MON-449 Serum Neuroactive Steroid Levels in Postmenopausal Women with Treatment-Resistant Major Depressive Disorder

Background: Neuroactive steroids such as 3α-5α-tetrahydroprogesterone (allopregnanolone) and 5α-androstane-3α,17β-diol (3α-androstanediol) are modulators of traditional neurotransmitter receptors and have been implicated in the etiopathology of psychiatric disorders, including depression, but levels have not been assessed in women with treatment-resistant major depressive disorder (MDD). We hypothesized that allopregnanolone, 3α-androstanediol, and the ratio of these steroid levels to their precursors (progesterone and testosterone, respectively) would be lower in postmenopausal women with treatment-resistant MDD than non-depressed controls. Methods: Fasting serum neuroactive steroid levels measured by gas chromatography/mass spectrometry were compared in women with treatment-resistant MDD (MDD, n=12) [Montgomery-Asberg Depression Rating Scale (MADRS) >12 despite an adequately dosed antidepressant] and in healthy controls without depression (HC, n=28). All subjects were postmenopausal nonsmokers; none were receiving systemic estrogen. Results: Mean age and BMI did not differ between groups. In MDD, mean number of antidepressants per subject was 1.5±0.5 (SD), with 58% receiving selective serotonin reuptake inhibitors and 50% bupropion. Mean MADRS was 24.4±5.8 (moderate depression severity). In MDD vs HC, the mean allopregnanolone/progesterone ratio was lower (0.20±0.19 vs 0.47±0.46, p=0.03) and progesterone levels were higher (153±177 vs 57±50 pg/mL, p=0.04). There was no difference in mean allopregnanolone levels between groups. Compared with HC, MDD subjects had lower serum free testosterone (0.21±0.16 vs 0.38±0.18 ng/dL, p=0.006) and a trend toward lower total testosterone (13.3±5.9 vs 18.6±9.9 ng/dL, p=0.06). There was no difference in 3α-androstanediol levels or 3α-androstanediol/total testosterone ratio between groups. There was a trend toward a positive association between progesterone levels and depression severity (r=0.34, p=0.06) and an inverse association between the allopregnanolone/progesterone ratio and depression severity (r=-0.36, p=0.07). Lower free testosterone levels were associated with greater depression severity (r=-0.45, p=0.03). Conclusion: In postmenopausal women with treatment-resistant MDD, the allopregnanolone/progesterone ratio was lower and progesterone levels higher than in non-depressed controls. Allopregnanolone levels did not differ between groups. This may be due to reduced metabolism of progesterone to allopregnanolone and could have treatment implications. Additionally, testosterone levels were lower in depressed women, but there was no difference in 3α-androstanediol levels or the 3α-androstanediol/total testosterone ratio between depressed and non-depressed women, suggesting that testosterone may play a greater role in depression symptomatology than its metabolite.