Adjunctive testosterone ineffective for antidepressant-resistant MDD among women

Adjunctive transdermal testosterone was well tolerated but not more effective than placebo for symptoms of depression, fatigue or sexual dysfunction, according to study results published in American Journal of Psychiatry.

“In patients with major depressive disorder, nonresponse to treatment with selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) is common, particularly in women, occurring in about 70% of patients despite adequate dosing,” Laura E. Dichtel, MD, of the department of medicine at Massachusetts General Hospital, and colleagues wrote. “Additional well-tolerated augmentation strategies are needed, particularly ones that do not cause or exacerbate symptoms such as fatigue and sexual dysfunction. Modest preclinical and clinical data suggest that transdermal testosterone, in dosages designed to raise levels into or near the physiologically normal range for women (10% to 20% of male levels), is a candidate for such a therapy.”

Results of preclinical and animal models supported the hypothesis that androgens can modulate mood. Further, clinical data have suggested a beneficial effect of testosterone on mood among hypogonadal men with refractory depression, and small, randomized placebo-controlled trials among women not selected for major depression also produced similar results.

In the current 8-week, randomized placebo-controlled study, Dichtel and colleagues aimed to determine whether adjunctive low-dose transdermal testosterone cream improved sexual function, fatigue and depression symptom severity among 101 women aged 21 to 70 years with antidepressant-resistant major depression. They also conducted a functional MRI substudy to evaluate the effects on activity in the anterior cingulate cortex (ACC), a mood-regulating brain region. Specifically, they assessed effects of adjunctive testosterone cream among 1010 women aged 21 to 70 years. Depression symptom severity according to the Montgomery-Åsberg Depression Rating Scale (MADRS) served as the primary outcome, and fatigue, sexual function and safety measures served as the secondary endpoints. The fMRI substudy’s primary outcome was change in ACC activity.

Mean participant age was 47 years, and mean baseline MADRS score was 26.6. A total of 87 participants completed 8 weeks of treatment. Results showed decreased MADRS score among both study arms from baseline to 8 weeks, with the testosterone arm decreasing from 26.8 to 15.3 and the placebo arm from 26.3 to 14.4. The researchers considered this an insignificant difference between groups. Moreover, fatigue and sexual function improvements, as well as their side effects, were the same between groups. According to results of the fMRI substudy, there was a relationship between ACC activation and androgen levels before treatment; however, there was no difference in ACC activation with testosterone compared with placebo, the researchers reported.

“Based on our findings and the results of several other recent clinical trials, we conclude that the addition of low-dose testosterone to ongoing, ineffective antidepressant medications should not be recommended for women with major depression,” they wrote. “These negative results are important given the number of women who use off-label male-branded or compounded testosterone. Further studies of adjunctive testosterone in antidepressant-resistant major depression using strategies designed to reduce placebo effects may be warranted.”