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Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.
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Int J Neuropsychopharmacol. 2013 July ; 16(6): 1205–1218. doi:10.1017/S1461145712001277.
Efficacy and Safety of Individual Second-Generation vs First-

Generation Antipsychotics in First Episode Psychosis: A
Systematic Review and Meta-analysis
Jian-Ping Zhang, MD, PhD1, Juan A. Gallego, MD1,2, Delbert G. Robinson, MD1,3,4, Anil K.
Malhotra, MD1,2,3,4, John M. Kane, MD1,2,3,4, and Christoph U. Correll, MD1,2,3,4
1The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health
System, Glen Oaks, New York, USA

2Albert Einstein College of Medicine, Bronx, New York, USA
3The Feinstein Institute for Medical Research, Manhasset, New York, USA
4Hofstra North Shore LIJ School of Medicine, Hempstead, NY
Abstract
Because early treatment choice is critical in first episode schizophrenia-spectrum disorders (FES),
this meta-analysis compared efficacy and tolerability of individual second-generation
antipsychotics (SGAs) with first-generation antipsychotics (FGAs) in FES. We conducted
systematic literature search (until 12/31/2010) and meta-analysis of acute, randomized trials with
≥1 FGA vs. SGA comparison; patients in their first episode of psychosis and diagnosed with
schizophrenia-spectrum disorders; available data for psychopathology change, treatment response,
treatment discontinuation, adverse effects, or cognition. Across 13 trials (n=2,509), olanzapine (7
trials) and amisulpride (1 trial) outperformed FGAs (haloperidol: 9/13 trials) in 9/13 and 8/13
efficacy outcomes, respectively, risperidone (8 trials) in 4/13, quetiapine (1 trial) in 3/13, and
clozapine (2 trials) and ziprasidone (1 trial) in 1/13, each. Compared to FGAs, EPS-related
outcomes were less frequent with olanzapine, risperidone and clozapine, but weight gain was
greater with clozapine, olanzapine and risperidone. Pooled SGAs were similar to FGAs regarding
total psychopathology change, depression, treatment response, and metabolic changes. SGAs
significantly outperformed FGAs regarding lower treatment discontinuation, irrespective of cause,
negative symptoms, global cognition, and less EPS and akathisia, while SGAs increased weight
Corresponding author: Christoph U. Correll, MD, Division of Psychiatry Research, The Zucker Hillside Hospital, 75-59 263rd Street,
Glen Oaks, NY 11004, ccorrell@lij.edu.
Financial Disclosures/Conflict of Interests:
Dr. Zhang has received grant support from the National Alliance for Research in Schizophrenia and Depression (NARSAD) and the
National Institute of Mental Health (1K23MH097108-01).
Dr. Gallego has nothing to disclose.
Dr. Robinson has been a consultant for Asubio. He has received grant support from Bristol-Myers Squibb, Janssen, the National
Institute of Health and the NARSAD.
Dr. Malhotra has been a consultant and/or advisor to or has received honoraria from: Eli Lilly, Schering-Plough/Merck, Sunovion,
Genomind, and Shire. He has received grant support from the National Institute of Mental Health and the NARSAD.
Dr. Kane has been a consultant to Astra-Zeneca, Janssen, Pfizer, Eli Lilly, Bristol-Myers Squibb, Dainippon Sumitomo/Sepracor/
Sunovion, Johnson & Johnson, Otsuka, Vanda, Proteus, Takeda, Targacept, IntraCellular Therapies, Merck, Lundbeck, Novartis
Roche, Rules Based Medicine, Sunovion and has received honoraria for lectures from Otsuka, Eli Lilly, Esai, Boehringer-Ingelheim,
Bristol-Myers Squibb, and Janssen. He has received grant support from The National Institute of Mental Health.
Dr. Correll has been a consultant and/or advisor to or has received honoraria from: Actelion, Alexza; AstraZeneca, Biotis, Bristol-
Myers Squibb, Cephalon, Desitin, Eli Lilly, GSK, IntraCellular Therapies, Lundbeck, Medavante, Medscape, Merck, Novartis, Ortho-
McNeill/Janssen/J&J, Otsuka, Pfizer, ProPhase, and Sunovion. He has received grant support from BMS, Feinstein Institute for
Medical Research, Janssen/J&J, National Institute of Mental Health (NIMH), National Alliance for Research in Schizophrenia and
Depression (NARSAD), and Otsuka.
Zhang et al. Page 2
more (p’s<0.05-0.01). Results were not affected by FGA dose or publication bias, but industry-
sponsored studies favored SGAs more than federally funded studies. To summarize, in FES,
olanzapine, amisulpride and, less so, risperidone and quetiapine showed superior efficacy, greater
treatment persistence and less EPS than FGAs. However, weight increase with olanzapine,
risperidone and clozapine and metabolic changes with olanzapine were greater. Additional FES
studies including broader-based SGAs and FGAs are needed.
Keywords
Schizophrenia; First Episode; First-generation Antipsychotics; Second-generation antipsychotics;
Meta-analysis
Introduction
Schizophrenia is a chronic, debilitating mental disorder(van Os and Kapur, 2009) with a life-
time prevalence of 0.30–0.66%, increasing to 2.3% when including other psychotic
disorders(Perala et al., 2007). Schizophrenia is associated with significant medical co-
morbidity and mortality, with an average life-span shortening by 10–30 years(Goff et al.,
2005). Illness onset typically occurs in late adolescence/young adulthood and life-time
treatment is required to maintain/improve social functioning and prevent symptom relapse,
which causes significant public health and economic burden. Successful first episode
schizophrenia (FES) treatment is crucial to minimize social and vocational
deterioration(Robinson et al., 2004).
Antipsychotics are the mainstay of schizophrenia treatment(Kane, 1999; van Os and Kapur,
2009). Typical or first-generation antipsychotics (FGAs) and atypical or second-generation
antipsychotics (SGAs) are effective for positive symptoms. However, as a class, FGAs cause
more extrapyramidal motor side effects (EPS) and tardive dyskinesia (TD) than SGAs,
whereas SGAs generally cause more weight gain and cardiometabolic adverse
effects(Leucht et al., 2009). Recent large randomized controlled trials (RCTs)(Jones et al.,
2006; Lieberman et al., 2005) and a meta-analysis(Leucht et al., 2009) of FGA vs. SGA
RCTs in chronic schizophrenia suggested no significant efficacy/effectiveness differences,
or few non-clozapine SGA advantages with effect size differences of only 0.1–0.3.
However, RCTs in chronic schizophrenia have limitations, including confounding effects of
prior medication use, possible over-representation of only partially responsive or treatment
non-adherent patients, and a tendency of recruiting patients with low pre-study functioning
levels, potentially reducing overall treatment responsiveness. Conversely, some trials might
enroll more responsive patients consenting to RCTs.
Compared to chronic patients, FES patients generally have higher response rates(Robinson
et al., 1999; Tohen et al., 2000), require lower antipsychotic doses, and are more sensitive to
adverse effects(Robinson et al., 2005). Hence, FES studies offer the unique opportunity to
examine antipsychotic therapeutic and adverse effects in more representative patients in
whom important initial treatment effects take place. Since in FES patients, therapeutic and
adverse response patterns are largely unknown, treatment recommendations must be based
upon research findings, rather than past treatment history. RCTs in FES have flourished in
the past decade. However, there is still a debate regarding the comparative efficacy and
effectiveness of FGAs vs. SGAs, because studies have yielded discrepant results. A recent
meta-analysis of FES trials(Crossley et al., 2010) showed no difference in efficacy between
FGAs and SGAs. However, this meta-analysis included one non-randomized trial(Saddichha
et al., 2007), failed to compare individual SGAs, investigated only two adverse effects and

