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

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1 ORIGINAL ARTICLE How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials S Leucht 1, D Arbter 1, RR Engel 2, W Kissling 1 and JM Davis 3 (2009) 14, & 2009 Nature Publishing Group All rights reserved /09 $ Department of Psychiatry and Psychotherapy, Klinik für Psychiatrie und Psychotherapie der TU-München, Klinikum rechts der Isar, Technische Universität München, München, Germany; 2 Department of Psychiatry and Psychotherapy, Psychiatrische Klinik der Ludwig-Maximilian-Universität München, München, Germany and 3 Department of Psychiatry, University of Illinois at Chicago, Chicago, IL, USA 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. (2009) 14, ; doi: /sj.mp ; published online 8 January 2008 Keywords: meta-analysis; schizophrenia; antipsychotic agents; treatment outcome; bias; methodology Introduction 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 Kirsch 2 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 secondgeneration (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 Correspondence: Dr S Leucht, Klinik für Psychiatrie und Psychotherapie der TU-München, Klinikum rechts der Isar, Technische Universität München, Ismaningerstr. 22, München 81675, Germany. stefan.leucht@lrz.tum.de Received 29 March 2007; revised 21 November 2007; accepted 26 November 2007; published online 8 January 2008 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 Search 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

2 430 language restrictions. The last search was made in August 2005; since then, studies from monthly MED- LINE 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 Group 3 ). We also searched the FDA web site and previous reviews 4,5 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 dosefinding studies as follows: amisulpride mg day 1 for predominantly negative symptoms and mg day 1 for positive symptoms, aripiprazole mg day, olanzapine mg day 1, quetiapine >250mgday 1, risperidone 4 6 mg day 1, sertindole mg day 1 and ziprasidone 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 (PANSS 8 ) total score from baseline, if not available the change of the Brief Psychiatric Rating Scale (BPRS 9 ), 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 Impression 10 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 (SAS 11 ), Extrapyramidal Symptoms Rating Scale (ESRS 12 )), 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 I 2 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 Laird 17 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, long-term studies on initially stable patients and one very short study of only 2 weeks duration. 29 Owing to space ations, 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 The exact

3 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) Study Antipsychotics and daily dose in mg, for flexible dose studies mean value (range) n Duration (weeks)/ minimum washout (days) Mean duration of illness in years Selected characteristics of patients Amisulpride 18 AMI (100; 300), 19 AMI (50; 100), 20 AMI 150, OLA (5; 20), 21 AMI 100, 22 AMI 50, (34; 36), , (70; 70), 34 69, 72 14, 13 6, (42) 11 Schizophrenia, disorganized, catatonic, undifferentiated or residual type, patients had to comply with Andreasen s criteria for negative schizophrenia (DSM-III) 12, (28) B10 Patients with residual schizophrenia and predominantly negative symptoms (DSM-III-R) 26, (2) NI Schizophrenia with predominantly negative symptoms (criteria, NI) 26, (0) 10 Patients with residual or hebephrenic schizophrenia and predominantly negative symptoms (DSM-III-R) 6, (8) 3 Schizophrenia and schizotypal personality disorder, young patients with mainly negative symptoms (DSM-III-R) 32 ARI (15; 30), HAL 10, 33 ARI (2; 5; 10), 24 ARI 15, 34 ARI (20; 30),, RIS 6 35 ARI (10; 15; 20), 36 ARI 30 (5 30), HAL 20 (5 20), 37 ARI (2; 10; 30), HAL 10, (102; 102), 104, 106 (93; 92; 94), , 155 (101; 101), (106; 106; 100), , 34, 35 (59; 60; 61), 63, 64 Aripiprazole 4, (5) 16.3 Schizophrenia or schizoaffective disorder with acute relapse (DSM-IV) 6, (NI) NI Hospitalized patients in acute relapse of schizophrenia (DSM-IV) 26, (3) NI Stabilized patients with chronic schizophrenia (DSM-IV) 4, (5) NI Schizophrenia or schizoaffective disorder with acute relapse (DSM-IV) 6, (2) NI Schizophrenia with acute relapse (DSM-IV) 4, (3) NI Schizophrenia with acute relapse (DSM-III-R) 4, (3) NI Schizophrenia with acute relapse (DSM-IV) 38 CLO 608 (NI), 16, 8 Clozapine 4, (3) NI Acute exacerbation of schizophrenia (clinical diagnosis) 39 OLA (5±2.5 a,10±2.5, 15±2.5), HAL 16.4, (65; 64; 69), 69, 68 Olanzapine 6, (4) 14 Acute exacerbation of schizophrenia (DSM-III-R) 431

