BJPsych Open (2016)
2, 5966. doi: 10.1192/bjpo.bp.115.002576
Long-term antipsychotic treatment in
schizophrenia: systematic review and network
meta-analysis of randomised controlled trials
Ying Jiao Zhao, Liang Lin, Monica Teng, Ai Leng Khoo, Lay Beng Soh, Toshiaki A. Furukawa,
Ross J. Baldessarini, Boon Peng Lim and Kang Sim
Background
For treatment of patients diagnosed with schizophrenia,
comparative long-term effectiveness of antipsychotic drugs to
reduce relapses when minimising adverse effects is of clinical
interest, hence prompting this review.
Aims
To evaluate the comparative long-term effectiveness of
antipsychotic drugs.
Method
We systematically searched electronic databases for reports
of randomised controlled trials (RCTs) of antipsychotic
monotherapy aimed at reducing relapse risks in schizophrenia.
We conducted network meta-analysis of 18 antipsychotics
and placebo.
Results
Studies of 10 177 patients in 56 reports were included;
treatment duration averaged 48 weeks (range 4156).
Olanzapine was significantly more effective than
chlorpromazine (odds ratio (OR) 0.35, 95% CI 0.140.88)
or haloperidol (OR=0.50, 95% CI 0.300.82); and
fluphenazine decanoate was more effective than
chlorpromazine (OR=0.31, 95% CI 0.110.88) in relapse
reduction. Fluphenazine decanoate, haloperidol, haloperidol
Chronic psychotic disorders diagnosed as schizophrenia are
severe, idiopathic conditions affecting 26 million people world-
wide and resulting in substantial disability in a majority of cases.1
Because of their early onset, chronic course and debilitating
effects, schizophrenia ranks among the top 20 causes of years
lived with disability.2 The course of the illness varies, but most
patients have a chronic course with erratic exacerbations or
relapses with repeated hospital admissions, decreased quality of
life and a high economic burden. Successive relapses also are
associated with progressively declining outcomes. Therefore,
relapse prevention is critical for adequate clinical management of
this devastating illness.3,4
Long-term maintenance treatment with antipsychotic medica-
tion has become the standard for the treatment of patients
diagnosed with schizophrenia, with the aim of limiting sympto-
matic relapses and disability. Although many effective antipsycho-
tic drugs have been developed since the 1950s, all are limited in
effectiveness and are associated with a range of potentially serious
adverse effects including neurological, metabolic and cardiovas-
cular problems which complicate their long-term use.5,6 Generally,
second-generation or atypical antipsychotics are better toler- strably, highly comparable conditions.16 We now report on results
ated than older antipsychotic agents, at least with regard to some
extrapyramidal neurological symptoms, but sometimes present
high risks of adverse effects associated with weight gain, including
decanoate and trifluoperazine produced more extrapyramidal
adverse effects than olanzapine or quetiapine; and
olanzapine was associated with more weight gain than
other agents.
Conclusions
Except for apparent superiority of olanzapine and fluphenazine
decanoate over chlorpromazine, most agents showed
intermediate efficacy for relapse prevention and differences
among them were minor. Typical antipsychotics yielded
adverse neurological effects, and olanzapine was associated
with weight gain. The findings may contribute to evidence-
based treatment selection for patients with chronic psychotic
disorders.
Declaration of interest
R.J.B. received grants from the Bruce J. Anderson Foundation
and the McLean Private Donors Psychopharmacology
Research Fund.
Copyright and usage
The Royal College of Psychiatrists 2016. This is an open
access article distributed under the terms of the Creative
Commons Non-Commercial, No Derivatives (CC BY-NC-ND)
licence.
metabolic syndrome.7 An additional, major limitation to all long-
term maintenance treatments is lack of sustained adherence
to them.810 Long-acting, injectable antipsychotic agents pro
mise to improve treatment adherence, but evidence of superior
clinical outcomes with such drugs compared with oral agents is
inconsistent.11,12
Given the pressing need for effective long-term treatments for
schizophrenia and a growing number of available antipsychotic
drugs, evidence of the relative merits of individual agents is of
great interest. Available reviews of evidence of efficacy and
tolerability of antipsychotic agents generally indicate minor and
variable differences between specific drugs, with the notable
exception of clozapine.6,7,1114 Such comparisons also are severely
limited by the paucity of direct, head-to-head comparisons of
specific agents. Recent developments in methods of meta-analysis
promise to improve this situation, even without direct compar-
isons of specific treatments, based on application of network
meta-analysis.15 In contrast to traditional pairwise meta-analyses,
network methods allow indirect comparisons between treatments
carried out in different trials, under presumably, if not demon-
of a network meta-analysis to evaluate a total of 18 orally
administered and long-acting injectable (LAI) antipsychotic drug
preparations.
59
Zhao et al
Method
Literature search
We first performed a PubMed search to identify recent systematic
reviews (20092015) evaluating the use of antipsychotics for
relapse prevention in patients diagnosed with schizophrenia.17
Then, individual reports of randomised controlled trials (RCTs)
identified in the reviews were added to those identified in
literature searches of the PubMed/Medline and Cochrane Library
databases. Searching was based on applying combinations of the
following search terms: schizophrenia, antipsychotics, amisulpride,
aripiprazole, chlorpromazine, flupenthixol decanoate, fluphena-
zine decanoate, haloperidol and its decanoate, olanzapine, paliper-
idone, long-acting injectable paliperidone, pipothiazine palmitate,
quetiapine, risperidone, long-acting injectable risperidone, sulpir-
ide, trifluoperazine, ziprasidone and zuclopenthixol decanoate (see
the search term list in the data supplement).
Study selection
Two reviewers (Y.J.Z. and L.L.) screened titles and abstracts
against pre-defined study inclusion criteria and promising articles
were reviewed as full texts. The degree of agreement as evaluated
by interrater reliability was 0.91. Any disagreements about reports
selected or data extracted were resolved by consensus with a third,
senior co-investigator (K.S.). Trials were eligible if they involved
the use of antipsychotic monotherapy for relapse prevention
among initially, clinically stable patients diagnosed with schizo-
phrenia. We excluded trials conducted in patients with predomi-
nant negative symptoms or known treatment resistance and trials
for acute illness. We included head-to-head and placebo-con-
trolled RCTs that were single or double-blinded. We did not
restrict the minimum trial length.
Data collection and quality assessment
Data regarding patient characteristics, study design, duration of
test treatments, outcomes (relapse rates, drop-out rates, adverse
effects) and funding sources were extracted independently by two
reviewers (Y.J.Z. and L.L.) with disagreement resolved through
consensus with the same third senior co-investigator (K.S.; Tables
DS1 and DS2 in the data supplement). The degree of agreement as
evaluated by interrater reliability was 0.90. Quality assessment of
included studies was performed using the Cochrane Risk of Bias
Tool, considering the following six domains of bias: random
sequence generation, allocation concealment, masking of partici-
pants and personnel, masking of outcome assessors, incomplete
data and selective reporting.18
Data synthesis and analysis
We carried out a random effects network meta-analysis using the
mvmeta routine in STATA 13 statistical software (StataCorp.
College Station, Texas, USA).19,20 Evidence from both direct
(head-to-head trials) and indirect comparisons (between appar-
ently similar trials using one or more common comparators) were
combined in the analysis. The primary outcome of interest was
relapse as defined in each study at its longest follow-up; and when
relapse was not reported, we used clinically assessed or rating
scale-based exacerbation of psychotic symptoms considered in the
reports to be clinically significant, or readmission, and verified
that outcome measures were sufficiently comparable between
trials compared. Additional outcomes considered included study
withdrawal for any reason as a proxy measure of adherence to
treatment, study withdrawal because of inefficacy, study with-
drawal because of adverse events and adverse events includ
ing extrapyramidal symptoms (EPS), substantial weight gain,
60
abnormally elevated serum glucose concentration, hyperprolacti-
naemia, death and suicide attempts. Relative effect size was based
on categorical outcomes, expressed as odds ratio (OR) with its
95% confidence interval (CI). We also used Surface Under the
Cumulative RAnking curve (SUCRA) values to provide a hier-
archy of efficacy and tolerability of the treatments considered.21
SUCRA is a transformation of the mean rank representing the
probability that a treatment was among the n best treatments,
where n ranges from 1 to the total number of treatments (here
118) in the data network. SUCRA of 1 indicates a treatment is
the most effective and 0 the least effective.
As the network meta-analysis combined both direct and
indirect comparisons to synthesise treatment effects, we assessed
agreement between these two sources of evidence with tests of
inconsistency.22 A loop-specific test evaluates inconsistency in all
closed loops formed by three or four treatments within each
network, by comparing direct with indirect estimates of a specific
treatment effect. A design6treatment interaction model evaluates
whether the network as a whole demonstrates inconsistency, by
evaluating the agreement of evidence generated by trials with
different treatment designs.
We investigated potential sources of heterogeneity among
trials with meta-regression modelling and sensitivity analysis
by taking account of study level characteristics. For meta-
regression, we analysed the impact of follow-up duration (<6,
611 or 12 months), trial setting (in-patient, out-patient or
both), trial quality (presence or absence of high risk of bias in any
of the Cochrane risk of bias domains defined above), funding
source (with or without industry sponsorship) and publication
year (published before or after year 2000). For sensitivity analysis,
we evaluated the impact of excluding trials with shorter follow-up
duration (<6 months), high doses (equivalent of >10 mg/day of
haloperidol) and published before 1980.23 Publication bias was
assessed using comparison-adjusted funnel plot. In the absence of
publication bias, the comparison-adjusted funnel plot is sym-
metric around zero line. This study-specific effect sizes do not
differ from the respective comparison-specific pooled effect
estimates for comparisons between antipsychotic treatments and
placebo.
Results
Description of included studies
Preliminary searching of 32 systematic reviews yielded a total of
186 potentially usable citations of reports of RCTs; another 2054
reports (total of 2477) were identified by direct searching of
electronic databases (Fig. 1). Based on preliminary screening of
abstracts and detailed review of full reports, 56 reports met study
inclusion criteria and were included for analysis, as indicated in
the study network of direct and indirect comparisons (Fig. 2,
reference list in the data supplement). Included trials involved 18
antipsychotic drug products: amisulpride, aripiprazole, chlorpro-
mazine, flupenthixol decanoate (flupenthixol LAI), fluphenazine
decanoate (fluphenazine LAI), haloperidol, haloperidol decanoate
(haloperidol LAI), olanzapine, paliperidone, paliperidone palmi-
tate (paliperidone LAI), pipothiazine palmitate (pipothiazine LAI),
quetiapine, risperidone, risperidone LAI, sulpiride, trifluoperazine,
ziprasidone and zuclopenthixol decanoate (zuclopenthixol LAI). A
total of 10 177 adult participants were represented in the 56 included
trials reported between 1960 and 2014; mean age (range) was 39
(1582) years, and 64% were men. Mean, nominal study duration
was 48 weeks (range 4156). Most trials were conducted in Europe
and American continents; 7% involved Asians. Out-patients were
represented in 29 (52%) trials; in-patients in 10 (18%), both in 10
 Comparative long-term efficacy and safety of antipsychotic treatment