Zhang et al. Page 3
ignored important outcomes, including positive and negative symptoms, depression,

cognitive functioning, specific-cause discontinuation, long-term remission and relapse.
Therefore, we conducted a meta-analysis comparing the efficacy, effectiveness, and adverse

effects of primarily individual and secondarily pooled SGAs vs. FGAs in FES patients.
Methods
Search
We conducted an electronic PubMed and Web of Science search (until 12/31/2010) for
RCTs comparing FGAs vs. SGAs in first-episode patients with schizophrenia-spectrum
disorders. The following key words were used: first episode, first episode psychosis, first
episode schizophrenia, early psychosis, early schizophrenia, recent onset, recent onset
psychosis, recent onset schizophrenia, antipsychotic(s), typical antipsychotic(s),
conventional antipsychotic(s), neuroleptic(s), atypical antipsychotic(s), first-generation and
second-generation antipsychotic(s). We also screened reference lists from identified papers
and reviews to identify additional studies. To find unpublished studies, we searched
published meeting abstracts that were likely to contain relevant studies and contacted
manufacturers of SGAs. Inclusion criteria were: 1) RCT with ≥1 FGA vs. SGA comparison;
2) patients in their first episode of non-affective psychosis; 3) diagnosis of schizophrenia,
schizoaffective disorder, schizophreniform disorder, brief psychotic disorder, or psychosis
NOS; 4) Data available for any of the following outcomes: efficacy, treatment
discontinuation, weight gain, metabolic parameters, or cognition; 5) Acute treatment study.
Maintenance studies were excluded, although long-term data from acute RCTs were
included.
Data extraction and outcome variables

Data were independently extracted by two authors (JPZ, JAG); any disagreement was
resolved. For missing information, first and/or last study authors were contacted requesting
additional/unpublished data. Short-term outcomes at 3 months (≤13 weeks) or closest
follow-up time point, and long-term outcomes at about 6–24 months were analyzed
separately. Primary variables included the following three short-term outcomes: 1) all-cause
discontinuation; 2) symptom reduction: changes in the Positive and Negative Syndrome
Scale (PANSS)(Kay et al., 1987) or Brief Psychiatric Rating Scale (BPRS)(Overall and
Gorham, 1962) total score from baseline; and 3) response rate: percentage of patients
achieving “clinical responder” status at follow-up. We chose ≥50% reduction in PANSS or
BPRS total scores from baseline to follow-up as the preferred definition of clinical response,
because this represents a clinically significant response(Leucht et al., 2007). When this
outcome was not available, study-defined response was used.
Secondary outcomes included last-observation-carried-forward (LOCF) change from

baseline in: 1) positive symptoms, measured by PANSS, Scale for the Assessment of
Positive Symptoms (SAPS)(Andreason, 1984), or BPRS; 2) negative symptoms, measured
by PANSS or Scale for the Assessment of Negative Symptoms (SANS)(Andreason, 1983);
3) depressive symptoms, measured by a validated depression scale; 4) Clinical Global
Impressions (CGI)-Severity or Improvement(Guy, 1976) score; 5) cognitive functioning,
measured by a composite score extracted from multiple neuropsychological tests.
Categorical outcomes included: 6) discontinuation due to inefficacy; 7) discontinuation due
to intolerability; 8) discontinuation due to non-adherence/patient choice; 9) study-defined
long-term (≥1 year) remission; and 10) long-term study-defined relapse and/or
rehospitalization after achieving response. We also analyzed common side effects: 11) EPS;
12) akathisia; 13) use of anticholinergic drugs, benzodiazepines and beta-blockers,

Zhang et al. Page 4
commonly used to manage antipsychotic side effects; 14) weight gain, as categorical and
continuous variables; and 15) metabolic changes (total cholesterol, triglycerides, glucose).
The following study and patient characteristics were examined as moderators in meta-
regression analyses: publication year, number of sites, blinding status, study duration,
location (US, Europe, Asia, etc.), primary follow-up time point, study sponsorship
(government-sponsored vs. industry-sponsored), sample size, mean age, percentage of
males, inpatient vs. outpatient status at randomization, age at illness onset, duration of
psychosis, diagnosis, percentage of antipsychotic-naïve patients (i.e., <2 weeks of lifetime
exposure), baseline PANSS/BPRS total score, baseline CGI-S score, and mean or modal
antipsychotic dose (converted to haloperidol equivalents)(Andreasen et al., 2010; Lehman et
al., 2004; Woods, 2003).
Statistical analysis
Outcomes were analyzed separately using Comprehensive Meta-Analysis software version 2
(Biostat, Eaglewood, NJ). For continuous outcomes, Hedge’s g was used as the effect size
measure, representing standardized groups differences. For dichotomous outcomes, risk
ratio (RR) was used as the effect size measure with FGAs as the reference group. The
primary focus was individual drug comparisons. Pooled SGA-FGA comparisons were
conducted to allow for meaningful moderator analyses across two antipsychotic classes that
were contrasted in the literature before. Pooled effect sizes were computed with a random
effects model(Borenstein et al., 2009). In each meta-analysis, a study was included only
once to avoid redundancy. If a study had multiple eligible comparisons, the average effect
size was used in the FGA-SGA comparison. For individual antipsychotic comparisons, the
FGA comparator was entered separately for each SGA.
Study heterogeneity was assessed using Q and I2 statistics, with I2 <25% representing low,
~50% moderate, and >75% representing high heterogeneity(Borenstein et al., 2009).
Whenever heterogeneity was present, moderator and meta-regression analyses were
conducted to explore the effects of the moderators described above. Sensitivity analyses
were conducted to assess potential influences of any one single study on the pooled effect
size. Within each meta-analysis, included studies were removed one at a time to check for
significant alterations to pooled effect sizes and associated p-values. Moreover, we assessed
for an influence of sponsorship bias (government vs industry) and of age group (in- or
excluding the only trial conducted in adolescents, i.e., TEOSS(Sikich et al., 2008)).
Publication bias was assessed with the funnel plot, Egger’s regression test(Egger et al.,
1997), and the “Trim and Fill” method(Duval and Tweedie, 2000), an iterative procedure to
assess whether small, extreme included studies and/or potentially unincluded studies biased
the true effect size estimate.
Results
Search and Study Characteristics
Of 776 hits, 22 papers reporting on 13 independent cohorts(Crespo-Facorro et al., 2006; de
Haan et al., 2003; Emsley, 1999; Fagerlund et al., 2004; Kahn et al., 2008; Lee et al., 2007;
Lieberman et al., 2003a; Lieberman et al., 2003b; Moller et al., 2008; Sanger et al., 1999;
Schooler et al., 2005; Sikich et al., 2008; Wu et al., 2006) and 20 comparisons across 12
individual SGA-FGA pairs (n=2,509) were identified (Fig S1) and meta-analyzed. Three
trials included in a prior meta-analysis on this topic(Crossley et al., 2010) were excluded due
to non-randomized design(Saddichha et al., 2008), skewed data(Brewer et al., 2007) and
absence of meta-analyzable data(Bustillo et al., 2008). The mean study duration was
32.1±36.6 (range: 6–104) weeks, mean age was 27.1 years, 69.5% were male, and the mean

