Does adding a second antipsychotic to clozapine improve clinical response in resistant schizophrenia?

Clozapine constitutes the treatment of choice in patients with schizophrenia with persisting symptoms despite antipsychotics at adequate dose and treatment duration. However, an important proportion does not respond to optimal doses of clozapine, so the addition of a second antipsychotic might increase clinical response. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified 17 systematic reviews comprising 62 studies addressing the question of this article, including 26 randomized trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded adding a second antipsychotic to clozapine in patients with refractory schizophrenia probably leads to little or no difference in clinical response, and increases adverse effects.