How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials


We conducted a systematic review and meta-analysis of randomized controlled trials that compared second-generation antipsychotic (SGA) drugs with placebo in schizophrenic patients and which considered 13 different outcome measures. Thirty-eight randomized controlled trials with 7323 participants were included. All SGA drugs were more effective than placebo, but the pooled effect size (ES) for overall symptoms (primary outcome) was moderate (−0.51). The absolute difference (RD) in responder rates was at 18% (41% responded to drug compared with 24% to placebo, number needed to treat=6). Similar ESs were found for the other efficacy parameters: negative symptoms (ES=−0.39), positive symptoms (ES=−0.48), depression (ES=−0.26), relapse (RD 20%) and discontinuation due to inefficacy (RD 17%). Curiously, the efficacy of haloperidol for negative and depressive symptoms was similar to that of the SGA drugs. In contrast to haloperidol, there was no difference in terms of EPS between any SGA drugs and placebo, and there was also no difference in terms of dropouts due to adverse events. Meta-regression showed a decline in treatment response over time, and a funnel plot suggested the possibility of publication bias. We conclude that the drug versus placebo difference of SGA drugs and haloperidol in recent trials was moderate, and that there is much room for more efficacious compounds. Whether methodological issues account in part for the relatively low efficacy ESs and the scarcity of adverse event differences compared with placebo needs to be established.


Recent critics of psychotropic agents have claimed that these drugs are not efficacious. For example, the efficacy of anticholinesterase inhibitors for Alzheimer's dementia has been questioned,1 as has the efficacy of modern antidepressants, where Moncrieff and Kirsch2 found only a two-point difference between drug and placebo on the Hamilton rating scale for depression is found. In this context, we present a meta-analysis of 38 randomly controlled trials with 7323 participants comparing second-generation (atypical) antipsychotics with placebo. The aim is to assess the efficacy and safety of SGA drugs based on 13 outcomes. This large database allows for some judgments on the efficacy of antipsychotic drugs in general, and the degree of efficacy has implications for the interpretation of comparisons between second-generation antipsychotic (SGA) drugs and conventional antipsychotics. The review also assesses how well it can be documented that the newer drugs cause certain adverse effects. New versus old drug comparisons may establish that the new drug has a lower incidence of adverse effects, but they do not establish whether the newer drug can cause that adverse effect. Finally, the database allows for the discussion of a number of design issues in the context of placebo-controlled research in schizophrenia.

Materials and methods


We searched the register of the Cochrane Schizophrenia Group (CSG) for randomized controlled trials that compared oral routes of administration of SGAs (search terms: amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine) with placebo and/or conventional antipsychotics in the treatment of schizophrenia or related disorders (schizoaffective, schizophreniform or delusional disorder, any diagnostic criteria). There were no language restrictions. The last search was made in August 2005; since then, studies from monthly MEDLINE searches until September 2006 were added. The CSG register is compiled by regular methodical searches in numerous electronic databases (BIOSIS, CINAHL, Dissertation abstracts, EMBASE, LILACS, MEDLINE, PSYNDEX, PsycINFO, RUSSMED and Sociofile), supplemented by the hand searching of relevant journals and numerous conference proceedings (for details see the description of the Cochrane Schizophrenia Group3). We also searched the FDA web site and previous reviews4, 5 including those of the Cochrane Collaboration. Only studies meeting the quality criteria A (adequate randomization) and B (usually studies stated to be randomized without further details) according to the Cochrane handbook were included.6 We used only optimum doses of SGA drugs in fixed-dose studies as determined in controlled dose-finding studies as follows: amisulpride 50–300 mg day−1 for predominantly negative symptoms and 400–800 mg day−1 for positive symptoms, aripiprazole 10–30 mg day, olanzapine 10–20 mg day−1, quetiapine >250 mg day−1, risperidone 4–6 mg day−1, sertindole 16–24 mg day−1 and ziprasidone 120–160 mg day−1. It should be noted that there is a debate about the optimum quetiapine doses, but there is no evidence from dose-finding studies that shows higher doses are more efficacious. Indeed, in the studies included here the 750 mg quetiapine per day group was the least effective one.7 Eleven studies had an additional haloperidol arm. The results of the studies' haloperidol groups as compared with placebo were also pooled as a benchmark.

Data extraction and outcome parameters

All data were extracted independently by two reviewers. The first authors (when addresses were available) and all SGA drugs manufacturers were contacted for missing data. The primary outcome of interest was the mean overall change of symptoms according to the following hierarchy: the change of the Positive and Negative Syndrome Scale (PANSS8) total score from baseline, if not available the change of the Brief Psychiatric Rating Scale (BPRS9), then values at study end point of these scales, all based on intent-to-treat data set whenever available. We also analyzed negative symptoms, positive symptoms, depressive symptoms and overall quality of life in a similar fashion. For dichotomous efficacy measures, we analyzed responder rates, relapse rates and dropout due to inefficacy. The hierarchy for responder rates was 50% or more reduction from baseline on the PANSS/BPRS or better; or a Clinical Global Impression10 of much improved in so far as available; followed by the authors' definitions, which were usually at least 20 or 30% PANSS/BPRS reduction. Adverse effect outcomes were based on use of antiparkinson medication, mean EPS score (Simpson Angus Scale (SAS11), Extrapyramidal Symptoms Rating Scale (ESRS12)), dropouts due to adverse events and sedation. Dropouts for any reason were analyzed as a measure of acceptability of treatment. In a ‘once randomized–analyzed’ approach, we assumed in the case of dichotomous data that participants who dropped out prior to completion had no change in their condition.

