Review: Antipsychotic drugs improve symptoms, with different levels of side effects, in schizophrenia

Leucht S, Cipriani A, Spineli L, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multipletreatments meta-analysis. Lancet. 2013:382:951-62.

Clinical impact ratings: F ★★★★★✩✩ M ★★★★★★✩ Questions What is the relative efficacy of 15 antipsychotic drugs in acute treatment of schizophrenia? Do drugs differ for side effects?

duration 12 y) met the selection criteria. 71 RCTs had adequate allocation concealment, 13 used single blinding and 199 used double blinding, and 35 had adequate follow-up.

Review scope

Main results

Included studies evaluated oral monotherapy with first- (chlorpromazine and haloperidol) or second-generation (amisulpride, aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, quetiapine, risperidone, sertindole, ziprasidone, and zotepine) antipsychotic drugs for acute treatment of patients ≥ 18 years of age with schizophrenia or schizoaffective, schizophreniform, or delusional disorders. Exclusion criteria were patients with mainly negative symptoms, stable disorders, treatment resistance, or serious concomitant medical illness. Outcomes included symptom change (Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale), sedation, and weight gain, each assessed at about 6 weeks.

Results for network meta-analyses including direct and indirect comparisons of antipsychotic drugs vs placebo are shown in the Table. Network meta-analyses that compared different drugs showed that clozapine improved symptoms more than all other drugs (standardized mean difference [SMD] range −0.55 to −0.22); amisulpride, olanzapine, and risperidone were better than most other drugs (SMD range −0.11 to −0.33).

Review methods Cochrane Schizophrenia Group Specialized Register to Aug 2009; MEDLINE, EMBASE/Excerpta Medica, PsycINFO, Cochrane Central Register of Controlled Trials, and to 1 Sep 2012; 7 previous systematic reviews; drug company and US Food and Drug Administration Web sites; and reference lists were searched for published and unpublished randomized controlled trials (RCTs) that used at least single blinding. Trials that were done in China, did not clearly use allocation concealment, had a high risk for bias in sequence generation, or allowed switching between treatments were excluded. Data from direct and indirect treatment comparisons were combined using Bayesian network meta-analysis. 212 RCTs (n = 43 049, mean age 38 y, mean illness Network meta-analysis of antipsychotic drugs vs placebo in acute treatment of schizophrenia* Antipsychotic drugs

Outcomes Symptom change SMD (95% CrI)

Weight gain SMD (CrI)

Sedation OR (CrI)


−0.88 (−1.03 to −0.73)

0.65 (0.31 to 0.99)

8.82 (4.72 to 15.06)


−0.66 (−0.78 to −0.53)

0.20 (0.05 to 0.35)

1.42 (0.72 to 2.51)


−0.59 (−0.65 to −0.53)

0.74 (0.67 to 0.81)

3.34 (2.46 to 4.50)


−0.56 (−0.63 to −0.50)

0.42 (0.33 to 0.50)

2.45 (1.76 to 3.35)


−0.50 (−0.60 to −0.39)

0.38 (0.27 to 0.48)

1.40 (0.85 to 2.19)


−0.49 (−0.66 to −0.31)

0.71 (0.47 to 0.96)

8.15 (3.91 to 15.33)


−0.45 (−0.51 to −0.39)

0.09 (−0.00 to 0.17)

2.76 (2.04 to 3.66)


−0.44 (−0.52 to −0.35)

0.43 (0.34 to 0.53)

3.76 (2.68 to 5.19)


−0.43 (−0.52 to −0.34)

0.17 (0.05 to 0.28)

1.84 (1.05 to 3.05)


−0.39 (−0.52 to −0.26)

0.53 (0.38 to 0.68)

1.53 (0.82 to 2.62)


−0.39 (−0.49 to −0.30)

0.10 (−0.02 to 0.22)

3.80 (2.58 to 5.42)


−0.38 (−0.54 to −0.23)

0.55 (0.34 to 0.76)

7.56 (4.78 to 11.53)


−0.38 (−0.51 to −0.25)

0.23 (0.07 to 0.39)

3.28 (1.37 to 6.69)


−0.33 (−0.45 to −0.21)

0.10 (−0.02 to 0.21)

2.45 (1.31 to 4.24)


−0.33 (−0.43 to −0.22)

0.62 (0.49 to 0.74)

1.71 (0.63 to 3.77)

*CrI = credible interval; OR = odds ratio; SMD = standardized mean difference; other abbreviations defined in Glossary. Data were pooled using Bayesian methods with direct and indirect treatment comparisons. SMD < 0 and OR < 1 indicate benefit with antipsychotic drug.

19 November 2013 | ACP Journal Club | Volume 159 • Number 10

Conclusion In patients with schizophrenia, acute treatment with first- or secondgeneration antipsychotic drugs improve symptoms compared with placebo; drugs differed for the magnitude of side effects. Source of funding: No external funding. For correspondence: Professor S. Leucht, Technische Universität München, Munich, Germany. E-mail [email protected]

Commentary Leucht and colleagues report the results of a network metaanalysis—a statistical process that allows comparison of interventions that have not been directly tested against one other. Most of the conclusions are consistent with past studies: Clozapine is the most effective antipsychotic for acute treatment of schizophrenia (1). In terms of adverse effects, olanzapine, zotepine, and clozapine are the worst metabolic offenders, and haloperidol was the worst for extrapyramidal symptoms, although it did not differ from zotepine, with odds ratios of 4.7 and 3.0, respectively, compared with placebo. No surprises so far. However, Leucht and colleagues’ ranking of antipsychotic effectiveness does surprise in several ways. Amisulpride placed second, ahead of olanzapine and risperidone, although all had similar effect sizes compared with placebo. Amisulpride’s solid efficacy/ adverse effect profile is supported by a discontinuation rate that is lower than most other drugs. These findings echo an earlier (nonnetwork) meta-analysis where the most effective neuroleptic was clozapine, followed by amisulpride, risperidone, and olanzapine (2). Surprisingly, haloperidol seems to be as effective as most of the other antipsychotic drugs beyond the top 4. Paliperidone and risperidone surpassed all other drugs, including haloperidol, for hyperprolactinemia. Some of the top efficacy drugs are associated with metabolic problems. The risks and benefits of individual drugs should be discussed with patients and families, and preventive measures taken (e.g., diet and exercise) with appropriate monitoring for adverse effects—checking blood sugars and lipids. Finally, caution is advised when interpreting results of network meta-analyses: As compelling as treatment rankings seem to be, indirect comparison is only a placeholder for head-to-head RCTs. Adrian Preda, MD University of California Irvine Orange, California, USA References 1. Attard A, Taylor DM. CNS Drugs. 2012;26:491-508. 2. Davis JM, Chen N, Glick ID. Arch Gen Psychiatry. 2003;60:553-64.

© 2013 American College of Physicians

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ACP Journal Club. Review: antipsychotic drugs improve symptoms, with different levels of side effects, in schizophrenia.

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