Psychiatric and Cognitive Effects of Testosterone Therapy in Adult Men: A Systematic Review of Clinical Evidence and Mechanistic Insights.

Testosterone plays a critical role in male physical and psychological health, influencing not only reproductive and metabolic functions but also mood, cognition, and overall mental well-being. Age-related testosterone decline has been associated with depressive symptoms, cognitive impairment, and reduced quality of life. Although testosterone therapy (TT) is well established for somatic outcomes, its psychiatric and cognitive effects remain inconsistently characterized across clinical trials. The objective is to systematically review the evidence on the effects of TT on psychiatric and cognitive outcomes in adult men, compared with placebo or standard care, and to evaluate associated safety findings. This systematic review followed PRISMA guidelines and was registered in PROSPERO (ID: 1163108). Comprehensive searches were conducted in MEDLINE, EMBASE, Cochrane Library, ScienceDirect, and Google Scholar up to October 2025. Eligible studies included randomized controlled trials (RCTs) and observational studies evaluating TT (any route or dose) in adult men with psychiatric or cognitive endpoints. Data extraction was performed independently by two reviewers, using the PICOS framework. Risk of bias was assessed using the Cochrane RoB 2 tool. A total of 11 RCTs, encompassing over 600 male participants (aged 18-85 years), were included. Populations ranged from healthy eugonadal men to older hypogonadal adults, and patients with treatment-resistant depression (TRD) or mild Alzheimer's disease. TT significantly improved depressive symptoms in men with TRD (p < 0.05), and enhanced specific cognitive domains - particularly verbal memory and visuospatial processing (p < 0.05) - in older or hypogonadal men. Global cognition and anxiety outcomes showed inconsistent effects. Quality of life and sexual function consistently improved across studies, while adverse events were mild and transient (mainly acne, edema, or skin irritation). No major cardiovascular, hepatic, or thromboembolic complications were reported. However, evidence certainty remains moderate due to small sample sizes, brief intervention periods, and heterogeneous methodologies. TT should be considered a complementary, not primary, approach in the management of depressive and cognitive symptoms in hypogonadal men, implemented under endocrinological supervision, with regular biochemical and clinical monitoring. Larger, long-term RCTs are warranted to confirm efficacy, optimize dosing, and define long-term neuropsychiatric safety.