Testosterone Gel Helpful in Refractory Depression

Laurie Barclay, MD

January 15, 2003

Jan. 15, 2003 — Men who have depression refractory to usual antidepressants may benefit from testosterone gel, according to the results of a randomized, placebo-controlled trial reported in the January issue of the American Journal of Psychiatry.

"Testosterone supplementation may produce antidepressant effects in men, but until recently it has required cumbersome parenteral administration," write Harrison G. Pope, Jr., MD, and colleagues from McLean Hospital in Belmont, Massachusetts.

The authors administered testosterone transdermal gel to men aged 30 to 65 years with refractory depression and low or borderline testosterone levels. Of 56 men screened, 24 (42.9%) had morning serum total testosterone levels of 350 ng/dL or lower (normal range, 270-1070 ng/dL).

Of 23 men enrolled in the study, one responded to an initial one-week, single-blind placebo period, and 22 were subsequently randomized to 1% testosterone gel, 10 g/day, or to identical-appearing placebo. All subjects continued their baseline antidepressant regimen. Ten of 12 subjects receiving testosterone and nine of 10 receiving placebo completed the eight-week trial. At baseline, both groups had similar demographic and psychiatric measures.

Compared with the placebo group, the testosterone gel group had significantly greater improvement in scores on the Hamilton Depression Rating Scale and on its vegetative and affective subscales, and on the Clinical Global Impression severity scale, but not on the Beck Depression Inventory. Testosterone gel appeared to improve psychological aspects of depression, as reflected in the depressed mood, guilt, and psychological anxiety items of the Hamilton Depression Rating Scale, to nearly the same extent as the somatic aspects of depression.

The only treatment-related adverse event was increased difficulty with urination in one subject, suggesting exacerbation of benign prostatic hyperplasia.

"These preliminary findings suggest that testosterone gel may produce antidepressant effects in the large and probably underrecognized population of depressed men with low testosterone levels," the authors write.

Although mean age in this study was 46.9 years, mean total testosterone level was only 403 ng/dL (SD = 152 ng/dL), dramatically lower than expected in the general population of men aged 45 to 54 years, and slightly lower than in an earlier study of depressed men in their 60s and 70s.

"These observations suggest that low testosterone levels may be unexpectedly common in middle-aged men with treatment-resistant major depressive disorder, perhaps because chronic depressive symptoms lead to blunting of the hypothalamic-pituitary-gonadal axis or, possibly, because of effects of the antidepressant medications themselves," the authors write.

Study limitations include limited statistical power, short duration, breaking the blind for each subject individually at termination rather than for all subjects at the conclusion of the study, use of a single serum total testosterone level to determine eligibility, addition of testosterone to existing antidepressant treatment, and inclusion of men only.

Potential risks of testosterone supplementation include development of paranoid symptoms, especially in subjects taking tricyclic antidepressants, and possible longer-term effects such as gynecomastia, adverse effects on lipid fractions, gradual exacerbation of benign prostatic hyperplasia, suppression of the hypothalamic-pituitary-testicular axis, and possible increased risk of prostate or other cancers.

"These findings may have important consequences for public health. In a given year, about 8% of American men over the age of 30 years exhibit major depressive disorder, and many of these cases will be partially or completely refractory to an adequate trial of antidepressant medication," the authors write. "If this subgroup withrefractory depression has a 43% prevalence of low testosterone levels, as found in the present study, then hundreds of thousands of men in a given year might at least theoretically be candidates for testosterone supplementation to treat depression. Given the size of this population, together with the increased availability and convenience of transdermal testosterone preparations, it seems important to assess carefully both the benefits and the risks of this antidepressant treatment strategy."

Am J Psychiatry. 2003;160:105-111

Reviewed by Gary D. Vogin, MD