

the

m

ediu

m-t

erm

, mai

nly

in t

erm

s of

met

abol

ic

and

card

iac

profi

les.

• Be

caus

e of

hig

h at

triti

on r

ates

, ri

sper

idon

e is

sug

gest

ed t

o

have

mod

erat

e bi

ases

in t

he

inte

rpre

tatio

n of

the

find

ings

, th

us d

raw

ing

no fi

rm c

oncl

usio

ns

abou

t its

effi

cacy

and

adv

erse

ev

ents

.•

The

re w

ere

mar

gina

l ben

efits

in

ter

ms

of a

few

pat

ient

ou

tcom

es b

y th

e fir

st fe

w w

eeks

, su

ch a

s im

prov

emen

ts in

m

enta

l sta

te a

nd g

loba

l fu

nctio

ning

.Si

lvei

ra d

a

Mot

a et

al50

19A

mis

ulpr

ide

vs

plac

ebo,

FG

As,

an

d/or

sec

ond-

ge

nera

tion

an

tipsy

chot

ics

N =

2,4

43; m

ainl

y

cond

ucte

d in

a

hosp

ital o

r

outp

atie

nt s

ettin

g;

four

stu

dies

with

no

nide

ntifi

ed

sett

ings

Mos

t fo

llow

ed-u

p

in s

hort

-ter

m (

17);

tw

o in

med

ium

- te

rm

• w

hen

com

pare

d w

ith a

pla

cebo

, fou

r R

CT

s

favo

red

a lo

w d

ose

of a

mis

ulpr

ide

in t

erm

s of

gl

obal

func

tioni

ng a

nd n

egat

ive

sym

ptom

s; t

wo

sh

owed

tha

t am

isul

prid

e ca

used

mor

e ad

vers

e

effe

cts.

• W

hen

com

pare

d w

ith F

GA

s, 1

4 R

CT

s co

nfirm

ed

the

drug

as

bein

g m

ore

effe

ctiv

e in

ter

ms

of g

loba

l fu

nctio

ning

, men

tal s

tate

, and

neg

ativ

e

sym

ptom

s.•

One

RC

T c

ompa

red

the

effic

acy

of t

he d

rug

with

th

at o

f ris

peri

done

and

foun

d no

diff

eren

ce

in m

ost

patie

nt o

utco

mes

.•

Dat

a on

ser

vice

use

, fam

ily b

urde

n, a

nd q

ualit

y

of li

fe w

ere

not

thor

ough

ly e

valu

ated

.

• M

ore

patie

nt b

enefi

ts w

ere

fo

und

in t

hose

with

low

dos

es

of a

mis

ulpr

ide

whe

n co

mpa

red

w

ith F

GA

s. S

imila

r ef

ficac

y

with

oth

er s

econ

d-ge

nera

tion

an

tipsy

chot

ics

was

not

ed.

• A

mis

ulpr

ide

can

be a

n ef

fect

ive

al

tern

ativ

e to

oth

er s

econ

d-

gene

ratio

n an

tipsy

chot

ics.

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1321

Current treatments for schizophrenia spectrum disorders

Sris

urap

anon

t

et a

l44

12Q

uetia

pine

vs

pl

aceb

o, F

GA

s,

and/

or s

econ

d-

gene

ratio

n

antip

sych

otic

s

N =

3,4

43; m

ost

st

udy

sett

ings

not

re

port

ed

Ten

sho

rt-t

erm

, tw

o m

ediu

m-t

erm

tr

ials

• Fo

ur R

CT

s re

port

ed t

hat

the

quet

iapi

ne g

roup

s

indi

cate

d hi

gher

att

ritio

n (.

50%

in s

hort

-ter

m

follo

w-u

ps)

than

the

pla

cebo

; one

RC

T

repo

rted

tw

o de

aths

in t

he g

roup

with

hig

her

dose

s

of q

uetia

pine

.•

whe

n co

mpa

red

with

FG

As,

six

RC

Ts

foun

d th

at t

he

quet

iapi

ne g

roup

s in

dica

ted

36%

dro

pout

s in

the

sh

ort-

term

; five

indi

cate

d th

at q

uetia

pine

pro

duce

d

mod

erat

e ch

ange

s in

glo

bal f

unct

ioni

ng a

nd m

enta

l st

ate

in t

he s

hort

-ter

m; a

nd s

ever

e ad

vers

e

effe

cts

wer

e fo

und

in fi

ve R

CT

s, w

here

as fo

ur

repo

rted

tha

t it

prod

uced

few

er m

ovem

ent

di

sord

ers.

• w

hen

com

pare

d w

ith r

ispe

rido

ne, 3

0% o

f peo

ple

le

ft th

e st

udy

in o

ne R

CT

, and

ano

ther

rep

orte

d

that

four

peo

ple

died

dur

ing

the

stud

y.•

One

RC

T fo

und

few

er p

eopl

e re

ceiv

ing

quet

iapi

ne

pres

entin

g w

ith e

xtra

pyra

mid

al a

dver

se e

ffect

s;

four

stu

dies

foun

d th

at t

he d

rug

prod

uced

a lo

wer

ri

sk fo

r m

ovem

ent

diso

rder

s bu

t hi

gher

ris

ks

for

dizz

ines

s, d

ry m

outh

, and

sle

epin

ess.

• Li

mite

d da

ta w

ere

foun

d on

ser

vice

use

, ec

onom

ic o

utco

mes

, soc

ial f

unct

ion,

and

qua

lity

of

life

.

• A

lthou

gh p

oten

tial b

iase

s

may

occ

ur b

ecau

se o

f hig

her

at

triti

on r

ates

am

ong

the

stud

ies,

qu

etia

pine

can

be

equa

lly

effe

ctiv

e in

impr

ovin

g pa

tient

s’

men

tal s

tate

and

glo

bal

func

tioni

ng a

s th

e FG

As

and

ot

her

typi

cal a

gent

s, b

ut w

ith

few

er e

xtra

pyra

mid

al a

dver

se

effe

cts

and

mov

emen

t di

sord

ers.

• H

owev

er, m

ore

rese

arch

ev

iden

ce o

f the

long

er-t

erm

ef

ficac

y of

thi

s dr

ug w

ith lo

w

attr

ition

rat

es is

nee

ded.

Not

e: a D

urat

ion

of s

tudy

or

follo

w-u

p, w

ith t

rial

s ra

ngin

g fr

om s

hort

-ter

m, u

p to

12

wee

ks, t

o m

ediu

m-t

erm

, 13–

24 w

eeks

, to

long

-ter

m, m

ore

than

24

wee

ks.

Abb

revi

atio

ns: F

GA

s, fi

rst-

gene

ratio

n an

tipsy

chot

ics;

RC

Ts,

ran

dom

ized

con

trol

led

tria

ls.

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1322

Chien and Yip

decrease relapse in both the short-term (,3 months; n = 310;

risk ratio, 0.59 [95% confidence interval, 0.45–0.77]) and

medium-term (3–6 months; n = 310; risk ratio, 0.66 [95%

confidence interval, 0.53–0.81]) when compared with pla-

cebo controls.48 Aripiprazole can also produce less attrition

and better compliance with study protocol (n = 2,275; risk

ratio, 0.74 [95% confidence interval, 0.59–0.93]), and lower

risk for raised prolactin level than that expected from the

placebo (n = 305; risk ratio, 0.21 [95% confidence interval,

0.11–0.37]).

Apart from oral medication, inhaled loxapine is consid-

ered a well-tolerated and rapid acute treatment for agitation

but needs further longer-term controlled trials to verify

its efficacy.53 Studies on relatively new second-generation

antipsychotics such as ziprasidone have shown that their

efficacy on positive symptoms is much better than that of

other second-generation antipsychotics, whereas ziprasidone

and lurasidone are clinically valuable and suggested to be

taken with food.34,54

Most of the reviews appear not only to be concerned

with their clinical efficacy and tolerability but also to pay

more attention to psychosocial functioning and cognitive

performance in activities of daily living. Among few sys-

tematic reviews/meta-analyses of the effect of FGAs on

cognition in schizophrenia, one meta-analysis by Mishara

and Goldberg55 included 34 randomized, placebo-controlled

trials and suggested that most FGAs can provide modest to

moderate benefits (ie, effect sizes ranged from 0.13 to 0.29)

