Elsevier

The Lancet

Volume 373, Issue 9657, 3–9 January 2009, Pages 31-41
The Lancet

Articles
Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis

https://doi.org/10.1016/S0140-6736(08)61764-XGet rights and content

Summary

Background

Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia.

Methods

We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation.

Findings

We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs. Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride −0·31 [95% CI −0·44 to −0·19, p<0·0001], clozapine −0·52 [−0·75 to −0·29, p<0·0001], olanzapine −0·28 [−0·38 to −0·18, p<0·0001], and risperidone −0·13 [−0·22 to −0·05, p=0·002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication.

Interpretation

Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost.

Funding

National Institute of Mental Health.

Introduction

The high costs of second-generation (atypical) antipsychotic drugs, with $7·5 billion sales in the USA in 2003,1 has led to a continuing debate about their benefits compared with first-generation compounds. Limitations of previous reviews2, 3 were that they analysed only one global efficacy outcome, even though the main advantage of second-generation antipsychotic drugs is claimed to be their broad efficacy spectrum. In particular, these drugs are thought to improve negative symptoms, depression, and quality of life more than do conventional antipsychotic drugs. Improved efficacy for these problems is thought to be a major characteristic of the atypicality of second-generation antipsychotic drugs, in addition to a reduction in extrapyramidal side-effects. In previous meta-analyses (apart from Cochrane reviews), side-effects were not assessed thoroughly, even though they are important criteria in drug choice. Furthermore, the number of randomised controlled trials in which antipsychotic drugs were assessed is continually increasing, making new meta-analyses necessary. We present a meta-analysis of randomised controlled trials to compare the effects of second-generation antipsychotic drugs with first-generation antipsychotic drugs on several outcomes in patients with schizophrenia.

Section snippets

Search

We searched (without language restrictions) the register of the Cochrane Schizophrenia Group,4 US Food and Drugs Administration website, and previous reviews2, 3, 4 for randomised controlled trials in which oral formulations of second-generation antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone, and zotepine) were compared with first-generation antipsychotic drugs for the treatment of schizophrenia or related disorders

Search

Our search yielded 4166 citations. Of 411 inspected, we excluded 107 studies for reasons of inadequate randomisation (n=50), no appropriate intervention or control group (n=29), inappropriate participants (n=2), no usable data (n=24), presentation of a subgroup only (n=1), and very short duration (ie, 5 days; n=1). Another 65 open or single-blind studies were excluded after the absence of double blind was detected as a bias.

We included a total of 239 publications of 150 double-blind studies

Discussion

Four second-generation antipsychotic drugs—amisulpride, clozapine, olanzapine, and risperidone—were more efficacious than first-generation drugs in the main domains (overall change in symptoms, and positive and negative symptoms). The other five second-generation antipsychotic drugs were only as efficacious as first-generation antipsychotic drugs, even in terms of negative symptoms. Second-generation antipsychotic drugs caused fewer extrapyramidal side-effects than did haloperidol, even when

References (51)

  • MS Swartz et al.

    Effects of antipsychotic medications on psychosocial functioning in patients with chronic schizophrenia: Findings from the NIMH CATIE Study

    Am J Psychiatry

    (2007)
  • R Rosenheck et al.

    A comparison of clozapine and haloperidol in hospitalized patients with refractory schizophrenia

    N Engl J Med

    (1997)
  • R Rosenheck et al.

    Effectiveness and cost of olanzapine and haloperidol in the treatment of schizophrenia—a randomized controlled trial

    JAMA

    (2003)
  • PB Jones 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)
  • S Leucht et al.

    Defining ‘response’ in antipsychotic drug trials: recommendations for the use of scale-derived cutoffs

    Neuropsychopharmacology

    (2007)
  • JPT Higgins et al.

    Measuring inconsistency in meta-analyses

    BMJ

    (2003)
  • AF Lehman et al.

    Practice guideline for the treatment of patients with schizophrenia, 2nd edn

    Am J Psychiatry

    (2004)
  • P Waraich et al.

    Haloperidol dose for the acutely ill phase of schizophrenia

    Cochrane Database Syst Rev

    (2002)
  • M Borenstein et al.

    Comprehensive meta-analysis version 2, 2006

  • Mosholder AD. Review and evaluation of clinical data. Application information. NDA 20-639. Food and Drug Administration...
  • JM Davis et al.

    Antipsychotic drugs

  • M Sernyak et al.

    Experience of VA psychiatrists with pharmaceutical detailing of antipsychotic medications

    Psychiatr Serv

    (2007)
  • RM Berman et al.

    The efficacy and safety of aripiprazole as adjunctive therapy in major depressive disorder: A multicenter, randomized, double-blind, placebo-controlled study

    J Clin Psychiatry

    (2007)
  • JR Calabrese et al.

    A randomized, double-blind, placebo-controlled trial of quetiapine in the treatment of bipolar I or II depression

    Am J Psychiatry

    (2005)
  • ND Woodward et al.

    A meta-analysis of neuropsychological change to clozapine, olanzapine, quetiapine and risperidone in schizophrenia

    Int J Neuropsychopharmacol

    (2005)
  • Cited by (1570)

    View all citing articles on Scopus
    View full text