Low-Dose Transdermal Testosterone in Antidepressant-Resistant Major Depression

In women with treatment-resistant major depression, no significant between-group differences were found with the use of adjunctive low-dose transdermal testosterone compared with placebo for antidepressant augmentation. Results of the study were published in The American Journal of Psychiatry.

Recognizing that low-dose testosterone has been shown to improved depression symptom severity, sexual function, and fatigue among women, the investigators sought to establish whether adjunctive low-dose transdermal testosterone can improve these same issues among women with antidepressant-resistant major depression.

The investigators conducted an 8-week, double-blind, randomized, placebo-controlled clinical trial (ClinicalTrials.gov identifier: NCT01783574). A functional magnetic resonance imaging (fMRI) substudy was also performed, which assessed the effects on activity in the anterior cingulate cortex (ACC)—an area of the brain that is involved in mood regulation.

The primary outcome measure was depression symptom severity, as evaluated by the Montgomery-Åsberg Depression Rating Scale (MADRS). The primary outcome of the fMRI substudy was change in ACC activity. Secondary outcomes were safety measures, fatigue, and sexual function. A total of 101 women underwent randomization to a treatment group, of whom 62% had experienced 1 failed antidepressant trial at baseline, 25% had experienced 2 failed trials, and 9% had experienced 3 failed trials. The mean age of the participants was 47 ± 14 years. The women’s mean MADRS score was 26.6 ± 5.9. Overall, 86% (87 of 101) of the women completed 8 weeks of treatment.

MADRS scores decreased from baseline to week 8 in both treatment groups—from

26.8 ± 6.3 to 15.3 ± 9.6 in the testosterone group and from 26.3 ± 5.4 to 14.4 ± 9.3 in the placebo group, which was not statistically significantly different (P =.91). Additionally, remission status (defined as a MADRS score of ≤10) was attained at the conclusion of the study by 36% of women in the testosterone arm compared with 44% in the placebo arm (P =.52), which also was not statistically significant. Improvement in sexual function and fatigue also did not differ between the 2 groups; side effects were similar in both arms as well.

In the fMRI substudy, in which 20 women participated, results demonstrated a link between ACC activation and androgen levels prior to treatment. No difference in ACC activation was observed, however, with testosterone treatment compared with placebo.

Limitations of the study include symptom heterogeneity and type II error in the context of a higher than expected placebo response.

The investigators concluded that although adjunctive transdermal testosterone was well tolerated by the women, use of the agent was no more effective than placebo in improving symptoms of depression, sexual function, and fatigue. Additionally, the use of imaging in a subset of women showed that testosterone therapy was not associated with greater activation of the ACC. Further studies of adjunctive testosterone in antidepressant-resistant major depression are warranted, with the use of strategies designed to decrease placebo effects.


Dichtel LE, Carpenter LL, Nyer M, et al. Low-dose testosterone augmentation for antidepressant-resistant major depressive disorder in women: an 8-week randomized placebo-controlled study [published online July 14, 2020]. Am J Psychiatry. doi: 10.1176/appi.ajp.2020.19080844