metaanaliza.pdf

Reviews and Overviews

A Meta-Analysis of Head-to-Head Comparisons

of Second-Generation Antipsychotics in the

Treatment of Schizophrenia

Stefan Leucht, M.D.

Objective: Whether there are differences

in efficacy among second-generation an-

tipsychotics in the treatment of schizo-

phrenia is a matter of heated debate. The

authors conducted a systematic review

and meta-analysis of blinded studies

comparing second-generation antipsy-

chotics head-to-head.

Method: Searches of the Cochrane

Schizophrenia Group’s register (May 2007)

and MEDLINE (September 2007) were

conducted for randomized, blinded stud-

ies comparing two or more of nine sec-

ond-generation antipsychotics in the

treatment of schizophrenia. All data were

extracted by at least three reviewers inde-

pendently. The primary outcome mea-

sure was change in total score on the Pos-

itive and Negative Syndrome Scale;

secondary outcome measures were posi-

tive and negative symptom subscores and

rate of dropout due to inefficacy. The re-

sults were combined in a meta-analysis.

Various sensitivity analyses and metare-

gressions were used to examine bias.

Results: The analysis included 78 studies

with 167 relevant arms and 13,558 partic-

ipants. Olanzapine proved superior to

aripiprazole, quetiapine, risperidone, and

ziprasidone. Risperidone was more effica-

cious than quetiapine and ziprasidone.

Clozapine proved superior to zotepine

and, in doses >400 mg/day, to risperi-

done. These differences were due to im-

provement in positive symptoms rather

than negative symptoms. The results

were rather robust with regard to the ef-

fects of industry sponsorship, study qual-

ity, dosages, and trial duration.

Katja Komossa, M.D.

Christine Rummel-Kluge, M.D.

Caroline Corves, M.Sc.

Heike Hunger

Franziska Schmid

Claudia Asenjo Lobos, M.Sc.

Sandra Schwarz

Conclusions: The findings suggest that

some second-generation antipsychotics

may be somewhat more efficacious than

others, but the limitations of meta-analy-

sis must be considered. In tailoring drug

treatment to the individual patient, small

efficacy superiorities must be weighed

against large differences in side effects

and cost.

John M. Davis, M.D.

(Am J Psychiatry 2009; 166:152–163)

D rug choice in the treatment of schizophrenia has

been controversial. Second-generation antipsychotic

drugs, which have a low propensity to cause extrapyra-

midal side effects, were introduced in the 1990s. As their

cost represents a large proportion of mental health bud-

gets, totaling $11.7 billion in the United States in 2005 (1),

there is a debate as to their superior effectiveness com-

pared with lower-cost first-generation antipsychotics,

such as haloperidol. Meta-analyses have shown that

some second-generation antipsychotics (amisulpride,

clozapine, olanzapine, and risperidone) are more effica-

cious than first-generation antipsychotics (2, 3). Some

evidence suggests that even these superiorities may be

due to an inappropriate choice of the comparator first-

generation antipsychotic, the dosage of the comparator

antipsychotic, or lack of prophylactic antiparkinson

medication (4, 5). Despite these controversies, second-

generation antipsychotics have become the most fre-

quently prescribed drugs in some countries, including

the United States. The question of whether there are effi-

cacy differences between these drugs thus becomes very

important.

The Cochrane Handbook notes that because of a multi-

plicity of possible confounders, indirect comparisons de-

rived from meta-analyses comparing second-generation

antipsychotics with first-generation antipsychotics do not

provide firm proof for an efficacy difference between sec-

ond-generation antipsychotics (6). The stakes are high for

patients, because the four second-generation antipsy-

chotics that have turned out to be more efficacious than

first-generation antipsychotics in meta-analyses either

commonly induce substantial weight gain (clozapine and

olanzapine [7]) or substantially increase prolactin levels

(amisulpride and risperidone [8]). Side effects are very im-

portant, but on the other hand, because schizophrenia is a

disease that lasts throughout life, and so even a small in-

crement in efficacy could increase the patient’s chances of

leading a more normal life. In this context, we present a

This article is the subject of a CME course (p. 259).