Meta-analytic calculations

Standardized mean differences (SMDs) based on Hedges's adjusted g and its 95% confidence intervals (CIs) were calculated for continuous data. When s.d. were not reported, we either derived them from other measures of variability or P-values, or we used the average s.d. of the other studies. For dichotomous data, relative risks (RRs) and risk differences (RDs) along with their 95% CIs were calculated. We believe that both measures are important. The mathematical properties of RR are somewhat better than those of RD, because they make an adjustment for baseline risks.13 But RRs are often misinterpreted by clinicians.14, 15 The number of patients needed to treat (NNT) or the number of participants needed to harm were calculated as the inverse of the RD. We also showed the percentages in each group, because we feel that this is crucial for the reader to be able to appreciate the results. For example, a RR reduction of 50% is not meaningful if the reader does not know whether these underlying percentages are 60 versus 30% or 4 versus 2%.

We explored study heterogeneity by using the I2 statistics, a measure estimating how much of the variance is explained by study heterogeneity.16 Since in some of the analyses there was considerable heterogeneity, we applied the random effects model by Der-Simonian and Laird17 throughout for the pooling of the studies. Random-effect models are in general more conservative than fixed-effect models, because they take heterogeneity among studies into account. When studies had several arms (for example, risperidone, quetiapine and placebo), we used the mean of the single arms to avoid counting the same participants twice.

Unrestricted maximum likelihood random effects meta-regression was used to find whether there was a change of the primary efficacy outcome (mean change of overall symptoms) over time using publication year as a moderator.

We made a sensitivity analysis excluding studies that consisted of patients with predominantly negative symptoms,18, 19, 20, 21, 22, 23 long-term studies on initially stable patients24, 25, 26, 27, 28 and one very short study of only 2 weeks duration.29 Owing to space limitations, we do not show the results here, but any result that deviated to an important extent from the primary analysis will be mentioned.

Studies with negative results are less likely to be published than studies with significant results. The possibility of such publication bias was examined applying the ‘funnel plot’ method to the primary outcome (mean change of overall symptoms) described by Egger et al.30 All calculations were done with Comprehensive Meta-Analysis Version 2.31 The exact formulae were reported there. Two-sided P-values <0.05 were considered statistically significant.


The search

The searches in the register of the Cochrane Schizophrenia Group yielded 4166 citations. Of those publications that we ordered for inspection, 107 studies were excluded for the following reasons: no or inadequate randomization (N=50), no appropriate intervention or control group (N=29), inappropriate participants (N=2), no usable data (N=24), presentation of only a subgroup (N=1) and very short duration (5 days, N=1). The results of 202 studies comparing SGAs with first-generation antipsychotics will be reported elsewhere. Thirty-eight studies with 7323 participants were included (only the principle publication of each study is referenced): amisulpride (N=5), aripiprazole (N=7), clozapine (N=1), olanzapine (N=6), quetiapine (N=5), risperidone (N=7), sertindole (N=3), ziprasidone (N=4), zotepine (N=3; three studies provided results on two SGA drugs). Most of the studies were short-term and examined patients with positive symptoms, while only six studies examined patients with predominantly negative symptoms (four amisulpride studies, one olanzapine and amisulpride study and one zotepine study). Almost all studies were conducted by pharmaceutical companies and usually for registrational purposes. The minimum duration of washout was usually not more than a few days. The median of mean age was 38 years (see Table 1).

Table 1 Characteristics of included randomized controlled double-blind studies comparing second-generation antipsychotics with placebo (studies that provided comparisons for two second-generation antipsychotics are listed twice)


The results in terms of SMDs or RRs for the single drugs are shown in Figures 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 and 11. Table 2 presents pooled results of the single drugs based on RDs and NNTs. Table 3 presents all results for dropout rates.

Figure 1

Antipsychotic drugs versus placebo—Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) total score. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies; diamonds of pooled results.

Figure 2

Antipsychotic drugs versus placebo—non-responder rates. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 3

Funnel plot Positive and Negative Syndrome Scale (PANSS)/Brief Psychiatric Rating Scale (BPRS) total score. The haloperidol arms were excluded from the funnel plot. Egger's regression intercept suggested statistically significant asymmetry (d.f.=33, P<0.001).

Figure 4

Meta-regression on the effects of publication year on the effect size for the difference between second-generation antipsychotic (SGA) drugs and placebo on reduction of overall symptoms. Slope=0.02, Q=6.83, d.f.=1, P=0.0090. Circle size reflects the weight a study obtained in the meta-regression. Note that excluding the outlier on the left (an early clozapine study by Honigfeld et al.38 did not reverse statistical significance (slope=0.02, Q=4.39, d.f.=1, P=0.0362), but using only those studies included in the sensitivity analysis did (slope=0.01, Q=1.44, d.f.=1, P=0.2295).

Figure 5

Antipsychotics versus placebo—relapse. AMI, amisulpride; ARI, aripiprazole; OLA, olanzapine; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 6

Antipsychotic drugs versus placebo—positive symptoms. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 7

Antipsychotic drugs versus placebo—negative symptoms. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 8

Antipsychotic drugs versus placebo—depressive symptoms. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 9

Antipsychotic drugs versus placebo—use of antiparkinson medication. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine, circles are effect sizes of single studies, diamonds of pooled results.

Figure 10

Antipsychotics versus placebo—extrapyramidal symptoms rating scales. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine; circles are effect sizes of single studies, diamonds of pooled results.

Figure 11

Antipsychotics versus placebo—sedation. AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; HAL, haloperidol; OLA, olanzapine; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine, circles are effect sizes of single studies; diamonds of pooled results.