Records (n=2477) identified

Identification through database searching
(n=2291) and reviews (n=186)

Duplicates removed
(n=423)
Screening

Initial screening
of abstracts (n=2054)

Abstracts not meeting

inclusion criteria excluded
(n=1948)
Eligibility

Full-text articles assessed

for eligibility
(n=106)

Full-text articles not meeting

inclusion criteria excluded
(n=50)
Included

Studies included
(n=56)

Fig. 1 Flowchart of selection of reports for inclusion in study-based PRISMA recommendations (www.prisma-statement.org/statement.htm) to yield
56 study reports included in analyses.

(18%), and setting was not reported in another 7 (12%) trials.
Financing was based on pharmaceutical industry support in 23 trials
(41%), public sponsors (11%), no support (25%), and unreported
sponsorship (23%). Definitions of relapse varied: rating scale-based
criteria (23%), hospital admission (15%), combination of rating scale
and hospital admission (23%), clinical worsening of symptoms
(29%), need for a change of medication (5%) and undefined
methods (5%).
Assessment of potential bias
Most trials did not provide details about randomisation proce-
dures and allocation concealment (Fig. DS1). One study (2% of
all reports) had high risk of bias in random sequence generation,
10 (18%) appear to have had adequate sequence generation and
4 (7%) had apparently adequate allocation concealment. Most
studies (47/56, 84%) were nominally double-blind and 21 (38%)
tested and confirmed the success of blinding. In most trials,
relapse represented an end-point leading to discontinuation from
the study; however, drop-out rates were balanced across interven-
tions in most studies (mean (range): 34% (086%)). No evidence
of selective reporting was found in 28 (50%) trials included and
the bias on selective report was judged to be unclear in 20 (36%)
trials because of the unavailability of study protocol. Most selective
reporting (5/8, 63%) was of adverse events, which some investi-
gators reported only when at least 510% of participants were
affected.
Consistency between direct and indirect evidence
Loop-specific tests revealed no significant inconsistency in 17
available loops (formed by three or four treatments) within

61
Zhao et al

Fig. 2 Network of all direct and indirect comparisons between antipsychotics. LAI, long-acting injection.

the data network for relapse prevention (based on the 95%
CI crossing a null value of 1.00). However, the CI was wide
for four of the loops: placebofluphenazine LAItrifluoperazine,
placebochlorpromazinetrifluoperazine, flupenthixol LAIhaloperi
dol LAIzuclopenthixol LAI and olanzapinequetiapine
risperidonerisperidone LAI. Data extraction was checked and there
were no apparent variables that differed across these comparisons.
Based on a design6treatment interaction model, no significant
inconsistency between direct and indirect evidence was identified
within the evidence network as a whole (P=0.14).

Fig. 3. Forest plot for relapse rate of antipsychotics compared with placebo. LAI, long-acting injection; OR, odds ratio.