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Am J Psychiatry 166:2, February 2009

LEUCHT, KOMOSSA, RUMMEL-KLUGE, ET AL.

meta-analysis of blinded trials comparing each second-

generation antipsychotic against other second-generation

antipsychotics.

3 [11]),

first-episode studies, effectiveness studies, studies from phase 2

of the Clinical Antipsychotic Trials in Intervention Effectiveness

(CATIE) study (the same subjects as those in phase 1 were reran-

domized [12, 13]), and Chinese studies (because of potential eth-

nic differences in metabolism or differences in methodological

rigor). We also addressed first-episode studies and treatment-re-

sistant populations separately; we analyzed studies with cloza-

pine dosages above 400 mg/day separately; and we analyzed

clozapine studies of at least 3 or 6 months’ duration separately.

We used a fixed-effects model instead of the random-effects

model.

Pharmaceutical companies sometimes do not publish studies

that did not favor their drug. We used funnel plots (14) and Or-

win’s fail-safe method (15) to estimate whether such a publication

bias exists.

All calculations were made with Stata, release 7 (Stata Corp.,

College Station, Tex.), and Comprehensive Meta-Analysis, version

2 (16). All analyses were two-tailed with alpha set at 0.05 without

adjustments for multiple comparisons, except for the homogene-

ity test, in which alpha was set to 0.1. (More information is pro-

vided in the data supplement that accompanies the online edi-

tion of this article.)

Method

We searched the Cochrane Schizophrenia Group’s (CSG) regis-

ter for randomized, at least single-blind trials with all 36 possible

head-to-head comparisons of nine second-generation antipsy-

chotics in the treatment of schizophrenia or related disorders

(schizoaffective, schizophreniform, or delusional disorder, any

diagnostic criteria). Two reviewers independently inspected all

reports. The last search of the CSG register was made in May 2007.

We also searched MEDLINE through September 2007. The CSG

(BIOSIS, CINAHL, Dissertation Abstracts, EMBASE, LILACS,

MEDLINE, PSYNDEX, PsycINFO, RUSSMED, Sociofile), supple-

mented by the hand searching of journals and conference pro-

ceedings (9). All manufacturers of second-generation antipsy-

chotics were contacted for further studies. Only studies that met

the Cochrane Handbook ’s quality criterion A or B were included

(6). Nonblinded studies were excluded because we found that

open studies favored the sponsor (3). There were no language

restrictions.

Data Extraction and Outcomes

All data were extracted independently by at least three review-

ers (S.L., K.K., C.R.-K., H.H., F.S., C.A.L., S.S.). The primary out-

come measure was change in total score on the Positive and Neg-

ative Syndrome Scale (PANSS); secondary outcomes measures

were positive and negative symptom subscores as well as rate of

dropout due to insufficient efficacy. Results based on mixed-ef-

fects models and last-observation-carried-forward results were

preferred to completer analyses, but when only the latter were

available, they were used. First authors and manufacturers were

contacted for missing data.

Meta-Analytic Calculations

We analyzed continuous outcomes using weighted (by N)

mean differences and their 95% confidence interval (CI), since

this preserves the original PANSS units, which are intuitively in-

terpreted (e.g., a weighted mean difference of 5 means a 5-point

difference in PANSS score between the two groups). For sensitiv-

ity analyses, we used the standardized effect size Hedges’ g to in-

clude a few more studies (13.3%) that used scales other than the

PANSS. For missing standard deviations, we either derived them

from other statistics or used the average standard deviations of

the other studies. Risk ratios were used for the dichotomous mea-

sure. Number needed to treat was calculated as the inverse of the

risk difference where appropriate. The studies were pooled with

the random-effects model of Der-Simonian and Laird (10). We ex-

plored study heterogeneity by a chi-square test of homogeneity.

