Raloxifene and Rimostil for Perimenopause-Related Depression

• Sponsor: National Institute of Mental Health (NIMH) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00030147
• Collaborator: (none)
• Enrollment: 65
• Location: 1
• Arms: 4
• Duration (Months): 159.9
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief 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.

Condition or Disease	Intervention/Treatment	Phase
Perimenopausal Depression; Depression	Drug: Raloxifene; Drug: Rimostil; Drug: Transdermal Estradiol; Drug: Placebo skin patch and placebo tablets	Phase 4

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?

Study Design

• Study Type: Interventional
• Actual Enrollment: 65 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Efficacy of Phytoestrogens and Selective Estrogen Receptor Modulators in Perimenopause-Related Depression
• Study Start Date: Feb 1, 2002
• Actual Primary Completion Date: Jun 1, 2015
• Actual Study Completion Date: Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Raloxifene Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks	Drug: Raloxifene; 60 mg a day orally administered; Other Names: Evista
Experimental: Rimostil Rimostil (phytoestrogen) 1000 mg twice a day and placebo skin patch for eight weeks	Drug: Rimostil; 1000 mg twice a day administered orally
Active Comparator: Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks	Drug: Transdermal Estradiol; 100 microgram per day transdermal estradiol; Other Names: Alora
Placebo Comparator: Placebo Placebo skin patch and placebo tablets for eight weeks.	Drug: Placebo skin patch and placebo tablets; matched placebo skin patch to transdermal estradiol and matched tablets to either Raloxifene or Rimostil

Outcome Measures

Primary Outcome Measures

1. Center for Epidemiologic Studies-Depression Scale (CES-D) [Baseline]

   Center for Epidemiologic Studies-Depression Scale (CES-D) cutoff scores are typically used as a screen to identify clinically significant depression; a cutoff score of greater than 16 has been shown to correlate with clinically significant depression. In addition, a score between 8 and 15 has been used to define subsyndromal depression. The possible range of scores is zero to 60, with the higher scores indicating more symptoms, weighted by frequency of occurrence during the past week.

2. Center for Epidemiologic Studies-Depression Scale (CES-D) [Week 8]

   Center for Epidemiologic Studies-Depression Scale (CES-D) cutoff scores are typically used as a screen to identify clinically significant depression; a cutoff score of greater than 16 has been shown to correlate with clinically significant depression. In addition, a score between 8 and 15 has been used to define subsyndromal depression. The possible range of scores is zero to 60, with the higher scores indicating more symptoms, weighted by frequency of occurrence during the past week.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 60 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

• 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.

1. 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.

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

3. 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.

4. Renal disease, asthma.

5. Hepatic dysfunction.

6. 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.

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

8. 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.

9. Pregnant women.

10. Porphyria.

11. Diabetes mellitus.

12. Cholecystitis or pancreatitis.

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

14. Recurrent migraine headaches.

15. Malignant melanoma.

16. History of familial hyperlipoproteinemia.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892

Sponsors and Collaborators

• National Institute of Mental Health (NIMH)

Investigators

• Principal Investigator: Peter J Schmidt, M.D., National Institute of Mental Health (NIMH)

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

None provided.

• Responsible Party: National Institute of Mental Health (NIMH)
• ClinicalTrials.gov Identifier: NCT00030147
• Other Study ID Numbers: 020120; ZIAMH002537-26; 02-M-0120
• First Posted: Feb 7, 2002
• Last Update Posted: Sep 5, 2016
• Last Verified: Jul 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by National Institute of Mental Health (NIMH): Gonadal Steroids; Estrogen Receptor; Mood Disorders; Perimenopause; Estradiol; Depression; Estrogen Response Element; Perimenopausal; Perimenopausal Depression
• Additional relevant MeSH terms: Depression; Depressive Disorder; Raloxifene Hydrochloride; Estradiol

Study Results

Participant Flow

Pre-assignment Detail	Two participants signed the consent but were not started (did not meet inclusion criteria.)

