Depression risk of 5-alpha reductase inhibitors: impact of active-comparator versus non-drug user control groups on risk measurement

Introduction The link between 5-alpha reductase inhibitors (5-ARIs) and depression has raised concerns due to the widespread and prolonged use. Previous studies and meta-analyses reported inconsistent results without clear explanations for the heterogeneity. This meta-analysis aims to quantify the depression risk associated with 5-ARIs and evaluate how control group selection contributes to the heterogeneity of reported results.Methods We conducted a systematic review and meta-analysis of articles from Scopus, Embase, and MEDLINE. The search was performed from database inception to January 2025.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 periods (1992 – 2018) were included. 5-alpha-reductase inhibitor use was associated with a 31% increased risk of depression (HR 1.31, 95% CI 0.98–1.76), with high heterogeneity (I2 = 95.5%, τ2 = 0.0984, p < 0.0001). When stratified by comparator type, studies using non-drug controls reported a significantly elevated risk (HR 1.61, 95% CI 1.20–2.16, I2 = 94.4%, τ2 = 0.0635, p < 0.0001), while those using alpha-blocker comparators showed decreased risk (HR 0.89, 95% CI 0.86–0.92, I2 = 0%, τ2 = 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.Conclusions The risk of depression with 5-ARI use is likely minimal. Observational data utilizing active comparators suggests a 10% reduction in risk, while randomized data from a cancer prevention trial suggests a potential risk increase of approximately 10%. Previous reports of up to 200% increased risk likely stem from inappropriate control group selection that failed to account for disease burden.