Study Type: Treatment

Expected Total Enrollment:

Study Dates:March 1990 -

This protocol is designed to accompany Clinical Protocol # 81-M-0126, The Phenomenology and Biophysiology of Menstrually-Related Mood and Behavioral Disorders. Its original purposes were as follows: 1) to evaluate the efficacy of the gonadotropin releasing hormone (GnRH) agonist depot leuprolide acetate (Lupron) in the treatment of menstrually-related mood disorders (MRMD) by determining whether mood and behavioral symptoms are eliminated when the cyclic secretion of both gonadotropic hormones and gonadal steroids is suppressed, and 2) to determine the possible relevance of gonadal steroids to affective state by sequentially replacing estradiol and progesterone during continued GnRH suppression in those patients whose premenstrual symptoms remit following administration of the GnRH agonist. We observed that GnRH agonist induced ovarian suppression was an effective treatment compared to placebo in women with MRMD. Additionally, women with MRMD but not asymptomatic controls (participating in companion protocol 92-M-0174) experienced a recurrence of mood and behavioral symptoms when either estradiol or progesterone (but not placebo) was added back. These data suggest that women with MRMD have a differential sensitivity to the mood destabilizing effects of gonadal steroids. Having established that women with MRMD show a differential behavioral response to estrogen and progesterone, we now hope to identify the underlying mechanisms and physiologic concomitants of the differential behavioral sensitivity by performing studies (described in companion protocols) under the three hormonal conditions created by this protocol, and comparing results obtained with those seen in normal controls (Protocol #92-M-0174). Planned studies include the following: cognitive testing, HPA axis function evaluation with Dex/CRH or exercise testing, brain imaging (3D PET, FMRI, MRS) and genetic studies.

INCLUSION CRITERIA:

The subjects of this study will be women who meet the criteria for MRMD as described in
Protocol No. 81-M-0126, 'The Phenomenology and Biophysiology of Menstrually-related Mood
and Behavioral Disorders.' In brief, these criteria include: 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; 2) symptoms should have a sudden
onset and offset; 3) age 18-45; 4) 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.

The Schedule for Affective Disorders and Schizophrenia will be administered to all
patients prior to study entry. Any patient with a current axis I psychiatric diagnosis
will be excluded from participating in this protocol.

Prior to treatment, a complete physical and neurological examination will have been
performed and the following routine laboratory data obtained:

A. Blood

Complete blood count; thyroid function tests; cortisol; renal function tests, such as BUN
and creatinine; electrolytes; glucose; liver function tests.

B. Urine

Routine urinalysis; urine pregnancy test.

GnRH agonist will not be administered to any subject with significant clinical or
laboratory abnormalities. The blood tests and urinalysis will be repeated 24-48 hours
aftr GnRH agonist administration to rule out any evidence of acute renal, hepatic or
hematologic toxicity.

Results of Pap smear performed within one year of the onset of treatment will be obtained.

EXCLUSION CRITERIA:

The following conditions will constitute contraindications to treatment with hormonal
therapy and will preclude a subject's participation in this protocol:

current Axis I psychiatric diagnosis

history consistent with endometriosis,

diagnosis of ill-defined, obscure pelvic lesions, particularly, undiagnosed ovarian
enlargement,

hepatic disease as manifested by abnormal liver function tests,

history of mammary carcinoma,

history of pulmonary embolism or phlebothrombosis

undiagnosed vaginal bleeding

porphyria

diabetes mellitus

history of malignant melanoma

cholecystitis or pancreatitis,

cardiovascular or renal disease

pregnancy

Subjects taking birth control pills will be excluded from the study. Subjects taking
diuretics, prostaglandin inhibitors, or pyridoxine (putative treatments for MRMD) will
similarly be excluded from the study, as will patients taking psychotropic agents.