Addressing Potential Moderator and Quality Variables

Unrestricted-maximum-likelihood-random-effects metare-

gression was used to assess the effects of mean daily dose, dose

ratio, study quality as rated by the Jadad et al. scale (11), study du-

ration, and pharmaceutical company sponsorship on the pri-

mary outcome measure.

All studies were included in the main analysis. In secondary

analyses of the primary outcome, we excluded studies with cer-

tain characteristics that could have biased the results. This proce-

dure, referred to as sensitivity analysis in meta-analysis, ad-

dresses the robustness of the results. We excluded studies that

were sponsored by manufacturers of the drugs being compared,

Results

The search yielded 3,620 citations. Of 612 studies in-

spected, 319 were excluded: 44 studies with no or inade-

quate randomization; 23 studies with no appropriate drug

group; 230 open-label studies (181 from China); one study

with inappropriate participants; six studies with no usable

data; and 15 studies that used groups of second-genera-

tion antipsychotics. We included 293 publications on 78

studies with 167 relevant arms and 13,558 participants

(only the principal publications are referenced). Nine

studies included amisulpride, four aripiprazole, 28 cloza-

pine, 48 olanzapine, 21 quetiapine, 44 risperidone, two

sertindole, nine ziprasidone, and two zotepine.

Forty-nine studies were mainly sponsored by pharma-

ceutical companies, and 22 were publicly funded; funding

was uncertain for seven studies despite written queries.

The participants had relatively chronic courses of illness,

with mean ages in the mid-30s, but five trials included

only first-episode patients. The diagnostic criteria used

were mainly those of DSM-III-R, DSM-IV, and ICD-10 (for

details, see the online data supplement).

Primary Outcome Measure: PANSS Total Score

The pooled effect sizes of each second-generation an-

tipsychotic versus every other one are shown in Figure 1

(forest plots with the single studies can be found in the on-

line data supplement). It should be noted that all results

are shown twice. For example, the comparison between

amisulpride and olanzapine is described under “amisul-

pride versus other second-generation antipsychotics” as

well as under “olanzapine versus other second-generation

antipsychotics.” Despite the redundancy, the results are

easier to understand in this format; otherwise the reader

interested in a given drug would have to look up the find-

ings in different sections, making it difficult to see the ge-

Am J Psychiatry 166:2, February 2009

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153

single-blind studies, lower-quality studies ( Jadad score

META-ANALYSIS OF SECOND-GENERATION ANTIPSYCHOTICS

stalt. To save space, we present here, for the significant re-

sults, only the number of participants combined for the

two second-generation antipsychotics compared, the dif-

ference in PANSS scores (weighted mean difference), and

the p value, and, for nonsignificant results, the number of

participants combined for the two second-generation an-

tipsychotics compared. Negative values mean superiority

of the first second-generation antipsychotic throughout.

All statistical details are presented in figures and tables.

The data were rather homogeneous, and the few cases of

significant heterogeneity are reported in the text.

Amisulpride. There were no significant differences be-

tween amisulpride and olanzapine (N=701), risperidone

(N=291), and ziprasidone (N=122).

Aripiprazole. Aripiprazole was less efficacious than

olanzapine in two studies sponsored by aripiprazole’s

manufacturer (N=794, weighted mean difference=5.0, p=

0.002). Two further studies found no significant difference

compared with risperidone (N=372).

Clozapine. Clozapine was not significantly different

from olanzapine (N=619), quetiapine (N=232), risperi-

done (N=466), and ziprasidone (N=146). Clozapine was

significantly more efficacious than zotepine (N=59,

weighted mean difference=–6.0, p=0.002). The compari-

son with risperidone was significantly heterogeneous due

to one study sponsored by clozapine’s manufacturer (17);

excluding the study did not change the overall results.

Olanzapine. Olanzapine was significantly more effica-

cious than aripiprazole (N=794, weighted mean differ-

ence=–5.0, p=0.002), quetiapine (N=1,449, weighted mean

difference=–3.7, p

0.001)

and risperidone (N=1,016, weighted mean difference=4.6,

p=0.002). No significant differences compared with

amisulpride (N=122), clozapine (N=146), and quetiapine

(N=710) were found.