62
 Comparative long-term efficacy and safety of antipsychotic treatment

PBO 0.25 0.41 0.61 0.21 0.24 0.46 0.16 0.22 0.49 0.18 0.22 0.50 0.31 0.37 0.77 0.74 0.31 0.07
(0.09,0.66) (0.15,1.14) (0.19,1.92) (0.04,0.98) (0.11,0.54) (0.22,0.93) (0.05,0.47) (0.12,0.42) (0.15,1.62) (0.03,0.92) (0.06,0.76) (0.26,0.95) (0.13,0.76) (0.13,1.09) (0.16,3.76) (0.15,3.66) (0.14,0.68) (0.01,0.42)
0.18 AMI 1.64 2.44 0.84 0.98 1.83 0.64 0.89 1.98 0.71 0.87 2.00 1.26 1.50 3.08 2.95 1.23 0.29
(0.07,0.48) (0.42,6.38) (0.55,10.71) (0.14,5.04) (0.28,3.39) (0.81,4.12) (0.16,2.64) (0.38,2.10) (0.42,9.20) (0.11,4.64) (0.18,4.15) (0.76,5.26) (0.46,3.40) (0.29,5.73) (0.57,16.56) (0.48,18.22) (0.46,3.31) (0.04,2.09)
0.24 1.37 ARI 1.48 0.51 0.60 1.11 0.39 0.54 1.20 0.43 0.53 1.22 0.76 0.91 1.87 1.80 0.75 0.18
(0.09,0.66) (0.35,5.37) (0.32,6.89) (0.08,3.18) (0.16,2.17) (0.34,3.68) (0.09,1.69) (0.17, 1.72) (0.25,5.77) (0.06,2.93) (0.11,2.63) (0.41,3.60) (0.21,2.82) (0.33,2.53) (0.29,12.05) (0.27,11.91) (0.21,2.61) (0.02,1.32)
0.31 1.73 1.27 CHL 0.35 0.40 0.75 0.26 0.37 0.81 0.29 0.36 0.82 0.52 0.62 1.26 1.21 0.50 0.12
(0.15,0.64) (0.52,5.78) (0.37,4.36) (0.05,2.37) (0.10,1.63) (0.20,2.80) (0.05,1.29) (0.10,1.33) (0.15,4.26) (0.04,2.18) (0.07,1.96) (0.22,3.04) (0.12,2.15) (0.13,2.95) (0.18,8.75) (0.17,8.67) (0.13,2.02) (0.01,0.97)
0.13 0.74 0.54 0.43 FLX LAI 1.17 2.18 0.77 1.06 2.35 0.84 1.04 2.38 1.49 1.79 3.67 3.52 1.46 0.34
(0.04,0.45) (0.15,3.56) (0.11,2.62) (0.10,1.77) (0.25,5.50) (0.41,11.56) (0.20,2.93) (0.20,5.48) (0.34,16.47) (0.14,5.24) (0.27,4.08) (0.48,11.92) (0.26,8.61) (0.28,11.23) (0.42,32.34) (0.41,30.09) (0.26,8.09) (0.08,1.50)
0.10 0.54 0.40 0.31 0.73 FLZ LAI 1.87 0.66 0.91 2.02 0.72 0.89 2.04 1.28 1.53 3.14 3.01 1.25 0.29
(0.04,0.20) (0.16,1.88) (0.11,1.39) (0.11,0.88) (0.23,2.28) (0.66,5.33) (0.19,2.23) (0.33,2.50) (0.48,8.47) (0.13,4.13) (0.29,2.77) (0.75,5.58) (0.39,4.16) (0.41,5.75) (0.56,17.48) (0.61,14.84) (0.41,3.83) (0.05,1.80)
0.21 1.21 0.88 0.70 1.63 2.23 HAL 0.35 0.49 1.08 0.39 0.48 1.09 0.69 0.82 1.68 1.61 0.67 0.16
(0.11,0.42) (0.51,2.85) (0.28,2.80) (0.27,1.77) (0.41,6.48) (0.82,6.05) (0.10,1.23) (0.29,0.80) (0.27,4.32) (0.07,2.26) (0.12,1.96) (0.52,2.31) (0.37,1.28) (0.25,2.68) (0.38,7.45) (0.30,8.65) (0.30,1.48) (0.02,1.02)
0.15 0.82 0.60 0.47 1.11 1.52 0.68 HAL LAI 1.38 3.07 1.10 1.36 3.11 1.95 2.33 4.79 4.59 1.91 0.45
(0.06,0.35) (0.22,3.03) (0.16,2.24) (0.15,1.48) (0.33,3.75) (0.53,4.31) (0.23,2.00) (0.41,4.69) (0.61,15.39) (0.32,3.81) (0.38,4.89) (0.98,9.88) (0.50,7.61) (0.59,11.00) (0.72,31.69) (0.70,30.28) (0.51,7.07) (0.10,2.00)
0.11 0.60 0.44 0.35 0.81 1.11 0.50 0.73 OLA 2.22 0.80 0.98 2.25 1.41 1.68 3.46 3.32 1.38 0.32
(0.06,0.20) (0.24,1.49) (0.14,1.37) (0.14,0.88) (0.21,3.19) (0.42,2.96) (0.30,0.82) (0.25,2.11) (0.57,8.61) (0.14,4.53) (0.25,3.91) (1.13,4.46) (0.70,2.84) (0.54,5.30) (0.74,16.26) (0.62,17.76) (0.67,2.85) (0.05,2.06)
0.12 0.65 0.48 0.38 0.88 1.21 0.54 0.80 1.09 PAL 0.36 0.44 1.01 0.64 0.76 1.56 2.06 0.62 0.15
