Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: meta-analysis

 Source:

Stefan Leucht, MD, Andrea Cipriani, MD, Loukia Spineli, Dimitris Mavridis, PhD, Deniz Örey, MD, Franziska Richter, MD, Myrto Samara, MD, Corrado Barbui, MD, Rolf R Engel, PhD, John R Geddes, MD, Werner Kissling, MD, Marko Paul Stapf, Bettina Lässig, Georgia Salanti, PhD, John M Davis, MD

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

The Lancet, Volume 382, Issue 9896, 14–20 September 2013, Pages 951–962

http://dx.doi.org/10.1016/S0140-6736(13)60733-3

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis

• Andrea Cipriani, MD^{b, e},
• Loukia Spineli^c,
• Dimitris Mavridis, PhD^c,
• Deniz Örey, MD^a,
• Franziska Richter, MD^a,
• Myrto Samara, MD^a,
• Prof Corrado Barbui, MD^b,
• Prof Rolf R Engel, PhD^d,
• Prof John R Geddes, MD^e,
• Werner Kissling, MD^a,
• Marko Paul Stapf^a,
• Bettina Lässig^a,
• Georgia Salanti, PhD^c,
• Prof John M Davis, MD^{f, g}

• ^a Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Munich, Germany
• ^b Department of Medicine and Public Health, Section of Psychiatry, University of Verona, Verona, Italy
• ^c Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece
• ^d Psychiatrische Klinik der Ludwig-Maximilian–Universität München, Munich, Germany
• ^e Department of Psychiatry, University of Oxford, Warneford Hospital, Oxford, UK
• ^f Psychiatric Institute, University of Illinois at Chicago, Chicago, IL, USA
• ^g Maryland Psychiatric Research Center, Baltimore, MD, USA

Refers To

• Christoph U Correll, Marc De Hert
• Antipsychotics for acute schizophrenia: making choices
• The Lancet, Volume 382, Issue 9896, 14–20 September 2013, Pages 919-920
• PDF (116 K)         

Referred to by

• Christoph U Correll, Marc De Hert
• Antipsychotics for acute schizophrenia: making choices
• The Lancet, Volume 382, Issue 9896, 14–20 September 2013, Pages 919-920
• PDF (116 K)         

• Department of Error
• The Lancet, Volume 382, Issue 9896, 14–20 September 2013, Page 940
• PDF (107 K)         

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Summary

Background

The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.

Methods

We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.

Findings

We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: 

clozapine 0·88, 0·73–1·03; 

amisulpride 0·66, 0·53–0·78; 

olanzapine 0·59, 0·53–0·65; 

risperidone 0·56, 0·50–0·63; 

paliperidone 0·50, 0·39–0·60; 

zotepine 0·49, 0·31–0·66; 

haloperidol 0·45, 0·39–0·51; 

quetiapine 0·44, 0·35–0·52; 

aripiprazole 0·43, 0·34–0·52; 

sertindole 0·39, 0·26–0·52; 

ziprasidone 0·39, 0·30–0·49; 

chlorpromazine 0·38, 0·23–0·54; 

asenapine 0·38, 0·25–0·51; 

lurasidone 0·33, 0·21–0·45; and 

iloperidone 0·33, 0·22–0·43. 

Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from −0·09 for the best drug (haloperidol) to −0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to −1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to −0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.

Interpretation

Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.

Funding

None.

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Figures and tables from this article:

Figure 1. 

Network of treatment comparisons for overall efficacy

The size of the nodes corresponds to the number of trials that study the treatments. Directly comparable treatments are linked with a line, the thickness of which corresponds to the number of trials that assess the comparison. AMI=amisulpride. ARI=aripiprazole. ASE=asenapine. CLO=clozapine. CPZ=chlorpromazine. HAL=haloperidol. ILO=iloperidone. LURA=lurasidone. OLA=olanzapine. PAL=paliperidone. PBO=placebo. QUE=quetiapine. RIS=risperidone. SER=sertindole. ZIP=ziprasidone. ZOT=zotepine.

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Figure 2. 

