Raloxifene and Rimostil for Perimenopause-Related Depression
Condition: Perimenopausal Depression; Depression
MeSH terms: Depression; Depressive Disorder
Intervention: Raloxifene; Rimostil; Transdermal Estradiol; Placebo skin patch and placebo tablets
Intervention description: 60 mg a day orally administered; 1000 mg twice a day administered orally; 100 microgram per day transdermal estradiol; matched placebo skin patch to transdermal estradiol and matched tablets to either Raloxifene or Rimostil
Intervention MeSH terms: Raloxifene Hydrochloride; Estradiol
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 65.0
Sex: Female
Minimum age: 40 Years
Maximum age: 60 Years
Healthy volunteers: No
Keywords: Gonadal Steroids; Estrogen Receptor; Mood Disorders; Perimenopause; Estradiol; Depression; Estrogen Response Element; Perimenopausal; Perimenopausal Depression

Summary:

      The purpose of this study is to evaluate the effectiveness of the drugs raloxifene and
      rimostil in treating perimenopause-related depression.

      Perimenopause-related mood disorders cause significant distress to a large number of women;
      the demand for effective therapies to treat these mood disorders is considerable. Estradiol
      replacement therapy (ERT) has demonstrated efficacy in treating perimenopause-related
      depression. Unfortunately, there are long-term risks associated with ERT. Selective estrogen
      receptor modulators (SERMS), such as raloxifene, and phytoestrogens, such as rimostil, have
      estrogen-like properties and may offer a safer alternative to ERT. The effect of SERMS and
      phytoestrogens on mood and cognitive functioning need to be examined in women with
      perimenopause-related depression.

      Participants in this study will undergo a medical history, physical examination,
      electrocardiogram (EKG), and blood and urine tests. They will then be randomly assigned to
      receive one of four treatments for 8 weeks: raloxifene pills plus a placebo (an inactive
      substance) skin patch, rimostil pills plus placebo skin patch, estradiol skin patch plus
      placebo pills, or placebo patch plus placebo pills. Participants will have clinic visits
      every 2 weeks. During the visits, blood will be drawn and participants will meet with staff
      members and complete symptom self-rating scales. A urine and blood sample will be collected
      at the beginning and end of the study. At the end of the study, participants who received
      placebo or whose study medication was ineffective will be offered treatment with standard
      antidepressant medications for 8 weeks. Non-menstruating women will receive progesterone for
      10 days to induce menstrual bleeding and shedding of the inner layer of the uterus, which may
      have been stimulated by the study medications.
    

Eligibility criteria:

        -  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 Diagnostic and
             Statistical Manual of Mental Disorders (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,
        Federal Food, Drug, and Cosmetic Act (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.