Zotepine. Zotepine was less efficacious than clozapine

(N=59, weighted mean difference=6.0, p=0.002).

Secondary Outcomes: Positive and Negative

Symptoms

The findings suggest that a substantial portion of the ef-

ficacy differences was due to superior improvement in

positive symptoms. Results for positive symptoms paral-

leled those found for overall symptoms except that olan-

zapine was not significantly more efficacious than risperi-

done (Figure 2; see also the online data supplement).

There were no significant differences for negative symp-

toms, with the exception of a superiority of quetiapine

compared with clozapine in two small Chinese studies of

first-episode schizophrenia (Figure 3). The comparisons

of quetiapine with risperidone and olanzapine with

ziprasidone were heterogeneous, and the results did not

change when outliers were excluded (see also the online

data supplement).

0.001), risperidone (N=2,404, weighted

mean difference=–1.9, p=0.006), and ziprasidone (N=

1,291, weighted mean difference=–8.3, p

Dropout Due to Inefficacy of Treatment

The rates of dropout due to poor efficacy were consis-

tent with the primary outcome measure, except that clo-

zapine was significantly more effective than risperidone,

and amisulpride was superior to ziprasidone. Further-

more, there was no significant difference in a single study

comparing aripiprazole and olanzapine, and no signifi-

cant difference between risperidone and ziprasidone (Fig-

ure 4; see also the online data supplement).

0.001). No signif-

icant difference between olanzapine and amisulpride (N=

701) or clozapine (N=619) emerged.

Quetiapine. Quetiapine was significantly less efficacious

than olanzapine (N=1,449, weighted mean difference=3.7,

0.001) and risperidone (N=1,953, weighted mean differ-

ence=3.2, p=0.003). There was no significant difference

compared with clozapine (N=232) and ziprasidone (N=

710).

Risperidone. Risperidone was significantly more effica-

cious than quetiapine (N=1,953, weighted mean differ-

ence=–3.2, p=0.003) and ziprasidone (N=1,016, weighted

mean difference=–4.6, p=0.002). It was less efficacious

than olanzapine (N=2,404, weighted mean difference=1.9,

p=0.006). No difference compared with amisulpride (N=

291), aripiprazole (N=372), clozapine (N=466), and sertin-

dole (N=493) emerged.

Sertindole. There was no significant difference between

sertindole and risperidone in two studies sponsored by

sertindole’s manufacturer, one in treatment-resistant pa-

tients, which found results with risperidone to be 7 points

better, the other without this criterion finding sertindole

Metaregressions

Metaregression did not detect significant effects of

study duration, antipsychotic dosages or dose ratios, or

study quality. Nor were there significant effects for spon-

sorship, with the exception of clozapine versus risperi-

done (coefficient=6.3 in the expected direction, p=0.015).

Sensitivity Analyses

The results of the extensive sensitivity analyses (phar-

maceutical sponsorship, single-blind studies, lower-qual-

ity studies, effectiveness studies, CATIE phase 2, first-

episode studies, Chinese studies, etc.) did not alter the pri-

mary findings (see the online data supplement). The im-

portant results are summarized below.

Pharmaceutical sponsorship and study quality. Ex-

cluding studies sponsored by pharmaceutical companies

(see the online data supplement) or excluding studies with

a Jadad quality score

3 did not change the results.

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Am J Psychiatry 166:2, February 2009

3.5 points better (N=493), leading to significant heteroge-

neity.

Ziprasidone. Ziprasidone was less efficacious than olan-

zapine (N=1,291, weighted mean difference=8.3, p

LEUCHT, KOMOSSA, RUMMEL-KLUGE, ET AL.