Zhang et al. Page 5
baseline PANSS total score was 85.8±8.8 (Table S1). Five studies each compared
olanzapine vs. haloperidol(Crespo-Facorro et al., 2006; de Haan et al., 2003; Kahn et al.,
2008; Lieberman et al., 2003b; Sanger et al., 1999), risperidone vs. haloperidol(Crespo-
Facorro et al., 2006; Emsley, 1999; Lee et al., 2007; Moller et al., 2008; Schooler et al.,
2005). The other 10 SGA-FGA comparisons were examined in one study each.
Nine studies (69%) were double-blinded, four were open label(Crespo-Facorro et al., 2006;
Fagerlund et al., 2004; Kahn et al., 2008; Wu et al., 2006). Eight studies (62%) were short-
term (≤13 weeks), five lasted ≥1 year. The most commonly studied FGA was haloperidol (9
studies, 69%); and one study each included chlorpromazine(Lieberman et al., 2003a),
molindone(Sikich et al., 2008), sulpiride(Wu et al., 2006), or zuclopenthixol(Fagerlund et
al., 2004). The most commonly studied SGAs were risperidone (N=8) and olanzapine
(N=7), followed by clozapine (N=2), and quetiapine, ziprasidone, and amisulpride(Kahn et
al., 2008), (N=1 each). The number of patients per trial ranged from 24–555. At baseline,
most studies reported a diagnosis of schizophrenia in >50% of patients, except for 2
trials(Emsley, 1999; Schooler et al., 2005). The mean duration of psychosis ranged from 13–
18.4 months, except for one study(Wu et al., 2006) where it was 2.6 months. The mean age
of illness onset ranged from 23–27 years, except for the TEOSS study(Sikich et al., 2008),
which, due to its design, had a mean age of onset of 11.1 years. Pharmaceutical companies
sponsored 54% of the studies, with government agency sponsorship of the remaining trials.
The proportion of antipsychotic-naïve subjects at baseline ranged from 8.3–100% (mean:
62.7%). Among 9 studies with data on response, 3 used a ≥50% cut-off as the responder
definition, 3 used ≥40%, and 3 used either ≥30% or ≥20%.
Primary Outcomes
Short-term all-cause discontinuation—Olanzapine (RR=0.53, p=0.001, N=5, n=689)
and risperidone (RR=0.79, p=0.03, N=4, n=1,146) caused less all-cause discontinuation than
haloperidol (Table 1; Fig S2). Among single trial comparisons, only amisulpride was
superior to haloperidol (RR=0.63, p<0.01). Pooled SGAs had significantly lower
discontinuation rates than FGAs (RR=0.74, p<0.001, N=10, n=1,952). Pooled risk
difference was −0.08 (CI=−0.14~−0.02, NNT=12, p<0.01). No moderating variables were
found.
Short-term total symptom reduction—Only olanzapine (ES=0.26, p=0.01, N=5,

n=676) and amisulpride (ES=0.40, p<0.01, N=1) were superior to haloperidol (Table 1, Fig
S3). Pooled SGAs showed only trend-level superiority compared to FGAs (ES=0.11,
p=0.09, N=12, n=1,951). Study sponsorship significantly moderated the effect (Q=6.68,
p=0.01). Government-sponsored studies trended in favor of FGAs (ES=−0.10, p>0.10, N=5,
n=525), while industry-sponsored studies significantly favored SGAs (ES=0.19, p=0.007,

N=7, n=1,426; Fig S4). The EUFEST trial(Kahn et al., 2008) was investigator-designed and
then sought industry funding, but excluding EUFEST did not significantly alter the results.
No other significant moderator emerged.
Short-term response—Only olanzapine (RR=1.29, p=0.02, N=4, n=652) and

amisulpride were superior to haloperidol (RR=1.56, p<0.01, N=1, Table 1, Fig S5). Pooled
SGAs were marginally better than FGAs (RR=1.13, p=0.06, N=9, n=1,724). Excluding the
TEOSS study(Sikich et al., 2008) conducted in adolescents resulted in a significant RR
favoring SGAs (RR=1.14, CI=1.02~1.29, p=0.026). Again, industry-sponsored studies
showed higher response for SGAs (RR=1.23, CI=1.06~1.42, p=0.005), while non-industry-
sponsored studies did not (RR=0.97, CI=0.81~1.16, p=0.75), with significant sponsorship
effect (Q=3.97, p=0.046) (Fig S6). There was no other significant moderator.

Zhang et al. Page 6
Long-term primary outcomes—Individual SGAs vs. FGAs were similar regarding

long-term all-cause discontinuation, but pooled results still trended favoring SGAs
(RR=0.78, CI=0.60~1.01, p=0.06, N=5, n=1,133). Neither long-term symptom reduction
(ES=0.01, CI=−0.11~0.14, p>0.10, N=4, n=953) nor long-term response (RR=1.05,

CI=0.95~1.16, p>0.10, N=5, n=1,133) differed in individual or pooled SGA-FGA
comparisons.
Secondary Outcomes
Positive symptoms—No significant difference emerged between SGAs and FGAs,
except that amisulpride outperformed haloperidol (Table 2). Olanzapine had trend-level
superiority (ES=0.26, p=0.08, N=4, n=653). Pooled SGA-FGA comparison also revealed no
significant difference.
Negative Symptoms—Several SGAs outperformed their FGA comparators (Table 2),

including olanzapine vs. haloperidol (ES=0.30, p<0.001, N=4, n=653), quetiapine vs.
haloperidol (ES=0.32, p<0.05), and clozapine vs. chlorpromazine (ES=0.41, p<0.01). Pooled
SGAs outperformed FGAs (ES=0.16, p=0.009, N=11, n=1,931). However, sponsorship bias
may exist, as industry-sponsored studies showed results favoring SGAs (N=7, n=1,430,
p=0.001), while independently funded studies did not (N=4, n=501, p=0.72), without
significant group difference (p>0.10, Fig S7).
Depression—Only olanzapine (ES=0.28, p=0.001, N=4, n=565) and amisulpride

(ES=0.32, p<0.05) outperformed haloperidol (Table 2). Pooled SGAs showed trend-level
superiority over FGAs (ES=0.12, p=0.06, N=6, n=1,376). However, again, industry-
sponsored studies more likely favored SGAs.
Clinical Global Impressions-Severity—Only amisulpride was superior to haloperidol

(ES=0.38, p<0.01). Pooled SGAs and FGAs were also similar (N=6, n=1038, Table 2).
Again, industry-sponsored studies were more likely to favor SGAs.
Global cognition—Olanzapine (ES=0.27), risperidone (ES=0.23) and pooled SGAs

(ES=0.25, p=0.001, N=5, n=693) were superior to FGAs in improving cognitive composite
scores at 3–6 months (Table 2, Fig S8).
Specific-cause discontinuation—Olanzapine (RR=0.38, p<0.001), amisulpride

