Continuous Oral Contraceptive Treatment in Premenstrual Dysphoric Disorder (PMDD)
Condition: Premenstrual Dysphoric Disorder
MeSH terms: Premenstrual Dysphoric Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      The purpose of this study is to compare a low dose oral contraceptive (OC) given continuously
      (every day for three months) with the same low dose oral contraceptive given in an
      interrupted regimen (one week of inactive placebo pills each month) and with continuous
      placebo (inactive placebo given every day for three months). The primary hypothesis is that
      continuous OC will be significantly more effective in reducing premenstrual symptoms compared
      with either the interrupted OC or continuous placebo.
    

Detailed description: 
      Premenstrual Dysphoric Disorder (PMDD) describes the cyclic appearance of affective symptoms
      and resultant impairment during the luteal phase of the menstrual cycle. The objective of
      this trial is to determine if extended oral contraceptive (OC) regimens with eliminated
      pill-free intervals will successfully prevent the expression of PMDD symptoms. The central
      hypothesis of this application is that continuous administration of OCs will minimize the
      destabilizing effects of changing reproductive steroid levels and prevent PMDD symptom
      emergence. The cause of PMDD is unknown, the morbidity substantial, and the identified
      treatments limited in their effectiveness, since 40% of PMDD women are non-responders to
      elective serotonin re-uptake inhibitors (SSRIs). Earlier controlled studies of OCs to treat
      PMDD failed to find OCs superior to placebo using the traditional 21/7 platform (21 active
      pills followed by a 7 day pill-free interval (PFI)). Two recent trials of a low dose OC using
      a 24/4 platform did report greater reductions in premenstrual symptoms relative to placebo,
      presumably due to the shortened PFI. Despite the apparent efficacy of the 3-day extended
      dosing of this OC, the placebo response rate was substantial in these studies, resulting in a
      low effect size. Moreover, no steroid hormone levels were examined in these prior studies. In
      the absence of hormonal data, inferences about the mechanism of efficacy of extended OCs must
      remain speculative and untested.

      Our proposed research will addresses the critical role of hormonal change in the
      precipitation of PMDD symptoms before and after treatment with a continuous OC regimen, an
      interrupted OC regimen (21/7 platform) and continuous placebo. This study will also permit us
      to examine the role of neurosteroids in PMDD. While acting acutely as anxiolytic positive
      modulators of the gamma-aminobutyric acid A (GABAA) receptor, these neurosteroids may
      paradoxically reduce the response of the GABAA receptor and cause irritability (in rats)
      following either extended exposure or withdrawal. Further, our prior research suggests that
      elevated levels of or changes in peripheral neurosteroid levels are associated with dysphoric
      mood symptoms in women with PMDD. Our hypothesis is that changes in neurosteroids modulate
      symptom severity rather than appearance in PMDD. The results of our study will suggest
      therapeutic targets and will inform future studies of both PMDD and related affective
      disorders.
    

Intervention name(s): Continuous OC (EE/DROS); Intermittent OC (EE/DROS); placebo
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Continuous EE(20ug)+DROS(3mg) daily for 3 months; Intermittent EE(20ug)+DROS(3mg) daily for 21 days each month; daily placebo
Other intervention name(s): Yaz; Yaz; oral placebo
Intervention MeSH terms: Drospirenone and ethinyl estradiol combination
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: PMDD; Oral contraceptives; steroid hormones; neurosteroids