Sex Differences in Psychotropic Drug Exposure and Safety: A Systematic Review Toward Personalized Dosing Strategies

Background: Biological sex contributes to variability in drug metabolism, receptor sensitivity, and susceptibility to adverse drug reactions (ADRs). Despite this, dosing recommendations for selective serotonin reuptake inhibitors (SSRIs) and second-generation antipsychotics (SGAs) are still largely sex-neutral. This systematic review examines sex-related differences in pharmacokinetics (PK), pharmacodynamics (PD), and safety outcomes, with the aim of clarifying their potential implications for personalized psychopharmacology. Methods: A systematic search of PubMed was conducted for studies published between January 2010 and March 2026. The strategy combined MeSH terms and free-text keywords related to SSRIs, SGAs, sex differences, pharmacokinetics, pharmacodynamics, and ADRs. Two independent reviewers performed study selection and data extraction. Studies reporting sex-stratified PK, PD, or safety outcomes in humans were included. Owing to methodological heterogeneity, results were synthesized narratively. Results: Twenty-seven studies met the inclusion criteria. Overall, the evidence indicates clinically meaningful sex-related differences in psychotropic drug exposure and response. Women more frequently exhibited higher dose-adjusted serum concentrations, particularly for risperidone and some SSRIs, with age-related increases more evident in females. Pharmacodynamic findings suggest that women may reach comparable dopamine D2 receptor occupancy at lower olanzapine doses. Pharmacovigilance analyses revealed sex-specific adverse event patterns, including greater reporting of endocrine-related effects and QT prolongation in women. Conclusions: Sex influences psychotropic drug exposure, pharmacodynamic sensitivity, and safety profiles in ways that may be clinically relevant. Integrating sex-aware considerations into dosing strategies could improve therapeutic precision and reduce adverse outcomes, reinforcing the importance of sex as a key variable in personalized psychiatric care.