(0.04,0.31) (0.16,2.66) (0.12,1.95) (0.11,1.29) (0.18,4.23) (0.35,4.17) (0.17,1.78) (0.21,2.97) (0.34,3.50) (0.05,2.74) (0.08,2.48) (0.26,3.93) (0.14,2.81) (0.15,3.76) (0.21,11.36) (0.23,18.48) (0.15,2.61) (0.02,1.22)
0.19 1.08 0.79 0.62 1.45 1.99 0.89 1.31 1.78 1.64 PAL LAI 1.23 2.82 1.77 2.11 4.34 4.16 1.73 0.41
(0.07,0.50) (0.27,4.28) (0.20,3.15) (0.18,2.08) (0.35,6.07) (0.6106.44) (0.28,2.86) (0.49,3.46) (0.57,5.61) (0.41,6.53) (0.21,7.32) (0.52,15.37) (0.28,11.15) (0.31,14.40) (0.45,41.60) (0.44,39.78) (0.28,11.15) (0.06,2.83)
0.11 0.64 0.47 0.37 0.87 1.19 0.53 0.78 1.07 0.98 0.60 PIP LAI 2.29 1.44 1.72 3.53 3.38 1.40 0.33
(0.04,0.35) (0.14,2.87) (0.10,2.12) (0.10,1.41) (0.31,2.43) (0.45,3.16) (0.15,1.95) (0.24,2.56) (0.30,3.85) (0.22,4.38) (0.15,2.37) (0.59,8.93) (0.32,6.51) (0.34,8.66) (0.49,25.41) (0.50,22.82) (0.32,6.08) (0.06,1.90)
0.21 1.16 0.85 0.67 1.56 2.14 0.96 1.41 1.92 1.77 1.08 1.80 QUE 0.63 0.75 1.54 1.47 0.61 0.14
(0.11,0.39) (0.42,3.23) (0.29,2.49) (0.26,1.75) (0.4076.03) (0.80,5.73) (0.45,2.05) (0.51,3.91) (0.94,3.94) (0.55,5.76) (0.35,3.35) (0.50,6.43) (0.25,1.57) (0.28,2.03) (0.30,7.81) (0.27,8.04) (0.26,1.43) (0.02,0.88)
0.15 0.86 0.63 0.50 1.16 1.59 0.71 1.05 1.43 1.31 0.80 1.33 0.74 RIS 1.20 2.45 2.35 0.98 0.23
(0.07,0.33) (0.32,2.29) (0.19,2.12) (0.18,1.39) (0.27,4.90) (0.54,4.68) (0.42,1.21) (0.33,3.31) (0.78,2.59) (0.37,4.61) (0.23,2.75) (0.34,5.19) (0.32,1.74) (0.33,4.38) (0.49,12.26) (0.40,13.81) (0.38,2.54) (0.03,1.61)
0.17 0.94 0.69 0.54 1.27 1.74 0.78 1.14 1.56 1.44 0.87 1.46 0.81 1.09 RIS LAI 2.05 1.97 0.82 0.19
(0.06,0.47) (0.25,3.58) (0.25,1.87) (0.15,1.90) (0.26,6.21) (0.48,6.22) (0.25,2.41) (0.31,4.29) (0.52,4.72) (0.34,6.01) (0.22,3.55) (0.32,6.64) (0.31,2.15) (0.34,3.57) (0.32,13.20) (0.29,13.27) (0.23,2.85) (0.03,1.45)
0.16 0.90 0.66 0.52 1.22 1.67 0.75 1.10 1.50 1.38 0.84 1.40 0.78 1.05 0.96 SUL 0.96 0.40 0.09
(0.03,0.91) (0.14,5.82) (0.09,4.80) (0.08,3.24) (0.15,10.06) (0.25,10.89) (0.14,3.96) (0.16,7.60) (0.27,8.37) (0.19,10.18) (0.12,6.11) (0.18,10.92) (0.13,4.68) (0.18,5.99) (0.13,6.92) (0.15,6.27) (0.08,2.09) (0.01,0.97)
0.28 1.60 1.17 0.93 2.16 2.96 1.33 1.95 2.66 2.45 1.49 2.49 1.38 1.87 1.71 1.78 TRI 0.42 0.10
(0.06,1.25) (0.28,9.18) (0.20,6.98) (0.21,4.09) (0.33,14.17) (0.60,14.55) (0.28,6.36) (0.36,10.73) (0.55,12.82) (0.41,14.51) (0.26,8.69) (0.41,15.20) (0.28,6.84) (0.37,9.49) (0.28,10.25) (0.25,12.74) (0.07,2.040) (0.01,1.00)
0.13 0.74 0.54 0.43 1.00 1.37 0.62 0.91 1.24 1.14 0.69 1.16 0.64 0.87 0.79 0.83 0.46 ZIP 0.23
(0.06,0.31) (0.25,2.25) (0.15,1.95) (0.14,1.28) (0.23,4.39) (0.45,4.24) (0.26,1.46) (0.27,2.99) (0.55,2.76) (0.31,4.13) (0.19,2.48) (0.29,4.66) (0.25,1.64) (0.34,2.24) (0.22,2.81) (0.13,5.24) (0.09,2.48) (0.03,1.59)
0.05 0.31 0.22 0.18 0.41 0.57 0.25 0.37 0.51 0.47 0.29 0.48 0.27 0.36 0.33 0.34 0.19 0.41 ZUC LAI
(0.01,0.38) (0.03,2.71) (0.03,2.00) (0.02,1.42) (0.08,2.27) (0.08,3.91) (0.03,1.98) (0.06,2.47) (0.07,3.92) (0.05,4.15) (0.04,2.24) (0.07,3.21) (0.03,2.01) (0.04,2.89) (0.04,2.93) (0.03,4.59) (0.02,2.15) (0.05,3.40)

