Raloxifene and Rimostil for Perimenopause-Related Depression

This study has been completed.
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Mental Health (NIMH) )
ClinicalTrials.gov Identifier:
First received: February 6, 2002
Last updated: June 24, 2015
Last verified: May 2015

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.

Condition Intervention Phase
Perimenopausal Depression
Drug: Raloxefine (Evista)
Drug: Rimostil
Drug: Evista, Rimostil, Alora
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: The Efficacy of Phytoestrogens and Selective Estrogen Receptor Modulators in Perimenopause-Related Depression

Resource links provided by NLM:

Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Mood Rating Scales [ Time Frame: Every 2 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Cognitive Test Measures [ Time Frame: Basaeline and Week 6 ] [ Designated as safety issue: No ]

Enrollment: 65
Study Start Date: February 2002
Study Completion Date: June 2015
Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1
Dose of 60 mg per day for eight weeks
Drug: Raloxefine (Evista)
Experimental: 2
Dose of 1000 mg twice a day for eight weeks
Drug: Rimostil
Active Comparator: 3
Dose of 100 micrograms a day by skin patch for eight weeks.
Drug: Evista, Rimostil, Alora

Detailed Description:

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?


Ages Eligible for Study:   40 Years to 60 Years   (Adult)
Genders Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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).


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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00030147

United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
National Institute of Mental Health (NIMH)
Principal Investigator: Peter J Schmidt, M.D. National Institute of Mental Health (NIMH)
  More Information

Additional Information:
Responsible Party: National Institute of Mental Health (NIMH)
ClinicalTrials.gov Identifier: NCT00030147     History of Changes
Other Study ID Numbers: 020120  02-M-0120 
Study First Received: February 6, 2002
Last Updated: June 24, 2015
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Gonadal Steroids
Estrogen Receptor
Mood Disorders
Estrogen Response Element
Perimenopausal Depression

Additional relevant MeSH terms:
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Estrogen Receptor Modulators
Raloxifene Hydrochloride
Selective Estrogen Receptor Modulators
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Hormone Antagonists
Estrogen Antagonists
Bone Density Conservation Agents

ClinicalTrials.gov processed this record on August 23, 2016