Elsevier

The Lancet

Volume 379, Issue 9831, 2–8 June 2012, Pages 2063-2071
The Lancet

Articles
Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis

https://doi.org/10.1016/S0140-6736(12)60239-6Get rights and content

Summary

Background

Relapse prevention with antipsychotic drugs compared with placebo in patients with schizophrenia has not been sufficiently addressed by previous systematic reviews. We aimed to assess the association between such drugs and various outcomes in patients with schizophrenia to resolve controversial issues.

Methods

We searched the Cochrane Schizophrenia Group's specialised register for reports published before Nov 11, 2008; and PubMed, Embase, and ClinicalTrials.gov for those before June 8, 2011. We also contacted pharmaceutical companies and searched the reference lists of included studies and previous reviews. Randomised trials of patients with schizophrenia continued on or withdrawn from any antipsychotic drug regimen after stabilisation were eligible. Our primary outcome was relapse between 7 and 12 months. We also examined safety and various functional outcomes. We used the random effects model and verified results for the primary outcome with a fixed effects model. Heterogeneity was investigated with subgroup and meta-regression analyses.

Findings

We identified 116 suitable reports from 65 trials, with data for 6493 patients. Antipsychotic drugs significantly reduced relapse rates at 1 year (drugs 27% vs placebo 64%; risk ratio [RR] 0·40, 95% CI 0·33–0·49; number needed to treat to benefit [NNTB] 3, 95% CI 2–3). Fewer patients given antipsychotic drugs than placebo were readmitted (10% vs 26%; RR 0·38, 95% CI 0·27–0·55; NNTB 5, 4–9), but less than a third of relapsed patients had to be admitted. Limited evidence suggested better quality of life (standardised mean difference −0·62, 95% CI −1·15 to −0·09) and fewer aggressive acts (2% vs 12%; RR 0·27, 95% CI 0·15–0·52; NNTB 11, 6–100) with antipsychotic drugs than with placebo. Employment data were scarce and too few deaths were reported to allow significant differences to be identified. More patients given antipsychotic drugs than placebo gained weight (10% vs 6%; RR 2·07, 95% CI 2·31–3·25), had movement disorders (16% vs 9%; 1·55, 1·25–1·93), and experienced sedation (13% vs 9%; 1·50, 1·22–1·84). Substantial heterogeneity in size of effect was recorded. In subgroup analyses, number of episodes, whether patients were in remission, abrupt or gradual withdrawal of treatment, length of stability before trial entry, first-generation or second-generation drugs, and allocation concealment method did not significantly affect relapse risk. Depot preparations reduced relapse (RR 0·31, 95% CI 0·21–0·41) more than did oral drugs (0·46, 0·37–0·57; p=0·03); depot haloperidol (RR 0·14, 95% CI 0·04–0·55) and fluphenazine (0·23, 0·14–0·39) had the greatest effects. The effects of antipsychotic drugs were greater in two unblinded trials (0·26, 0·17–0·39) than in most blinded studies (0·42, 0·35–0·51; p= 0·03). In a meta-regression, the difference between drug and placebo decreased with study length.

Interpretation

Maintenance treatment with antipsychotic drugs benefits patients with schizophrenia. The advantages of these drugs must be weighed against their side-effects. Future studies should focus on outcomes of social participation and clarify the long-term morbidity and mortality of these drugs.

Funding

German Ministry of Education and Research.

Introduction

Schizophrenia is a debilitating, often lifelong disease. Naturalistic studies have shown that about 80% of patients relapse within 5 years.1, 2 Although the half-life of many oral antipsychotic drugs is roughly 24 h, relapses often occur only months or years after last treatment. In 1995, Gilbert and co-workers3 reported that antipsychotic maintenance treatment reduces relapse rates, but many issues remain unresolved and guidelines are not consistent.4

Should patients who have had one episode of acute psychosis—20% of whom will not have another2, 5—receive maintenance treatment and for how long? Previous reviews3, 6 grouped remitted and symptomatic patients together, but remitted individuals might relapse at a decreased rate. Long-term treatment with antipsychotics has been associated with increased mortality,7 but in another study8 mortality was reduced, possibly because suicide is prevented. The acquisition expense of antipsychotic drugs is substantial (estimated US$18·5 billion worldwide in 2010),9 but schizophrenia's main cost is admission to hospital. Therefore, policy makers need to know by how much antipsychotic drugs reduce this outcome. Whether depot drugs are better than oral forms because of improved compliance is unclear.10 Additionally, previous reviews3, 6, 11, 12 have not assessed side-effects (eg, weight gain, sedation, or socially disfiguring tardive dyskinesia), or addressed whether antipsychotic drugs improve functional outcomes (eg, employment or quality of life). Finally, the evidence for so-called supersensitivity psychosis13 needs to be examined. The theory suggests that long-term use of antipsychotic drugs increases dopamine receptor sensitivity; abrupt rather than gradual withdrawal of antipsychotics could then cause rebound psychoses.

