Depression risk of 5-alpha reductase inhibitors: A systematic review and meta-analysis with a focus on comparator groups
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Abstract
ABSTRACT Objective To investigate the association of 5-ARI 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 databased inception to January 2025. Eligibility criteria for study selection Peer-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 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-ARI 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, 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 (I² = 95.5%, τ 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, I² = 94.4%, τ 2 = 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%, τ 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, I² = 97.4%, τ 2 = 0.1541, P < 0.0001; Dutasteride HR 1.45, 95% CI 0.51–4.10, I² = 96%, τ 2 = 0.1688, 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
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Abstract
Objective To investigate the association of 5-ARI 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 databased inception to January 2025.
Eligibility criteria for study selection Peer-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 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-ARI 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, 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 (I² = 95.5%, τ2 = 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, 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-ARIs showed similar results (Finasteride HR 1.38, 95% CI 0.51–3.72, I² = 97.4%, τ2 = 0.1541, P < 0.0001; Dutasteride HR 1.45, 95% CI 0.51–4.10, I² = 96%, τ2 = 0.1688, 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
Competing Interest Statement
The authors have declared no competing interest.
Funding Statement
This study did not receive any funding
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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).
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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.
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Data Availability
All data produced in the present work are contained in the manuscript
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