From the Journals

Adjunctive testosterone may reduce depressive symptoms in men

Key clinical point: Testosterone appears to be moderately effective in reducing depressive symptoms in men.

Major finding: Testosterone treatment was associated with a significant reduction in depressive symptoms, compared with placebo, with an efficacy of odds ratio of 2.30 (95% confidence interval, 1.30-4.06).

Study details: A systematic review and meta-analysis involving 27 randomized, placebo-controlled trials involving a broad range of men who were treated with testosterone and reported depressive symptoms on validated depression scales.

Disclosures: No conflicts of interest were reported.

Source: Walther A et al. JAMA Psychiatry. 2018 Nov 14. doi: 10.1001/jamapsychiatry.2018.2734.

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Are these improvements clinically meaningful?

The role of testosterone in the pathophysiology and treatment of depressive disorders in men is controversial. The meta-analysis by Walther et al. is well performed and adds to the body of evidence suggesting that testosterone treatment can lead to small improvements in men with depressive symptoms.

However, it is uncertain whether these improvements are clinically meaningful. The data should not be interpreted as testosterone treatment leads to remission or enhances response to antidepressant treatment in this population. In short, the current meta-analysis suggests testosterone replacement may enhance mood among nondepressed hypogonadal men. It is worth noting that the long-term safety of testosterone treatment remains unknown. Until more research is available, clinicians should continue to follow the Endocrine Society guideline for testosterone replacement therapy of androgen-deficient men. The data do not currently support the use of testosterone therapy, particularly in supraphysiologic doses, for the treatment of depressive disorders in men.

Shalender Bhasin, MD, is affiliated with the Brigham and Women’s Hospital in Boston, and Stuart Seidman, MD, is affiliated with Columbia University, New York. These comments are taken from an accompanying editorial (JAMA Psychiatry. 2018 Nov 14. doi: 10.1001/jamapsychiatry.2018.2661). Dr. Bhasin reported receiving research grants from several sources, and Dr. Seidman reported no disclosures.



Testosterone treatment has potential as an adjunct therapy for men with depressive disorders, a meta-analysis has suggested. However, more research is needed.

“This meta-analysis provides important new evidence that testosterone treatment may also be effective and efficacious for eugonadal and older men when higher testosterone dosages are administered,” Andreas Walther, PhD, and his coauthors wrote Nov. 14 in JAMA Psychiatry. However, they noted that safety monitoring in testosterone treatment trials remained important because of an absence of sufficiently powered, long-term studies to assess the increased risk of adverse events with treatment.

The link between testosterone and depression has been debated extensively because testosterone is a neuroactive steroid hormone known to influence mood and appetitive behavior, Dr. Walther and his coauthors wrote. Although testosterone treatment for various disorders in hypogonadal men has been backed by evidence, the results of randomized, placebo-controlled clinical trials for its use in depression have been inconsistent. Indeed, testosterone treatment was currently not recommended in national or international guidelines because of an “prevailing uncertainty about its efficacy, age criteria, dosage, ideal duration and method of application,” wrote Dr. Walther, of the department of biological psychology at Technische Universität Dresden (Germany).

For the current review, the researchers identified 27 randomized, controlled trials altogether including 1,890 men who were receiving testosterone treatment and had reported depressive symptoms on validated depression scales.

Results showed evidence for a moderate antidepressant association of testosterone treatment, compared with placebo (Hedges g, 0.21; 95% confidence interval, 0.10-0.32), and an efficacy odds ratio of 2.30 (95% CI, 1.30-4.06). According to the researchers, based on reference ranges for depressive symptoms, the effect translated into a clinically relevant symptom reduction of 2.2 points on the Beck Depression Inventory II. “The National Institute for Health and Care Excellence guidelines on depression suggest a reduction of 3.0 and 2.0 points on BDI scores to be clinically significant for normal depression and treatment-resistant depression, respectively,” they wrote.

Testosterone treatment also showed an efficacy OR of 2.30, a finding that the authors said suggested the “potential of testosterone treatment as adjunct therapy for men with depressive disorders.”

They said the results suggested that better treatment response might require higher doses but acknowledged that the finding required replication.

In addition, Dr. Walther and his coauthors found acceptability of testosterone treatment was high, with an OR of 0.79 for testosterone treatment–related loss to follow-up, compared with placebo. Remarkably, they added, initial testosterone status did not moderate the effects of testosterone treatment on depressive symptoms.

“Large, preregistered RCTs of good quality investigating testosterone treatment’s effect in men on depression as the primary outcome” are needed, they concluded.

Dr. Walther and his coauthors cited a few limitations, including the low number of randomized, controlled trials addressing the effects of testosterone treatment in men who were depressed but otherwise healthy.

No conflicts of interest were reported.

SOURCE: Walther A et al. JAMA Psychiatry. 2018 14 Nov. doi: 10.1001/jamapsychiatry.2018.2734.

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