This R21 application is intended to investigate a novel hypothesis: that serotonin reuptake inhibitor (SRI) antidepressants suppress production of gonadal steroid hormones. We have preliminary evidence that SRI treatment reduces circulating levels of the steroid hormones 17-OH pregnenolone and 17a-OH progesterone which are intermediary precursors in the gonadal steroid synthesis pathway, and that SRI treatment may also reduce levels of the downstream androgenic hormones DHEA and androstenedione. To confirm this pilot data and to begin to determine whether this effect is a specific characteristic of SRIs, the effect of chronic treatment with an SRI, fluoxetine, on the gonadal steroid precursor hormone 17a-OH pregnenolone will be compared to the effect of a non-SRI, bupropion, in healthy volunteer women. As a potential functional assay of gonadal steroid activity, we will also compare the effects of fluoxetine and bupropion on sexual functioning in the same group of healthy women, and investigate whether changes in circulating 17-OH pregnenolone levels are related to changes in sexual function during antidepressant treatment. There has been little study of whether changes in gonadal steroid hormone activity play a role in the pathophysiology of sexual side effects during SRI treatment, or whether severity of sexual side effects varies across the menstrual cycle. Healthy female volunteers will be used for this study to avoid the confounding effects of psychiatric illness on sexual function and on the activity of the hypothalamic-pituitary-adrenal and ovarian axes. Subjects will undergo one month of baseline hormonal sampling and then will be randomized to two months of treatment with either fluoxetine or bupropion. Blood sampling and sexual function assessments will occur in three phases of the menstrual cycle (early follicular, ovulatory, mid-luteal) in all three months of the study. This study is intended to expand our understanding of the mechanism of action of SRIs. If fluoxetine, but not bupropion treatment, is associated with a reduction in circulating levels of 17-OH pregnenolone, the potential importance of this effect to the distinct clinical efficacy of SRIs for PMDD and OCD will be examined in future studies. This research also may lead to development of hormonally based treatments for PMDD and OCD. Currently, for the 30% of subjects with PMDD and OCD who do not respond to SRI treatment, there are few, if any, alternative pharmacologic strategies.