(RR=0.24, p<0.01) and pooled SGAs (RR=0.60, p=0.001, N=9, n=1,792) led to less
discontinuation due to inefficacy than FGAs (Table 3). Olanzapine (RR=0.29, p=0.001,
Figure S40), risperidone (RR=0.50, p=0.02), quetiapine (RR=0.13, p<0.01) and pooled
SGAs (RR=0.46, p<.001, N=8, n=1,768) led to less discontinuation due to intolerability than
the FGA comparator. Only quetiapine led to less discontinuation due to patient decision/
non-adherence than haloperidol (RR=0.15, p<0.05), without differences in pooled SGA-
FGA comparisons.
Long-term remission and relapse rates—Regarding long-term remission, olanzapine

(RR=1.57, p=0.03) and amisulpride (RR=2.35, p=0.001) were superior to haloperidol.
Pooled SGAs (N=4, n=740) showed only trend-level advantage over FGAs (RR=1.26,
p=0.06) (Table 3). However, risperidone (RR=0.77, p=0.01), ziprasidone (RR=0.32, p=0.03)
and pooled SGAs (RR=0.84, p=0.04, N=6, n=1,092, Table 3), had lower relapse rates than
FGAs.
Long-term discontinuation due to inefficacy was lower with olanzapine than haloperidol
(RR=0.51, CI=0.27~0.95, p=0.04, N=3, n=582), but pooled SGA-FGA comparisons were

Zhang et al. Page 7
non-significant (RR=0.66, CI=0.37~1.17, p=0.16, N=5, n=1295). Regarding long-term

discontinuation due to intolerability, olanzapine outperformed haloperidol (RR=0.31,
p<0.001) and SGAs outperformed FGAs (RR=0.49, CI=0.32~0.75, p=0.001, N=5, n=1295).
Adverse Events
EPS and akathisia-related outcomes—EPS was less frequent and severe in patients
on several SGAs than their FGA comparators, including olanzapine (ES=−0.69, p<0.001,
N=4, n=609) and risperidone (ES=−0.33, p<0.001, N=3, n=588) compared to haloperidol,
and clozapine compared to chlorpromazine (ES=−0.72, p<0.01), although all patients on
chlorpromazine received prophylactic benztropine (Table 4). Pooled SGAs produced
significantly less EPS than FGAs (ES=−0.43, p<0.001, N=9, n=1,338). Two significant
moderators emerged: More recent studies had smaller SGA-FGA differences in EPS
(b=0.04, p=0.02). Conversely, higher patient age was associated with larger effect sizes (b=
−0.04, p=0.006). At long-term follow-up, SGAs still produced less EPS (RR=0.42,
CI=0.24~0.73, p=0.002, N=2, n=319).
Short-term akathisia was also less likely with olanzapine (ES=−0.61, p<0.05) and
risperidone (ES=−0.29, p<0.05), and with pooled SGAs vs. FGAs (ES=−0.48, p<0.001,
N=7, n=998) (Table 4). At 1–2-year follow-up, akathisia was still less severe/prevalent with
SGAs (ES=−0.33, CI=−0.48~−0.19, p<.001, N=4, n=930).
Compared to haloperidol, patients on olanzapine took less anticholinergics (RR=0.21,

p<0.001, N=3, n=445), benzodiazepines (RR=0.83, p=0.02, N=3, n=445), and beta-blockers
(RR=0.11, p<0.01, N=1, n=251) (Table 4). Olanzapine was also superior to molindone
regarding less anti-cholinergic co-administration (RR=0.31, p<0.01), although all patients
on molindone received prophylactic benztropine (Table 4). Pooled SGAs were associated
with less anticholinergic (RR=0.47, p<0.01, N=6, n=999) and benzodiazepine use
(RR=0.84, p<0.01, N=5, n=999) (Table 4). Moderator analyses revealed that in open-label
studies more patients on FGAs took anticholinergics than in double-blind studies.
Significantly less anticholinergic use with SGAs than FGAs was associated with smaller
sample size, younger age, male sex, and longer follow-up. SGAs and FGAs did not differ
regarding beta-blocker use.
At 1–2-year follow-up, SGAs were still associated with less anticholinergic use than FGAs
(RR=0.55, CI=0.34~0.88, p=0.01, N=4, n=1,083). Conversely, benzodiazepine use did not
differ between SGAs and FGAs (RR=0.91, CI=0.80~1.03, p=0.14, N=3, n=820). Only one
study reported long-term beta-blocker use (n=555), showing lower use with risperidone than
haloperidol (RR=1.48, CI=0.26~0.88, p=0.02).
Weight and metabolic outcomes—Olanzapine increased weight significantly more

than haloperidol, molindone, and sulpiride (ES=0.61–3.56) (Table 5). Risperidone also
caused significantly more weight gain than haloperidol and molindone (ES=0.22–0.93).
Clozapine was associated with more weight gain than sulpiride (ES=4.95) in one study.
Pooled SGAs caused more weight gain than FGAs (ES=0.65, p<0.001, N=7, n=1,059).
Moderator analysis revealed that larger differences in weight gain between SGAs and FGAs
were associated with shorter follow-up time, smaller sample size, younger age, female sex,
and schizophrenia diagnosis. While at long-term follow-up, SGAs were still associated with
more weight gain than FGAs (N=5, n=996), the ES was about halved (pooled ES=0.33,
CI=0.07~0.59, p=0.01). Likewise, weight gain ≥7% was significantly more likely with
olanzapine (RR=3.31, p<0.01) and risperidone (RR=1.61, p<0.01) than haloperidol, and
with SGAs than FGAs (RR=2.26, CI=1.33~3.69, p=0.001, NNH=4, N=3, n=733) (Table 5).
Weight gain ≥7% during long-term follow-up was still more likely with SGAs than FGAs,
but the RR was smaller (RR=1.45, CI=1.17~1.79, p=0.001, N=3, n=778, NNH=5.35).

