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

ObjectiveTo investigate the association of 5-ARI use with depression, specifically focusing on explanations for the heterogeneity in results. DesignSystematic review and meta-analysis Data SourcesA systematic search from Scopus, Embase, and MEDLINE was performed from databased inception to January 2025. Eligibility criteria for study selectionPeer-reviewed empirical studies that reported on measurements of record depression associated with 5-ARIs usage were included. Studies with insufficient data and non-English publications were excluded. Data synthesisStudy 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-ARI usage to investigate heterogeneity. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline was followed. ResultsFive longitudinal studies (n= 2,517,859 patients, effect size = 8), across a wide range of populations (US, UK, Cananda, South Korea) and time-period (1992 - 2018) were included. 5-ARI use was associated with a 31% increased risk of depression (HR 1.31, 95% CI 0.98-1.76), with high heterogeneity (I{superscript 2} = 95.5%, {tau}2 = 0.0984, P < 0.0001). When stratified by comparator type, studies using non-drug controls reported significantly elevated risk (HR 1.61, 95% CI 1.20-2.16, I{superscript 2} = 94.4%, {tau}2 = 0.0635, P < 0.0001), while those using alpha-blocker comparators showed decreased risk (HR 0.89, 95% CI 0.86-0.92, I{superscript 2} = 0%, {tau}2 = 0, P = 0.9711). The choice of comparator group explained the most heterogeneity across studies while the type of 5-ARIs showed similar results (Finasteride HR 1.38, 95% CI 0.51-3.72, I{superscript 2} = 97.4%, {tau}2 = 0.1541, P < 0.0001; Dutasteride HR 1.45, 95% CI 0.51-4.10, I{superscript 2} = 96%, {tau}2 = 0.1688, P < 0.0001). ConclusionsOur 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 registrationPROSPERO CRD42024620917