Sex-based Differences in the Efficacy and Tolerability of Selective Serotonin Reuptake Inhibitors in Adults with Major Depressive Disorder: A Systematic Review and Meta-analysis

Purpose of the Review: Sex-based differences in antidepressant outcomes may influence treatment decisions in major depressive disorder (MDD). This systematic review and meta-analysis evaluated sex-based differences in the efficacy and tolerability of selective serotonin reuptake inhibitors (SSRIs) in adults with MDD. Collection and Analysis of Data: PubMed, Cochrane Library, and Scopus were searched electronically, supplemented by citation searching. Two reviewers independently screened records and assessed full-text articles for eligibility. Of 3,523 records identified, 100 duplicates were removed, and 237 full-text articles were assessed, resulting in 10 included studies published between 2005 and 2025. Eligible studies included at least one SSRI arm with extractable sex-stratified outcome data specific to SSRIs. Risk of bias was assessed using RoB 2, the Newcastle–Ottawa Scale, and design-appropriate appraisal tools. Certainty of evidence was evaluated using GRADE. Pooled estimates were generated using random-effects meta-analysis. Results: Ten studies (2005–2025) were included. Remission (six studies, 3,865 participants) showed OR: 1.18 (95% CI: 0.96–1.44; I ² = 0%); response (two studies, 3,006 participants) OR: 1.39 (95% CI: 0.87–2.22; I ² = 51.8%); and continuous symptom improvement (three studies, 3,050 participants) standardized mean difference 0.40 (95% CI: 0.04–0.75; I ² = 74.9%), each favoring female. Certainty ranged from moderate (remission) to low (response, continuous improvement). Conclusions: SSRI efficacy outcomes showed a consistent female-favoring direction, clearest for continuous symptom improvement, but estimates were limited by heterogeneity, imprecision, and incomplete sex-stratified reporting. The evidence does not support sex-based prescribing; adequately powered, prospectively sex-stratified studies are needed.