FIGURE 1. Results of Comparisons of PANSS Total Score in Meta-Analysis of Second-Generation Antipsychotics a

VERSUS:

Olanzapine: 4 studies, N=701, WMD=1.6 (–2.9 to 6.1), p=0.494

Risperidone: 2 studies, N=291, WMD=0.4 (–4.6 to 5.3), p=0.880

Ziprasidone: 1 study, N=122, WMD=–2.7 (–8.9 to 3.5), p=0.397

Olanzapine: 2 studies, N=794, WMD=5.0 (1.9 to 8.1), p=0.002

Risperidone: 2 studies, N=372, WMD=1.5 (–3.0 to 6.0), p=0.509

Olanzapine: 7 studies, N=619, WMD=1.3 (–1.3 to 4.0), p=0.327

Quetiapine: 4 studies, N=232, WMD=0.5 ( –1.9 to 2.9), p=0.679

Risperidone: 5 studies, N=466, WMD=–0.04 (–5.1 to 5.0), p=0.987

Ziprasidone: 1 study, N=146, WMD=0.5 (–6.7 to 7.7), p=0.892

Zotepine: 1 study, N=59, WMD=–6.0 b (–9.8 to –2.2), p=0.002

Amisulpride: 4 studies, N=701, WMD=–1.6 (–6.1 to 2.9 ), p=0.494

Aripiprazole: 2 studies, N=794, WMD=–5.0 (–8.1 to –1.9), p=0.002

Clozapine: 7 studies, N=619, WMD=–1.3 (–4.0 to 1.3), p=0.327

Quetiapine: 10 studies, N=1,449, WMD=–3.7 (–5.4 to –1.9), p<0.001

Risperidone: 15 studies, N=2,404, WMD=–1.9 (–3.3 to –0.6), p=0.006

Ziprasidone: 4 studies, N=1,291, WMD=–8.3 (–11.0 to –5.6), p<0.001

Clozapine: 4 studies, N=232, WMD=–0.5 (–2.9 to 1.9), p=0.679

Olanzapine: 10 studies, N=1,449, WMD=3.7 (1.9 to 5.4), p<0.001

Risperidone: 9 studies, N=1,953, WMD=3.2 (1.1 to 5.4), p=0.003

Ziprasidone: 2 studies, N=710, WMD=–0.1 (–6.4 to 6.1), p=0.974

Amisulpride: 2 studies, N=291, WMD=–0.4 (–5.3 to 4.6), p=0.880

Aripiprazole: 2 studies, N=372, WMD=–1.5 (–6.0 to 3.0), p=0.509

Clozapine: 5 studies, N=466, WMD=0.04 (–5.0 to 5.1), p=0.987

Olanzapine: 15 studies, N=2,404, WMD=1.9 (0.6 to 3.3), p=0.006

Quetiapine: 9 studies, N=1,953, WMD=–3.2 (–5.4 to –1.1), p=0.003

Sertindole: 2 studies, N=493, WMD=–2.0 (–12.2 to 8.2), p=0.704

Ziprasidone: 3 studies, N=1,016, WMD=–4.6 (–7.6 to –1.7), p=0.002

Risperidone: 2 studies, N=493, WMD=2.0 (–8.2 to 12.2 ), p=0.704

Amisulpride: 1 study, N=122, WMD=2.7 (–3.5 to 8.9 ), p=0.397

Clozapine: 1 study, N=146, WMD=–0.5 (–7.7 to 6.7), p=0.892

Olanzapine: 4 studies, N=1,291, WMD=8.3 (5.6 to 11.0), p<0.001

Quetiapine: 2 studies, N=710, WMD=0.1 (–6.1 to 6.4), p=0.974

Risperidone: 3 studies, N=1,016, WMD=4.6 (1.7 to 7.6 ), p=0.002

Clozapine: 1 study, N=59, WMD=6.0 b (2.2 to 9.8), p=0.002

–12,5 –10,5 –8,5 –6,5 –4,5 –2,5 –0,5 1,5 3,5 5,5 7,5 9,5 11,5

Weighted mean difference in PANSS points

Favors

1st drug c

Favors

2nd drug c

a Numbers in parentheses are 95% confidence intervals. WMD=weighted mean difference.

b Data based on Brief Psychiatric Rating Scale.

c The first drug is the one written vertically on the left side, and the second is the one written horizontally on the right side of the graph.

