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