Zhang et al. Page 8
Olanzapine, risperidone, and clozapine were associated with lower glucose change than
sulpiride in one study (Wu et al., 2006). Compared to haloperidol, glucose changes were
similar with olanzapine, risperidone, amisulpride, and quetiapine haloperidol; only
ziprasidone was significantly better than haloperidol in one study (ES=−0.36, p<0.05)
(Table 5). Pooled SGAs and FGAs were similar (ES=−0.16, CI=−0.57~0.25, p=0.44, N=6,
n=749). Heterogeneity across studies was high (Q=36.10, p<0.001, I2=86.15%). Even when
excluding an outlier (Wu et al., 2006), pooled ES remained non-significant. No SGA-FGA
difference emerged regarding long-term glucose change (N=3).
Regarding short-term total cholesterol change, olanzapine was significantly worse than
molindone and sulpiride, and marginally worse than haloperidol (ES=0.17, p=0.051, N=3,
n=501) (Table 5). Risperidone was not different from haloperidol, but significantly better
than sulpiride. Pooled SGAs were associated with a marginally larger total cholesterol
increase than FGAs (ES=0.46, p=0.053, N=5, n=593). Heterogeneity was large (Q=24.64,
p<0.001, I2=83.76%). Excluding Wu et al(Wu et al., 2006) resulted in a much smaller ES
(ES=0.15, p=0.08). No significant SGA-FGA difference emerged regarding long-term
cholesterol change (N=2).
Only few studies reported on triglyceride changes. Olanzapine and clozapine were worse
than sulpiride, and amisulpride was worse than haloperidol. However, risperidone was better
than sulpiride (Table 5). Pooled SGAs showed marginally greater short-term triglyceride
increase than FGAs (ES=0.71, p=0.057, N=4, n=371). Heterogeneity was high (Q=25.54,
p<0.001, I2=88.25%). Excluding Wu 2006, the pooled ES became much smaller (ES=0.20,
p=0.08).
Discussion
In this comprehensive meta-analysis of head-to-head trials, several SGAs outperformed
FGAs in FES patients: olanzapine, amisulpride and risperidone were associated with
significantly lower treatment discontinuation rates; olanzapine and amisulpride were
superior regarding dropout due to inefficacy; and olanzapine, risperidone and quetiapine led
to less dropouts due to intolerability. Only quetiapine had less discontinuation due to non-
adherence/patient choice. Pooled together, SGAs vs FGAs had lower treatment
discontinuation rates due to any cause (NNT=12), inefficacy and intolerability, reducing
these events by 26%, 40% and 54%, respectively (Fig S9). Regarding total symptom
reduction, only olanzapine and amisulpride outperformed FGAs, and FGA-SGA class
differences were non-significant. Moreover, olanzapine outperformed haloperidol on
negative symptoms, depression, global cognition and long-term remission; amisulpride
outperformed haloperidol regarding positive symptoms, depression, CGI severity and long-
term remission; and clozapine and quetiapine, each, outperformed chlorpromazine and
haloperidol regarding negative symptoms, while risperidone and ziprasidone had lower
relapse rates. Pooled SGAs outperformed FGAs on negative symptoms (ES=0.16), global
cognition (ES=0.25) and relapse (Fig S9).
Interestingly, some of the important factors in treating first episode psychosis such as
haloperidol equivalent dosing and percentage of drug-naïve patients were not significant in
moderator analysis of any outcome. The same was true for blinding status. Notably,
however, government-sponsored studies tended to favor FGAs, whereas industry-sponsored
studies tended to favor SGAs in total symptom reduction and response rate. While being a
post hoc finding, it is possible that in industry-sponsored studies raters had a subtle bias
against FGAs, especially when EPS unmasked drug assignment, but more independently
funded studies are needed.

Zhang et al. Page 9
Results of drug-induced adverse events were robust, and effect sizes were large. Olanzapine,
risperidone, clozapine and pooled SGAs caused significantly less EPS, akathisia, and/or co-
treatment with anticholinergics and benzodiazepines than FGAs. Conversely, clozapine,
olanzapine, risperidone and pooled SGAs showed larger weight gain than FGA comparators,
but without significantly greater increases in glucose and lipid parameters, except for
isolated findings with clozapine, olanzapine and amisulpride, at least in these shorter-term
trials.
First episode patients are especially sensitive to drug-induced side effects including EPS and
weight gain. Therefore, the lower EPS risk with most SGAs, also found in chronic
patients(Fischer-Barnicol et al., 2008), is beneficial. Interestingly, in more recent studies, the
ES favoring SGAs has been diminishing. This is likely attributable to lower FGA
comparator doses and less uniform use of haloperidol. The fact that older subjects showed
greater FGA-SGA differentiation is consistent with the fact that young and pediatric patients
are at particular risk for EPS, even with SGAs(Correll et al., 2006).
Consistent with data in chronic patients, continuous and categorical “significant” weight
gain outcomes disfavored most SGAs being more pronounced in younger patients, females,
and schizophrenia patients. That schizophrenia emerged as a risk factor suggests that illness
severity and/or negative symptoms might also play a role in weight gain. The lack of
glucose differences (except for a favorable outcome with ziprasidone) is not surprising,
since (pre)diabetes generally emerges only after a period of insulin resistance(De Hert et al.,
2011), and insulin levels were not measured. Moreover, since mostly short-term results were
available, longer-term risk for more distal outcomes, such as diabetes and cardiovascular
illness, were not available in first-episode patients, except for a data base study(Nielsen et
al., 2010). Interestingly, SGA-FGA effect size differences for weight and lipid outcomes
declined with longer follow-up, suggesting that non-medication effects, such as unhealthy
lifestyle, the underlying illness, environment and, possibly, genetics, start playing a relevant
role.
Taken together, these meta-analytic results confirm that SGAs are not a homogeneous class,
being associated with different efficacy and side effect profiles(Kane and Correll, 2010;
Leucht et al., 2009). Notably, like a prior meta-analyses in chronic schizophrenia(Crossley
et al., 2010), we also found small effect size differences favoring amisulpride and
olanzapine and, less so, risperidone compared to FGAs. The superior outcome regarding a
global cognitive index with olanzapine and risperidone compared to FGAs, even given at
relatively low doses, is noteworthy, being inconsistent with chronic schizophrenia
data(Keefe et al., 2007). The potential for greater treatment differences in earlier illness
phases, although unclear to date, deserves follow-up, as cognitive dysfunction has been
associated with poor functional outcomes(Brekke et al., 2007). However, the superiority of
olanzapine, risperidone and amisulpride, but not of other SGAs, compared to FGAs could be
due to a cohort effect, in that these three SGAs were studied earlier, at a time when higher
haloperidol were commonly used, causing potentially higher dropout rates. In fact, in our
analyses, EPS differences between SGAs and FGAs diminished over time. Moreover, during
the past decade, effect sizes have decreased in schizophrenia and CNS trials in
general(Correll et al., 2011). Nevertheless, neither FGA comparator doses nor year of study
publication emerged as significant moderators in any analyses. Another interesting finding is
that clozapine was not more efficacious or effective than chlorpromazine in FES patients.
This is inconsistent with chronic schizophrenia data, but confirmed the notion that clozapine
should be reserved for treatment refractory schizophrenia due to its significant side effect
profile. However, these results were based on one single study conducted in Chinese
patients; yet additional FES studies with clozapine are unlikely to be conducted due to its