Fig. 4. Relapse rate and discontinuation because of all reasons for all antipsychotics.
AMI, amisulpride; ARI, aripiprazole; CHL, chlorpromazine; FLX, flupenthixol decanoate; FLZ, fluphenazine decanoate; HAL, haloperidol; LAI, long-acting injection; OLA, olanzapine; PAL,
paliperidone; PBO, placebo; PIP, pipothiazine palmitate; QUE, quetiapine; RIS, risperidone; SUL, sulpiride; TRI, trifluoperazine; ZIP, ziprasidone; ZUC, zuclopenthixol decanoate.

Efficacy ranked by their SUCRA values were zuclopenthixol LAI (0.85),

All antipsychotic treatments were significantly better than placebo fluphenazine LAI (0.78), olanzapine (0.76), pipothiazine LAI (0.68)
for relapse prevention, with the single and surprising exception of and paliperidone (0.67). Findings for relapse prevention were
trifluoperazine. However, most CIs overlapped between treatments consistent when we analysed oral and long-acting agents separately
so that few comparisons were different in statistical significance (Fig. DS2).
(Figs. 3 and 4). Olanzapine was significantly more effective than Fourteen trials (2886 participants) were included for the
chlorpromazine (OR=0.35, 95% CI 0.140.88) and haloperidol network meta-analysis of hospital admissions. Oral agents includ-
(OR=0.50, 95% CI 0.300.82) in reducing relapses, and fluphenazine ing amisulpride, haloperidol, olanzapine, quetiapine and ziprasi-
LAI was superior to chlorpromazine (OR=0.31, 95% CI done were significantly more effective in reducing readmissions
0.110.88; Fig. 4). Differences between other pairs of drugs were than placebo, but aripiprazole, chlorpromazine, paliperidone,
minor and not significant. We also evaluated hierarchies of efficacy trifluoperazine did not differ from placebo (Fig. DS3). There was
on the basis of SUCRA rankings for relapse rate. The top five drugs a lack of data on hospital admission rates with long-acting agents