4 Table 1 Study Continued Antipsychotics and daily dose in mg, for flexible dose studies mean value (range) n Duration (weeks)/ minimum washout (days) Mean duration of illness in years Selected characteristics of patients OLA (1; 10), 41 OLA NI (10 20), 42 OLA 15, 43 OLA 12.5, 20 OLA (5; 20), AMI 150, 7 QUE (75; 150; 300; 600; 750), HAL 12, 44 QUE 307 (75 750), 45 QUE 250, 29 QUE 484, RIS, 46 QUE 209 ( < 250), QUE 360 ( > 250), (52; 50), , , 87 72, 35 (70; 70), 70, 34 (53; 48; 52; 51; 54), 52, 51 54, 55 8, 4 156, 153, 73 94, 96, 96 6, (4) 16 Schizophrenia with an acute exacerbation (DSM-III-R) 28, (0) 11 Healthy outpatients with schizophrenia or schizoaffective disorder (DSM-IV) 6, (3) 13 Schizophrenia (DSM-IV) 7, (2) NI Schizophrenia (DSM-IV) 26, (2) NI Schizophrenia with predominantly negative symptoms (criteria, NI) Quetiapine 6, (7) 15 Acute exacerbation of (sub-) chronic schizophrenia (DSM-III-R) 6, (2) 15 Acute exacerbation of (sub-) chronic schizophrenia (DSM-III-R) 3, (2) 12 (Sub-) chronic schizophrenia (DSM-III-R) 2, (NI) NI Acute exacerbation of schizophrenia (DSM-IV) or schizoaffective disorder (MINI-PLUS) 6, (1) 15 Acute exacerbation of (sub-) chronic schizophrenia (DSM-III-R) 25 RIS NI (2 6), 47 RIS 7.8 (2 10), HAL 15.0 (4 20), 48 RIS (2; 6; 10; 16), HAL 20, 49 RIS (2; 6; 10; 16), HAL 20, 34 RIS 6, ARI (20; 30), 22, 20 53, 53, 54 (24; 22; 22; 24), 21, 22 (63; 64; 65; 64), 66, 66 99, (101; 101), 103 Risperidone 50.2, (28) NI Chronic schizophrenia (DSM-IV) 6, (7) 15 Schizophrenia (DSM-III-R) 8, (3) 16 Chronic schizophrenia (DSM-III-R) 8, (3) 16 Chronic schizophrenia (DSM-III-R) 4, (5) NI Schizophrenia or schizoaffective disorder with acute relapse (DSM-IV)