in multiple cognitive domains, whereas motor function was

affected negatively. Although most of the newest second-

generation antipsychotics have shown similar treatment

efficacy in improving mental state and general functioning,

they have not yet shown significant differences or consis-

tent effects on reducing negative symptoms or cognitive

dysfunction.36,56–60 Although one review reported that social

functioning was better for people with schizophrenia tak-

ing the newer second-generation antipsychotics,36 most

of the controlled trials only evaluated their efficacy over

3–6 months, and very high attrition rates and limited long-

term effects on cognitive functioning, quality of life, service

use and satisfaction, and other psychosocial functioning and

behaviors were noted.36,57–62 Therefore, it is difficult to draw

conclusions with regard to these second-generation antipsy-

chotics, both on most patient outcomes, particularly in the

longer-term, or on their cost benefits.46,49,63 Nevertheless, it

is noteworthy that a recent population-based cohort study

in Finland with 11 years of follow-up indicated decreased

rates of mortality with perphenazine when compared with

the other FGAs and a few second-generation antipsychotics

and that only the use of clozapine was associated with lower

rates of overall mortality.64

In conclusion, FGAs and second-generation antipsychot-

ics are found to be similar and robust in treatment efficacy

among acute and sometimes chronic schizophrenia, par-

ticularly against positive and disorganization symptoms.65

Their efficacy varies according to the course or stage of the

illness; people with first-episode schizophrenia can respond

faster and better to antipsychotics than those at later stages

of the illness. In contrast, neither is effective in reducing

negative symptoms, and they can even worsen the negative

symptoms associated with extrapyramidal adverse effects

(eg, antipsychotic-induced dysphoria).66 The efficacy of

FGAs and second-generation antipsychotics on cognitive

and social functioning, as well as other longer-term effects

such as mortality and quality of life, are inconsistent.

However, individual antipsychotics have shown significant

differential efficacy in particular illness conditions and

related problems, as well as different adverse effects. All

of them reveal their onset of action within a few days and

achieve optimal antipsychotic effect over the course of sev-

eral weeks. Although antipsychotics substantially decrease

patients’ relapse from schizophrenia, it is not possible to

ensure medication or other treatment compliance; thus, long-

term injectable antipsychotics (eg, oil-based fluphenazine

decanoate) may be considered. In view of the significantly

varied pharmacokinetics of and treatment responses to

antipsychotics among people with schizophrenia, it is rec-

ommended not only to examine the overall efficacy within

and across patient groups but also to consider the efficacy

of each antipsychotic medication for each individual patient

when it is prescribed.67,68

Safety and tolerability of antipsychoticsAntipsychotics, particularly FGAs, can have a wide range of

undesirable and adverse effects on patients, mainly includ-

ing neurological, metabolic, cardiovascular, hematological,

endocrine, and genitourinary disturbances. In addition, they

differ from one to another in the levels and nature of these

adverse effects. Although a few had less-extreme adverse

effects (eg, perphenazine and sulpiride),26,29 all of the reviews

indicated that the profile of adverse events concerning these

adverse effects found in most FGAs (eg, acute extrapyramidal

symptoms and tardive dyskinesia) is substantial and of major

concern, thus reducing patients’ medication compliance and

treatment efficacy.23,24,26–30,33

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Current treatments for schizophrenia spectrum disorders

Nevertheless, most second-generation antipsychotics

have comparatively fewer and lower levels of adverse effects

such as movement disorder, increased prolactin, and cardiac

and sedative problems, than FGAs. In contrast, there may be

higher risks for dizziness, sedation, weight gain, substantial

increases in serum prolactin, and tachycardia for individual

second-generation antipsychotics.44–48,69 However, there has

not been any systematic work or classification to categorize

or distinguish the risks of these adverse effects between antip-

sychotics, particularly the second-generation antipsychotics.

As these adverse effects may affect aspects of patients’ lives

and treatment adherence and satisfaction, more work on

such classification of antipsychotics in terms of their types

or levels of adverse effects should be considered.

Clozapine, the first second-generation antipsychotic, does

not show any extrapyramidal effects or tardive dyskinesia,

but other serious adverse effects such as agranulocytosis

and metabolic syndrome have limited its utility. In contrast,

Tiihonen et al64 reported that clozapine was associated with

a significantly lower mortality rate than other antipsychot-

ics and also concluded that a lower mortality rate could

be associated with a longer-term use of antipsychotics.

Although clozapine is expected to have higher risks of a few

adverse effects, inducing increased mortality, the researchers

explained it has been shown to demonstrate very positive

effects on symptom reduction and treatment compliance.

Studies on relatively new second-generation antipsychotics

such as ziprasidone have shown that they had fewer adverse

effects in terms of metabolic profile (eg, metabolic distur-

bance and weight gain) and cognitive functioning and that

their effects on positive symptoms are much better than those

of other second-generation antipsychotics.34,44 Lurasidone

has also indicated a highly favorable metabolic profile but

is still not free from adverse events such as akathisia and

Parkinson’s syndrome.35

A large, 25-year cohort study measuring the mortality

of 370 people with schizophrenia in Southampton, United

Kingdom, reported that the cohort had an all-cause stan-

dardized mortality ratio of 289 (95% confidential interval,

247–337), indicating small and nonsignificant changes

between 1981 and 2006 but falling sharply from 376

(1981–1986) to 264 (1986–1991) in the first 10 years.70 This

considerable reduction of mortality rate in the 1980s was

mainly a result of a significant fall in unnatural deaths over

the period (ie, the mortality ratio of suicide decreased from

6,110 in 1981–1986 to 0 in 1986–1991). In addition, the

findings of the study support previous findings that people

with schizophrenia have a mortality between two and three

times that of the general populations,74 as well as raise con-

cern about the cardiovascular mortality of schizophrenia,

which has significantly increased during the past 25 years.80

Nevertheless, the effects of clozapine and other second-

generation antipsychotics on mortality and treatment compli-

ance among patients with schizophrenia reveal the difficulties

in linking medium- or long-term patient outcomes with

short-term drug effects; that is, whether symptom reduction

can be mainly explained by the efficacy of antipsychotic use.

It is therefore recommended that more longitudinal research

be conducted with longer-term follow-up on predictors or

mediators of patient outcomes in schizophrenia in relation

to antipsychotic use.

Patterns in medication use: mono- and polypharmacyTreatment of people with schizophrenia who are resistant

to treatment and have persistent cognitive and negative

symptoms remains a challenge to most clinicians. Many

controlled trials of antipsychotics and their combined use

with other psychotropic drugs (eg, acetylcholinesterase

inhibitors, glutamatergic agents, antidepressants, benzo-

diazepines, and anticonvulsants) have been carried out in

people with treatment-resistant and chronic schizophrenia,

particularly on the means for improvement of negative

symptoms, quality of life, and social function. However,

very limited and weak evidence has been shown to confirm

whether a particular antipsychotic medication or any of the

combination strategies used could be efficacious in main

patient outcomes and/or superior to the others in the treat-

ment of schizophrenia,71–76 and none can be considered a

robust treatment or prevention prescription for schizophrenia

care.77–84 Nevertheless, psychosocial interventions, together

with pharmacological treatment, are recommended to be the

most effective strategies in the treatment and rehabilitation

of people with schizophrenia.85

Despite such inconclusive and weak evidence on

pharmacological agents to control negative symptoms or

treatment-resistant cases, some combinations of medica-

tion use have indicated modest to satisfactory benefits in

targeting specific psychotic symptoms.71,86–88 For instance,

anticonvulsants such as valproic acid and carbamazepine are

found to be useful as adjuncts to antipsychotics in treating

aggression and impulsivity in schizophrenia,75,76 and adjunc-

tive antidepressants can be useful in treating depression and

anxiety symptoms and in reducing craving in comorbid

substance use.83,84,89 Interestingly, a double-blinded, multi-

center randomized placebo-controlled trial on the effects

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1324

Chien and Yip

of a Warm- Supplementing Kidney Yang capsule containing

13 traditional Chinese herbs indicated that the capsule had

demonstrated significant improvements in quality of life

and social function, as well as in depression symptoms, in

200 patients with schizophrenia at a 4-week follow-up.90

Depot injections have also been used extensively for con-

trolling treatment noncompliance and long-term maintenance

therapy, thus reducing the risk of relapse.91–93 Reviews on

second-generation antipsychotic or FGA depots (eg, bro-

mperidol decanoate, haloperidol depot, risperidone depot,

and fluphenazine decanoate) versus oral antipsychotic drugs

and placebo indicated that patients with FGA depots had few

relapses and fewer oral medications, even though the differ-

ence did not reach statistical significance.94–96 Together with

similar levels of adverse effects found in depot medications,

it was also difficult to conclude that a particular depot was

no better than any other depot or oral medication.96 Despite

showing similar clinical efficacy between oral and depot

medications, depot injections can avoid frequent regular

administration of and nonadherence to oral medication,

rendering them more desirable for maintenance or compli-

ance therapy.