Table 2 Risk differences and numbers needed to treat/harm for the outcomes non-response, relapse, antiparkinson medication and somnolence
Table 3 Summary results of the outcomes dropout rates (any reason, inefficacy of treatment and adverse events)

Overall efficacy

All antipsychotics were significantly more efficacious than placebo in the treatment of overall symptoms (primary outcome). Nevertheless, with the exception of clozapine (SMD=–1.65, based on only one study), the effect sizes (ESs) were moderate (pooled ES of all SGA drugs: N=35, n=5568, SMD=−0.51, CI: −0.58 to −0.43, P<0.0001). This point is underscored by the difference in responder rates. Sertindole was not significantly more efficacious than placebo, and quetiapine and zotepine were only significant in the sensitivity analysis (see Figure 2). The pooled RR across SGA drugs was 0.78 (CI: 0.73–0.83, N=28, n=4498, P<0.0001), and the associated RD was –0.18 (CI: −0.22 to −0.14, n=4498, P<0.0001), thus reflecting an 18% difference in responder rates (overall 41 versus 24% responded under SGA drugs and placebo, respectively) or an NNT of 6 (CI: 5–7). The sensitivity analysis found an almost identical RR (0.79) and RD (−0.17). The funnel plot was asymmetrical, raising the possibility that studies with negative results have not been published (Egger's regression intercept, d.f.=33, P<0.001, see Figure 3). The meta-regression with publication year as a moderator suggested the drug–placebo difference may have become smaller over time (see Figure 4). This effect was no longer statistically significant in the sensitivity analysis excluding patients with predominantly negative symptoms and long-term or very short-term studies. It should be noted that the subset in the sensitivity analysis was more homogeneous, but statistical power was also reduced (see Figures 1, 2 and 4; Table 2).

Seven studies on relapse of 6–12 months duration showed that aripiprazole, olanzapine, ziprasidone and zotepine reduced the relapse risk significantly more than placebo. The RR for relapse suggested a more pronounced superiority of the SGA drugs than the RR for responder rates, but the RD was similar (all SGA drugs combined: N=7, n=1371, RR=0.41, CI: 0.28 to 0.59, RD=−0.20, CI: −11 to −30, NNT=5, CI: 3–9, P<0.0001). Amisulpride was not superior to placebo. Data on clozapine, risperidone and sertindole were not available (see Figure 5).

Positive symptoms

Amisulpride and zotepine showed no difference in positive symptoms compared with placebo, but for both drugs only studies on patients with predominantly negative symptoms were available. While there were no data on clozapine, the other antipsychotics were significantly more effective than placebo in the treatment of positive symptoms, with ESs ranging between −0.36 (aripiprazole) and −0.82 (risperidone). The pooled ES across SGA drugs was: N=30, n=4941, SMD=−0.48, CI: −0.57 to −0.38, P<0.0001 (see Figure 6).

Negative symptoms

In contrast to clozapine (only one study) and quetiapine (P=0.07, the effect was significant in the sensitivity analysis excluding the only 2-week study), the other antipsychotics improved negative symptoms more than placebo. The ESs for negative symptoms were usually lower than those for positive symptoms (ES across SGA drugs: N=36, n=5403, SMD=−0.39, CI: −0.45 to −0.33, P<0.0001). It should be noted that most of the studies investigated patients with predominantly positive symptoms. Amisulpride is the only compound for which several studies on patients suffering predominantly from negative symptoms are available. Such populations are more appropriate for examining effects on negative symptoms. One such study showed no superiority of zotepine.23 In one such olanzapine study, the 5 mg day−1 group was effective, but the 20 mg day−1 group was not.20 Haloperidol also reduced overall negative symptoms significantly more than placebo (see Figure 7).

Depressive symptoms

On the basis of more limited data (14 studies), the SGA drugs also reduced depressive symptoms more than placebo (N=14, n=1910, SMD=−0.26, CI: −0.38 to −0.15, P<0.0001). Amisulpride, haloperidol, olanzapine, ziprasidone and zotepine were found statistically significantly superior to placebo. Haloperidol also significantly reduced depression scores (see Figure 8).

Quality of life

Two olanzapine studies20, 41 found olanzapine significantly superior to placebo on overall quality of life (N=2, n=406, SMD=−0.38, CI: −0.59 to −0.17, P=0.0003). Möller et al.23 found no significant superiority of zotepine (combined effect on the physical and the psychic components of the SF-36 scale: n=72, SMD=−0.24, CI: −0.70 to 0.22, P=0.309). No data on the other SGA drugs and haloperidol compared with placebo are available.

Extrapyramidal adverse effects

In contrast to haloperidol, no SGA induced significantly more EPS than placebo, whether in terms of use of antiparkinson medication or in terms of EPS rating scales. Only risperidone showed a trend of higher EPS on the rating scales (P=0.075) (see Figures 9 and 10 and Table 2).


Although all antipsychotics were numerically more sedating than placebo (see Figure 10), statistical significance was reached only for haloperidol, quetiapine and zotepine using the RR and for aripiprazole, haloperidol and quetiapine using the RD. The pooled effect across SGA drugs was: N=21, n=3367, RR=1.91, CI: 1.44–2.52; RD=0.08, CI: 0.04–0.11, NNT=13, CI: 9–25. It is not possible to disentangle the effects of concomitant benzodiazepines from those of the antipsychotics using meta-analysis (see Figure 11 and Table 2).

