madman
Super Moderator
Low-Dose Testosterone Augmentation for Antidepressant-Resistant Major Depressive Disorder in Women: An 8-Week Randomized Placebo-Controlled Study
Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.
Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21–70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.
Results: The participants’ mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.
Conclusions: Adjunctive transdermal testosterone, although well-tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
CONCLUSIONS
This rigorously designed double-blind clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant major depression and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially affect overall depression symptom severity, fatigue, or sexual dysfunction in women treated for 8 weeks with dosages titrated to achieve blood levels near the upper end of the normal reference range. Additionally, testosterone did not result in greater activity compared with placebo in a brain region (ACC and PCC) implicated in major depression etiopathology. 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. 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.
* Limitations of this study were those inherent in all blinded clinical trials of a disorder characterized by symptom heterogeneity and response vulnerable to placebo effect, in this case, major depression. It is possible that a more homogeneous population of postmenopausal women with lower levels of testosterone at baseline would allow the detection of differences in adjunctive testosterone compared with placebo. Moreover, we cannot rule out type II error in the context of a higher than expected placebo response.
Objective: Low-dose testosterone has been shown to improve depression symptom severity, fatigue, and sexual function in small studies in women not formally diagnosed with major depressive disorder. The authors sought to determine whether adjunctive low-dose transdermal testosterone improves depression symptom severity, fatigue, and sexual function in women with antidepressant-resistant major depression. A functional MRI (fMRI) substudy examined effects on activity in the anterior cingulate cortex (ACC), a brain region important in mood regulation.
Methods: The authors conducted an 8-week randomized double-blind placebo-controlled trial of adjunctive testosterone cream in 101 women, ages 21–70, with antidepressant-resistant major depression. The primary outcome measure was depression symptom severity as assessed by the Montgomery-Åsberg Depression Rating Scale (MADRS). Secondary endpoints included fatigue, sexual function, and safety measures. The primary outcome of the fMRI substudy (N=20) was change in ACC activity.
Results: The participants’ mean age was 47 years (SD=14) and their mean baseline MADRS score was 26.6 (SD=5.9). Eighty-seven (86%) participants completed 8 weeks of treatment. MADRS scores decreased in both study arms from baseline to week 8 (testosterone arm: from 26.8 [SD=6.3] to 15.3 [SD=9.6]; placebo arm: from 26.3 [SD=5.4] to 14.4 [SD=9.3]), with no significant difference between groups. Improvement in fatigue and sexual function did not differ between groups, nor did side effects. fMRI results showed a relationship between ACC activation and androgen levels before treatment but no difference in ACC activation with testosterone compared with placebo.
Conclusions: Adjunctive transdermal testosterone, although well-tolerated, was not more effective than placebo in improving symptoms of depression, fatigue, or sexual dysfunction. Imaging in a subset of participants demonstrated that testosterone did not result in greater activation of the ACC.
CONCLUSIONS
This rigorously designed double-blind clinical trial did not find significant group differences between adjunctive low dose transdermal testosterone and placebo for antidepressant augmentation in women with treatment-resistant major depression and had a high placebo response rate. Low-dose testosterone was well tolerated but failed to differentially affect overall depression symptom severity, fatigue, or sexual dysfunction in women treated for 8 weeks with dosages titrated to achieve blood levels near the upper end of the normal reference range. Additionally, testosterone did not result in greater activity compared with placebo in a brain region (ACC and PCC) implicated in major depression etiopathology. 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. 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.
* Limitations of this study were those inherent in all blinded clinical trials of a disorder characterized by symptom heterogeneity and response vulnerable to placebo effect, in this case, major depression. It is possible that a more homogeneous population of postmenopausal women with lower levels of testosterone at baseline would allow the detection of differences in adjunctive testosterone compared with placebo. Moreover, we cannot rule out type II error in the context of a higher than expected placebo response.
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