• INCLUSION CRITERIA:

Subjects for this study will meet the following criteria:

1. Self-report of the onset of depression associated with menstrual cycle irregularity or amenorrhea;
2. A current episode of minor (meeting 3-4 criterion symptoms) or major depression (of moderate severity or less on the Structured Clinical Interview for DSM-IV (SCID) severity scale and not meeting DSM-IV criteria symptom 9 (suicide)) as determined by the administration of the minor depression module of the Schedule for Affective Disorders and Schizophrenia - Lifetime Version (SADS-L). Additionally, to ensure that subjects meet a minimum threshold for severity of depression, subjects will have scores greater than or equal to 10 on either the Beck Depression Inventory (BDI) or the Center for Epidemiologic Studies - Depression (CES-D) Scale during at least three of the four clinic visits during the two month screening phase, as well as a 17 item Hamilton Depression score greater than or equal to 10. Subjects will be excluded if they meet any of the following criteria: major depression of greater than moderate severity, DSM-IV criteria # 9 (suicide), or anyone requiring immediate treatment after clinical assessment or functional impairment ratings of five or six for more than seven consecutive days on daily ratings;
3. Evidence of perimenopausal reproductive status;
4. Age 40 to 60;
5. No prior hormonal therapy for the treatment of perimenopause-related mood or physical symptoms within the last six months;
6. No history of psychiatric illness during the two years prior to the reported onset of the current episode of depression;
7. In good medical health, and not taking any medication or dietary and herbal supplements on a regular basis (with the exception of multivitamins and calcium supplements).

EXCLUSION CRITERIA:

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

1) Severe major depression with any of the following:

1. positive (threshold) response to SCID major depression section item # 9, suicidal ideation;
2. anyone requiring immediate treatment after clinical assessment;
3. severity ratings greater than moderate on the SCID IV interview;
4. functional impairment ratings of five or six for more than seven consecutive days on daily ratings.

2) Current treatment with antidepressant medications. Our main concern is to exclude subjects taking medications that would treat or precipitate depression or adversely interact with reproductive hormones, phytoestrogens (e.g., anticoagulants), or SERMs. Thus, we wish to exclude only women receiving psychotropic medications, medications that have been reported to induce a change in mood or behavior, hormone replacement therapy, oral contraceptive agents, or medications that may have a potential adverse interaction with the compounds employed in this study.

3) History of psychiatric illness during the two years before the reported onset of the current episode of depression.

4) History of ischemic cardiac disease, pulmonary embolism, retinal thrombosis, or thrombophlebitis; any subject with risk factors for thrombo-embolic phenomena including cigarette smokers; varicose veins, patients with prolonged periods of immobilization (including prolonged travel), and active heart disease. The literature suggests that although both smoking and hormone replacement/oral contraceptives have associated risks of thromboembolic phenomena and cardiovascular events, these individual risks do not become significantly greater when combined until greater than 10 cigarettes a day are consumed. Thus we wish to exclude only subjects for this study who smoke greater than 10 cigarettes per day.

5) Renal disease, asthma.

6) Hepatic dysfunction.

7) Women with a history of carcinoma of the breast, or any 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 postmenopausal breast cancer.

8) Women with a history of uterine cancer, endometriosis, ill-defined pelvic lesions, particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding.

9) Patients with a known hypersensitivity to raloxifene, phytoestrogens (including Rimostil, isoflavones, genistein, daidzein, red clover extract and soy-related compounds), estradiol, Alora, medroxyprogesterone acetate, or the excipients (inactive compounds) contained within these medications including: Rimostil -tocopherols, cellulose, calcium hydrogen phosphate, magnesium stearate, silica-colloidal anhydrous; Provera - calcium stearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc; Alora - sorbitan monooleate, acrylic adhesive; Evista - anhydrous lactose, carnauba wax, crospovidone, FD& C blue # 2 aluminum lake, hydroxypropyl methylcellulose, lactose monohydrate, magnesium stearate, modified pharmaceutical glaze, polyethylene glycol, polysorbate 80, povidone, and titanium dioxide.

10) Pregnant women.

11) Porphyria.

12) Diabetes mellitus.

13) Cholecystitis or pancreatitis.

14) History of cerebrovascular disease (stroke), epilepsy, hypertension, hypercalcemia.

15) Recurrent migraine headaches.

16) Malignant melanoma.

17) History of familial hyperlipoproteinemia.