Dropout rates

Amisulpride, olanzapine, sertindole and zotepine were not associated with significantly lower rates of all-cause dropouts than placebo, whereas aripiprazole, clozapine, quetiapine, risperidone and ziprasidone were. This composite measure of efficacy, tolerability and other factors has been used as a proxy measure for acceptability of treatment.3 The overall dropout rate when all studies were combined was as high as 47% (pooled ES SGA drugs versus PBO: N=37, n=6001, RR=0.75, CI: 0.69–0.82; RD=−0.14, CI: −0.10 to −0.18, NNT=7, CI: 6–10, P<0.0001) (see Table 3).

Dropouts due to insufficient efficacy confirmed that all antipsychotics were superior to placebo (pooled results across SGA drugs: N=36, n=5809, RR=0.52, CI: 0.45–0.59, RD=−0.17, CI: −0.20 to −0.13, NNT=6, CI: 5–8, P<0.0001).

No antipsychotic, not even haloperidol, was associated with significantly increased RR in terms of dropouts due to adverse events, but there was a significantly increased RD for haloperidol and sertindole. The pooled ES across SGA drugs was also not significant: N=31, n=5320, RR=1.1, CI: 0.72–1.51, P=0.81, RD=0.01, CI: −0.01 to 0.03, P=0.46. In the sensitivity analysis, aripiprazole was even associated with fewer dropouts due to adverse events than placebo, while an increased risk was found for ziprasidone, haloperidol and sertindole.


This review, based on 38 randomized controlled trials with 7323 participants, demonstrates the efficacy of SGA drugs over placebo on various measures of response, relapse and discontinuation due to poor efficacy. Nevertheless, the relatively small absolute difference in responder rates of 18%, translating into an NNT of six, and the medium ES for the primary outcome (change of overall symptoms) of −0.51 are striking. Furthermore, we found that the drug–placebo difference diminished over time. This effect had already been reported in an analysis of psychiatric trials by Trikalinos et al.57

Cohen58 described an ES of −0.50 as large enough to be visible to the naked eye, for example, the difference between 14-year-old and 18-year-old girls (about 1 inch) or the difference in IQ between clerical and semiskilled workers. We pooled the (usually earlier) studies using the BPRS and found an absolute difference of nine BPRS points between SGA drugs and placebo, which we translate into a difference of one point on the Clinical Global Impression Scale.59 We pooled the more recent studies using the PANSS and found a difference of 10 points. According to Leucht et al.,59 a PANSS total score difference of 15 points reflects minimal improvement according to the CGI.

The meta-analysis confirms that the SGA drugs are no ‘wonder drugs’ in terms of efficacy, and that there is much room for better medication, confirming recent naturalistic studies.60, 61 But the fact that the ESs of the haloperidol arm studies also revealed a moderate effect raises the question whether antipsychotic drugs have previously been overestimated. An early NIMH study has often been quoted as a proof for a strong effect of antipsychotic drugs.62 In this study (n=344), the response rate to drug was 61% compared with 22% in the placebo group, resulting in a response rate difference of 41% or an NNT of 2. In contrast to the more chronic participants in our studies, half of the participants had a first episode of schizophrenia and received antipsychotic drugs for the first time. The Cochrane Review comparing the standard drug chlorpromazine to placebo found an NNT of 4 in the short-term (n=590, 11 studies, response rate drug 65.9%, placebo 41.5%, weighted RD 25%) and 6 in the medium term (n=1121, 13 randomized controlled trials, response rate drug 28.1%, response rate placebo 13.1%, weighted RD 18%).63 The Cochrane Review on haloperidol showed a pronounced superiority over placebo, with an NNT of 3 in both short- and medium-term studies (medium-term results: n=308, eight studies, response rate drug 43.8%, placebo 14.4%, weighted RD 32%64). An older review on maintenance treatment found substantially lower relapse rates of 16% in the antipsychotic group compared with 53% in the placebo group.65 The relapse results of our review also suggested a more pronounced long-term superiority of SGA drugs, at least in terms of RRs. In summary, these reviews highlight that there is a substantial placebo response, which in our sample was 24% based on a response definition of at least 20–30% total score reduction in two-thirds of the studies. Consistent with our meta-regression analyzing publication year as a moderator, the degree of improvement seems to decrease over time.

An obvious question is whether design issues can, at least partly, account for these findings. A mean age of 37.5 years suggests that the participants were relatively chronic. Less chronic patients respond better to antipsychotic drugs. For example, the mean age in the early NIMH study mentioned above was 28.2 years.62 Remission rates of more than 80% have been achieved in 1-year studies of first-episode patients.66, 67 The generalizability of recent studies is called into question by the fact that only 10–15% of the eligible schizophrenic patients are entered into clinical trials.68, 69 ‘Failed studies’ in which neither haloperidol nor the SGA drugs were better than placebo cannot explain the relatively small difference, because the pooled ES of studies with a significantly effective haloperidol arm was similar (Hedges's g=−0.54, RD=−0.16). The high dropout rates in the studies (overall 47%) may decrease the drug–placebo difference, because the antipsychotic drugs do not have time to develop their full effects, and the full deterioration under placebo is also decreased if participants are prematurely taken out of the trial. The Cochrane Review on haloperidol excluded studies with dropout rates higher than 50% and found an NNT of 3.64 We did not apply such an approach, because it is not clear what degree of attrition will clearly bias the results and in which direction. On the other hand, the studies in the Cochrane Review were all published before 1993 and were arguably less ‘sophisticated,’ for example, because some did not use standardized diagnostic criteria and rating scales, had small sample sizes or were carried out in single centers. It should also be noted that haloperidol is a high-potency antipsychotic drug. CATIE and CUtLASS suggested that these results are not necessarily representative for low-potency or intermediate-potency antipsychotics.60, 61 Preliminary work by Davis et al.4 had revealed a similar ES for the difference between haloperidol and placebo equaling 0.60.

