Abstract

Clozapine and risperidone are commonly used antipsychotics in schizophrenia and related disorders, but their comparative efficacy and safety remain unclear. This systematic review and meta-analysis included double-blind Randomized Clinical Trials (RCT) comparing these agents in adults with schizophrenia-spectrum disorders. A comprehensive search included databases in different languages up to September 2023. Analyzing data from 10 relevant studies out of 405 identified. Risperidone was associated with less weight gain while metabolic side effects remained a concern for both agents. Clozapine demonstrated superior efficacy on the Clinical Global Impression-Severity scale but was linked to a higher incidence of somnolence, hypersalivation, seizures, and discontinuations due to adverse events. Conversely, clozapine showed lower attrition rates due to inefficacy, suggesting the potential superior efficacy of clozapine over risperidone in managing schizophrenia despite not translating into improved mental state, global state, or general functioning outcomes compared to risperidone. These findings underscore the need for future studies to prioritize efficacy measures, patient-centered outcomes, and cardiometabolic safety, to better guide clinical decision-making. Moreover, the integration of long-term observational studies into evidence appraisal is essential, as it offers a more pragmatic understanding of anti-psychotic use in real-world settings.