Dutasteride to Treat Women With Menstrually Related Mood Disorders
Condition: Premenstrual Syndrome; PMS; Healthy; Depression
MeSH terms: Premenstrual Syndrome; Depression; Mood Disorders
Study type: Interventional
Phase: Phase 1

Summary: 
      This study will explore the effects of dutasteride on mood and the stress response across the
      menstrual cycle. Dutasteride blocks production of neurosteroids-hormones that help regulate
      the stress response systems. These systems may be disturbed in women with menstrually related
      mood disorders (MRMD). The effects of the drug will be compared in women with and without
      MRMD to determine how neurosteroids regulate mood and the stress response across the
      menstrual cycle. Dutasteride is approved by the Food and Drug Administration to treat benign
      prostatic hyperplasia (excess growth of the prostate gland) in men.

      Menstruating women 30 to 45 years of age with and without MRMD may be eligible for this
      study. Candidates are screened with a medical and psychiatric history, physical examination,
      screening for symptoms of depression, and routine blood and urine tests. Participants are
      required to use barrier contraception (condoms or diaphragm) during the 3-month study and
      6-month follow-up.

      Participants undergo the following tests and procedures:

        -  Dutasteride or placebo treatment: Participants receive 1 month of dutasteride and 2
           months of placebo. Neither the participants nor the investigators know when the subject
           is taking the active medication or the placebo.

        -  Biweekly follow-up visits: Every 2 weeks during the 3-month treatment period, patients
           come to the NIH Clinical Center to have blood drawn and to complete mood symptoms
           ratings.

        -  Monthly follow-up visits: Participants return to the Clinical Center once a month for 6
           months after the end of the treatment period to monitor hormone levels and pregnancy
           status.
    

Detailed description: 
      Studies of premenstrual syndrome (PMS) to date have demonstrated that the syndrome represents
      an abnormal response to normal physiological events. Specifically patients with PMS
      experience a dysphoric mood state in response to normal luteal phase levels of progesterone
      and additionally fail to demonstrate the augmentation of the hypothalamic-pituitary-adrenal
      (HPA) axis normally seen in the luteal phase. A parsimonious explanation for the
      dysregulation of both mood and HPA axis function in PMS is that both are mediated by abnormal
      levels of or response to the progesterone neurosteriod metabolite, allopregnanolone. Both
      exposure to and withdrawal from allopregnanolone have been shown to precipitate adverse mood
      states in animal studies, presumably consequent to induced conformational changes in the
      GABA(A) receptor (increased alpha-4 subunit) that impair GABA receptor function. This
      impairment of GABA receptor function may also be associated with loss of restraint of HPA
      axis activity and hence may underlie the luteal phase increases in HPA activity in normal
      women. In this protocol, we propose to block conversion of progesterone to allopregnanolone
      in women with menstrual-related mood disorder (MRMD; equivalent in most reports to a severe
      form of PMS called premenstrual dysphoric disorder (PMDD)) and in normal (control) women. We
      will block progesterone metabolism (and hence exposure to allopregnanolone) with a newly
      approved 5 alpha-reductase inhibitor, dutasteride. We hypothesize the following: 1)
      Elimination of exposure to allopregnanolone in women with MRMD will eliminate dysphoric mood
      in the luteal phase; 2) Elimination of exposure of normal control women to allopregnanolone
      will eliminate the luteal phase enhancement of stimulated stress axis activity response.

      These hypotheses, if confirmed, will increase the precision with which we can dissect the
      pathophysiological mechanisms involved in MRMD and in menstrual-related stress physiology.

      In this protocol, our study objectives are as follows: Primary Objectives: 1) Determine
      whether suppression of neurosteroid synthesis will diminish mood symptoms in women with MRMD.
      2) Determine if suppression of neurosteroid synthesis will eliminate luteal phase-related
      increases in stimulated HPA axis activity in control women. Secondary Objectives: 1)
      Determine whether differences in response to allopregnanolone account for the divergent
      effects of menstrual cycle phase on HPA axis activity in patients with MRMD and controls. 2)
      Determine if the Dex-CRH test, like the graded stressor treadmill test, can reveal the
      effects of menstrual cycle phase on HPA axis function.
    

Intervention name(s): Dutasteride; Placebo oral capsule
Intervention type(s): Drug; Drug
Intervention MeSH terms: Dutasteride
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Neurosteroids; 5 Alpha-Reductase Inhibitor; Depression; Menstrual Cycle; Gonadal Steroids; Menstrual Cycle Related Mood Disorder; MRMD; Healthy Volunteer