Sexual dysfunction and other prolactin-related side effects of antipsychotic drugs in schizophrenia: Protocol for a systematic review with single-arm, pairwise, and network meta-analyses of randomized controlled trials and non-randomized studies [ver

Introduction Sexual dysfunctions are common yet underreported side effects of antipsychotics for schizophrenia, affecting 30-80% of treated individuals. These side effects can severely impact social interactions and treatment adherence for individuals with schizophrenia, but comprehensive comparative evidence assessing the risk profiles of different antipsychotics is lacking. This study aims to address this gap using network meta-analysis that integrates data from both randomized-controlled trials (RCTs) and non-randomized studies (NRS).ProtocolThis systematic review will include both RCTs and NRS focusing on participants with schizophrenia or schizophrenia-like psychoses, without restrictions on symptoms, gender, ethnicity, age, or setting. For interventions, all second-generation antipsychotics will be included. The primary outcome will be the occurrence of at least one sexual adverse event of any kind. Secondary outcomes will be the occurrence of any sexual adverse event evaluated in men and women separately, and any adverse event related to the three phases of sexual response cycle separately: desire (e.g. libido, sexual thoughts), arousal (e.g. erection, lubrication) and orgasm (e.g. ejaculation, anorgasmia), and any adverse effect related to breast dysfunction and menstruation irregularities. Study selection and data extraction will be performed independently by two reviewers. The Cochrane Risk of Bias tool 1 and ROBINS-I will be employed to evaluate the risk of bias for RCTs and NRS, respectively. Single-arm meta-analysis of proportions will synthesize the average frequency of sexual adverse events in treated participants. Pairwise and network meta-analysis of RCTs and NRS will be used to evaluate comparative tolerability. Subgroup and sensitivity analyses will explore possible heterogeneity in results and validate the findings' robustness. The quality of the evidence will be evaluated using GRADE. Discussion This study will provide vital insights into the sexual side effects of antipsychotics by combining evidence from clinical trials and real-world practice, facilitating better decision-making in choosing the optimal antipsychotic for individuals.