The funnel plots raised the possibility of publication bias. This method must be interpreted with caution, because there can be other reasons for the plot asymmetry, especially true heterogeneity, because studies with different SGA drugs and possibly different efficacy were pooled.30 Another issue is that almost all included studies were organized by pharmaceutical companies, who may have not published studies with small drug–placebo difference, raising the possibility of an ‘industry bias.’70 Nevertheless, even if methodological issues accounted, in part, for the small differences, it is difficult to interpret the effectiveness of SGA drugs in clinical practice. On the one hand, the data clearly show that the SGA drugs are no wonder drugs in terms of efficacy, producing a moderate ES (0.49) in comparison with placebo. But what then do the ESs of those SGA drugs that were more efficacious than first-generation antipsychotics in the analysis by Davis et al.4 mean? They ranged between 0.21 (olanzapine) and 0.49 (clozapine).

Other problems are evident when negative symptoms and depression are considered. With the exception of amisulpride and olanzapine (5 but not 20 mg day−120), there is still no proof that SGA drugs are effective for predominantly negative symptoms, because populations with predominantly positive symptoms are simply not appropriate to examine this issue due to secondary effects, and statistical methods such as path analysis can only, in part, account for these effects.71 Even more surprising was that haloperidol decreases not only negative symptoms, but also depressive symptoms significantly more than placebo. It has been said that conventional antipsychotics induce depression rather than alleviate it.72 It may be that the depression-inducing effect is a long-term one, while haloperidol improves depression in the short run. But it is also possible that all these symptoms are truly related and the expression of the same underlying pathology.

While there was substantial evidence that haloperidol produces EPS, none of the SGA drugs induced significantly more EPS than placebo. This finding demonstrates that the EPS risks of all SGA drugs are low, but it does not prove that they are all free from these adverse effects. A meta-analysis comparing SGA drugs with placebo in bipolar mania suggested that some SGA drugs do induce EPS.73 There is some evidence that bipolar patients are more sensitive to EPS than people with schizophrenia.74 But many participants in schizophrenia trials were previously treated with antipsychotics for long periods with washout periods often lasting only a few days. In contrast, many mania patients had much less exposure to antipsychotics. Consequently, carryover effects of prior treatment may have reduced drug–placebo differences. Indeed, if overall rates of use of antiparkinson medication under the different SGA drugs are considered rather than ESs compared with placebo, these rates were considerable for some SGA drugs (amisulpride 2%—please note that these were low doses up to only 300 mg day−1, aripiprazole 13.3%, clozapine—no data available, olanzapine 15.6%, quetiapine 9.5%, risperidone 32.3%, sertindole 12.7%, ziprasidone 21.3%, zotepine 9.5%), although all were clearly lower than for haloperidol (47.6%). The placebo rates varied from 2.5% (amisulpride studies) to 25.9% (risperidone studies). Longer washout periods would improve the sensitivity for detecting EPS differences but are problematic from an ethical point of view.

There were few differences between antipsychotics and placebo in terms of dropouts due to adverse events. Unfortunately, some efficacy-related adverse events such as agitation due to insufficient efficacy are counted as adverse events and falsely inflate the placebo ‘adverse event’ tabulation. For example, we found fewer dropouts due to adverse events with aripiprazole than with placebo. We suggest that only adverse events reflecting side effects should be presented as dropouts due to adverse events to make this outcome a useful global measure of tolerability.

For perspective, even internal medicine drugs rarely cure. It is impossible to make direct comparisons of different treatments of different diseases, but (to give an example of a contemporary drug) the NNT to avoid vascular events or death by statins is higher than 100.75 The implication of our findings for antipsychotic drug development is that there is a great deal of room for improvement, let alone cure.


  1. 1

    Bentham P, Gray R, Raftery J, Hills R, Sellwood E, Courtney C et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet 2004; 363: 2105–2115.

    Article  Google Scholar 

  2. 2

    Moncrieff J, Kirsch I . Efficacy of antidepressants in adults. BMJ 2005; 331: 155–157.

    Article  Google Scholar 

  3. 3

    Adams CE, Coutinho E, Davis JH, Duggan L, Leucht S, Tharyan P, Cochrane Schizophrenia Group In: The Cochrane Library. John Wiley & Sons Ltd: Chichester, UK, 2007.

    Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Geddes J, Freemantle N, Harrison P, Bebbington P . Atypical antipsychotics in the treatment of schizophrenia: systematic overview and meta-regression analysis. BMJ 2000; 321: 1371–1376.

    CAS  Article  Google Scholar 

  6. 6

    Higgins JPT, Green S . Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. In: The Cochrane Library. John Wiley & Sons Ltd: Chichester, UK, 2005.

    Google Scholar 

  7. 7

    Arvanitis LA, Miller BG, Seroquel Trial 13 Study Group. Multiple fixed doses of ‘seroquel’ (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. Biol Psychiatry 1997; 42: 233–246.

    CAS  Article  Google Scholar 

  8. 8

    Kay SR, Fiszbein A, Opler LA . The positive and negative syndrome scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–275.

    CAS  Article  Google Scholar 

  9. 9

    Overall JE, Gorham DR . The brief psychiatric rating scale. Psychol Rep 1962; 10: 790–812.