Pharmacological treatment used in different developmental stages of lifeDuring the last decade, there have been an increasing number

of randomized controlled trials of the efficacy and safety

of the FGAs and secondary-generation antipsychotics in

children and adolescents with schizophrenia, involving

double-blind, placebo-controlled, or open-labeled design and

short- to medium-term follow-up (ie, 4–8 weeks).97–103 Those

aged 12–17 years were usually included in the controlled

trials, and a wide variety of second-generation antipsychot-

ics such as quetapine,97 risperidone,98 paliperidone,99 and

olanzapine100 were tested. A few main patient outcomes were

commonly used, including global functioning, symptom

severity, and quality-of-life assessment; however, few of the

studies involved any long-term follow-up (ie, .8 weeks).97–103

In addition, a few types of treatment-emergent adverse events

specifically for the second-generation antipsychotic used

were observed (eg, metabolic and endocrine abnormalities

for olanzapine and somnolence, agitation and electrocardio-

gram (ECG) and ophthalmic abnormalities for quetiapine).

Similar to other age groups, most of the antipsychotics have

had positive benefits for adolescents on reducing psychotic

symptoms and global functioning, and the treatment was

well- tolerated with acceptable levels of adverse events in low

and medium dosages. None of the FGAs or second-genera-

tion antipsychotics has shown its superiority over the others,

and the benefits of polypharmacy to any psychotic symptoms

and comorbidities such as mood disorders for adolescents

are also inconclusive.102,103 Nonetheless, it is suggested that

antipsychotics are generally better tolerated and more effec-

tive in early psychosis.

Interestingly, a case study on a 17-year-old patient with

intractable catatonic schizophrenia showed moderate effects

in the resumption of spontaneous movement as a result of

ECT as an adjunct to clozapine treatment.104 The researchers

suggested that appropriate combinations of antipsychotic

medication and other treatment modalities could also be con-

sidered in young patients, although it would be unusual.

It is estimated globally that about 23% of hospitalized

patients with schizophrenia are older than 40 years and that

more than 0.1% of elderly people have a diagnosis of late-

onset schizophrenia.105 Very few studies have been done on

those aged more than 65 years, and thus there are inadequate

data and evidence to support any guidelines for treatment

of late-onset schizophrenia or to serve these older patients’

quality of life, functioning, and service use.105,106

ECT and other treatmentsECT, in which clonic seizure is electrically induced in anes-

thetized patients for therapeutic effects such as improved

mood and volition, was commonly used in the 1930s–1970s.

One of the major patient groups for this treatment com-

prised those with schizophrenia or schizoaffective disorder.

Although recent research findings are limited, ECT is con-

sidered an alternative treatment for those with unfavorable

responses to antipsychotics alone after receiving different

courses of medical or psychological treatment, and/or those

with very strong suicidality and catatonic features.107,108 It

is an effective adjunct to clozapine in treating refractory

schizophrenia.104 There is certainly no strong or conclu-

sive evidence to suggest that ECT alone or as an adjunct

to antipsychotics is superior to antipsychotics alone or

to any combination of different treatment modalities for

schizophrenia. In addition, ECT may cause short-term, or

occasionally long-term, memory impairment and leaves

many unanswered questions about its role and mechanisms

in the treatment of schizophrenia.108 Similarly, transcranial

magnetic stimulation (a procedure that uses magnetic fields

to stimulate the depolarization or hyperpolarization of the

neuron cells in the cortical regions of the brain) has shown

preliminary positive evidence in treating refractory negative

symptoms and auditory hallucinations.109,110

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Current treatments for schizophrenia spectrum disorders

It is also believed that Chinese herbal medicine pro-

duces progressive positive changes in physiological and

mental state and fewer adverse effects when compared with

Western medicine. The adverse effects of antipsychotics-

induced psycho- and physiopathological changes (eg,

dysfunctions of the body organs and sleep–wake cycle) in

the body can be treated with such herbal medicine, which is

considered to promote the Yin–Yang balance and maintain a

homeostatic environment of the internal bodily condition.111

Electroacupuncture for schizophrenia sufferers with auditory

hallucination who were partially or fully nonresponsive to

risperidone monotherapy was studied with a small-sized

sample. The results showed that there was no significance

difference between the two treatment modalities in terms of

adverse effects, whereas electroacupuncture could induce

a satisfactory improvement in auditory hallucination and a

few other positive symptoms.112 Nevertheless, no conclusions

were drawn on the potential efficacy of traditional Chinese

medicine in treating schizophrenia, because of the very

limited empirical evidence on this topic.

Approaches to treatment for schizophrenia from prodromal to later stages of illnessVarious pharmacological treatments and psychosocial inter-

ventions for people with schizophrenia have been developed

and evaluated over the last four decades. Although these

innovative treatments and interventions have aroused much

attention and accelerated deinstitutionalization, moderately

low improvements in recovery, community-based rehabili-

tation, and quality of life among people with schizophrenia

have been the result. The modest nature of these improve-

ments may be because of the limited accessibility and

availability of different alternatives or combined treatments

and/or very advanced pathological and severe symptoms of

patients when they present to and seek treatments from the

mental healthcare system.66 More important, current treat-

ments demonstrate that fairly positive patient outcomes in

schizophrenia can be explained by the fact that most treat-

ment plans do not vary across the course of the illness, even

though different psychopathological processes are closely

linked with different stages of schizophrenia. The three

main stages of schizophrenia can include the premorbid and

prodromal stage, the first onset or episode of acute illness,

and the later stages of ongoing management, rehabilitation,

and recovery.

To better understand the common treatment modali-

ties, their main purposes, and their levels of effectiveness

and reproducibility, a summary of current approaches to

treatments for schizophrenia specific to the three stages of

schizophrenia mentioned earlier is presented in Table 3. In

the summary of the current body of knowledge about phase-

specific treatment approaches (Table 3), it is essential to note

that the mainstay treatments and management strategies of

schizophrenia seem to have evolved at a slow pace and are

highly reliant on antipsychotic agents as the basic treatment

for all schizophrenia sufferers. The effectiveness and/or cost-

benefit analysis of most psychosocial interventions used, as

well as their superiority and therapeutic components, are

somewhat inconsistent and inconclusive.

Throughout the course of schizophrenia, more than 70 types

of antipsychotic agents classified into first- and second-

generation groups can be useful for symptom management.

Nearly all antipsychotics share similar properties to block the

dopamine D-2 receptor in terms of different potencies relating

to their affinity for the receptor.19 They show no major differ-

ences in clinical efficacy for the overall schizophrenia group

in meta-analyses of recent placebo-controlled studies.40,66,113

Although antipsychotics are found to significantly reduce a

wide range of psychotic symptoms, and thus relapses, their

effects on psychosocial functioning, cognitive and vocational

skills, and longer-term community living skills in schizo-

phrenia are vague and inadequately studied.114,115 It is also

essential to point out that this similar overall efficacy reported

in schizophrenia is not equal to and does not signify the same

desirability or adverse effects, safety, tolerance, and/or other

clinical responses in each individual patient.

Nevertheless, new pharmacological treatments for schizo-

phrenia have been merging as a result of better understanding

of its etiology and pathophysiology and the specific targeting

of individual symptom domains.114 For instance, N-methyl-

D-aspartate glutamate receptor agonists and glycine site ago-

nists have been used in combination with antipsychotics, or

the activating agents of the metabotropic glutamate 2/3 recep-

tors, and can be successful in reducing negative symptoms.115

Alpha 7 nicotinic receptor agonists, dopamine 1 receptor

agonists, and modulators of glutamatergic aminomethyl-

phosphonic acid (AMPA) receptors have been found to be

useful in reducing cognitive impairments in schizophrenia.116

Therefore, different pharmacological treatment plans can

be designed to target different pathophysiological processes

relevant to different stages of schizophrenia.

For the premorbid phase (Table 3), most people with

psychotic features experience a lengthy prodromal period

of nonspecific symptoms and slowly progressive functional

impairments before the full emergence of the diagnostic

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1326

Chien and Yip

Tab

le 3

App

roac

hes

to c

ontin

uity

of c

are

for

peop

le w

ith s

chiz

ophr

enia

in t

hree

sta

ges

of il

lnes

s

Pha

se o

f illn

ess

App

roac

hes

to c

are

Leve

l of e

vide

nce

Dur

atio

nA

pplic

abili

ty

Prem

orbi

d or

pro

drom

al

phas

eC

omm

unity

-bas

ed a

ppro

ache

s to

car

e, t

arge

ted

at p

reve

ntio

n an

d ea

rly

inte

rven

tions

of t

he il

lnes

s.1.

Pop

ulat

ion-

base

d or

sel

ecte

d at

-ris

k gr

oup

illne

ss p

reve

ntio

n pr

ogra

ms

reco

gniz

e ea

rlie

r

the

risk

fact

ors

for

schi

zoph

reni

a an

d re

duce

the

dev

elop

men

t of

beh

avio

ral a

nd c

ogni

tive

pa

thol

ogy

with

tar

get

med

icat

ions

and

tre

atm

ent

appr

oach

es.

