Association of Testosterone Treatment With Alleviation of Depressive Symptoms in Men: A Systematic Review and Meta-analysis

Abstract

Importance: Countering depressive disorders is a public health priority. Currently, antidepressants are the first-line treatment, although they show modest effects. In men, testosterone treatment is a controversial alternative or adjunct treatment option.

Objectives: To examine the association of testosterone treatment with alleviation of depressive symptoms in men and to clarify moderating effects of testosterone status, depression status, age, treatment duration, and dosage.

Data sources: English-language studies published in peer-reviewed journals identified from PubMed/Medline, Embase, Scopus, PsychINFO, and the Cochrane Controlled Trials Register from database inception to March 5, 2018, using the search terms testosterone, mood, administration, dosage, adverse effects, deficiency, standards, therapeutic use, therapy, treatment, and supplementation.

Study selection: Randomized placebo-controlled clinical trials (RCTs) of testosterone treatment that together cover a broad age range and hypogonadal or eugonadal men reporting depressive symptoms on psychometrically validated depression scales.

Data extraction and synthesis: Of 7690 identified records, 469 were evaluated against full study inclusion criteria after removing duplicates, reviews, and studies that did not examine male patients or testosterone. Quality assessment and data extraction from the remaining 27 RCTs were performed.

Main outcomes and measures: Primary outcomes were testosterone treatment effectiveness (standardized score difference after treatment), efficacy (proportion of patients who responded to testosterone treatment with a score reduction of 50% or greater), and acceptability (proportion of patients who withdrew for any reason).

Results: Random-effects meta-analysis of 27 RCTs including 1890 men suggested that testosterone treatment is associated with a significant reduction in depressive symptoms compared with placebo (Hedges g, 0.21; 95% CI, 0.10-0.32), showing an efficacy of odds ratio (OR), 2.30 (95% CI, 1.30-4.06). There was no significant difference between acceptability of testosterone treatment and placebo (OR, 0.79; 95% CI, 0.61-1.01). Meta-regression models suggested significant interactions for testosterone treatment with dosage and symptom variability at baseline. In the most conservative bias scenario, testosterone treatment remained significant whenever dosages greater than 0.5 g/wk were administered and symptom variability was kept low.

Conclusions and relevance: Testosterone treatment appears to be effective and efficacious in reducing depressive symptoms in men, particularly when higher-dosage regimens were applied in carefully selected samples. However, given the heterogeneity of the included RCTs, more preregistered trials are needed that explicitly examine depression as the primary end point and consider relevant moderators.

Figure 1.. PRISMA Flow Diagram of Study Selection

Figure 2.. Forest Plots of Treatment Effectiveness and Efficacy

A, Effectiveness of testosterone treatment in each respective study and their meta-analytical estimates. The naive estimate is based on an analysis set including the outlying study; the robust estimate is based on analysis excluding the outlying study. The dotted vertical line signifies the “no efficacy of testosterone treatment” scenario. Square data markers indicate study effects, and their size indicates relative sample size. Error bars indicate 95% CI. Diamond data markers indicate meta-analytical effect estimates. B, Relation between testosterone treatment effectiveness and testosterone treatment efficacy, estimated by Bayesian errors-in-variables modeling. The dashed line indicates the estimated correspondence line of the efficacy and effectiveness outcomes. The vertical dotted line indicates the (robust) meta-analytical effect estimate for efficacy, and the horizontal dotted line indicates the meta-analytical effect estimate for effectiveness. The size of data markers indicates the sample size of each study. C, Efficacy of testosterone treatment (as odds ratios [ORs]) in each respective study and their meta-analytical estimates. In all panels, positive estimates represent depression-alleviating effects of testosterone treatment compared with placebo. RE indicates random effects.

Figure 3.. Funnel and Moderator Plots

A, Contour-enhanced funnel plot of observed testosterone treatment effects from all included randomized clinical trials. B, Observed (circles) and estimated (lines) testosterone treatment effectiveness as a function of the administered testosterone dosage per week. The size of the circles in Figure 3B indicates the relative sample size of each study. The shaded area represents the 95% CI of the precision-adjusted estimate (PEESE) of testosterone treatment effectiveness. RE indicates random effects.