Augmentation of clozapine with a second antipsychotic - a meta-analysis of randomized, placebo-controlled studies

Objective: Inadequate response to clozapine treatment is frequently encountered in practice and augmentation strategies have been developed in an attempt to improve response. Aims of the study were to evaluate the therapeutic effect of adding an antipsychotic drug to clozapine treatment. Method: Meta‐analysis of randomized, placebo‐controlled studies of antipsychotic augmentation of clozapine treatment. Results: Ten studies (including 522 subjects) met inclusion criteria. Antipsychotic augmentation showed significant benefit over the addition of placebo on only one outcome measure examined [mean effect size for rating scale score (BPRS/PANSS) −0.180, 95% CI −0.356 to −0.004]. Antipsychotic augmentation showed no advantage on withdrawals from trials (risk ratio 1.261, 95% CI 0.679–2.345) or on CGI scores (effect size −0.661, 95% CI −1.475 to 0.151). Duration of study was not associated with outcome (P = 0.95). There was no evidence of publication bias. Conclusion: In studies lasting up to 16 weeks, the addition of an antipsychotic to clozapine treatment has marginal therapeutic benefit. Longer and larger trials are necessary to demonstrate the precise therapeutic utility of antipsychotic co‐therapy with clozapine.