**

*

2. L

ow d

osag

e of

pro

phyl

actic

ant

ipsy

chot

ics

and/

or a

ntid

epre

ssan

ts c

an e

xert

opt

imal

effe

cts

on

sym

ptom

red

uctio

n w

ithin

1–2

wee

ks.

****

**

3. i

n th

e pr

odro

mal

pha

se, c

ogni

tive

ther

apy

as a

n ad

junc

t to

a lo

w d

ose

of a

ntip

sych

otic

s ca

n pr

even

t

tran

sitio

n to

psy

chot

ic d

isor

ders

and

red

uce

med

icat

ion

use

and

the

seve

rity

of s

ubcl

inic

al s

ympt

oms.

***

**

4. A

sser

tive

outr

each

ser

vice

with

evi

denc

e-ba

sed

inte

rven

tions

ada

pted

to

the

need

s of

indi

vidu

als

w

ith s

ubcl

inic

al o

r pr

odro

mal

sym

ptom

s, in

clud

ing

low

-dos

e an

tipsy

chot

ics,

cog

nitiv

e th

erap

y, fa

mily

co

unse

ling,

and

voc

atio

nal t

rain

ing.

**

*

Acu

te p

hase

or

first

-epi

sode

Effe

ctiv

e tr

eatm

ent

and

care

are

pro

vide

d in

the

acu

te p

hase

of t

he il

lnes

s fo

r ac

tive

and

effic

ient

in

terv

entio

ns t

o co

ntro

l sev

ere

sym

ptom

s an

d pr

epar

e fo

r lo

nger

-ter

m il

lnes

s m

anag

emen

t.

Ant

ipsy

chot

ics

prod

uce

sign

ifica

nt p

ositi

ve e

ffect

s on

the

sho

rt-t

erm

clin

ical

out

com

es o

f acu

te

schi

zoph

reni

a; fo

r ex

ampl

e, s

ympt

om r

educ

tion

and

rela

pse

and

suic

ide

prev

entio

n.1.

Psy

chot

ropi

c dr

ugs

are

pres

crib

ed fo

r ef

ficie

nt c

ontr

ol o

f acu

te p

sych

iatr

ic s

ympt

oms:

  •

Ant

ipsy

chot

ics

(bot

h th

e fir

st a

nd s

econ

d ge

nera

tion)

are

the

mos

t ef

fect

ive

for

posi

tive

sym

ptom

s

and

atte

ntio

n (b

ut h

ave

limite

d ef

fect

s fo

r co

gniti

ve a

nd n

egat

ive

sym

ptom

s).

  •

Clo

zapi

ne is

rel

ativ

ely

mor

e ef

fect

ive

than

oth

er a

ntip

sych

otic

s in

ref

ract

ory

schi

zoph

reni

a an

d su

icid

ality

. 

 • A

ntid

epre

ssan

ts a

re e

ffect

ive

in t

reat

ing

depr

essi

ve a

nd a

nxie

ty s

ympt

oms

in s

ome

patie

nts

w

ith le

ss-p

rom

inen

t po

sitiv

e sy

mpt

oms.

  •

Ant

icon

vuls

ants

suc

h as

car

bam

azep

ine

and

valp

roic

aci

d, a

s ad

junc

ts t

o an

tipsy

chot

ics,

ca

n tr

eat

aggr

essi

on a

nd im

puls

ivity

.

***

**

**

*

***

* * *

***

**

**

**

2. e

lect

roco

nvul

sive

the

rapy

can

be

effe

ctiv

e in

tre

atin

g ve

ry s

ever

e ps

ycho

tic a

nd c

atat

onic

sym

ptom

s.

Thi

s th

erap

y, t

oget

her

with

clo

zapi

ne, c

an a

lso

be u

sed

for

trea

ting

refr

acto

ry s

chiz

ophr

enia

.**

***

**

3. T

rans

cran

ial m

agne

tic s

timul

atio

n de

mon

stra

tes

effe

cts

in t

reat

ing

nega

tive

sym

ptom

s

and

audi

tory

hal

luci

natio

ns.

***

*

4. F

amily

psy

choe

duca

tion

(6–9

mon

ths)

con

sist

ing

of e

duca

tion

abou

t th

e ill

ness

and

its

trea

tmen

t,

prob

lem

-sol

ving

ski

lls, a

nd c

risi

s in

terv

entio

n ca

n re

duce

rel

apse

rat

es, f

amily

bur

den,

an

d tr

eatm

ent

adhe

renc

e.

***

**

Late

r st

ages

of i

llnes

sw

ide

vari

etie

s of

app

roac

hes

to t

reat

men

t an

d ca

re a

re a

imed

at

enha

ncin

g th

e co

ntin

uity

and

qu

ality

of o

ngoi

ng il

lnes

s m

anag

emen

t, ps

ycho

soci

al r

ehab

ilita

tion,

and

rel

apse

pre

vent

ion.

1. A

ntip

sych

otic

age

nts

are

effe

ctiv

e in

the

per

sist

ent

cont

rol a

nd r

educ

tion

of p

sych

otic

sy

mpt

oms

in v

ario

us il

lnes

s co

nditi

ons:

  •

A fe

w s

econ

d-ge

nera

tion

antip

sych

otic

s su

ch a

s ol

anza

pine

indi

cate

per

sist

ent

trea

tmen

t ef

fect

s

in s

ympt

om r

educ

tion,

as

wel

l as

few

er e

xtra

pyra

mid

al a

dver

se e

ffect

s an

d an

ticho

liner

gic

activ

ity.

  •

Lon

g-ac

ting

inje

ctio

n of

ant

ipsy

chot

ics

as a

tre

atm

ent

regi

men

indi

cate

s so

me

adva

ntag

es o

ver

or

al m

edic

atio

n in

com

mun

ity c

are

and

redu

cing

non

adhe

renc

e an

d re

laps

e. 

 • H

owev

er, p

eopl

e w

ith la

ter

stag

es o

f sch

izop

hren

ia h

ave

been

sho

wn

to b

e le

ss r

espo

nsiv

e

to a

ntip

sych

otic

age

nts.

**

**

**

* **

*

* **

*

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1327

Current treatments for schizophrenia spectrum disorders

2. P

sych

osoc

ial i

nter

vent

ions

are

use

d in

com

bina

tion

with

ant

ipsy

chot

ics

to h

elp

in r

educ

ing

sym

ptom

s

and

impr

ovin

g tr

eatm

ent

adhe

renc

e, s

ocia

l and

cog

nitiv

e fu

nctio

ns, a

nd q

ualit

y of

life

. 

 • P

atie

nt a

nd fa

mily

psy

choe

duca

tion

prog

ram

s ar

e ef

fect

ive

in p

rovi

ding

illn

ess-

rela

ted

info

rmat

ion

an

d ps

ycho

soci

al s

uppo

rt, a

s w

ell a

s ef

fect

ive

copi

ng s

trat

egie

s an

d pr

oble

m-s

olvi

ng s

kills

. 

 • C

ogni

tive-

beha

vior

al t

hera

py d

emon

stra

tes

sign

ifica

nt e

ffect

s in

red

ucin

g po

sitiv

e sy

mpt

oms

an

d di

sorg

aniz

ed t

houg

hts

in t

hose

with

per

sist

ent

and

resi

dual

psy

chot

ic s

ympt

oms.

  •

Cog

nitiv

e re

med

iatio

n is

effe

ctiv

e in

tre

atin

g im

pair

ed c

ogni

tion

(eg,

att

entio

n, w

orki

ng m

emor

y,

exec

utiv

e fu

nctio

n, a

nd s

ocia

l cog

nitio

n) a

nd is

ass

ocia

ted

with

impr

ovem

ents

in

psy

chos

ocia

l fun

ctio

ning

. 

 • S

ocia

l ski

lls t

rain

ing

can

impr

ove

perf

orm

ance

-bas

ed s

ocia

l and

com

mun

ity fu

nctio

ning

but

has

lit

tle e

ffect

on

sym

ptom

con

trol

and

rel

apse

pre

vent

ion.

  •

Sup

port

ive

empl

oym

ent

with

wor

k sk

ills

trai

ning

is t

ailo

red

to t

hose

who

nee

d jo

b pl

acem

ent

or

voc

atio

nal t

rain

ing

and

is e

ffect

ive

in h

elpi

ng p

atie

nts

obta

in a

nd m

aint

ain

open

com

petit

ive

em

ploy

men

t. H

owev

er, t

here

is li

mite

d ev

iden

ce o

n lo

nger

-ter

m e

mpl

oym

ent

outc

omes

suc

h

as jo

b re

tent

ion

and

econ

omic

inde

pend

ence

.