Zhang et al. Page 10
significantly more severe side effect burden and the overall greater responsiveness of FES
patients compared to chronic patients.
Nevertheless, overall, effect sizes of the efficacy differences, either in pooled or individual
analyses, were relatively small, with the exception of significantly lower all-cause and
specific-cause discontinuation rates with SGAs. This suggests that FES patients who are
generally more treatment responsive than chronic patients have a reasonable chance of
benefiting from any antipsychotic treatment. By contrast, side effect differences were larger.
Therefore, antipsychotic choice should take into consideration the safety profile of each
agent and the patient’s willingness to accept specific adverse effect clusters. Moreover, the
robust finding of lower treatment discontinuation with SGAs is quite relevant, given that
engagement and continued antipsychotic treatment are crucial for relapse prevention,
remission, recovery, and other beneficial outcomes(Kane and Correll, 2010). It is unclear,
however, if the lower treatment discontinuation was affected by less frequent EPS and
akathisia compared FGAs, as patient choice-related discontinuation did not differ between
SGAs and FGAs, except for quetiapine that has particularly low EPS and akathisia rates.
Nevertheless, the coding of reasons for treatment discontinuing treatment mostly lacked
detail. Furthermore, despite the neuromotor adverse effect advantage of SGAs, significant
weight gain induced by SGAs, especially olanzapine and clozapine, but also risperidone, is
of major concern for patients’ long-term health(Correll et al., 2009). More studies are
needed to better understand predictors of antipsychotic-induced weight gain, including
genetic markers.
Several limitations of the present study require consideration. The number of relevant RCTs
in first-episode patients was small and some outcomes were not reported by all studies. Only
one study was available for amisulpride, quetiapine and ziprasidone, and studies were
missing for aripiprazole, asenapine, iloperidone, lurasidone and paliperidone. Therefore,
specific drug recommendations should be viewed with caution. Moreover, studies included
in any meta-analysis are heterogeneous, but we used random effects models and performed
sensitivity and moderator analyses to deal with this limitation. In addition, haloperidol was
used as the SGA comparator in 9/13 studies and was frequently used in relatively high
doses. This might have caused higher EPS and discontinuation rates, although haloperidol
dose was not a significant moderator in our analyses. Moreover, most data were available
for short-term outcomes and data on tardive dyskinesia were generally lacking. Also,
unmeasured medication non-adherence may have affected these findings. Finally, head-to-
head trials comparing SGAs with SGAs in FES were not included, being beyond the scope
of this meta-analysis.
In summary, in FES, pooled SGAs were either similarly effective or modestly better than
FGAs regarding several efficacy and tolerability outcomes, being associated with greater
weight gain. Among individual SGAs, amisulpride and olanzapine and, to a lesser degree,
risperidone were most consistently superior to their respective FGA comparator, but weight
and metabolic problems were also greater with olanzapine. Overall, risperidone appears to
be reasonably efficacious and is associated with relatively benign side effects, so it should
be considered as a first line therapy for first-episode schizophrenia. However, studies with
aripiprazole and newer SGAs that generally have less metabolic liability(De Hert et al.,
2012) are clearly needed and mid-potency FGAs should strongly be considered as
comparators. Furthermore, since SGAs were significantly superior for negative symptom,
global cognition and long-term relapse outcomes compared to FGAs, future studies need to
study the real world functional implications of these potential differences and include
subjective well-being and cost-effectiveness outcomes to inform broader health care
strategies and resource allocation.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgments
Supported in part by The Zucker Hillside Hospital Advanced Center for Intervention and Services Research for the
Study of Schizophrenia (MH090590) and Center for Intervention Development and Applied Research (MH080173)
from the National Institute of Mental Health, Bethesda, MD. We thank those authors who provided additional,
unpublished data on their studies relevant for this meta-analysis.
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NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
Table 1
Pooled effect sizes (95% confidence interval in parenthesis) of short-term primary outcome variables in comparison of SGAs and FGAs.
SGA FGA # studies n All-cause Discontinuation Rate (RR) Symptom Reduction (Hedges’ g) Response Rate (RR)
Zhang et al.
Olanzapine Haloperidol 5 689 0.53 (0.37~0.77)** 0.26 (0.05~0.47)* 1.29 (1.05~1.58)*b
Olanzapine Molindone 1 75 1.37 (0.82~2.29) −0.02 (−0.47~0.43) 0.68 (0.39~1.19)
Risperidone Haloperidol 5 1146 0.79 (0.63~0.97)*a −0.04 (−0.19~0.11) 1.04 (0.90~1.20)c
Risperidone Molindone 1 81 0.85 (0.46~1.54) −0.15 (−0.58~0.28) 0.92 (0.58~1.45)
Risperidone Zuclopenthixol 1 25 NR 0.50 (−0.29~1.28) 1.34 (0.30~5.96)
Clozapine Chlorpromazine 1 160 0.91 (0.37~2.25) 0.15 (−0.16~0.46) 1.03 (0.88~1.20)
Amisulpride Haloperidol 1 207 0.63 (0.47~0.85)** 0.40 (0.13~0.68)** 1.56 (1.13~2.15)**
Quetiapine Haloperidol 1 207 0.81 (0.63~1.05) 0.26 (−0.02~0.53) 1.30 (0.92~1.84)
Ziprasidone Haloperidol 1 185 0.89 (0.68~1.15) 0.22 (−0.07~0.51) 1.11 (0.76~1.64)
Pooled SGAs Pooled FGAs 12 1952 0.74 (0.62~0.87)** 0.11 (−0.02~0.24) 1.13 (0.99~1.27)
Note: # studies and n are the largest possible for each comparison pair, but # of studies and n for each outcome may vary.
*
p < .05;
**
p < .01.
a
N=4, n=1146;
b
N=4, n=652;
c
N=4, n=1089.

Page 14
Table 2
Pooled effect sizes (95% confidence interval in parenthesis) of short-term secondary outcome variables in comparison of SGAs and FGAs.
SGA FGA # studies n Positive Symptoms Negative Symptoms Depression (Hedges’ g) CGI-S (Hedges’ g) Cognitive Function
(Hedges’ g) (Hedges’ g) (Hedges’ g)
Zhang et al.
Olanzapine Haloperidol 4 653 0.26 (−0.03~0.54) 0.30 (0.15~0.46)** 0.28 (0.11~0.44)** 0.15 (−0.14~0.44) 0.27 (0.06~0.49)*d
Olanzapine Molindone 1 75 0.02 (−0.43~0.47) −0.07 (−0.52~0.38) NR NR NR
Risperidone Haloperidol 5 1136 −0.05 (−0.17~0.07) 0.03 (−0.09~0.14) 0.00 (−0.13~0.14)a −0.14 (−0.34~0.05)b 0.23 (0.04~0.43)*c
Risperidone Molindone 1 81 −0.06 (−0.49~0.37) −0.10 (−0.53~0.34) NR NR NR
Risperidone Zuclopenthixol 1 25 0.35 (−0.43~1.13) 0.29 (−0.49~1.06) NR NR 0.63 (−0.17~1.42)
Clozapine Chlorpromazine 1 160 0.15 (−0.16~0.46) 0.41 (0.10~0.72)** NR 0.24 (−0.07~0.55) NR
Amisulpride Haloperidol 1 207 0.54 (0.27~0.82)** 0.24 (−0.03~0.52) 0.32 (0.05~0.59)* 0.38 (0.10~0.65)** −0.01 (−0.39~0.36)
Quetiapine Haloperidol 1 207 0.22 (−0.06~0.49) 0.32 (0.05~0.59)* 0.23 (−0.04~0.50) 0.09 (−0.18~0.36) 0.20 (−0.17~0.57)
Ziprasidone Haloperidol 1 185 0.27 (−0.03~0.56) 0.25 (−0.04~0.54) 0.06 (−0.23~0.34) 0.18 (−0.11~0.47) 0.11 (−0.28~0.51)
Pooled SGAs Pooled FGAs 11 1932 0.09 (−0.03~0.21) 0.16 (0.04~0.28)** 0.12 (−0.00~0.24) 0.10 (−0.09~0.29) 0.25 (0.10~0.40)**
*
p < .05;
**
p < .01.
a
N=2, n=817.
b
N=2, n=406.
c
N=2, n=396.
d

