Our prior work indicates that women with premenstrual dysphoric disorder (PMDD), may be more vulnerable to dysphoric mood states induced by changes in gonadal hormones and their neuroactive metabolites, and not resulting from absolute hormone levels per se. One objective of the proposed research is to determine if an extended oral contraceptive (OC) regimen that eliminates the hormone free interval (HFI) and produces stable, low endogenous hormone levels will prevent the expression of PMDD symptoms. A second objective is to demonstrate that changing hormones trigger affective symptoms in PMDD, and to establish which gonadal hormones and their neuroactive metabolites are associated with symptoms. Eighty women with prospectively confirmed PMDD will be randomized to one of four, 12 week treatment arms: Treatment #1) continuous administration of 20 ug ethinyl estradiol/3mg drospirenone [EE/P]; Treatment #2) interrupted EE/P, substituting placebo for EE/P during weeks 4, 8, & 12; Treatment # 3) continuous EE/P with menses - identical to arm # 1 except a local progesterone (P) antagonist will be administered during weeks 4, 8, & 12, inducing shedding of the endometrium and controlling for un-blinding with interrupted OCs; Treatment #4) continuous placebo. Primary outcome measure will be the total PMDD score assessed daily at baseline and throughout the treatments. Secondary measures will include Response Rate, Clinical Global Impression Scale, and mood scales. Serum levels of estradiol (E2) and P, as well as plasma levels of neuroactive steroids, allopregnanolone, allotetrahydroDOC, pregnanolone and pregnenolone sulfate, all potent modulators of the GABAA receptor will be sampled on cycle days 17, 21, 25, 1, & 5 at pretreatment and also during treatment month 3. Primary predictions are: 1) Continuous EE/P (arm #1) will be associated with the greatest reduction in PMDD symptoms relative to pretreatment levels, and will be associated with lower symptom levels in months 2 and 3 of treatment relative to both placebo and interrupted EE/P (arms #2 and #4); 2) Women treated with interrupted OC (arm #2) will show symptom severity similar to women treated with placebo (arm #4), and will continue to show cyclicity of symptoms though there will be a shift in peak symptoms to the follicular phase, corresponding to the changes in E2 and P induced during the HFI; 3) the increase in E2 during the HFI in women treated with interrupted OC (arm #2) will predict the development and severity of symptoms in that group; and 4) since OCs suppress the synthesis of neurosteroids, the magnitude of the change in neuroactive steroids from days 1-5 to days 17 – 25 will predict PMDD symptoms in the placebo group, but not in the women treated with continuous OC (arms #1 and #3). The results of this study are expected to advance our knowledge on the pathophysiology of PMDD and help illuminate a substrate for affective dysregulation in women. Confirmation of the role of hormonal change in precipitating PMDD will suggest therapeutic targets for future research.
|Effective start/end date||7/11/08 → 9/30/14|
- NIH National Institute of Mental Health (NIMH)
Premenstrual Dysphoric Disorder
Outcome Assessment (Health Care)