PBO
0.99 AMI
(0.50,1.97)
0.87 0.88 ARI
(0.38,1.98) (0.34,2.24)
1.28 1.29 1.47 CHL
(0.67,2.43) (0.53,3.16) (0.51,4.19)
1.53 1.54 1.76 1.20 FLX LAI
(0.20,11.54) (0.18,13.04) (0.20,15.52) (0.14,10.00)
4.63 4.68 5.32 3.62 3.03 FLZ LAI
(1.22,17.51) (1.05,20.87) (1.12,25.34) (0.82,15.91) (0.32,28.55)
2.34 2.36 2.69 1.83 1.53 0.51 HAL
(1.28,4.29) (1.50,3.71) (1.10,6.57) (0.80,4.21) (0.19,12.60) (0.12,2.18)
6.02 6.08 6.91 4.71 3.93 1.30 2.57 HAL LAI
(1.71,21.19) (1.45,25.47) (1.54,30.96) (1.14,19.44) (0.81,19.12) (0.26,6.39) (0.64,10.39)
0.51 0.51 0.58 0.40 0.33 0.11 0.22 0.08 OLA
(0.26,0.97) (0.29,0.89) (0.23,1.45) (0.16,0.97) (0.04,2.76) (0.02,0.48) (0.14,0.33) (0.02,0.35)
2.40 2.43 2.76 1.88 1.57 0.52 1.03 0.40 4.75 PAL
(0.86,6.67) (0.71,8.30) (0.74,10.23) (0.56,6.28) (0.16,15.11) (0.10,2.78) (0.31,3.37) (0.08,2.02) (1.41,16.00)
2.89 2.92 3.32 2.26 1.89 0.63 1.24 0.48 5.73 1.21 PAL LAI
(0.95,8.82) (0.79,10.81) (0.83,13.25) (0.62,8.21) (0.34,10.63) (0.13,2.95) (0.35,4.40) (0.24,0.96) (1.58,20.84) (0.27,5.47)
4.66 4.70 5.35 3.64 3.05 1.01 1.99 0.77 9.22 1.94 1.61 PIP LAI
(0.97,22.26) (0.85,25.94) (1.12,25.34) (0.67,19.88) (0.41,22.76) (0.20,5.06) (0.37,10.65) (0.22,2.68) (1.70,50.07) (0.30,12.57) (0.41,6.27)
0.69 0.70 0.80 0.54 0.45 0.15 0.30 0.12 1.37 0.29 0.24 0.15 QUE
(0.39,1.24) (0.37,1.32) (0.37,1.70) (0.23,1.26) (0.06,3.72) (0.04,0.64) (0.16,0.53) (0.03,0.46) (0.73,2.59) (0.09,0.94) (0.07,0.84) (0.03,0.79)
0.96 0.97 1.10 0.75 0.63 0.21 0.41 0.16 1.90 0.40 0.33 0.21 1.38 RIS
(0.49,1.88) (0.56,1.67) (0.43,2.79) (0.31,1.84) (0.07,5.25) (0.05,0.92) (0.29,0.58) (0.04,0.66) (1.27,2.83) (0.12,1.35) (0.09,1.21) (0.04,1.12) (0.72,2.65)
1.19 1.21 1.37 0.93 0.78 0.26 0.51 0.20 2.36 0.50 0.41 0.26 1.72 1.25 RIS LAI
(0.55,2.58) (0.51,2.85) (0.80,2.36) (0.35,2.52) (0.09,6.78) (0.06,1.20) (0.23,1.16) (0.05,0.87) (1.01,5.52) (0.14,1.79) (0.11,1.60) (0.04,1.46) (0.92,3.23) (0.53,2.05)
7.38 7.45 8.47 5.77 4.82 1.59 3.15 1.23 14.61 3.07 2.55 1.58 10.64 7.71 6.18 TRI
(1.51,21.19) (1.34,41.46) (1.41,50.86) (1.23,27.17) (0.37,63.21) (0.20,12.68) (0.59,17.00) (0.16,9.34) (2.64,80.88) (0.46,20.33) (0.37,17.78) (0.17,14.78) (1.97,57.29) (1.39,42.81) (1.06,36.01)
1.45 1.46 1.66 1.13 0.95 0.31 0.62 0.24 2.86 0.60 0.50 0.31 2.09 1.51 1.21 0.20 ZIP
(0.20,2.92) (0.77,2.79) (0.64,4.33) (0.45,2.86) (0.11,8.02) (0.07,1.41) (0.34,1.14) (0.06,1.02) (1.51,5.44) (0.17,2.08) (0.13,1.87) (0.06,1.72) (1.06,4.12) (0.78,2.94) (0.50,2.95) (0.03,1.11)
2.68 2.70 3.07 2.09 1.75 0.58 1.14 0.44 5.30 1.11 0.92 0.57 3.86 2.80 2.24 0.36 1.85 ZUC LAI
(0.49,14.49) (0.44,16.72) (0.47,20.05) (0.34,12.80) (0.58,5.31) (0.08,4.06) (0.19,6.88) (0.14,1.37) (0.87,32.33) (0.15,8.02) (0.25,3.47) (0.11,3.08) (0.65,23.03) (0.45,17.18) (0.35,14.33) (0.04,3.70) (0.30,11.51)

Fig. 5. Extrapyramidal symptoms in the context of antipsychotic use.

AMI, amisulpride; ARI, aripiprazole; CHL, chlorpromazine; FLX, flupenthixol decanoate; FLZ, fluphenazine decanoate; HAL, haloperidol; LAI, long-acting injection; OLA, olanzapine; PAL,
paliperidone; PBO, placebo; PIP, pipothiazine palmitate; QUE, quetiapine; RIS, risperidone; SUL, sulpiride; TRI, trifluoperazine; ZIP, ziprasidone; ZUC, zuclopenthixol decanoate.