N=3, n=340.
Page 15
Table 3
Pooled effect sizes (95% confidence interval in parenthesis) of short-term discontinuation rate due to specific reasons and long-term remission and relapse
rates in comparison of SGAs and FGAs.
Zhang et al.
SGA FGA # studies n Due to inefficacy (RR) Due to intolerability Due to patient choice/ Long-term Remission Long-term Relapse Rate
(RR) non-adherence (RR) Rate (RR) (RR)
Olanzapine Haloperidol 5 689 0.38 (0.25~0.59)** 0.29 (0.14~ 0.59)**a 0.64 (0.16~2.57)b 1.57 (1.06~2.32)*d 1.00 (0.77~1.31)f
Olanzapine Molindone 1 75 0.69 (0.18~2.67) 0.86 (0.33~2.23) 4.00 (0.89~18.01) NR NR
Risperidone Haloperidol 4 1146 0.88 (0.51~1.53) 0.50 (0.28~0.89)* 0.78 (0.53~1.15)c 1.40 (0.79~2.46)e 0.77 (0.64~0.95)*g
Risperidone Molindone 1 81 0.78 (0.23~2.70) 0.61 (0.22~1.71) 1.95 (0.38~10.06) NR NR
Clozapine Chlorpromazine 1 160 NR NR NR 1.03 (0.88~1.20) 1.20 (0.38~3.77)
Amisulpride Haloperidol 1 207 0.24 (0.12~0.49)** 0.47 (0.20~1.08) 0.69 (0.31~1.52) 2.35 (1.45~3.83)** 0.73 (0.37~1.41)
Quetiapine Haloperidol 1 207 1.06 (0.73~1.55) 0.13 (0.03~0.55)** 0.15 (0.04~0.65)* 1.41 (0.82~2.44) 1.05 (0.54~2.01)
Ziprasidone Haloperidol 1 185 0.67 (0.41~1.09) 0.47 (0.19 ~1.16) 0.77 (0.34~1.75) 1.65 (0.95~2.86) 0.32 (0.11~0.89)*
Pooled SGAs Pooled FGAs 9 1792 0.60 (0.43~0.82)** 0.46 (0.31~0.68)** 0.84 (0.57~1.24) 1.26 (0.99~1.60) 0.84 (0.72~0.99)*
*
p < .05;
**
p < .01.
RR = Relative Risk.
a
N=4, n=665.
b
N=4, n=606.
c
N=3, n=963.

d
N=3, n=582.
e
N=1, n=119.
f
N=3, n=394.
g
N=3, n=663.
Page 16
Table 4
Pooled effect sizes (95% confidence interval in parenthesis) of short-term common side effects and co-medications treating side effects in comparison of
SGAs and FGAs. A negative effect size and an RR below 1 indicate worse side effects from FGAs.
Zhang et al.
SGA FGA EPS (Hedges’ g) Akathisia (Hedges’ g) Co-meds: Anticholinergerics (RR) Co-meds: Benzodiazepines (RR) Co-meds: Beta-blockers (RR)
Olanzapine Haloperidol −0.69 (−1.02~ −0.61 (−0.79~−0.42)** 0.21 (0.09~0.51)** (N=3, n=445) 0.83 (0.71~0.96)* (N=3, n=445) 0.11 (0.03~0.40)** (N=1,
−0.35)** (N=4, (N=4, n=611) n=251)
n=609)
Olanzapine Molindone 0.14 (−0.31~0.59) −0.35 (−0.81~0.10) 0.31 (0.13~0.76)**a (N=1, n=75) 0.51 (0.24~1.11) (N=1, n=75) 0.85 (0.25~2.92) (N=1, n=75)
(N=1, n=75) (N=1, n=75)
Risperidone Haloperidol −0.33 (−0.51~ −0.29 (−0.52~−0.06)* 0.71 (0.45~1.11) (N=3, n=591) 0.88 (0.73~1.06) (N=2, n=408) 0.62 (0.22~1.69) (N=1, n=289)
−0.16)** (N=3, (N=2, n=406)
n=588)
Risperidone Molindone 0.21 (−0.22~0.64) −0.28 (−0.71~0.16) 0.76 (0.44~1.31)a (N=1, n=81) 1.05 (0.62~1.79) (N=1, n=81) 0.54 (0.14~2.13) (N=1, n=81)
(N=1, n=81) (N=1, n=81)
Risperidone Zuclopenthixol −0.72 (−1.52~0.08) −0.71 (−1.51~0.09) NR NR NR

(N=1, n=25) (N=1, n=25)
Clozapine Chlorpromazine −0.72 (−1.04~ NR NRb NR NR

−0.41)** (N=1,
n=160)
Amisulpride Haloperidol 0.24 (−0.34~0.82) −0.46 (−1.00~0.08) NR NR NR

(N=1, n=163) (N=1, n=163)
Quetiapine Haloperidol 0.21 (−0.37~0.80) −0.33 (−0.83~0.17) NR NR NR

(N=1, n=167) (N=1, n=167)
Ziprasidone Haloperidol 0.28 (−0.33~0.89) −0.28 (−0.82~0.26) NR NR NR

(N=1, n=142) (N=1, n=142)
Pooled SGAs Pooled FGAs −0.43 (−0.64~ −0.48 (−0.62~−0.34)** 0.47 (0.29~0.77)** (N=6, n=999) 0.84 (0.75~0.95)** (N=5, n=816) 0.37 (0.12~1.12) (N=3, n=618)
−0.22)** (N=9, (N=7, n=998)
n=1338)
Note:

*
p < .05;
**
p < .01.
RR = Relative Risk.
a
In the TEOSS study, all patients on molindone were also given benztropine 1mg daily by study design, but some patients received additional benztropine due to side effects. Calculation of ES was based
on number of patients on molindone received additional benztropine.
b
In Lieberman 2003 clozapine vs chlorpromazine study, all patients on chlorpromazine also took benztropine 2mg twice daily by study design.
Page 17
Table 5
Pooled effect sizes (95% confidence interval in parenthesis) of short-term weight gain and metabolic changes in comparison of SGAs and FGAs. A
negative effect size and an RR below 1 indicate worse side effects from FGAs.
Zhang et al.
SGA FGA Comparator Weight Change (Hedges’ g) Weight Gain (>7%) Glucose change (Hedges’ Cholesterol change (Hedges’ Triglyceride change
(RR) g) g) (Hedges’ g)
Olanzapine Haloperidol 0.61 (0.35~0.87)** (N=4, 3.31 (1.83~5.98)** (N=2, 0.08 (−0.17~0.32) (N=3, 0.17 (−0.00~0.35) (N=3, 0.20 (−0.25~0.65) (N=2,
n=572) n=362) n=496) n=501) n=280)
Olanzapine Molindone 1.77 (1.24~2.30)** (N=1, n = NR −0.02 (−0.70~0.66) (N=1, 1.02 (0.30~1.75)** (N=1, 0.51 (−0.20~1.21) (N=1, n=33)
75) n=35) n=35)
Olanzapine Sulpiride 3.56 (2.70~4.42)** (N=1, NR −1.21 (−1.79~−0.63)** 5.12 (4.01~6.23)** (N=1, 3.32 (2.49~4.15)** (N=1,
n=53) (N=1, n=53) n=53) n=53)
Risperidone Haloperidol 0.22 (0.03~0.40)* (N=2, 1.61 (1.25~2.09)** (N=2, −0.40 (−0.83~0.03) (N=1, −0.07 (−0.50~0.36) (N=1, −0.03 (−0.47~0.41) (N=1,
n=443) n=485) n=84) n=84) n=78)
Risperidone Molindone 0.93 (0.48~1.3)** (N=1, n=81) NR 0.03 (−0.55~0.60) (N=1, −0.46 (−1.04~0.12) (N=1, 0.32 (−0.28~0.92) (N=1, n=42)
n=0.92) n=45)
Risperidone Sulpiride −3.86 (−4.73~−3.00)** (N=1, NR −1.99 (−2.61~−1.36)** −1.36 (−1.93~−0.80)** (N=1, −1.18 (−1.74~−0.63)** (N=1,
n=58) (N=1, n=58) n=58) n=58)
Clozapine Chlorpromazine NR NR 0.25 (−0.06~0.56) (N=1, NR NR

