Sex differences in the efficacy and tolerability of antipsychotic drugs in people with an acute exacerbation of schizophrenia: protocol for an individual-participant-data, dose-response, network meta-analysis [version 1].

Background There are currently no sex-specific recommendations for antipsychotic prescribing in schizophrenia, although women may be more susceptible to certain side-effects and may require lower doses to achieve comparable efficacy to men. However, sex differences remain insufficiently studied to inform treatment decisions. Methods We plan a systematic review and individual-participant-data meta-analysis of randomized trials comparing different antipsychotic drugs, doses, formulations with each other or with placebo in adults with acute schizophrenia. Eligible studies will be identified through the Vivli platform, and their individual-participant-data will be harmonized into a common dataset. Two independent reviewers will screen search results and assess risk of bias using the Risk of Bias 2 tool. The primary outcome will be overall symptoms of schizophrenia, and secondary outcomes will include a broad range of efficacy, tolerability, acceptability, and dosing measures. A stepwise approach to data synthesis will be adopted, depending on individual-participant-data availability, aiming to examine sex differences in the effects of antipsychotic drugs compared to placebo. If sufficient data are available, we will conduct random-effects meta-analyses using regression models to evaluate biological sex, typically categorised as male or female, as both a prognostic factor and an effect modifier, network meta-analyses to synthesize direct and indirect evidence, and dose-response meta-analyses using restricted cubic splines to explore dose-effect relationships. The robustness of the findings will be assessed through sensitivity analyses adjusting for additional covariates. The certainty of evidence on sex differences will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach for subgroup analysis. If the certainty is judged to be moderate or high, sex-specific treatment effects will be further assessed using the Confidence in Network Meta-Analysis (CINeMA) framework. Discussion This study will examine sex differences in the efficacy, tolerability, and dosing of antipsychotics in acute schizophrenia, potentially contributing to evidence-based, sex-specific treatment recommendations for antipsychotic prescribing.