63
Zhao et al
except for fluphenazine LAI and risperidone LAI, which both
reduced readmission risk more than placebo. In reducing read-
mission, olanzapine and ziprasidone were significantly more
effective than haloperidol or quetiapine; amisulpride, fluphenazine
LAI, haloperidol, olanzapine, risperidone LAI and ziprasidone all
were superior to aripiprazole, and ziprasidone alone outperformed
chlorpromazine and trifluoperazine.
Safety and tolerability
Most drugs were less associated with all-cause discontinuation
than placebo, except for aripiprazole, chlorpromazine, paliperi-
done, risperidone LAI, sulpiride and trifluoperazine. In general,
long-acting agents tended to be better tolerated than oral agents,
but not statistically significant (Fig. 4). Olanzapine was associated
with less all-cause discontinuation than quetiapine (OR=0.44, 95%
CI 0.220.88) or haloperidol (OR=0.49, 95% CI 0.290.80),
whereas zuclopenthixol LAI yielded less all-cause discontinua
tion than chlorpromazine (OR=0.12 (0.010.97)), quetiapine
(OR=0.14 (0.020.88)) or sulpiride (OR=0.09 (0.010.97)). In
separate analyses of discontinuation because of lack of efficacy or
adverse events, most antipsychotics demonstrated lower disconti-
nuation rates because of lack of efficacy compared with placebo,
whereas no drug demonstrated a significant difference in disconti-
nuation rates because of adverse events in comparison with placebo
(Fig. DS4).
Thirty trials (7381 participants) were included for the analysis
of EPS. Only fluphenazine LAI, haloperidol, haloperidol LAI
and trifluoperazine, but not other antipsychotics, were associated
with more reported EPS than placebo (Fig. 5). Olanzapine
was associated with less risk of EPS than other agents except
aripiprazole, flupenthixol LAI, quetiapine and zuclopenthixol LAI.
As expected, quetiapine had less reported EPS than fluphenazine
LAI, haloperidol, haloperidol LAI, paliperidone, paliperidone LAI,
pipothiazine LAI, trifluoperazine and ziprasidone. Fluphenazine
LAI, haloperidol, haloperidol LAI and trifluoperazine were
associated with significantly more EPS than several other agents.
Only 15 trials (5147 participants) were synthesised for weight
gain. Olanzapine produced significantly more weight gain than
amisulpride, haloperidol, quetiapine, risperidone, ziprasidone and
placebo. Ziprasidone was associated with less weight gain than
amisulpride, quetiapine and risperidone (Fig. DS5).
Amisulpride, haloperidol, olanzapine, quetiapine, ziprasidone
and paliperidone LAI were not associated with higher rate of
glucose intolerance than placebo or as compared with each other.
Aripiprazole, paliperidone and paliperidone LAI did not lead to
more hyperprolactinaemia than placebo, whereas amisulpride,
risperidone and risperidone LAI produced hyperprolactinaemia
more often than haloperidol, olanzapine, quetiapine or ziprasi-
done (Fig. DS6). Additionally, we found no differences between
antipsychotics and placebo or among antipsychotics in terms of
death or suicide attempt (Fig. DS7).
Meta-regression analysis and sensitivity analysis
Treatment effects in reducing relapse rate did not differ signifi-
cantly (P>0.05) with length of follow-up, trial setting, quality of the
trials, funding source and publication year as assessed in network
meta-regressions. When analysing the association between relapse
rate and trial duration regardless of the treatment administered,
we found that relapse rate was strongly related to nominal
trial duration (t=6.00, P<0.0001). Accordingly, we carried out a
sensitivity analysis that excluded trials with nominal trial follow-up
for <6 months, the difference in relapse prevention between
fluphenazine LAI and chlorpromazine became insignificant (OR=
0.39, 95% CI 0.121.21). Other treatments except sulpiride
excluded from the analysis as its two trials involved brief exposures
64
demonstrated a consistent trend in reducing relapse rate compared
with the primary analysis (Fig. DS8a). By excluding trials with
relatively high doses of haloperidol (>10 mg/day), the treatment
effects in relapse prevention remained largely unchanged (Fig.
DS8b). By excluding trials published before 1980, sulpiride and
trifluoperazine were excluded from the analysis and other treat-
ments demonstrated a consistent trend in preventing relapse
compared with the primary analysis (Fig. DS8c). There was no
evidence of publication bias given that comparison-adjusted funnel
plot was symmetric around the zero line (Fig. DS9).
Discussion
This study compared effectiveness of 18 antipsychotics in
preventing relapses among initially stable patients with schizo-
phrenia and provided evidence-based hierarchies using network
meta-analysis. This method can extend existing data derived from
traditional pairwise meta-analyses and help to overcome limited
availability of head-to-head comparisons of most psychotropic
treatments.15 The present findings support the conclusion that
maintenance treatment with most clinically available antipsycho-
tics reduced relapse rate in patients with schizophrenia over time,
averaging 1 year. Olanzapine was significantly more effective than
chlorpromazine or haloperidol, and fluphenazine decanoate
yielded significant lower relapse rate than chlorpromazine. Of
the top five drugs, ranked by their SUCRA values for relapse
prevention, three were LAI preparations: fluphenazine decanoate,
olanzapine, paliperidone, pipothiazine palmitate and zuclo-
penthixol decanoate. These findings corroborate the results of
earlier reviews which found olanzapine to be significantly superior
to older, typical antipsychotic agents in relapse prevention within
schizophrenia,7 and found fluphenazine decanoate to be more
effective than several oral antipsychotics.11 Although zuclo-
penthixol decanoate was associated with apparently particularly
favourable effects on relapse prevention, it did not differ
statistically from other agents, based on findings of only two trials
involving fewer than 40 participants per trial.24,25 Additionally, the
apparent superiority of sulpiride and inferiority of trifluoperazine
compared with placebo need to be interpreted with caution
because of relatively wide CIs associated with their treatment
effects.
With respect to readmission rates, olanzapine was also found
to be significantly more effective than aripiprazole, haloperidol or
quetiapine. Also, ziprasidone was associated with lower read-
mission rates than aripiprazole, chlorpromazine, haloperidol,
quetiapine or trifluoperazine, which were consistent with other
evidence of superiority of ziprasidone to some first-generation
antipsychotics, at least, in preventing readmission.7
LAI agents tended generally to be less likely to be discontinued
prematurely for all causes (intolerability or inefficacy) than
oral antipsychotics, but most of these comparisons were not
statistically significant. However, zuclopenthixol decanoate was
significantly less associated with all-cause discontinuation than
quetiapine or trifluoperazine, but it is not clear whether these
differences reflect superior benefit or better tolerability. Similarly,
olanzapine had significantly lower all-cause discontinuation rates
than other agents including haloperidol and quetiapine. As
expected, most drugs were associated with less discontinuation
because of lack of efficacy than placebo but such differences were
not sustained for adverse events.
In general, as expected, older, typical antipsychotics were
associated with more EPS than modern, atypical agents or
placebo.7 However, this association was driven by only some
antipsychotics: fluphenazine decanoate, haloperidol, haloperidol