5 Table 1 Continued Study Antipsychotics and daily dose in mg, for flexible dose studies mean value (range) n Duration (weeks)/ minimum washout (days) Mean duration of illness in years Selected characteristics of patients 29 RIS, QUE 484, 50 RIS 4, RIS 8, 153, 156, 73 85, 78, 83 2, (NI) NI Acute exacerbation of schizophrenia (DSM-IV) or schizoaffective disorder (MINI-PLUS) 4, (NI) NI Chronic schizophrenia (DSM-III-R) 51 SER (8; 12; 20), 52 SER (20; 24), HAL (16), 53 SER (12; 20; 24), HAL (4; 8; 16), (52; 51; 54), 48 (117; 113), 115, 116 (76; 68; 72), (71; 67; 70), 73 Sertindole 6, (4) 14 Schizophrenia, history of a previous response to antipsychotic drugs (DSM-III-R) 8, (4) 15 Schizophrenia (DSM-III-R or DSM-IV) 8, (4) 16 Schizophrenia, history of a previous response to antipsychotic drugs (DSM-III-R or DSM-IV) 26 ZIP (40; 80; 160), 54 ZIP (80; 160), 55 ZIP (40; 120), 56 ZIP (40; 120; 200), HAL 15, 28 ZOT 241 (150 or 300), CHLOR 532 (300 or 600), 27 ZOT NI ( ), 23 ZOT 131 (25 225), (76; 72; 71), 75 (106; 104), 92 (44; 47), 48 (87; 78; 86), 85, 83 53, 53, 53 63, 58 39, 46 Ziprasidone 52, (0) NI Chronic, stable, in-patients with schizophrenia (DSM-III-R) 6, (3) 14 Acute exacerbation of (sub-) chronic schizophrenia or schizoaffective disorder (DSM-III-R) 4, (4) 16 Acute exacerbation of schizophrenia or schizoaffective disorder (DSM-III-R) 6, (3) NI Acute exacerbation of schizophrenia or schizoaffective disorder (DSM-III-R) Zotepine 8, (0) 11 Acute exacerbation of (sub-) chronic schizophrenia (DSM-III-R 26, (0) 14 Chronic schizophrenia (DSM-III-R) 8, (B5) 11 Residual schizophrenia with stable primary negative symptoms (ICD-10) Abbreviations: AMI, amisulpride; ARI, aripiprazole; CLO, clozapine; DSM-III, -III-R, -IV, different versions of the Diagnostic and Statistical Manual of Mental Disorders; HAL, haloperidol; ICD-9/ICD-10, International Classification of Diseases, 9th/10th Revision; MDI, mean duration of illness (years); n, number of patients; NI, not indicated; OLA, olanzapine;, placebo; QUE, quetiapine; RIS, risperidone; SER, sertindole; ZIP, ziprasidone; ZOT, zotepine. a Marks dosage groups that were excluded because they lay outside the optimum dose according to randomized dose finding studies. 433

6 434 formulae were reported there. Two-sided P-values < 0.05 were considered statistically significant. Results 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). Outcomes The results in terms of SMDs or RRs for the single drugs are shown in Figures Table 2 presents pooled results of the single drugs based on RDs and NNTs. Table 3 presents all results for dropout rates. Overall efficacy All antipsychotics were significantly more efficacious than placebo in the treatment of overall symptoms Study name Comparison Statistics for each study Hedges's g and 95% CI Hedges's Lower Upper g p-value Total Danion 1999 AMI Amisulpride pooled Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Potkin 2003 ARI Study ARI Study ARI Study ARI Aripiprazole pooled Honigfeld 1984a CLO Clozapine pooled Arvanitis 1997 HAL Beasley 1996 HAL Borison 1992 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Study HAL Study HAL Zborowski 1995 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Beasley 2003 OLA Corrigan 2004 OLA Kryzhanovskaya 2006 OLA Lecrubier 1999 OLA Olanzapine pooled Arvanitis 1997 QUE Borison 1996 QUE Fabre 1995 QUE Potkin 2006 QUE Small 1997 QUE Quetiapine pooled Bai 2003 RIS Borison 1992 RIS Chouinard 1993 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Study Ris-USA RIS Risperidone pooled van Kammen1996 SER Zborowski 1995 SER Zimbroff 1997 SER Sertindole pooled Arato 2002 ZIP Daniel 1999 ZIP Keck 1998 ZIP Study ZIP Ziprasidone pooled Cooper 2000a ZOT Cooper 2000b ZOT Möller 2004 ZOT Zotepine pooled Favours Antipsychotic Favours Placebo 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.

7 Study name Comparison Statistics for each study Risk ratio and 95% CI Risk ratio Lower Upper p-value Danion 1999 AMI Lecrubier 1999 AMI Loo 1997 AMI Amisulpride pooled Kane 2002 ARI Potkin 2003 ARI Study ARI Study ARI Study ARI Aripiprazole pooled Arvanitis 1997 HAL Beasley 1996 HAL Borison 1992 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Study HAL Zborowski 1995 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Kryzhanovskaya 2006 OLA Lecrubier 1999 OLA Olanzapine pooled Arvanitis 1997 QUE Borison 1996 QUE Fabre 1995 QUE Potkin 2006 QUE Small 1997 QUE Quetiapine pooled Bai 2003 RIS Borison 1992 RIS Chouinard 1993 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Study Ris-USA RIS Risperidone pooled van Kammen 1996 SER Zborowski 1995 SER Zimbroff 1997 SER Sertindole pooled Daniel 1999 ZIP Keck 1998 ZIP Ziprasidone pooled Cooper 2000a ZOT Cooper 2000b ZOT Zotepine pooled Favours Antipsychotic Favours Placebo 435 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. (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 < ). 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: , N = 28, n = 4498, P < ), and the associated RD was 0.18 (CI: 0.22 to 0.14, n = 4498, P < ), 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 < ). Amisulpride was not superior to

