Raloxifene and Rimostil for Perimenopause-Related Depression

Perimenopause-related mood disorders cause significant distress to a potentially large
number of women. The demand for effective therapeutic alternatives to estrogen for treating
these mood disorders is considerable, as is the need to define clinical or biologic markers
that may predict successful response of mood disturbances to phytoestrogens or selective
estrogen receptor modulators (SERMs). Further, the study of potential biological mechanisms
underlying both perimenopause-related mood disorders and their response to treatment may
offer the possibility of uncovering some etiopathogenic mechanisms involved in these and
related mood disorders.

Results of protocol # 90-M-0077 demonstrated the therapeutic efficacy of estradiol therapy
(ET) in perimenopausal depression, independent of its effects on vasomotor symptoms.
Nevertheless, the long term risks of ET to endometrial and breast tissues continue to deter
many women from its use. Recently, selective estrogen receptor modulators (SERMs) and
phytoestrogens (plant-derived estrogen-like compounds) have become available and are
reported to display both tissue-specific profiles of estrogen agonist and antagonist actions
and differential affinities for the two forms of estrogen receptor. For many women, these
novel compounds would represent a safer alternative to ET for the prevention of osteoporosis
and the treatment of menopausal symptoms. However, the effects of SERMs and phytoestrogens
on mood and cognitive function in perimenopausal women remain undetermined.

In this protocol we wish both to investigate the effects of SERMs and phytoestrogens on mood
and cognition under placebo controlled conditions and to compare these effects with
estradiol therapy. This protocol will address the following questions: 1) Do selective
estrogen receptor modulators or phytoestrogens improve mood and cognition in perimenopausal
depressed women? 2) Are the mood and cognitive effects of SERMs and phytoestrogens
comparable to those of ET? and 3) Do selective estrogen receptor modulators and
phytoestrogens improve measures of bone metabolism in perimenopausal depressed women?

- 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.