    Google Scholar 

  10. 10

    Guy W . Clinical Global Impression. In: ECDEU Assessment Manual for Psychopharmacology, Revised (DHEW Publ No ADM 76-338). National Institute of Mental Health: Rockville, MD, 1976, pp 218–222.

    Google Scholar 

  11. 11

    Simpson M, Angus JW . A rating scale for extrapyramidal side effects. Acta Psychiatr Scand Suppl 1970; 212: 11–19.

    CAS  Article  Google Scholar 

  12. 12

    Chouinard G, Ross-Chouinard A, Annable L, Jones BD . The extrapyramidal symptom rating scale. Can J Neurol Sci 1980; 7: 233.

    Google Scholar 

  13. 13

    Smeeth L, Haines A, Ebrahim S . Numbers needed to treat derived from meta-analyses—sometimes informative, usually misleading. BMJ 1999; 318: 1548–1551.

    CAS  Article  Google Scholar 

  14. 14

    Elmore JG, Gigerenzer G . Benign breast disease—the risks of communicating risk. N Engl J Med 2005; 353: 297–299.

    CAS  Article  Google Scholar 

  15. 15

    Boissel JP, Cucherat M, Li W, Chatellier G, Gueyffier F, Buyse M et al. The problem of therapeutic efficacy indices. 3. Comparison of the indices and their use. Therapie 1999; 54: 405–411.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16

    Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

    Article  Google Scholar 

  17. 17

    Der-Simonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    CAS  Article  Google Scholar 

  18. 18

    Boyer P, Lecrubier Y, Puech AJ, Dewailly J, Aubin F . Treatment of negative symptoms in schizophrenia with amisulpride. Br J Psychiatry 1995; 166: 68–72.

    CAS  Article  Google Scholar 

  19. 19

    Danion JM, Rein W, Fleurot O . Improvement of schizophrenic patients with primary negative symptoms treated with amisulpride. Am J Psychiatry 1999; 156: 610–616.

    CAS  PubMed  Google Scholar 

  20. 20

    Lecrubier Y, Bouhassira M, Olivier V, Lancrenon S, Crawford AM . Olanzapine versus amisulpride and placebo in the treatment of negative symptoms and deficit states of chronic schizophrenia. Eur Neuropsychopharmacol 1999; 9: S288.

    Article  Google Scholar 

  21. 21

    Loo H, Poirier-Littre MF, Theron M, Rein W, Fleurot O . Amisulpride versus placebo in the medium-term treatment of the negative symptoms of schizophrenia. Br J Psychiatry 1997; 170: 18–22.

    CAS  Article  Google Scholar 

  22. 22

    Paillère Martinot ML, Lecrubier Y, Martinot JL, Aubin F . Improvement of some schizophrenic deficit symptoms with low doses of amisulpride. Am J Psychiatry 1995; 152: 130–134.

    Article  Google Scholar 

  23. 23

    Möller HJ, Riedel M, Müller N, Fischer W, Kohnen R . Zotepine versus placebo in the treatment of schizophrenic patients with stable primary negative symptoms: a randomized double-blind multicenter trial. Pharmacopsychiatry 2004; 37: 270–278.

    Article  Google Scholar 

  24. 24

    Pigott TA, Carson WH, Saha AR, Torbeyns AF, Stock EG, Ingenito GG . Aripiprazole for the prevention of relapse in stabilized patients with chronic schizophrenia: a placebo-controlled 26-week study. J Clin Psychiatry 2003; 64: 1048–1056.

    CAS  Article  Google Scholar 

  25. 25

    Bai YM, Yu SC, Lin CC . Risperidone for severe tardive dyskinesia: a 12-week randomized, double-blind, placebo-controlled study. J Clin Psychiatry 2003; 64: 1342–1348.

    CAS  Article  Google Scholar 

  26. 26

    Arato M, O'Connor R, Meltzer H, Zeus Study Group. Ziprasidone in the long-term treatment of negative symptoms and the prevention of exacerbation of schizophrenia. Int Clin Psychopharmacol 2002; 17: 207–215.

    CAS  Article  Google Scholar 

  27. 27

    Cooper SJ, Butler A, Tweed J, Welch C, Raniwalla J . Zotepine in the prevention of recurrence: a randomised, double-blind, placebo-controlled study for chronic schizophrenia. Psychopharmacology 2000a; 150: 237–243.

    CAS  Article  Google Scholar 

  28. 28

    Cooper SJ, Tweed J, Raniwalla J, Butler A, Welch C . A placebo controlled comparison of zotepine versus chlorpromazine in patients with acute exacerbation of schizophrenia. Acta Psychiatr Scand 2000b; 101: 218–225.

    CAS  Article  Google Scholar 

  29. 29

    Potkin SG, Gharabawi GM, Greenspan AJ, Mahmoud R, Kosik-Gonzalez C, Rupnow MF et al. A double-blind comparison of risperidone, quetiapine and placebo in patients with schizophrenia experiencing an acute exacerbation requiring hospitalization. Schizophr Res 2006; 85: 254–265.

    Article  Google Scholar 

  30. 30

    Egger M, Davey SG, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    CAS  Article  Google Scholar 

  31. 31

    Borenstein M, Hedges LV, Higgins JPT, Rothstein H . Comprehensive Meta-analysis Version 2, 2006.

  32. 32

    Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL et al. Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 2002; 63: 763–771.

    CAS  Article  Google Scholar 

  33. 33

    Modell S, Werner C, Spevakne-Gorocs T, Kungel M, Ebrecht M . Efficacy and safety of lower doses of aripiprazole. Pharmacopsychiatry 2005; 38: 264.