8 436 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). Standard Error Hedges's g Funnel Plot of Standard Error by Hedges's g 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). The pooled ES across SGA drugs was: N = 30, n = 4941, SMD = 0.48, CI: 0.57 to 0.38, P < (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 < ). 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 ed 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 < ). Amisulpride, haloperidol, olanzapine, ziprasidone and zotepine were found statistically significantly superior to placebo. Haloperidol also significantly reduced depression scores (see Figure 8). 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 = 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 = ), but using only those studies included in the sensitivity analysis did (slope = 0.01, Q = 1.44, d.f. = 1, P = ).

9 Study name Comparison Statistics for each study Risk ratio Lower Upper p-value Total Loo 1997 AMI Lecrubier 2006 AMI Amisulpride pooled Pigott 2003 ARI Aripiprazole pooled Beasley 2000 OLA Beasley 1996 OLA Lecrubier 2006 OLA Olanzapine pooled Arato 2002 ZIP Ziprasidone pooled Cooper 2000 ZOT Zotepine pooled Risk ratio and 95% CI Favours Antipsychotics Favours Placebo 437 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. Study name Comparison Statistics for each study Hedges's g and 95%CI Hedges's g Lower Upper p-value Total Danion 1999 AMI Loo 1997 AMI Pallière-Martinot 1995 AMI Amisulpride pooled Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Potkin 2003 ARI Study ARI Study ARI Aripiprazole pooled Arvanitis 1997 HAL Beasley 1996 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Study HAL Zborowski 1995 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Corrigan 2004 OLA Kryzhanovskaya 2006 OLA Lecrubier 1999 OLA Olanzapine pooled Arvanitis 1997 QUE Borison 1996 QUE Fabre 1995 QUE Potkin 2006 QUE Small 1997 QUE Quetiapine pooled Chouinard 1993 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Study Ris-USA RIS Risperidone pooled van Kammen1996 SER Zborowski 1995 SER Zimbroff 1997 SER Sertindole pooled Arato 2002 ZIP Daniel 1999 ZIP Keck 1998 ZIP Study ZIP Ziprasidone pooled Möller 2004 ZOT Zotepine pooled Favours Antipsychotic Favours Placebo 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.

10 438 Study name Comparison Statistics for each study Hedges's g Lower Upper p-value Total Boyer 1995 AMI Danion 1999 AMI Lecrubier 1999 AMI Loo 1997 AMI Palliere-Martinot 1995 AMI Amisulpride pooled Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Potkin 2003 ARI Study ARI Study ARI Study ARI Aripiprazole pooled Honigfeld 1984a CLO Clozapine pooled Arvanitis 1997 HAL Beasley 1996 HAL Borison 1992 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Study HAL Study HAL Zborowski 1995 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Corrigan 2004 OLA Kryzhanovskaya 2006 OLA Lecrubier 1999 OLA Olanzapine pooled Arvanitis 1997 QUE Borison 1996 QUE Fabre 1995 QUE Potkin 2006 QUE Small 1997 QUE Quetiapine pooled Borison 1992 RIS Chouinard 1993 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Study Ris-USA RIS Risperidone pooled van Kammen 1996 SER Zborowski 1995 SER Zimbroff 1997 SER Sertindole pooled Arato 2002 ZIP Daniel 1999 ZIP Keck 1998 ZIP Study ZIP Ziprasidone pooled Cooper 2000a ZOT Cooper 2000b ZOT Moller 2004 ZOT Zotepine pooled Hedges's g and 95% CI Favours Antipsychotic Favours Placebo 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. Quality of life Two olanzapine studies 20,41 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 = ). 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). Sedation 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: ; RD = 0.08, CI: , NNT = 13, CI: It is not possible to disentangle the