n=160)
Clozapine Sulpiride 4.95 (3.92~5.97)** (N=1, NR −1.54 (−2.12~−0.97)** 3.07 (2.32~3.82) (N=1, n=59) 5.02 (3.98~6.05)** (N=1,
n=59) (N=1, n=59) n=59)
Amisulpride Haloperidol 0.12 (−0.20~0.43) (N=1, NR −0.03 (−0.30~0.24) (N=1, 0.19 (−0.08~0.47) (N=1, 0.34 (0.06~0.61)* (N=1,
n=155) n=207) n=207) n=207)
Quetiapine Haloperidol 0.30 (−0.01~0.62) (N=1, NR −0.11 (−0.38~0.16) (N=1, −0.03 (−0.30~0.25) (N=1, 0.15 (−0.12~0.42) (N=1,
n=157) n=207) n=207) n=207)
Ziprasidone Haloperidol −0.12 (−0.46~0.22) (N=1, NR −0.36 (−0.65~−0.06)* 0.02 (−0.27~0.31) (N=1, 0.10 (−0.19~0.39) (N=1,
n=132) (N=1, n=185) n=185) n=185)

Pooled SGAs Pooled FGAs 0.65 (0.33~0.98)** (N=7, 2.26 (1.33~3.69)** (N=3, −0.20 (−0.61~0.22) (N=6, 0.46 (−0.01~0.92) (N=5, 0.71 (−0.02~1.44) (N=4,
n=1059) n=733) n=749) n=593) n=371)
Note:
*
p < .05;
**
p < .01.
RR = Relative Risk.
Page 18

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Int J Neuropsychopharmacol. 2013 July ; 16(6): 1205–1218. doi:10.1017/S1461145712001277.

Efficacy and Safety of Individual Second-Generation vs First-

System, Glen Oaks, New York, USA

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

ignored important outcomes, including positive and negative symptoms, depression,

Therefore, we conducted a meta-analysis comparing the efficacy, effectiveness, and adverse

Data extraction and outcome variables

outcome was not available, study-defined response was used.

Secondary outcomes included last-observation-carried-forward (LOCF) change from

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

the true effect size estimate.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Short-term total symptom reduction—Only olanzapine (ES=0.26, p=0.01, N=5,

n=525), while industry-sponsored studies significantly favored SGAs (ES=0.19, p=0.007,

Short-term response—Only olanzapine (RR=1.29, p=0.02, N=4, n=652) and

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Long-term primary outcomes—Individual SGAs vs. FGAs were similar regarding

(ES=0.01, CI=−0.11~0.14, p>0.10, N=4, n=953) nor long-term response (RR=1.05,

Negative Symptoms—Several SGAs outperformed their FGA comparators (Table 2),

Depression—Only olanzapine (ES=0.28, p=0.001, N=4, n=565) and amisulpride

Clinical Global Impressions-Severity—Only amisulpride was superior to haloperidol

Global cognition—Olanzapine (ES=0.27), risperidone (ES=0.23) and pooled SGAs

Specific-cause discontinuation—Olanzapine (RR=0.38, p<0.001), amisulpride

Long-term remission and relapse rates—Regarding long-term remission, olanzapine

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

non-significant (RR=0.66, CI=0.37~1.17, p=0.16, N=5, n=1295). Regarding long-term

Compared to haloperidol, patients on olanzapine took less anticholinergics (RR=0.21,

Weight and metabolic outcomes—Olanzapine increased weight significantly more

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Crespo-Facorro B, Perez-Iglesias R, Ramirez-Bonilla M, Martinez-Garcia O, et al. A practical clinical

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

analysis. Journal of the American Statistical Association. 2000; 95:89–98.

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

of psychiatry. 2004; 161(3):473–479. [PubMed: 14992973]

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Olanzapine Haloperidol 5 689 0.53 (0.37~0.77)** 0.26 (0.05~0.47)* 1.29 (1.05~1.58)*b

Olanzapine Molindone 1 75 1.37 (0.82~2.29) −0.02 (−0.47~0.43) 0.68 (0.39~1.19)

Risperidone Haloperidol 5 1146 0.79 (0.63~0.97)*a −0.04 (−0.19~0.11) 1.04 (0.90~1.20)c

Risperidone Molindone 1 81 0.85 (0.46~1.54) −0.15 (−0.58~0.28) 0.92 (0.58~1.45)

Risperidone Zuclopenthixol 1 25 NR 0.50 (−0.29~1.28) 1.34 (0.30~5.96)

Clozapine Chlorpromazine 1 160 0.91 (0.37~2.25) 0.15 (−0.16~0.46) 1.03 (0.88~1.20)

Amisulpride Haloperidol 1 207 0.63 (0.47~0.85)** 0.40 (0.13~0.68)** 1.56 (1.13~2.15)**

Quetiapine Haloperidol 1 207 0.81 (0.63~1.05) 0.26 (−0.02~0.53) 1.30 (0.92~1.84)

Ziprasidone Haloperidol 1 185 0.89 (0.68~1.15) 0.22 (−0.07~0.51) 1.11 (0.76~1.64)

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Olanzapine Molindone 1 75 0.02 (−0.43~0.47) −0.07 (−0.52~0.38) NR NR NR

Risperidone Molindone 1 81 −0.06 (−0.49~0.37) −0.10 (−0.53~0.34) NR NR NR

Risperidone Zuclopenthixol 1 25 0.35 (−0.43~1.13) 0.29 (−0.49~1.06) NR NR 0.63 (−0.17~1.42)

Clozapine Chlorpromazine 1 160 0.15 (−0.16~0.46) 0.41 (0.10~0.72)** NR 0.24 (−0.07~0.55) NR

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Olanzapine Molindone 1 75 0.69 (0.18~2.67) 0.86 (0.33~2.23) 4.00 (0.89~18.01) NR NR

Risperidone Molindone 1 81 0.78 (0.23~2.70) 0.61 (0.22~1.71) 1.95 (0.38~10.06) NR NR

Clozapine Chlorpromazine 1 160 NR NR NR 1.03 (0.88~1.20) 1.20 (0.38~3.77)

Int J Neuropsychopharmacol. Author manuscript; available in PMC 2013 July 01.

Risperidone Zuclopenthixol −0.72 (−1.52~0.08) −0.71 (−1.51~0.09) NR NR NR

Clozapine Chlorpromazine −0.72 (−1.04~ NR NRb NR NR

Amisulpride Haloperidol 0.24 (−0.34~0.82) −0.46 (−1.00~0.08) NR NR NR

Quetiapine Haloperidol 0.21 (−0.37~0.80) −0.33 (−0.83~0.17) NR NR NR

Ziprasidone Haloperidol 0.28 (−0.33~0.89) −0.28 (−0.82~0.26) NR NR NR

Amisulpride Haloperidol 1 207 0.63 (0.47~0.85) 0.40 (0.13~0.68) 1.56 (1.13~2.15)**