Dutasteride to Treat Women With Menstrually Related Mood Disorders

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.

- INCLUSION CRITERIA:

Healthy controls and women who meet the criteria for MRMD.

The criteria for MRMD, from Protocol 81-M-126, "The Phenomenology and Biophysiology of
Menstrually Regulated Mood and Behavior Disorders," briefly are as follows:

1. History within the last two years of at least six months with menstrually-related mood
or behavioral disturbances of a severity sufficient to cause at least moderate
subjective distress;

2. Symptoms should have a sudden onset and offset, with symptoms most severe during the
week prior to menstruation and tending to disappear abruptly on or about the first day
menstruation;

3. Age 30-50 years;

4. In good physical health;

5. To qualify for study inclusion, women with MRMD will have prospectively demonstrated
in at least two of three menstrual cycles a 30% worsening of mean negative mood
symptoms in the premenstrual period compared to the week following menses, corrected
for the range of the scales employed.

Healthy controls will have no symptoms of MRMD (confirmed prospectively), be between the
ages of 30 and 50, and be in good physical health.

In addition all subjects will have a normal clinical breast exam prior to study entry.

EXCLUSION CRITERIA:

Subjects will be excluded from the study for the following reasons:

1. Pregnancy or any intent to become pregnant;

2. Medical illness, in particular diabetes, cardiac or renal disease;

3. Use of psychotropic or hormonal medications within three months prior to the study;

4. Current prescription medication use;

5. History of or current alcohol or drug abuse or dependence;

6. A history of (within the past two years) or current psychiatric disorder determined by
administration of the Structured Clinical Interview for DSM-IV Axis I Disorders
(SCID);

7. Male gender;

8. Age less than 30 years; and

9. Women with a history of carcinoma of the breast, or women with a family history of the
following: premenopausal breast cancer or bilateral breast cancer in a first degree
relative; multiple family members (greater than three relatives) with a history of
postmenopausal breast cancer.

In addition to the above, due to the long half life of dutasteride and its teratogenic
effects on male fetuses, only women who have already decided to discontinue child-bearing
and are willing to continue barrier contraception for 6 months after the study will be
included in the protocol.