On treatment of schizophrenia with medication, evidence-based guidelines agree on definitive recommendations for only a small number of issues: antipsychotic drugs should be used to reduce symptoms and the risk of relapse and rehospitalization, and clozapine is indicated for treatment-resistant schizophrenia and people with persistent suicidality or hostility.^1,2 The guidelines also provide more granular recommendations on how and when to use antipsychotic drugs. The evidence and guidelines are murkier on other issues, such as the use of other types of psychotropic medications, combinations of antipsychotic agents, and the role of long-acting, injectable antipsychotic drugs.

In a meta-analysis of cohort studies published in this issue of JAMA Psychiatry, Masuda et al³ found that clozapine was associated with better effectiveness outcomes than standard (ie, nonclozapine second-generation) antipsychotic drugs.³ People who took clozapine had lower risks of hospitalization and all-cause discontinuation, in spite of evidence that they were more severely ill than patients taking standard antipsychotic medications. The motivation for the study was prior meta-analyses of randomized clinical trials (RCTs) that failed to confirm the superior efficacy of clozapine, possibly because patients who enroll in RCTs are not representative of patients in typical settings, who might be more severely ill, less adherent to medication regimens, and less insightful into illness than those who enroll in treatment studies.