Efficacy and all-cause discontinuation of antipsychotic drugs

Drugs are reported in order of efficacy ranking. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. For efficacy, standard mean differences (SMDs) lower than 0 favour the column-defining treatment. For all-cause discontinuation, odds ratios (ORs) higher than 1 favour the column-defining treatment. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values, and vice versa. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underlined. CLO=clozapine. AMI=amisulpride. OLA=olanzapine. RIS=risperidone. PAL=paliperidone. ZOT=zotepine. HAL=haloperidol. QUE=quetiapine. ARI=aripiprazole. SER=sertindole. ZIP=ziprasidone. CPZ=chlorpromazine. ASE=asenapine. LUR=lurasidone. ILO=iloperidone. PBO=placebo.

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Figure 3. 

Forest plot for efficacy of antipsychotics drugs compared with placebo

Treatments are ranked according to their surface under the cumulative ranking (SUCRA) values (appendix p 98). SMD=standardised mean difference. CrI=credible interval.

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Figure 4. 

Forest plots for effect sizes of antipsychotic drugs compared with placebo for secondary outcomes

Results are shown for all-cause discontinuation (A), weight gain (B), extrapyramidal side-effects (C), prolactin increase (D), QTc prolongation (E), and sedation (F). Treatments are ranked according to their surface under the cumulative ranking (SUCRA) values (appendix pp 97–104). Extrapyramidal side-effects are defined by at least one use of antiparkinson drugs. OR=odds ratio. CrI=credible interval. SMD=standardised mean difference. *In one small study,⁴³ amisulpride (mean 473 mg per day) produced less prolactin increase than haloperidol (mean 28 mg per day), but prolactin concentrations were highly imbalanced at baseline, so we excluded this result (inclusion of this study in the analysis did not affect the ranking of the other drugs).

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Figure 5. 

Weight gain and extrapyramidal side-effects of antipsychotic drugs

Drugs are reported in order of weight-gain ranking. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. For weight gain, standard mean differences (SMDs) lower than 0 favour the column-defining treatment. For movement disorders, odds ratios (ORs) higher than 1 favour the row-defining treatment. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values, and vice versa. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underlined. Extrapyramidal side-effects are defined by at least one use of antiparkinson drugs. PBO=placebo. HAL=haloperidol. ZIP=ziprasidone. LUR=lurasidone. ARI=aripiprazole. AMI=amisulpride. ASE=asenapine. PAL=paliperidone. RIS=risperidone. QUE=quetiapine.

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Figure 6. 

Prolactin increase and QTc prolongation effects of antipsychotic drugs

Drugs are reported in order of prolactin increase ranking. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. For prolactin increase, standard mean differences (SMDs) lower than 0 favour the column-defining treatment. For QTc prolongation, SMDs lower than 0 favour the row-defining treatment. To obtain SMDs for comparisons in the opposite direction, negative values should be converted into positive values, and vice versa. Significant results are in bold and underlined. Clozapine and zotepine could not be included in the analysis, because their only comparison with each other was not linked with any other drug in the network. ARI=aripiprazole. QUE=quetiapine. PBO=placebo. ASE=asenapine. OLA=olanzapine. CPZ=chlorpromazine. ILO=iloperidone. ZIP=ziprasidone. LUR=lurasidone. SER=sertindole. HAL=haloperidol. RIS=risperidone. PAL=paliperidone. AMI=amisulpride.

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Figure 7. 

Sedation effects of antipsychotic drugs

Drugs are reported in order of sedation ranking. Comparisons between treatments should be read from left to right and the estimate is in the cell in common between the column-defining treatment and the row-defining treatment. For sedation, odds ratios (ORs) higher than 1 favour the column-defining treatment. To obtain ORs for comparisons in the opposite direction, reciprocals should be taken. Significant results are in bold and underlined. PBO=placebo. AMI=amisulpride. PAL=paliperidone. SER=sertindole. ILO=iloperidone. ARI=aripiprazole. LUR=lurasidone. RIS=risperidone. HAL=haloperidol. ASE=asenapine. OLA=olanzapine. QUE=quetiapine. ZIP=ziprasidone. CPZ=chlorpromazine. ZOT=zotepine. CLO=clozapine.

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