Official Title: “The Treatment of Menstrually-Related Mood Disorders With Continuous Gonadal Steroid Replacement”

This study investigates the effects on symptoms of combined treatment with estrogen and progesterone in women with severe premenstrual syndrome (PMDD).

Studies indicate that women with PMS experience improvement in symptoms following treatment with leuprolide acetate, when estrogen and progesterone levels are low. Women with PMS, but not women without the disorder, experience a return of symptoms within approximately a week after re-exposure to either estrogen or progesterone. The cause of this hormone-induced depression remains unclear. It is not known whether this depressed mood is due simply to the change in the levels of estrogen and progesterone and whether it would remit following continued exposure to stable levels of estrogen and progesterone. This study will determine whether the maintenance of stable hormone levels will prevent mood disturbances in women with PMS.

Participants in this study will receive leuprolide acetate injections once a month for up to 6 months. After 2 months, women whose symptoms have improved will receive a skin patch containing either estrogen or placebo (an inactive substance) and will be asked to take daily suppositories containing either progesterone or placebo. Women whose symptoms of PMS do not respond to leuprolide treatment after 2 months will end the study and be offered other treatment. Participants will be seen by a nurse in the clinic every two weeks and will fill out ratings and have blood drawn to measure hormone levels. ...

Study Type: Interventional

Study Design: Treatment

Results from previous protocols (#90-M-0088 and 92-M-0174) have demonstrated that women with menstrually-related mood disorder (MRMD), but not women lacking this disorder, experience mood deterioration within approximately a week after exposure to either estradiol or progesterone in the context of gonadal suppression (induced by use of the depot gonadotropin releasing hormone agonist, leuprolide acetate). It is unknown whether this hormone-induced depression occurs consequent to changes in gonadal steroid levels or to simple exposure to levels above a critical threshold. Additionally, since the symptoms of depression stimulated by hormone addback appeared to remit by the fourth week of hormone administration, it is unclear whether continued administration of hormone would result in continued or repeated experience of depression or whether no further symptoms would appear subsequent to the initial precipitated episode. To address these points of uncertainty, we first will establish the efficacy of gonadal suppression in our MRMD subjects by administering depot leuprolide acetate for three months and then will administer both estradiol and progesterone in a continuous fashion for three months to determine whether maintenance of stable gonadal steroid levels will prevent the characteristic cyclic mood disorder.

Intervention(s) in this Clinical Trial

• Drug: Depot Leuprolide Acetate
  • N/A

INCLUSION CRITERIA:

• The subjects of this study will be women who meet the criteria for MRMD as described in Protocol # 81-M-0126, The Phenomenology and Biophysiology of Menstrually-related Mood and

Behavioral Disorders. In brief, these criteria include the following:

• 1. history within the last two years of at least six months with menstrually-related mood or behavioral disturbances of at least moderate severity--i.e., disturbances that are distinct in appearance and associated with a notable degree of subjective distress and interference with life activities;
• 2. symptoms with a sudden offset and absence of significant symptomatology during the follicular phase;
• 3. age 18-50;
• 4. regular menstrual cycles (21-35 days in length), not pregnant, and in good medical health;
• 5. medication free.
• All patients participating in this protocol will have already participated in Protocol No.
• 81-M-0126 and will have a prospectively confirmed and predictable relationship between their mood disorder and the premenstrual phase of the menstrual cycle; i.e., a 30% change in severity of symptom self rating scales, relative to the range of the scale employed, during the seven days premenstrually compared with the seven days post-menstrually in two out of three months of study. This method formed the basis of the NIMH PMS Workgroup diagnostic guidelines and produces results that are highly convergent with the effect size method for diagnosing PMS.
• All subjects will be required to use non-hormonal forms of birth control (e.g. barrier methods with the exception of IUD's) to avoid pregnancy during this study.

EXLUSION CRITERIA:

• Any patient with a current axis I psychiatric diagnosis will be excluded from participating in this protocol.
• Subjects taking birth control pills or psychotropic agents (e.g. antidepressants, anxiolytics or lithium carbonate) will be excluded from the study.
• The following conditions, also, will constitute contraindications to treatment with hormonal therapy and will preclude a patient's participating in this protocol:
• 1. history of endometriosis;
• 2. diagnosis of ill-defined, obscure pelvic lesions, particularly undiagnosed ovarian enlargement;
• 3. hepatic disease as manifested by abnormal liver function tests;
• 4. history of breast carcinoma;
• 5. history of pulmonary embolism or phlebothrombosis;
• 6. undiagnosed vaginal bleeding;
• 7. porphyria;
• 8. history of malignant melanoma;
• 9. history of cholecystitis or pancreatitis;
• 10. history of cardiovascular or renal disease;
• 11. pregnancy.

Gender Eligibility for this Clinical Trial: Female

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 50 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute of Mental Health (NIMH)

Overall Clinical Trial Officials and Contacts

Overall Contact: Linda Simpson-St. Clair, R.N. (301) 496-9576 simpsonl@irp.nimh.nih.gov

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00005011

Study ID Number: 000103

ClinicalTrials.gov Identifier: NCT00005011

Health Authority: United States: Federal Government

NIH Clinical Center Detailed Web Page