***

**

* **

*

**

**

* **

**

***

***

* **

**

3. P

eer-

led

patie

nt a

nd fa

mily

sup

port

gro

up p

rogr

ams

prov

ide

flexi

ble

and

nonh

iera

rchi

cal p

sych

osoc

ial

supp

ort

to p

atie

nts

and/

or t

heir

fam

ily m

embe

rs a

nd h

ave

an e

ffect

on

redu

cing

pat

ient

rel

apse

, im

prov

ing

fam

ily a

nd s

ocia

l sup

port

, enh

anci

ng m

edic

atio

n ad

here

nce,

and

impr

ovin

g co

ping

ski

lls.

**

**

4. A

sser

tive

com

mun

ity t

reat

men

t of

fers

a m

ultid

isci

plin

ary

appr

oach

to

inte

nsiv

e pa

tient

car

e, s

uppo

rt

and

cont

acts

in t

he c

omm

unity

, or

in a

hom

eles

s si

tuat

ion

is e

ffect

ive

in r

educ

ing

hosp

italiz

atio

ns a

nd

impr

ovin

g so

cial

inte

grat

ion

for

thos

e w

ho a

re t

reat

men

t-re

sist

ant

and

pron

e to

hig

h re

adm

issi

on r

ates

.

***

**

5. M

ultif

acet

ed il

lnes

s m

anag

emen

t pr

ogra

ms,

incl

udin

g so

cial

ski

lls t

rain

ing,

med

icat

ion

adhe

renc

e

ther

apy,

pro

blem

-sol

ving

and

com

mun

icat

ion

skill

s tr

aini

ng, s

uppo

rted

em

ploy

men

t,

and

even

fam

ily b

ehav

iora

l and

cas

e m

anag

emen

t, ca

n im

prov

e pa

tient

s’ r

ecov

ery,

tre

atm

ent

co

mpl

ianc

e, a

nd s

ocia

l rei

nteg

ratio

n.

**

**

Not

es: “

Leve

l of e

vide

nce”

den

otes

the

thre

e le

vels

of e

vide

nce

on th

e ap

proa

ches

to c

arin

g fo

r sc

hizo

phre

nia

in te

rms

of th

e am

ount

and

con

sist

ency

of t

he r

esea

rch

evid

ence

: ***

, ver

y m

uch

cons

iste

nt a

nd c

oncl

usiv

e, p

ositi

ve fi

ndin

gs;

**, s

atis

fact

ory

cons

iste

ncy

and

repl

icab

ility

with

a fe

w n

onsi

gnifi

cant

or

nega

tive

findi

ngs;

and

*, f

ew o

r in

cons

iste

nt fi

ndin

gs. “

Dur

atio

n” in

dica

tes

the

dura

tion

of th

e re

sear

ch e

vide

nce

on th

e ap

proa

ches

to c

are

iden

tified

in th

e lit

erat

ure,

in

clud

ing

***,

evi

denc

e no

ted

for

mor

e th

an 2

0 ye

ars;

**,

evi

denc

e no

ted

for

10–2

0 ye

ars;

and

*, e

vide

nce

note

d fo

r no

t mor

e th

an 1

0 ye

ars.

“A

pplic

abili

ty”

deno

tes

the

leve

ls o

f fea

sibi

lity

and

appl

icab

ility

for

the

inte

rven

tion

to b

e ap

plie

d to

men

tal h

ealth

care

pra

ctic

e: *

**, v

ery

flexi

ble

and

appl

icab

le t

o fie

ld p

ract

ice;

**,

sat

isfa

ctor

y ap

plic

abili

ty t

o pr

actic

e; a

nd *

, not

eas

ily o

r co

mm

only

app

lied

to p

ract

ice.

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Chien and Yip

psychotic symptoms. The development of higher levels

of dysfunction and disability during the prodromal period

creates major inhibitory factors influencing recovery, thus

providing very strong rationale for premorbid assessment

and interventions. To promote accurate and valid assess-

ment of high-risk individuals or groups, specific scales are

being developed, such as the Bonn Scale for the Assessment

of Basic Symptoms and the Comprehensive Assessment of

At-Risk Mental State, as well as the Scale of Prodromal

Symptoms.117,118 Without any of the strategies currently used,

specific population-based prevention and assessment efforts

should be made, targeting high-risk groups with mild early

psychotic symptoms. Most important, identification of risk

factors and symptomatic indicators is critical for accurately

selecting at-risk persons and matching them to the most

appropriate preventive treatment. As suggested by Birch-

wood, Todd, and Jackson’s hypothesis of critical periods

of onset and early intervention of psychosis,119 therapeutic

interventions such as cognitive–behavioral therapy and asser-

tive outreach services are most effective if they are offered

at the earliest possible moment during the most vulnerable

periods of illness onset.120,121 Research evidence suggesting

that these cognitive and behavioral interventions can help

people in the prodromal stage of schizophrenia is emerging,

but is as yet inconclusive.122

In acute-episode or first-onset schizophrenia, the use of

different antipsychotic agents is found to be crucial and effec-

tive in symptom reduction, especially for positive symptoms

and attention. Second-generation (atypical) antipsychotics

showing less risk for extrapyramidal adverse effects and tar-

dive dyskinesia can be considered as the first-line treatment

for acute psychosis. The second-generation antipsychotic

clozapine is more effective in treating refractory schizo-

phrenia and suicidality.123 Other psychotropic drugs such as

antidepressants and anticonvulsants can be used as an adjunct

to antipsychotics to control specific psychiatric symptoms

such as depression, anxiety, aggression, and impulsivity.

Physical treatments, especially ECT, are found effective

in controlling a few treatment-resistive symptoms such as

catatonic state, strongly depressive and suicidal ideation, and

some negative symptoms.107 Repetitive transcranial magnetic

stimulation studies have demonstrated some promise in

the treatment of schizophrenia, particularly for those with

treatment-resistant auditory hallucinations and severe mood

problems.124 Family psychoeducation (6–9 months) can reduce

relapse rates, family burden, and treatment adherence.7

For ongoing management and later-stage schizophre-

nia, a variety of psychosocial interventions are found

useful in reducing patients’ relapses and rehospitalizations,

enhancing their functioning and medication adherence, and

facilitating their rehabilitation and recovery. As indicated

in Table 3, the more conclusive and consistent therapeutic

interventions with moderate to large effect sizes in symp-

tom control, relapse prevention, and levels of psychosocial

functioning included patient and/or family psychoeducation

programs,125 cognitive–behavioral therapy,126 and an inte-

grated program with antipsychotics and different approaches

to psychosocial care.127,128 Although small effect sizes to

relapse prevention were found, a few commonly used

approaches to psychosocial intervention for schizophrenia

show increasingly consistent effects on specific patient out-

comes, such as patients’ social and community functioning

being improved by social and vocational skills and short-

term competitive employment being enhanced by supported

employment with work skills training.65,129

Similar to Amsterdam’s first-aid service in the 1970s,

crisis intervention models for people with schizophrenia

and other serious mental illnesses have at times emerged,

aimed at treating psychiatric crises in the community and

reducing relapses and/or the number of hospitalizations.129

Multidisciplinary, around-the-clock crisis intervention ser-

vices advocate prompt detection of symptom exacerbation

and immediate intensive treatments as needed (eg, psychotro-

pic agents, individual and family counseling, psychological

therapies, and practical assistance in activities of daily living)

in both community and home settings. Programs in Australia

and the United States, such as mobile crisis teams, crisis units

in hospitals, crisis day treatment centers, and crisis residential

programs, have been integrated into routine mental healthcare

services.64,130 Nevertheless, recent clinical trials suggested

that about half of the crisis intervention groups indicated

nonsignificant effects on improvements in mental state or

reducing hospitalization during the treatment period, as well

as lacking evidence of their long-term benefits in terms of

patient outcomes.131 In addition, recent research has also

evaluated the effectiveness of multifaceted illness manage-

ment programs consisting of a wide variety of biological/

physical, psychological, and social interventions and sug-

gested these programs might efficiently and effectively

improve patient recovery and social reintegration.65,127,131

ConclusionAntipsychotics (first- and/or second-generation antipsychot-

ics) are shown to be effective in reducing overall psychotic

symptoms and relapse in patients with schizophrenia. It is

therefore recommended in most of the literature as first-line

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Current treatments for schizophrenia spectrum disorders

treatment for people with schizophrenia, at least in the

short-term or at the acute stage of illness. However, the use

of antipsychotics alone as the main treatment modality may

be limited not only by their inability to tackle the frequently

occurring negative symptoms and cognitive impairments but

also by producing a wide variety of adverse effects in the

internal body or organ functioning. The FGAs and second-

generation antipsychotics are two distinct classes of antipsy-

chotics with quite different potency and adverse effects, but

these two classes do not have any definitive categorization

between them in terms of efficacy, safety, and tolerability or

in their clinical outcomes. However, because of the varied

pharmacokinetics and patients’ treatment responsiveness

across different agents, the medication regimen should be

determined on an individual basis to ensure optimal effect in

their long-term use. Other medical and psychological treat-

ments should be considered as an adjunct to antipsychotic

agents. However, many of these alternative treatments are

not strongly evidenced or conclusive in producing specific

therapeutic effects in treating schizophrenia. More con-

trolled trials are recommended to enhance understanding

about their efficacy as a monotherapy or in combined use

with antipsychotics, other medication, and/or psychosocial

interventions.

