Depression risk of 5-alpha reductase inhibitors: A systematic review and meta-analysis with a focus on comparator groups

Objective: To investigate the association of 5-alpha reductase inhibitors use with depression, specifically focusing on explanations for the heterogeneity in results. Design: Systematic review and meta-analysis. Data Sources: A systematic search from Scopus, Embase, and MEDLINE was performed from database inception to January 2025. Eligibility Criteria for Study Selection: Peer-reviewed empirical studies that reported on measurements of recorded depression associated with 5-alpha reductase inhibitors usage were included. Studies with insufficient data and non-English publications were excluded. Data Synthesis: Study characteristics and relative risk estimates were extracted from each article. Estimates were pooled using random-effects meta-analysis. Studies were further stratified by control groups and type of 5-alpha reductase inhibitors usage to investigate heterogeneity. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Results: Five longitudinal studies (n=2,517,859 patients, effect size=8), across a wide range of populations (US, UK, Canada, South Korea) and time-period (1992-2018) were included. 5-alpha reductase inhibitors use was associated with a 31% increased risk of depression (HR 1.31, 95% CI 0.98 to 1.76), with high heterogeneity (I-squared=95.5%, P<0.0001). When stratified by comparator type, studies using non-drug controls reported significantly elevated risk (HR 1.61, 95% CI 1.20 to 2.16, I-squared=94.4%, P<0.0001), while those using alpha-blocker comparators showed decreased risk (HR 0.89, 95% CI 0.86 to 0.92, I-squared=0%, P=0.9711). The choice of comparator group explained the most heterogeneity across studies while the type of 5-alpha reductase inhibitors showed similar results (Finasteride HR 1.38, 95% CI 0.51 to 3.72, I-squared=97.4%, P<0.0001; Dutasteride HR 1.45, 95% CI 0.51 to 4.10, I-squared=96%, P<0.0001). Conclusions: Our findings underscore the importance of comparator selection in pharmacoepidemiologic research and suggest that prior concerns about 5-ARIs may be overstated in studies that use inappropriate control groups. Systematic Review Registration: PROSPERO CRD42024620917