In the last review of all maintenance antipsychotic drugs, Gilbert and colleagues3 did not undertake a full meta-analysis or subgroup analyses. We aimed to obtain information about antipsychotic drugs compared with palcebo as maintenance treatment in patients with schizophrenia to update guidelines and practice.

Section snippets

Search strategy and selection criteria

For a full version of our methods see the published protocol14 and appendix. Briefly, we searched the Cochrane Schizophrenia Group's specialised register (compiled by regular systematic searches; appendix p 12) for reports published before Nov 18, 2008; and PubMed, Embase, and ClinicalTrials.gov for those published before June 8, 2011. We used the search term “[cessation* or withdr?w* or discontinu* or halt* or stop* or drop?out* or dropout* or rehospitalis* or relaps* or maintain* or

Results

We identified 1923 records, of which 116 reports of 65 randomised controlled trials (63 double-blind, placebo-controlled; two open with no treatment as comparator) with a total of 6493 participants were eligible (appendix pp 12, 16–30). However, one of these reports could not be included in the meta-analyses (appendix p 31). We obtained one unpublished study from a pharmaceutical company (Vanderburg D, Pfizer, personal communication), and additional information about seven trials.23, 24, 25, 26

Discussion

We have established that antipsychotic maintenance treatment substantially reduces relapse risk in all patients with schizophrenia for up to 2 years of follow-up. The effect was robust in important subgroups such as patients who had had only one episode and those in remission, but seemed to decrease in size with time. Moreoever, we present novel results for outcomes other than relapse, particularly social participation.

Clinicians and guideline developers need to know whether patients who have

References (52)

  • M Shepherd et al.

    The natural history of schizophrenia: a five-year follow-up study of outcome and prediction in a representative sample of schizophrenics

    Psychol Med Suppl

    (1989)
  • P Gilbert et al.

    Neuroleptic withdrawal in schizophrenic patients: a review of the literature

    Arch Gen Psychiatry

    (1995)
  • JM Kane et al.

    Optimising pharmacologic treatment of psychotic disorders

    J Clin Psychiatry

    (2003)
  • DG Robinson et al.

    Predictors of treatment response from a first episode of schizophrenia or schizoaffective disorder

    Am J Psychiatry

    (1999)
  • JM Davis

    Overview: maintenance therapy in psychiatry: I Schizophrenia

    Am J Psychiatry

    (1975)
  • WA Ray et al.

    Atypical antipsychotic drugs and the risk of sudden cardiac death

    N Engl J Med

    (2009)
  • Antipsychotic drugs: technologies and global markets

    (2010)
  • J Tiihonen et al.

    A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia

    Am J Psychiatry

    (2011)
  • Schizophrenia: core interventions in the treatment and management of schizophrenia in primary and secondary care (update)

    (2009)
  • S Leucht et al.

    Relapse prevention in schizophrenia with new-generation antipsychotics: a systematic review and exploratory meta-analysis of randomized, controlled trials

    Am J Psychiatry

    (2003)
  • G Chouinard et al.

    Lack of tolerance to long-term neuroleptic treatment in dopamine tuberoinfundibular system

    Acta Psychiatr Scand

    (1980)
  • K Komossa et al.

    Maintenance treatment with antipsychotic drugs for schizophrenia

  • JPT Higgins et al.

    Cochrane Handbook for Systematic Reviews of Interventions

    (2008)
  • WT Carpenter et al.

    Continuous versus targeted medication in schizophrenic outpatients: outcome results

    Am J Psychiatry

    (1990)
  • JPT Higgins et al.

    Measuring inconsistency in meta-analyses

    BMJ

    (2003)
  • AC Viguera et al.

    Clinical risk following abrupt and gradual withdrawal of maintenance neuroleptic treatment

    Arch Gen Psychiatry

    (1997)
  • Cited by (684)

    View all citing articles on Scopus
    View full text