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META-ANALYSIS OF SECOND-GENERATION ANTIPSYCHOTICS

FIGURE 2. Results of Comparisons of PANSS Positive Symptom Subscore in Meta-Analysis of Second-Generation Antipsy-

chotics a

VERSUS:

Olanzapine: 4 studies, N=701, WMD=0.7 (–0.6 to 1.9), p=0.287

Risperidone: 3 studies, N=519, WMD=–0.03 (–1.3 to 1.2), p=0.966

Risperidone: 2 studies, N=372, WMD=1.3 (–0.3 to 2.8), p=0.103

Olanzapine: 6 studies, N=593, WMD=0.2 (–1.2 to 0.9), p=0.744

Quetiapine: 2 studies, N=142, WMD=0.7 (–0.7 to 2.1), p=0.320

Risperidone: 4 studies, N=541, WMD=–0.7 (–2.4 to 1.0), p=0.412

Ziprasidone: 1 study, N=144, WMD=–1.0 (–3.4 to 1.4), p=0.411

Amisulpride: 4 studies, N=701, WMD=–0.7 (–1.9 to 0.6), p=0.287

Clozapine: 6 studies, N=593, WMD=–0.2 (–0.9 to 1.2), p=0.744

Quetiapine: 6 studies, N=646, WMD=–1.9 (–2.7 to –1.1), p<0.001

Risperidone: 12 studies, N=1,545, WMD=–0.3 (–0.8 to 0.3), p=0.332

Ziprasidone: 2 studies, N=730, WMD=–3.1 (–4.3 to –1.9), p<0.001

Clozapine: 2 studies, N=142, WMD=–0.7 (–2.1 to 0.7), p=0.320

Olanzapine: 6 studies, N=646, WMD=1.9 (1.1 to 2.7), p<0.001

Risperidone: 7 studies, N=1,264, WMD=1.8 (1.2 to 2.5), p<0.001

Ziprasidone: 1 study, N=198, WMD=0.0 (–2.2 to 2.2), p=1.000

Amisulpride: 3 studies, N=519, WMD=0.03 (–1.2 to 1.3), p=0.966

Aripiprazole: 2 studies, N=372, WMD=–1.3 (–2.8 to 0.3), p=0.103

Clozapine: 4 studies, N=541, WMD=0.7 (–1.0 to 2.4), p=0.412

Olanzapine: 12 studies, N=1,545, WMD=0.3 (–0.3 to 0.8), p=0.332

Quetiapine: 7 studies, N=1,264, WMD=–1.8 (–2.5 to –1.2), p<0.001

Sertindole: 1 study, N=172, WMD=0.8 (–1.4 to 3.0), p=0.467

Ziprasidone: 1 study, N=204, WMD=–2.5 (–4.6 to –0.4), p=0.021

Risperidone: 1 study, N=172, SMD –0.8 (–3.0 to 1.4), p=0.467

Clozapine: 1 study, N=144, WMD=1.0 (–1.4 to 3.4), p=0.411

Olanzapine: 2 studies, N=730, WMD=3.1 (1.9 to 4.3), p<0.001

Quetiapine: 1 study, N=198, WMD=0.0 (–2.2 to 2.2), p=1.000

Risperidone: 1 study, N=204, WMD=2.5 (0.4 to 4.6 ), p=0.021

–6.5 –4.5 –2.5 –0.5 1.5 3.5 5.5

Weighted mean difference in PANSS points

Favors

1st drug b

Favors

2nd drug b

a Numbers in parentheses are 95% confidence intervals. WMD=weighted mean difference.

b The first drug is the one written vertically on the left side, and the second is the one written horizontally on the right side of the graph.

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