    Article  Google Scholar 

  34. 34

    Potkin SG, Saha AR, Kujawa MJ, Carson WH, Ali M, Stock E et al. Aripiprazole, an antipsychotic with a novel mechanism of action, and risperidone vs placebo in patients with schizophrenia and schizoaffective disorder. Arch Gen Psychiatry 2003; 60: 681–690.

    CAS  Article  Google Scholar 

  35. 35

    Center for Drug Evaluation and Research. Study 138001. Application number 21-436. Medical review(s)., 2002.

  36. 36

    Center for Drug Evaluation and Research. Study 93202. Application number 21-436. Medical review(s)., 2002.

  37. 37

    Center for Drug Evaluation and Research. Study 94202. Application number 21-436. Medical review(s)., 2002.

  38. 38

    Honigfeld G . Clozapine: antipsychotic activity in treatment-resistant schizophrenics. Adv Ther 1984; 1: 77–97.

    Google Scholar 

  39. 39

    Beasley CM, Tollefson GD, Tran P, Satterlee W, Sanger T, Hamilton S et al. Olanzapine versus haloperidol and placebo. Acute phase results of the American double-blind olanzapine trial. Neuropsychopharmacology 1996a; 14: 111–123.

    CAS  Article  Google Scholar 

  40. 40

    Beasley CM, Sanger T, Satterlee W . Olanzapine versus placebo: results of a double-blind fixed dose olanzapine trial. Psychopharmacology 1996b; 124: 159–167.

    CAS  Article  Google Scholar 

  41. 41

    Beasley CM, Sutton VK, Hamilton SH, Walker DJ, Dossenbach M, Taylor CC et al. A double-blind, randomized, placebo-controlled trial of olanzapine in the prevention of psychotic relapse. J Clin Psychopharmacol 2003; 23: 582–594.

    CAS  Article  Google Scholar 

  42. 42

    Corrigan MH, Gallen CC, Bonura ML, Merchant KM . Effectiveness of the selective D-4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry 2004; 55: 445–451.

    CAS  Article  Google Scholar 

  43. 43

    Kryzhanovskaya L, Schulz C, McDougle CJ, Frazier JA, Dittmann R, Robertson-Plouch C et al. A double-blind, placebo-controlled study of olanzapine in adolescents with schizophrenia. Biol Psychiatry 2006; 59: 224S.

    Article  Google Scholar 

  44. 44

    Borison RL, Arvanitis LA, Miller BG . ICI 204,636 an atypical antipsychotic efficacy and safety in a multicenter placebo-controlled trial in patients with schizophrenia. J Clin Psychopharmacol 1996; 16: 158–169.

    CAS  Article  Google Scholar 

  45. 45

    Fabre LF, Arvanitis L, Pultz J, Jones VM, Malick JB, Slotnick VB . Seroquel™ (ICI 204,636), a novel, atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 1995; 17: 366–378.

    Article  Google Scholar 

  46. 46

    Small JG, Hirsch SR, Arvanitis LA, Miller BG, Link CGG, Seroquel Study Group. Quetiapine in patients with schizophrenia. A high- and low-dose comparison with placebo. Arch Gen Psychiatry 1997; 54: 549–557.

    CAS  Article  Google Scholar 

  47. 47

    Borison RL, Pathiraja AP, Diamond BI, Meibach RC . Risperidone—clinical safety and efficacy in schizophrenia. Psychopharmacol Bull 1992; 28: 213–218.

    CAS  PubMed  Google Scholar 

  48. 48

    Chouinard G, Jones B, Remington G . Canadian placebo-controlled study of fixed doses of risperidone and haloperidol in the treatment of chronic schizophrenic patients. J Clin Psychopharmacol 1993; 13: 25–40.

    CAS  Article  Google Scholar 

  49. 49

    Marder SR, Meibach RC . Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–835.

    CAS  Article  Google Scholar 

  50. 50

    Office of Clinical Pharmacology and Biopharmacy Review. Study Ris-USA-72. NDA number: 20272. Janssen-Cilag, Data on File 1996.

  51. 51

    van Kammen DP . A randomized, controlled, dose-ranging trial of sertindole in patients with schizophrenia. Psychopharmacology 1996; 124: 168–175.

    CAS  Article  Google Scholar 

  52. 52

    Zborowski J, Schmitz P, Staser J, O'Neil J, Giles K, Wallin B et al. Efficacy and safety of sertindole in a trial of schizophrenic patients. Presented at the Congress of the American Psychiatric Association in Miami 1995.

  53. 53

    Zimbroff DL, Kane JM, Tamminga CA, Daniel DG, Mack RJ, Wozniak PJ et al. Controlled, dose response study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 1997; 154: 782–791.

    CAS  Article  Google Scholar 

  54. 54

    Daniel DG, Zimbroff DL, Potkin SG, Reeves KR, Harrigan EP, Lakshminarayanan M . Ziprasidone 80 and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Neuropsychopharmacology 1999; 20: 491–505.

    CAS  Article  Google Scholar 

  55. 55

    Keck P, Buffenstein A, Ferguson J, Feighner J, Jaffe W, Harrigan EP et al. Ziprasidone 40 and 120 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 4-week placebo controlled trial. Psychopharmacology 1998; 140: 173–184.

    CAS  Article  Google Scholar 

  56. 56

    Center for Drug Evaluation and Research. Study 115. Approval package for application number 20-825. Medical review., 2000.

  57. 57

    Trikalinos TA, Churchill R, Ferri M, Leucht S, Tuunainen A, Wahlbeck K et al. Effect sizes in cumulative meta-analyses of mental health randomized trials evolved over time. J Clin Epidemiol 2004; 57: 1124–1130.

