Raloxifene and Rimostil for Perimenopause-Related Depression

• INCLUSION CRITERIA: Subjects for this study will meet the following criteria:

1. Self-report of the onset of depression associated with menstrual cycle irregularity oramenorrhea;

2. A current episode of minor (meeting 3-4 criterion symptoms) or major depression (ofmoderate severity or less on the Structured Clinical Interview for Diagnostic andStatistical Manual of Mental Disorders (DSM)-IV (SCID) severity scale and not meetingDSM-IV criteria symptom 9 (suicide)) as determined by the administration of the minordepression module of the Schedule for Affective Disorders and Schizophrenia - LifetimeVersion (SADS-L). Additionally, to ensure that subjects meet a minimum threshold forseverity of depression, subjects will have scores greater than or equal to 10 oneither 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 thetwo month screening phase, as well as a 17 item Hamilton Depression score greater thanor 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), oranyone requiring immediate treatment after clinical assessment or functionalimpairment ratings of five or six for more than seven consecutive days on dailyratings;

3. Evidence of perimenopausal reproductive status;

4. Age 40 to 60;

5. No prior hormonal therapy for the treatment of perimenopause-related mood or physicalsymptoms within the last six months;

6. No history of psychiatric illness during the two years prior to the reported onset ofthe current episode of depression;

7. In good medical health, and not taking any medication or dietary and herbalsupplements on a regular basis (with the exception of multivitamins and calciumsupplements).

EXCLUSION CRITERIA: The following conditions will constitute contraindications to treatment and will preclude asubject 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, suicidalideation;

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 ondaily ratings.

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

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

4. History of ischemic cardiac disease, pulmonary embolism, retinal thrombosis, orthrombophlebitis; any subject with risk factors for thrombo-embolic phenomena includingcigarette smokers; varicose veins, patients with prolonged periods of immobilization (including prolonged travel), and active heart disease. The literature suggests thatalthough both smoking and hormone replacement/oral contraceptives have associated risks ofthromboembolic phenomena and cardiovascular events, these individual risks do not becomesignificantly 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 cigarettesper 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 ofthe following: premenopausal breast cancer or bilateral breast cancer in a first degreerelative; multiple family members (greater than three relatives) with postmenopausal breastcancer.

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 (includingRimostil, 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, calciumhydrogen phosphate, magnesium stearate, silica-colloidal anhydrous; Provera - calciumstearate, corn starch, lactose, mineral oil, sorbic acid, sucrose, talc; Alora - sorbitanmonooleate, acrylic adhesive; Evista - anhydrous lactose, carnauba wax, crospovidone,Federal Food, Drug, and Cosmetic Act (FD& C) blue # 2 aluminum lake, hydroxypropylmethylcellulose, 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.