Cardiovascular

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

TL;DR

Testosterone therapy significantly improved depressive symptoms in men with treatment-resistant depression and enhanced specific cognitive domains in older or hypogonadal men, but should be considered a complementary rather than primary approach implemented under endocrinological supervision.

Key Findings

Testosterone therapy significantly improved depressive symptoms in men with treatment-resistant depression.

  • Statistical significance was reported at p < 0.05 for depressive symptom improvement in men with treatment-resistant depression (TRD).
  • The review included 11 RCTs encompassing over 600 male participants aged 18-85 years.
  • Populations included patients with treatment-resistant depression as well as healthy eugonadal men, older hypogonadal adults, and patients with mild Alzheimer's disease.
  • Risk of bias was assessed using the Cochrane RoB 2 tool, and evidence certainty was rated as moderate.

Testosterone therapy enhanced specific cognitive domains, particularly verbal memory and visuospatial processing, in older or hypogonadal men.

  • Improvements in verbal memory and visuospatial processing were statistically significant at p < 0.05.
  • Cognitive benefits were observed specifically in older or hypogonadal men rather than in all populations studied.
  • Global cognition outcomes showed inconsistent effects across studies.
  • Anxiety outcomes also showed inconsistent effects across the included studies.

Quality of life and sexual function consistently improved across studies examining testosterone therapy.

  • Improvements in quality of life and sexual function were reported as consistent findings across the included studies.
  • This consistency contrasted with the more variable findings for global cognition and anxiety.
  • Studies evaluated testosterone therapy administered by any route or dose.
  • Participants ranged from healthy eugonadal men to older hypogonadal adults.

Adverse events associated with testosterone therapy were mild and transient, with no major cardiovascular, hepatic, or thromboembolic complications reported.

  • Adverse events were mainly acne, edema, or skin irritation.
  • No major cardiovascular, hepatic, or thromboembolic complications were reported across the 11 included RCTs.
  • The safety profile was characterized as mild and transient.
  • The review covered studies up to October 2025 drawn from MEDLINE, EMBASE, Cochrane Library, ScienceDirect, and Google Scholar.

The certainty of evidence remains moderate due to methodological limitations across included studies.

  • Limitations included small sample sizes, brief intervention periods, and heterogeneous methodologies.
  • The systematic review included 11 RCTs with over 600 total participants, which the authors considered insufficient for high-certainty conclusions.
  • The review followed PRISMA guidelines and was registered in PROSPERO (ID: 1163108).
  • Data extraction was performed independently by two reviewers using the PICOS framework.

Age-related testosterone decline has been associated with depressive symptoms, cognitive impairment, and reduced quality of life.

  • Testosterone plays a role in mood, cognition, and overall mental well-being in addition to reproductive and metabolic functions.
  • This association with psychiatric and cognitive decline formed the rationale for systematically reviewing testosterone therapy's effects on these outcomes.
  • Although testosterone therapy is described as well established for somatic outcomes, its psychiatric and cognitive effects were characterized as inconsistently described across clinical trials prior to this review.

The authors concluded that testosterone therapy should be considered a complementary, not primary, approach in the management of depressive and cognitive symptoms in hypogonadal men.

  • Implementation was recommended to be under endocrinological supervision with regular biochemical and clinical monitoring.
  • The authors called for larger, long-term RCTs to confirm efficacy, optimize dosing, and define long-term neuropsychiatric safety.
  • This recommendation was based on the moderate certainty of evidence and the observed benefits in specific subpopulations (hypogonadal, older, or TRD patients).

What This Means

This research suggests that testosterone therapy may offer meaningful mental health and cognitive benefits for certain groups of men, particularly those with low testosterone levels (hypogonadism), older adults, and men whose depression has not responded to standard treatments. Across 11 clinical trials involving more than 600 men aged 18 to 85, testosterone therapy was associated with reduced depressive symptoms in treatment-resistant depression and improvements in specific thinking skills — especially verbal memory and the ability to process visual and spatial information. Quality of life and sexual function also improved consistently across studies. Importantly, no serious side effects like heart problems, liver issues, or blood clots were observed, though minor effects like acne or mild swelling were noted. However, the picture is not entirely clear. Effects on overall thinking ability and anxiety were inconsistent across studies, meaning testosterone therapy did not reliably help everyone in these areas. The authors note that the studies included were relatively small, often short in duration, and varied considerably in how they were designed, which limits confidence in drawing firm conclusions. This research suggests that the benefits are real but specific — most apparent in men who already have low testosterone or significant depression that hasn't responded to other treatments. Practically, this research suggests that testosterone therapy could be a useful addition to existing treatments for depression or cognitive decline in men with confirmed low testosterone, but it should not replace standard first-line treatments. The authors recommend that any such therapy be managed by an endocrinologist with regular monitoring of hormone levels and overall health. Future studies with larger groups of participants and longer follow-up periods are needed to better understand who benefits most, what the right doses are, and whether the benefits and safety hold up over time.

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Citation

Luis M Canal de Velasco, J. E. González Flores, Laura Vargas, J. L. Morales Arteaga. (2026). Psychiatric and Cognitive Effects of Testosterone Therapy in Adult Men: A Systematic Review of Clinical Evidence and Mechanistic Insights. Cureus. https://doi.org/10.7759/cureus.102894