    Article  Google Scholar 

  58. 58

    Cohen J . Statistical Power Analysis for the Behavioral Sciences. Academic Press: New York, 1969.

    Google Scholar 

  59. 59

    Leucht S, Kane JM, Etschel E, Kissling W, Hamann J, Engel RR . Linking the PANSS, BPRS, and CGI: clinical implications. Neuropsychopharmacology 2006; 31: 2318–2325.

    Article  Google Scholar 

  60. 60

    Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    CAS  Article  Google Scholar 

  61. 61

    Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. Randomized controlled trial of the effect on Quality of Life of second- vs first-generation antipsychotic drugs in schizophrenia—Cost Utility of the Latest Antipsychotic Drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–1086.

    CAS  Article  Google Scholar 

  62. 62

    Cole JO . Phenothiazine treatment in acute schizophrenia. Arch Gen Psychiatry 1964; 10: 246–261.

    Article  Google Scholar 

  63. 63

    Adams CE, Awad G, Rathbone J . Chlorpromazine versus placebo for schizophrenia. In: The Cochrane Library. Wiley and Sons: Chichester, UK, 2007.

    Google Scholar 

  64. 64

    Joy C, Adams CE, Laurie S . Haloperidol versus placebo for schizophrenia. In: The Cochrane Library. Wiley and Sons: Chichester, UK, 2006.

    Google Scholar 

  65. 65

    Gilbert P, Harris MJ, McAdams LA . Neuroleptic withdrawal in schizophrenic patients. A review of the literature. Arch Gen Psychiatry 1995; 52: 173–188.

    CAS  Article  Google Scholar 

  66. 66

    Lieberman JA, Phillips M, Gu H, Stroup S, Zhang P, Kong L et al. Atypical and conventional antipsychotic drugs in treatment-naive first-episode schizophrenia: a 52-week randomized trial of clozapine vs chlorpromazine. Neuropsychopharmacology 2003; 28: 995–1003.

    CAS  Article  Google Scholar 

  67. 67

    Robinson DG, Woerner MG, Alvir JMJ, Geisler S, Koreen A, Sheitman B et al. Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder. Am J Psychiatry 1999; 156: 544–549.

    CAS  Article  Google Scholar 

  68. 68

    Riedel M, Strassnig M, Muller N, Zwack P, Moller HJ . How representative of everyday clinical populations are schizophrenia patients enrolled in clinical trials? Eur Arch Psychiatry Clin Neurosci 2005; 255: 143–148.

    CAS  Article  Google Scholar 

  69. 69

    Hofer A, Hummer M, Huber R, Kurz M, Walch T, Fleischhacker WW . Selection bias in clinical trials with antipsychotics. J Clin Psychopharmacol 2000; 20: 699–702.

    CAS  Article  Google Scholar 

  70. 70

    Heres S, Davis J, Maino K, Jetzinger E, Kissling W, Leucht S . Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine: an exploratory analysis of head-to-head comparison studies of second-generation antipsychotics. Am J Psychiatry 2006; 163: 185–194.

    Article  Google Scholar 

  71. 71

    Leucht S, Pitschel-Walz G, Abraham D, Kissling W . Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 1999; 35: 51–68.

    CAS  Article  Google Scholar 

  72. 72

    Van Putten T, May RP . Akinetic depression in schizophrenia. Arch Gen Psychiatry 1978; 35: 1101–1107.

    CAS  Article  Google Scholar 

  73. 73

    Scherk H, Pajonk FG, Leucht S . Second generation antipsychotics in the treatment of acute mania: a systematic review and meta-analysis of randomized, controlled trials. Arch Gen Psychiatry 2007; 64: 442–455.

    CAS  Article  Google Scholar 

  74. 74

    Cavazzoni PA, Berg PH, Kryzhanovskaya LA, Briggs SD, Roddy TE, Tohen M et al. Comparison of treatment-emergent extrapyramidal symptoms in patients with bipolar mania or schizophrenia during olanzapine clinical trials. J Clin Psychiatry 2006; 67: 107–113.

    CAS  Article  Google Scholar 

  75. 75

    Cheung BM, Lauder IJ, Lau C-P, Kumana CR . Meta-analysis of large randomized controlled trials to evaluate the effect of statins on cardiovascular outcomes. Br J Clin Pharmacol 2004; 57: 640–651.

    CAS  Article  Google Scholar 

Download references


We are much indebted to the Cochrane Schizophrenia Group. Without access to its register of randomized controlled trials, this review would not have been possible. We also thank AstraZeneca, BristolMyersSquibb, EliLilly, Lundbeck and Sanofi-Aventis for providing unpublished data.

Author information



Corresponding author

Correspondence to S Leucht.

Additional information

Disclosure/Conflict of interest

This meta-analysis received no funding. Stefan Leucht has received speaker or consultancy honoraria from Sanofi-Aventis, BMS, Lilly, Janssen, Lundbeck and Pfizer. Lilly and Sanofi-Aventis sponsored research projects by Dr Leucht. Werner Kissling has received speaker or consultancy honoraria from Sanofi-Aventis, BMS, Lilly, Janssen, Lundbeck, Bayer and Pfizer. Dieter Arbter, Rolf R Engel and John M Davis have no conflict of interest to declare.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Leucht, S., Arbter, D., Engel, R. et al. How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials. Mol Psychiatry 14, 429–447 (2009).

Download citation


  • meta-analysis
  • schizophrenia
  • antipsychotic agents
  • treatment outcome
  • bias
  • methodology

Further reading