Evidence of Clozapine’s Effectiveness in Schizophrenia: A Systematic Review and Meta-Analysis of Randomized Trials

OBJECTIVE: The purpose of this study was to evaluate all available trial-based evidence on the effectiveness of clozapine in schizophrenia as compared with conventional neuroleptics. METHOD: All randomized, controlled trials comparing clozapine with a conventional neuroleptic in which there was satisfactory concealment of patients’ treatment allocation were located through electronic searches in all languages of several databases and through contacting authors of recent trials as well as the manufacturer of clozapine. At least two independent reviewers assessed trials for inclusion in the study and extracted data for meta-analysis. RESULTS: The review included 2,530 randomly assigned participants in 30 trials, most of them short-term. Clozapine-treated patients showed more clinical improvement and experienced significantly fewer relapses during treatment, although the risk of blood dyscrasias in long-term treatment may be as high as 7%. Scores on symptom rating scales showed greater improvement among clozapine-treated patients, who were also more satisfied with their treatment. However, there was no evidence that the superior clinical effect of clozapine is reflected in levels of functioning; on the other hand, global functional and pragmatic outcomes were frequently not reported. Clinical improvement was most pronounced in patients with treatment-resistant illness. CONCLUSIONS: This meta-analysis confirms that clozapine is more effective than conventional neuroleptics in reducing symptoms of patients with both treatment-resistant and nonresistant schizophrenia. Future trials should be long-term pragmatic community trials or should address the effectiveness of clozapine in special patient populations. An international standard set of outcomes, including pragmatic assessments of functioning, would greatly enhance the comparison and summation of trials and future assessments of effectiveness.