11 Study name Comparison Statistics for each study Hedges's g Lower Upper p-value Total Danion 1999 AMI Palliere-Martinot 1995 AMI Amisulpride pooled Honigfeld 1984a CLO Clozapine pooled Beasley 1996 HAL Study HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Corrigan 2004 OLA Olanzapine pooled Borison 1996 QUE Potkin 2006 QUE Quetiapine pooled Potkin 2006 RIS Study Ris-USA RIS Risperidone pooled van Kammen 1996 SER Sertindole pooled Study ZIP Daniel 1999 ZIP Keck 1998 ZIP Ziprasidone pooled Moller 2004 ZOT Zotepine pooled Hedges's g and 95% CI Favours Antipsychotic Favours Placebo 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. 439 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 : N = 37, n = 6001, RR = 0.75, CI: ; RD = 0.14, CI: 0.10 to 0.18, NNT = 7, CI: 6 10, P < ) (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: , RD = 0.17, CI: 0.20 to 0.13, NNT = 6, CI: 5 8, P < ). 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: , P = 0.81, RD = 0.01, CI: 0.01 to 0.03, P = 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. Discussion 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 Cohen 58 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

12 440 Study name Comparison Statistics for each study Risk ratio Lower Upper p-value Boyer 1995 AMI Danion 1999 AMI Loo 1997 AMI Amisulpride pooled Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Study ARI Study ARI Study ARI Aripiprazole pooled Arvanitis 1997 HAL Beasley 1996 HAL Borison 1992 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Study HAL Study HAL Zborowski 1995 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Corrigan 2004 OLA Olanzapine pooled Arvanitis 1997 QUE Borison 1996 QUE Small 1997 QUE Quetiapine pooled Bai 2003 RIS Borison 1992 RIS Chouinard 1993 RIS Marder 1994 RIS Risperidone pooled van Kammen 1996 SER Zborowski 1995 SER Zimbroff 1997 SER Sertindole pooled Arato 2002 ZIP Daniel 1999 ZIP Keck 1998 ZIP Study ZIP Ziprasidone pooled Cooper 2000a ZOT Cooper 2000b ZOT Zotepine pooled Total Risk ratio and 95% CI Favours Antipsychotic Favours Placebo 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. 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

13 Study name Comparison Statistics for each study Hedges's g Lower Upper p-value Total Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Potkin 2003 ARI Study ARI Study ARI Aripiprazole pooled Arvanitis 1997 HAL Beasley 1996 HAL Chouinard 1993 HAL Kane 2002 HAL Marder 1994 HAL Study HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Beasley 2003 OLA Risperidone pooled Arvanitis 1997 QUE Borison 1996 QUE Potkin 2006 QUE Quetiapine pooled Bai 2003 RIS Chouinard 1993 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Sertindole pooled van Kammen 1996 SER Zimbroff 1997 SER Ziprasidone pooled Keck 1998 ZIP Zotepine pooled Cooper 2000a ZOT Moller 2004 ZOT Olanzapine pooled Hedges's g and 95% CI Favours Antipsychotic Favours Placebo 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. 441 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 metaregression 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 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,

14 442 Study name Comparison Statistics for each study Risk ratio and 95% CI Risk ratio Lower Upper p-value Kane 2002 ARI Modell 2005 ARI Pigott 2003 ARI Potkin 2003 ARI Aripiprazole pooled Arvanitis 1997 HAL Beasley 1996 HAL Borison 1992 HAL Kane 2002 HAL Marder 1994 HAL Zimbroff 1997 HAL Haloperidol pooled Beasley 1996 OLA Beasley 1996a OLA Kryzhanovskaya 2006 OLA Risperidone pooled Arvanitis 1997 QUE Borison 1996 QUE Fabre 1995 QUE Potkin 2006 QUE Small 1997 QUE Quetiapine pooled Borison 1992 RIS Marder 1994 RIS Potkin 2003 RIS Potkin 2006 RIS Sertindole pooled van Kammen 1996 SER Zimbroff 1997 SER Ziprasidone pooled Daniel 1999 ZIP Keck 1998 ZIP Zotepine pooled Cooper 2000a ZOT Cooper 2000b ZOT Moller 2004 ZOT Olanzapine pooled Total Favours Antipsychotics Favours Placebo 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. 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 lowpotency 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 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 firstgeneration 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

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