decanoate and trifluoperazine, whereas others, including chlor-
promazine, flupenthixol decanoate, pipothiazine palmitate and
zuclopenthixol decanoate, were not associated with more EPS than
placebo. Among atypical antipsychotics, olanzapine and quetia-
pine had less risk of EPS than most other modern agents
evaluated. However, atypical agents, on average, and especially
olanzapine, produced more weight gain than placebo. Olanzapine
also produced significantly more weight gain than amisulpride,
haloperidol, quetiapine, risperidone and ziprasidone, whereas
ziprasidone was associated with less weight gain than amisulpride,
quetiapine and risperidone. These findings accord with previous
research indicating that olanzapine and quetiapine have low risks
of EPS, but are more likely to lead to weight gain and metabolic
syndrome,26 whereas ziprasidone had relatively low risks of both
EPS and weight gain.27
Amisulpride, aripiprazole, haloperidol, paliperidone, paliper-
idone palmitate, quetiapine and ziprasidone were associated with
similarly low rates of hyperglycaemia as with placebo. Risk of
hyperprolactinaemia was highest with amisulpride, risperidone
and risperidone LAI, consistent with previous reviews.28,29 Also,
there were no significant differences among drugs or between
antipsychotics and placebo in rates of suicidal behaviours or death
from all causes, although studies with such information were few
and their duration averaged less than a year. Finally, treatment
discontinuation, in turn, represents a major contribution to risk of
relapse, readmission and poor clinical outcomes in psychotic
disorders.810
This is the first study using network meta-analysis to compare
the comparative efficacy and tolerability of antipsychotic mono-
therapy aimed at reducing rates of relapse or readmission in
patients diagnosed with schizophrenia. The method of network
meta-analysis can overcome the lack of head-to-head clinical trials
in the search for evidence-based hierarchies of comparative
treatment effects, provided that the underlying assumptions
(notably very close similarity of compared trials) of the method
are met.16 We considered 18 antipsychotic drug preparations that
are commonly used internationally for maintenance treatment of
patients with schizophrenia, and considered several outcome
measures related to relapse, including risk of psychiatric hospital
admission, which is one of the main contributors to the cost of
care in schizophrenia. We also compared drugs for their risks of
early discontinuation because of various causes, as well as for
adverse events severe enough to produce treatment discontinua-
tion and which tend to counterbalance the benefits of treatment.
The results of this study should be interpreted in the context of
its limitations. It is difficult with any data network investigating
indirect drugdrug comparisons by network meta-analytic meth-
ods to consistently compare perfectly matched trials. In the present
analyses, notably the range of treatment exposure time ranged
from 1 month to 2 years, criteria for relapse varied greatly among
trials and were not always matched in the comparisons reported. In
addition, 44% (8/18) of the agents were represented in only 23
trials and placebo controls were available for only 45% (25/56) of
trials. Less certain is how broadly the present findings might
pertain to different types of typically heterogeneous patients with
chronic psychotic disorders that meet standard diagnostic criteria
for schizophrenia. That is, it was not possible with the available
data to consider potential effects of such clinical factors as age at
onset or current age, years of illness, rates of previous hospital
admission, diagnostic subtypes, prominence of particular symp-
toms, cognitive and social impairment or other functional
measures, or even to compare changes in standardised symptom
rating scales. Individuals also tend to be more adherent in clinical
trials than real-world setting that may diminish the difference
between oral and long-acting antipsychotics. Therefore, caution
Comparative long-term efficacy and safety of antipsychotic treatment
needs to be taken when we interpret the relative effectiveness
between oral and long-acting antipsychotics. Most adverse effects
reported appear to have arisen from typically passive and
incidental reports rather than deliberate, systematic and protocol-
guided assessments. Moreover, the findings on adverse events such
as glucose intolerance, hyperprolactinaemia and death or suicide
attempt need to be interpreted with caution given the limited
amount of evidence available. Ideally, a larger and more detailed
data-set would allow better examination of their relative effects. It
must be pointed out, however, that most of these limitations are
found in similar reviews and meta-analyses, be they pairwise or
network meta-analyses.
In conclusion, relatively minor differences in relapse preven-
tion were observed among most antipsychotics, although olanza-
pine and fluphenazine decanoate were associated with particularly
lower relapse rates. These relative apparent benefits need to be
weighed against the risks of adverse effects of all antipsychotic
drugs, notably of weight gain and metabolic syndrome with
olanzapine, and EPS with fluphenazine decanoate.
Ying Jiao Zhao, PhD, Liang Lin, MSc (IHTA), Monica Teng, MHSc, Ai Leng Khoo,
PhD, Pharmacy and Therapeutics Office, Group Corporate Development, National
Healthcare Group, Singapore, Singapore; Lay Beng Soh, BPharm, Department of
Pharmacy, Institute of Mental Health, Singapore, Singapore; Toshiaki A. Furukawa,
MD, Department of Health Promotion and Human Behavior, Graduate School of
Medicine, Kyoto University, Kyoto, Japan; Department of Clinical Epidemiology,
Graduate School of Public Health, Kyoto University, Kyoto, Japan; Ross J. Baldessarini,
MD, Department of Psychiatry, Harvard Medical School, Boston, Massachusetts, USA,
International Consortium for Psychotic and Mood Disorders Research, McLean
Hospital, Belmont, Massachusetts, USA; Boon Peng Lim, BPharm, Pharmacy and
Therapeutics Office, Group Corporate Development, National Healthcare Group,
Singapore, Singapore; Kang Sim, MBBS, MMed (Psychiatry), FAMS, Department of
General Psychiatry, Institute of Mental Health, Singapore, Singapore; Yong Loo Lin
School of Medicine, National University of Singapore, Singapore, Singapore
Correspondence: Ying Jiao Zhao, 3 Fusionopolis Link, #03-08 Nexus@one-north,
Singapore 138543. Email: ying_jiao_zhao@nhg.com.sg
First received 9 Dec 2015, accepted 13 Dec 2015
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