Many patients with schizophrenia often have unresolved

life events and psychological distress, as well as illness-

related or drug-induced problems, which significantly affect

their normalcy of daily life. In the last few decades, various

models of psychosocial intervention have been developed and

implemented as an adjunct to the pharmacological or other

medical treatments at different stages of schizophrenia. The

main purpose of these approaches to treatment is to provide

these patients (and their family members) with adequate

knowledge of and skills in this illness and its treatment

and care, emotional support, problem-solving and coping

skills, and/or enhancing cognitive and functional recovery.

The current models commonly used for schizophrenia care

include cognitive–behavioral therapy, psychoeducation,

family intervention, social skills training, and cognitive

remediation therapy. These psychosocial interventions and

their comparative efficacy in treating people with schizophre-

nia will be discussed in another article. Recent systematic

reviews on psychosocial interventions for schizophrenia

have indicated significant positive medium-term (up to

18 months) effects of a few approaches (eg, psychoeducation

and cognitive–behavioral therapy) integrated or embedded

into routine care (and medication use) in people with acute

or chronic schizophrenia. To overcome the shortcomings

of antipsychotics in the treatment of schizophrenia, clinical

guidelines and standards of practice have recommended that

a combination of treatment methods or modalities be adopted

to meet the complex psychiatric and other health needs of

people with schizophrenia. We are assured of and also highly

recommend more research in the clinical efficacy of differ-

ent existing and new models of psychosocial interventions,

together with antipsychotics or other psychotropic drugs, to

ascertain a treatment approach for people with schizophre-

nia with the highest possible levels of efficacy, safety, and

acceptability.

DisclosureThe authors report no conflicts of interest in this work.

References 1. American Psychiatric Association. Diagnostic and Statistical Manual

of Mental Disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994.

2. Dominguez Mde G, Viechtbauer W, Simons CJ, van Os J, Krabbendam L. Are psychotic psychopathology and neurocognition orthogonal? A systematic review of their associations. Psychol Bull. 2009;135(1):157–171.

3. Jablensky A. Prevalence and incidence of schizophrenia spectrum disorders: implications for prevention. Aust N Z J Psychiatry. 2000; 34 Suppl:S26–S34; discussion S35–S38.

4. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123–1131.

5. van Os J, Linscott RJ, Myin-Germeys I, Delespaul P, Krabbendam L. A systematic review and meta-analysis of the psychosis continuum: evidence for a psychosis proneness-persistence-impairment model of psychotic disorder. Psychol Med. 2009;39(2):179–195.

6. National Institute for Health and Clinical Excellence. Schizophrenia. Core Interventions in the Treatment and Management of Schizophrenia in Primary and Secondary Care. National Clinical Practice Guideline 82. London: National Institute for Clinical Excellence; 2009.

7. Bilder RM. Neurocognitive impairment in schizophrenia and how it affects treatment options. Can J Psychiatry. 1997;42(3):255–264.

8. Bustillo J, Lauriello J, Horan W, Keith S. The psychosocial treatment of schizophrenia: an update. Am J Psychiatry. 2001;158(2):163–175.

9. Carpenter WT Jr, Heinrichs DW, Wagman AM. Deficit and nondeficit forms of schizophrenia: the concept. Am J Psychiatry. 1988;145(5): 578–583.

10. Hogarty GE, Anderson CM, Reiss DJ, et al. Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia. I. One-year effects of a controlled study on relapse and expressed emotion. Arch Gen Psychiatry. 1986;43(7): 633–642.

11. Patterson TL, Leeuwenkamp OR. Adjunctive psychosocial therapies for the treatment of schizophrenia. Schizophr Res. 2008;100(1–3): 108–119.

12. Pfammatter M, Junghan UM, Brenner HD. Efficacy of psychological therapy in schizophrenia: conclusions from meta-analyses. Schizophr Bull. 2006;32 Suppl 1:S64–S80.

13. Rector NA, Beck AT. Cognitive behavioral therapy for schizophrenia: an empirical review. J Nerv Ment Dis. 2001;189(5):278–287.

14. Tandon R, Targum SD, Nasrallah HA, Ross R; Treatment Effectiveness in Schizophrenia Consortium. Strategies for maximizing clinical effectiveness in the treatment of schizophrenia. J Psychiatr Pract. 2006;12(6):348–363.

Neuropsychiatric Disease and Treatment 2013:9submit your manuscript | www.dovepress.com

Dovepress

Dovepress

1330

Chien and Yip

15. Pharoah F, Mari J, Rathbone J, Wong W. Family intervention for schizophrenia. Cochrane Database Syst Rev. 2010;(12):CD000088.

16. Kern RS, Glynn SM, Horan WP, Marder SR. Psychosocial treatments to promote functional recovery in schizophrenia. Schizophr Bull. 2009;35(2):347–361.

17. Jeppesen P, Petersen L, Thorup A, et al. Integrated treatment of first-episode psychosis: effect of treatment on family burden: OPUS trial. Br J Psychiatry Suppl. 2005;48:s85–s90.

18. Buchanan RW, Kreyenbuhl J, Kelly DL, et al; Schizophrenia Patient Outcomes Research Team (PORT). The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull. 2010;36(1):71–93.

19. Kapur S, Remington G. Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry. 1 2001;50(11):873–883.

20. World Health Organization. WHO Model List of Essential Medicines. 17th ed. Available from: http://www.who.int/medicines/publications/essentialmedicines/en/index.html. Accessed June 18, 2013.

21. Adams CE, Awad G, Rathbone J, Thornley B. Chlorpromazine versus placebo for schizophrenia. Cochrane Database Syst Rev. 2012;(6):CD000284.

22. Liu X, De Haan S. Chlorpromazine dose for people with schizophrenia. Cochrane Database Syst Rev. 2009;(2):CD007778.

23. Marques LDO, Soares B, Silva de Lima M. Trifluoperazine for schizophrenia. Cochrane Database Syst Rev. 2004(1):CD003545.

24. Fenton M, Rathbone J, Reilly J. Thioridazine for schizophrenia. Cochrane Database Syst Rev. 2007(3):CD001944.

25. Rathbone J, McMonagle T. Pimozide for schizophrenia or related psychoses. Cochrane Database Syst Rev. 2001;(5):CD001949.

26. Hartung B, Wada M, Laux G, Leucht S. Perphenazine for schizophrenia. Cochrane Database Syst Rev. 2010;(5):CD003443.

27. Matar HE, Almerie MQ, Sampson S. Fluphenazine (oral) versus placebo for schizophrenia. Cochrane Database Syst Rev. 2013;(7):CD006352.

28. Leucht S, Hartung B. Perazine for schizophrenia. Cochrane Database Syst Rev. 2006;(2):CD002832.

29. Soares BGO, Fenton M, Chue P. Sulpiride for schizophrenia. Cochrane Database Syst Rev. 1999;(1):CD001162.

30. Kumar A, Strech D. Zuclopenthixol dihydrochloride for schizophrenia. Cochrane Database Syst Rev. 2005;(4):CD005474.

31. Irving CB, Adams CE, Lawrie S. Haloperidol versus placebo for schizophrenia. Cochrane Database Syst Rev. 2006;(4):CD003082.

32. Leucht C, Kitzmantel M, Kane J, Leucht S, Chua WLLC. Haloperidol versus chlorpromazine for schizophrenia. Cochrane Database Syst Rev. 2008;(1):CD004278.

33. Soares BGO, Silva de Lima M. Penfluridol for schizophrenia. Cochrane Database Syst Rev. 2006(2):CD002923.

34. Alptekin K, Hafez J, Brook S, et al. Efficacy and tolerability of switch-ing to ziprasidone from olanzapine, risperidone or haloperidol: an international, multicenter study. Int Clin Psychopharmacol. 2009;24(5): 229–238.

35. Citrome L. Lurasidone for schizophrenia: a review of the efficacy and safety profile for this newly approved second-generation antipsychotic. Int J Clin Pract. 2011;65(2):189–210.

36. Tuunainen A, Wahlbeck K. Newer atypical antipsychotic medication versus clozapine for schizophrenia. Cochrane Database Syst Rev. 2000;(2):CD000966.

37. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet. 3 2009;373(9657):31–41.

38. Gabriel A. Risperidone, quetiapine, and olanzapine adjunctive treatments in major depression with psychotic features: a comparative study. Neuropsychiatr Dis Treat. 2019;485–492.

39. Davis JM, Chen N, Glick ID. A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry. 2003;60(6):553–564.

40. Leucht S, Wahlbeck K, Hamann J, Kissling W. New generation antip-sychotics versus low-potency conventional antipsychotics: a systematic review and meta-analysis. Lancet. 2003;361(9369):1581–1589.

41. Kerwin RW. The new atypical antipsychotics. A lack of extrapyramidal side-effects and new routes in schizophrenia research. Br J Psychiatry. 1994;164(2):141–148.

42. Silverstone T, Turner P. Drug Treatment in Psychiatry. 5th ed. London: Routledge; 1995.

43. Rattehalli RD, Jayaram MB, Smith M. Risperidone versus placebo for schizophrenia. Cochrane Database Syst Rev. 2010;(1):CD006918.

44. Srisurapanont M, Maneeton B, Maneeton N, Lankappa S, Gandhi R. Quetiapine for schizophrenia. Cochrane Database Syst Rev. 2004;(2): CD000967.

45. Nussbaum AM, Stroup TS. Oral paliperidone for schizophrenia. Cochrane Database Syst Rev. 2008;(2):CD006369.

46. Duggan L, Fenton M, Rathbone J, Dardennes R, El-Dosoky A, Indran S. Olanzapine for schizophrenia. Cochrane Database Syst Rev. 2005;(2): CD001359.

47. Chakrabarti A, Bagnall AM, Chue P, et al. Loxapine for schizophrenia. Cochrane Database Syst Rev. 2007;(4):CD001943.

48. Belgamwar RB, El-Sayeh HGG. Aripiprazole versus placebo for schizophrenia. Cochrane Database Syst Rev. 2011;(8):CD006622.

49. El-Sayeh HG, Morganti C. Aripiprazole for schizophrenia. Cochrane Database Syst Rev. 2006;(2):CD004578.

50. Silveira da Mota Neto JI, Soares BGO, Silva de Lima M. Amisulpride for schizophrenia. Cochrane Database Syst Rev. 2002;(2):CD001357.

51. Salimi K, Jarskog LF, Lieberman JA. Antipsychotic drugs for first-episode schizophrenia: a comparative review. CNS Drugs. 2009;23(10): 837–855.

52. Lieberman JA, Stroup TS, McEvoy JP, et al; Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med. 2005;353(12):1209–1223.

53. Lesem MD, Tran-Johnson TK, Riesenberg RA, et al. Rapid acute treatment of agitation in individuals with schizophrenia: multicentre, randomised, placebo-controlled study of inhaled loxapine. Br J Psychiatry. 2011;198(1):51–58.

54. Karayal ON, Glue P, Bachinsky M, et al. Switching from quetiapine to ziprasidone: a sixteen-week, open-label, multicenter study evaluating the effectiveness and safety of ziprasidone in outpatient subjects with schizophrenia or schizoaffective disorder. J Psychiatr Pract. 2011;17(2):100–109.

55. Mishara AL, Goldberg TE. A meta-analysis and critical review of the effects of conventional neuroleptic treatment on cognition in schizophrenia: opening a closed book. Biol Psychiatry. 2004;55(10): 1013–1022.

56. Gilbody S, Bagnall AM, Duggan L, Tuunainen A. Risperidone versus other atypical antipsychotic medication for schizophrenia. Cochrane Database Syst Rev. 2000;(3):CD002306.

57. Subramanian S, Rummel-Kluge C, Hunger H, et al. Zotepine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(10):CD006628.

58. Komossa K, Rummel-Kluge C, Hunger H, et al. Sertindole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009;(2):CD006752.

59. Komossa K, Rummel-Kluge C, Schwarz S, et al. Risperidone versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2011;(1):CD006626.

60. Komossa K, Rummel-Kluge C, Hunger H, et al. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(3):CD006654.

61. Asenjo Lobos C, Komossa K, Rummel-Kluge C, et al. Clozapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2010;(11);CD006633.

62. Komossa K, Rummel-Kluge C, Schmid F, et al. Aripiprazole versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev. 2009;(4):CD006569.

63. Essali A, Al-Haj Haasan N, Li C, Rathbone J. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009;(1):CD000059.

Neuropsychiatric Disease and Treatment 2013:9 submit your manuscript | www.dovepress.com

Dovepress

Dovepress

1331

Current treatments for schizophrenia spectrum disorders

64. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620–627.

65. Dixon L, Perkins D, Calmes C. Guideline Watch: Practice Guideline for the Treatment of Patients with Schizophrenia. Arlington, VA: American Psychiatric Association; 2009.

66. Tandon R, Nasrallah HA, Keshavan MS. Schizophrenia, “just the facts” 5. Treatment and prevention. Past, present, and future. Schizophr Res. 2010;122(1–3):1–23.

67. Hamann J, Kissling W, Leucht S, Rummel-Kluge C. New generation antipsychotics for first episode schizophrenia. Cochrane Database Syst Rev. 2003;(4):CD004410.

68. Bola J, Kao D, Soydan H, Adams CE. Antipsychotic medication for early episode schizophrenia. Cochrane Database Syst Rev. 2011;(6): CD006374.

69. Lewis R, Bagnall AM, Leitner M. Sertindole for schizophrenia. Cochrane Database Syst Rev. 2005;(3):CD001715.

70. Brown S, Kim M, Mitchell C, Inskip H. Twenty-five year mortality of a community cohort with schizophrenia. Br J Psychiatry. 2010;196(2): 116–121.

71. Singh J, Kour K, Jayaram MB. Acetylcholinesterase inhibitors for schizophrenia. Cochrane Database Syst Rev. 2012;(1):CD007967.

72. Shekhar A, Potter WZ, Lightfoot J, et al. Selective muscarinic receptor agonist xanomeline as a novel treatment approach for schizophrenia. Am J Psychiatry. 2008;165(8):1033–1039.

73. Wang J, Omori IM, Fenton M, Soares BGO. Sulpiride augmentation for schizophrenia. Cochrane Database Syst Rev. 2010;(1):CD008125.

74. Buchanan RW, Javitt DC, Marder SR, et al. The Cognitive and Negative Symptoms in Schizophrenia Trial (CONSIST): the efficacy of glutamatergic agents for negative symptoms and cognitive impairments. Am J Psychiatry. 2007;164(10):1593–1602.

75. Schwarz C, Volz A, Li C, Leucht S. Valproate for schizophrenia. Cochrane Database Syst Rev. 2008;(3):CD004028.

76. Leucht S, Kissling W, McGrath J, White P. Carbamazepine for schizophrenia. Cochrane Database Syst Rev. 2007;(3):CD001258.

77. Elias A, Kumar A. Testosterone for schizophrenia. Cochrane Database Syst Rev. 2007;(3):CD006197.

78. Irving CB, Mumby-Croft R, Joy LA. Polyunsaturated fatty acid supplementation for schizophrenia. Cochrane Database Syst Rev. 2006;(3);CD001257.

79. Leucht S, Kissling W, McGrath J. Lithium for schizophrenia. Cochrane Database Syst Rev. 2007;(3);CD003834.

80. Premkumar TS, Pick J. Lamotrigine for schizophrenia. Cochrane Database Syst Rev. 2006;(4):CD005962.

81. Tiihonen J, Wahlbeck K. Glutamatergic drugs for schizophrenia. Cochrane Database Syst Rev. 2006;(2):CD003730.

82. Dold M, Li C, Tardy M, Khorsand V, Gillies D, Leucht S. Benzodiazepines for schizophrenia. Cochrane Database Syst Rev. 2012;(11):CD006391.

83. Rummel-Kluge C, Kissling W, Leucht S. Antidepressants for the negative symptoms of schizophrenia. Cochrane Database Syst Rev. 2006;(3):CD005581.

84. Singh SP, Singh V, Kar N, Chan K. Efficacy of antidepressants in treating the negative symptoms of chronic schizophrenia: meta-analysis. Br J Psychiatry. 2010;197(3):174–179.

85. Swartz MS, Perkins DO, Stroup TS, et al; CATIE Investigators. Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: findings from the NIMH CATIE study. Am J Psychiatry. 2007;164(3):428–436.

86. Mico’ U, Bruno A, Pandolfo G, et al. Duloxetine as adjunctive treatment to clozapine in patients with schizophrenia: a randomized, placebo-controlled trial. Int Clin Psychopharmacol. 2011;26(6):303–310.

87. Lerner V, Miodownik C, Gibel A, et al. Bexarotene as add-on to antip-sychotic treatment in schizophrenia patients: a pilot open-label trial. Clin Neuropharmacol. 2008;31(1):25–33.

