Premenstrual Dysphoric Disorder
Conditions
Keywords
PMDD, Oral contraceptives, steroid hormones, neurosteroids
Brief 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.
Interventions
DRUGContinuous OC (EE/DROS)
Continuous EE(20ug)+DROS(3mg) daily for 3 months
DRUGIntermittent OC (EE/DROS)
Intermittent EE(20ug)+DROS(3mg) daily for 21 days each month
DRUGplacebo
daily placebo
Sponsors
National Institute of Mental Health (NIMH)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 52 Years
Healthy volunteers
No
Inclusion criteria
* meets prospective criteria for PMDD, AND * English speaking and reading skills.
Exclusion criteria
* current psychiatric disorder other than PMDD, * history of venous thromboembolism, * over 35 years of age and obese, * uncontrolled hypertension or end-organ vascular disease, * diabetes, * migraine headache with aura, * breastfeeding or pregnant, * cigarette smoking, * family history of premenopausal breast cancer or breast cancer in more than one first degree relative, * elevated serum potassium levels, use of prescription medications (except stable thyroid supplementation), * irregular menstrual cycles, OR * history of: endometriosis, hepatic disease, breast carcinoma, pulmonary embolism or phlebothrombosis, malignant melanoma, cholecystitis or pancreatitis.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pre-Post Change in Premenstrual Symptom Severity | monthly | Pre-post change (pre minus post) in mean premenstrual week severity of the worst emotional symptom as measured using the Daily Record of Severity of Problems items 1-8. Worst symptom for each individual was defined as the symptom in the baseline month demonstrating the highest mean severity during the premenstrual week. Mean premenstrual week severity scores were calculated to correspond to mean ratings; therefore, the mean premenstrual severity values ranged as follows: 1=Not at All, 2=Minimal, 3=Mild, 4=Moderate, 5=Severe, 6=Extreme. The change variable presented here is calculated as follows: mean rating on the individual's worst symptom during the premenstrual week at baseline minus mean rating during the premenstrual week during the last on-treatment cycle. Therefore, higher values on this outcome variable correspond to greater reductions in premenstrual symptoms across the trial. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Continuous Low Dose Oral Contraceptive continuous low dose oral contraceptive
low dose oral contraceptive (20 ug ethinyl estradiol + 3 mg drospirenone): daily for three months | 22 |
| Interrupted Low Dose Oral Contraceptive (21/7 Platform) interrupted low dose oral contraceptive (21/7 platform)
20 ug ethinyl estradiol + 3 mg drospirenone: daily for 21 days each month | 21 |
| Continuous Placebo continuous placebo
placebo: daily | 24 |
| Total | 67 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 3 | 1 | 0 |
| Overall Study | Physician Decision | 1 | 2 | 1 |
| Overall Study | Withdrawal by Subject | 2 | 1 | 1 |
Baseline characteristics
| Characteristic | Continuous Low Dose Oral Contraceptive | Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Continuous Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 33.2 years STANDARD_DEVIATION 8.1 | 32.2 years STANDARD_DEVIATION 8.6 | 32.1 years STANDARD_DEVIATION 6.7 | 32.5 years STANDARD_DEVIATION 7.7 |
| Region of Enrollment United States | 22 participants | 21 participants | 24 participants | 67 participants |
| Sex: Female, Male Female | 22 Participants | 21 Participants | 24 Participants | 67 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 22 / 22 | 21 / 21 | 24 / 24 |
| serious Total, serious adverse events | 0 / 22 | 0 / 21 | 0 / 24 |
Outcome results
Primary
Pre-Post Change in Premenstrual Symptom Severity
Pre-post change (pre minus post) in mean premenstrual week severity of the worst emotional symptom as measured using the Daily Record of Severity of Problems items 1-8. Worst symptom for each individual was defined as the symptom in the baseline month demonstrating the highest mean severity during the premenstrual week. Mean premenstrual week severity scores were calculated to correspond to mean ratings; therefore, the mean premenstrual severity values ranged as follows: 1=Not at All, 2=Minimal, 3=Mild, 4=Moderate, 5=Severe, 6=Extreme. The change variable presented here is calculated as follows: mean rating on the individual's worst symptom during the premenstrual week at baseline minus mean rating during the premenstrual week during the last on-treatment cycle. Therefore, higher values on this outcome variable correspond to greater reductions in premenstrual symptoms across the trial.
Time frame: monthly
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Continuous Low Dose Oral Contraceptive | Pre-Post Change in Premenstrual Symptom Severity | 1.93 units on a scale | Standard Deviation 0.22 |
| Interrupted Low Dose Oral Contraceptive (21/7 Platform) | Pre-Post Change in Premenstrual Symptom Severity | 1.73 units on a scale | Standard Deviation 0.22 |
| Continuous Placebo | Pre-Post Change in Premenstrual Symptom Severity | 1.64 units on a scale | Standard Deviation 0.19 |