88. Leucht S, Pitschel-Walz G, Engel RR, Kissling W. Amisulpride, an unusual “atypical” antipsychotic: a meta-analysis of randomized con-trolled trials. Am J Psychiatry. 2002;159(2):180–190.

89. Zisook S, Shear MK, Irwin SA. Death, dying, and bereavement. In: Sadock BJ, Sadock VA, Ruiz P, editors. Kaplan and Sadock’s Comprehensive Textbook of Psychiatry. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009:2378–2407.

90. Chen ZH, Wang GH, Wang XP, et al. Effect of Warm-Supplementing Kidney Yang (WSKY) added to risperidone on quality of life in patients with schizophrenia: a randomized controlled trial. Clin Rehabil. 2009;23(11):963–972.

91. West JC, Wilk JE, Olfson M, et al. Patterns and quality of treatment for patients with schizophrenia in routine psychiatric practice. Psychiatr Serv. 2005;56(3):283–291.

92. Kane JM, Aguglia E, Altamura AC, et al. Guidelines for depot antipsy-chotic treatment in schizophrenia. European Neuropsychopharmacology Consensus Conference in Siena, Italy. Eur Neuropsychopharmacol. 1998;8(1):55–66.

93. David AS, Cutting JC. The Neuropsychology of Schizophrenia. East Sussex, UK: Lawrence Erlbaum Associates; 1994.

94. Purgato M, Adams CE. Bromperidol decanoate (depot) for schizophrenia. Cochrane Database Syst Rev. 2012;(11):CD001719.

95. Dinesh M, David A, Quraishi SN. Depot pipotiazine palmitate and undecylenate for schizophrenia. Cochrane Database Syst Rev. 2004;(3):CD001720.

96. David A, Quraishi SN, Rathbone J. Depot perphenazine decanoate and enanthate for schizophrenia. Cochrane Database Syst Rev. 2005;(3): CD001717.

97. Shaw JA, Lewis JE, Pascal S, et al. A study of quetiapine: efficacy and tolerability in psychotic adolescents. J Child Adolesc Psychopharmacol. 2001;11(4):415–424.

98. Haas M, Eerdekens M, Kushner S, et al. Efficacy, safety and tolerability of two dosing regimens in adolescent schizophrenia: double-blind study. Br J Psychiatry. 2009;194(2):158–164.

99. Singh J, Robb A, Vijapurkar U, Nuamah I, Hough D. A randomized, double-blind study of paliperidone extended-release in treatment of acute schizophrenia in adolescents. Biol Psychiatry. 2011;70(12): 1179–1187.

100. Kryzhanovskaya L, Schulz SC, McDougle C, et al. Olanzapine versus placebo in adolescents with schizophrenia: a 6-week, randomized, double-blind, placebo-controlled trial. J Am Acad Child Adolesc Psychiatry. 2009;48(1):60–70.

101. Masi G, Liboni F. Management of schizophrenia in children and ado-lescents: focus on pharmacotherapy. Drugs. 2011;71(2):179–208.

102. Sikich L, Frazier JA, McClellan J, et al. Double-blind comparison of f irst- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treat-ment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry. 2008;165(11):1420–1431.

103. Findling RL, Robb A, Nyilas M, et al. A multiple-center, random-ized, double-blind, placebo-controlled study of oral aripiprazole for treatment of adolescents with schizophrenia. Am J Psychiatry. 2008;165(11):1432–1441.

104. Consoli A, Boulicot V, Cornic F, Fossati P, Barbeau M, Cohen D. Moderate clinical improvement with maintenance ECT in a 17-year-old boy with intractable catatonic schizophrenia. Eur Child Adolesc Psychiatry. 2009;18(4):250–254.

105. Essali A, Ali G. Antipsychotic drug treatment for elderly people with late-onset schizophrenia. Cochrane Database Syst Rev. 2012;(2): CD004162.

106. Marriott R, Neil W, Waddingham S. Antipsychotic medication for elderly people with schizophrenia. Cochrane Database Syst Rev. 2006;(1):CD005580.

107. Tharyan P, Adams CE. Electroconvulsive therapy for schizophrenia. Cochrane Database Syst Rev. 2005;(2):CD000076.

108. Fitzgerald PB. The emerging use of brain stimulation treatments for psychiatric disorders. Aust N Z J Psychiatry. 2011;45(11):923–938.

109. Blumberger DM, Fitzgerald PB, Mulsant BH, Daskalakis ZJ. Repetitive transcranial magnetic stimulation for refractory symptoms in schizophrenia. Curr Opin Psychiatry. 2010;23(2):85–90.

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110. Freitas C, Fregni F, Pascual-Leone A. Meta-analysis of the effects of repetitive transcranial magnetic stimulation (rTMS) on negative and positive symptoms in schizophrenia. Schizophr Res. 2009;108(1–3): 11–24.

111. Rathbone J, Zhang L, Zhang M, Xia J, Liu X, Yang Y. Chinese herbal medicine for schizophrenia. Cochrane Database Syst Rev. 2005;(4): CD003444.

112. Jing Cheng, Gaohua Wang, Ling Xiao, Huiling Wang, Xiaoping Wang, Chengyan Li. Electro-acupuncture versus sham electro-acupuncture for auditory hallucinations in patients with schizophrenia: a random-ized controlled trial. Clin Rehabil. 2009;23(7):579–588.

113. Correll CU, Rummel-Kluge C, Corves C, Kane JM, Leucht S. Antipsychotic combinations vs monotherapy in schizophrenia: a meta-analysis of randomized controlled trials. Schizophr Bull. 2009;35(2): 443–457.

114. Carpenter WT, Koenig JI. The evolution of drug development in schizophrenia: past issues and future oppor tunities. Neuropsychopharmacology. 2008;33(9):2061–2079.

115. Patil ST, Zhang L, Martenyi F, et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nat Med. 2007;13(9):1102–1107.

116. Harvey PD. Pharmacological cognitive enhancement in schizophrenia. Neuropsychol Rev. 2009;19(3):324–335.

117. Klosterkötter J, Hellmich M, Steinmeyer EM, Schultze-Lutter F. Diagnosing schizophrenia in the initial prodromal phase. Arch Gen Psychiatry. 2001;58(2):158–164.

118. Miller TJ, McGlashan TH, Woods SW, et al. Symptom assessment in schizophrenic prodromal states. Psychiatr Q. 1999;70(4):273–287.

119. Birchwood M, Todd P, Jackson C. Early intervention in psychosis. The critical period hypothesis. Br J Psychiatry Suppl. 1991;72(33): 53–59.

120. Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in people at ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291–297.

121. Tempier R, Balbuena L, Garety P, Craig TJ. Does assertive community outreach improve social support? Results from the Lambeth Study of early-episode psychosis. Psychiatr Serv. 2012;63(3):216–222.

122. Marshall M, Rathbone J. Early intervention for psychosis. Cochrane Database Syst Rev. 2011;(6):CD004718.

123. Remington G, Agid O, Foussias G, Hahn M, Rao N, Sinyor M. Clozapine’s role in the treatment of first-episode schizophrenia. Am J Psychiatry. 2013;170(2):146–151.

124. Poulet E, Haesebaert F, Saoud M, Suaud-Chagny MF, Brunelin J. Treatment of shizophrenic patients and rTMS. Psychiatr Danub. 2010;22 Suppl 1:S143–S146.

125. Rummel-Kluge C, Kissling W. Psychoeducation in schizophrenia: new developments and approaches in the field. Curr Opin Psychiatry. 2008;21(2):168–172.

126. Wykes T, Steel C, Everitt B, Tarrier N. Cognitive behavior therapy for schizophrenia: effect sizes, clinical models, and methodological rigor. Schizophr Bull. 2008;34(3):523–537.

127. Chien WT, Lee IY. The schizophrenia care management program for family caregivers of Chinese patients with schizophrenia. Psychiatr Serv. 2010;61(3):317–320.

128. Malla AK, Norman RM, Manchanda R, et al. Status of patients with first-episode psychosis after one year of phase-specific community-oriented treatment. Psychiatr Serv. 2002;53(4):458–463.

129. Weisman GK. Crisis intervention. In: Bellack AS, editor. A Clinical Guide for the Treatment of Schizophrenia. New York: Plenum Press; 1989:101–134.

130. Irving CB, Adams CE, Rice K. Crisis intervention for people with severe mental illnesses. Cochrane Database Syst Rev. 2006;(4): CD001087.

131. National Collaborating Centre for Mental Health. Clinical Guideline 1 – Schizophrenia: Core Intervention in the Treatment and Management of Schizophrenia in Primary and Secondary Care. London: National Institute for Clinical Excellence; 2002.