Arm/Group Title	Estradiol	Placebo	Raloxifene	Rimostil
Arm/Group Description	Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks	Placebo skin patch and placebo tablets for eight weeks	Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks	Rimostil (phytoestrogen) 1000mg twice a day and placebo skin patch for eight weeks
Period Title: Overall Study
STARTED	17	19	16	11
COMPLETED	17	18	16	11
NOT COMPLETED	0	1	0	0

Baseline Characteristics

Arm/Group Title	Estradiol	Placebo	Raloxifene	Rimostil	Total
Arm/Group Description	Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks	Placebo skin patch and placebo tablets for eight weeks	Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks	Rimostil (phytoestrogen) 1000mg twice a day and placebo skin patch for eight weeks	Total of all reporting groups
Overall Participants	17	19	16	11	63
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	17 100%	19 100%	16 100%	11 100%	63 100%
>=65 years	0 0%	0 0%	0 0%	0 0%	0 0%
Sex: Female, Male (Count of Participants)
Female	17 100%	19 100%	16 100%	11 100%	63 100%
Male	0 0%	0 0%	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 5.9%	3 15.8%	2 12.5%	0 0%	6 9.5%
Not Hispanic or Latino	15 88.2%	16 84.2%	14 87.5%	10 90.9%	55 87.3%
Unknown or Not Reported	1 5.9%	0 0%	0 0%	1 9.1%	2 3.2%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	1 5.3%	0 0%	1 9.1%	2 3.2%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%	0 0%
Black or African American	4 23.5%	7 36.8%	1 6.3%	0 0%	12 19%
White	13 76.5%	9 47.4%	13 81.3%	9 81.8%	44 69.8%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	2 10.5%	2 12.5%	1 9.1%	5 7.9%

Outcome Measures

1. Primary Outcome

Title	Center for Epidemiologic Studies-Depression Scale (CES-D)
Description	Center for Epidemiologic Studies-Depression Scale (CES-D) cutoff scores are typically used as a screen to identify clinically significant depression; a cutoff score of greater than 16 has been shown to correlate with clinically significant depression. In addition, a score between 8 and 15 has been used to define subsyndromal depression. The possible range of scores is zero to 60, with the higher scores indicating more symptoms, weighted by frequency of occurrence during the past week.
Time Frame	Baseline

Outcome Measure Data

Analysis Population Description

The analyses included those subjects who started the study.

Arm/Group Title	Estradiol	Placebo	Raloxifene	Rimostil
Arm/Group Description	Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks	Placebo skin patch and placebo tablets for eight weeks	Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks	Rimostil (phytoestrogen) 1000mg twice a day and placebo skin patch for eight weeks
Measure Participants	17	19	16	11
Mean (Standard Deviation) [Units on a scale]	27.4 (5.76)	29.1 (9)	28.8 (7.9)	24.6 (5.5)

2. Primary Outcome

Title	Center for Epidemiologic Studies-Depression Scale (CES-D)
Description	Center for Epidemiologic Studies-Depression Scale (CES-D) cutoff scores are typically used as a screen to identify clinically significant depression; a cutoff score of greater than 16 has been shown to correlate with clinically significant depression. In addition, a score between 8 and 15 has been used to define subsyndromal depression. The possible range of scores is zero to 60, with the higher scores indicating more symptoms, weighted by frequency of occurrence during the past week.
Time Frame	Week 8

Outcome Measure Data

Analysis Population Description

The analyses included those subjects who completed eight weeks of study

Arm/Group Title	Estradiol	Placebo	Raloxifene	Rimostil
Arm/Group Description	Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks	Placebo skin patch and placebo tablets for eight weeks	Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks	Rimostil (phytoestrogen) 1000mg twice a day and placebo skin patch for eight weeks
Measure Participants	16	17	16	11
Mean (Standard Deviation) [Units on a scale]	9.6 (9.4)	10.5 (11.3)	15.8 (8.9)	16.1 (8.8)

Adverse Events

Arm/Group Title	Estradiol		Placebo		Raloxifene		Rimostil
Arm/Group Description	Transdermal estradiol 17-beta estradiol 100 micrograms a day by skin patch and placebo tablets for eight weeks		Placebo skin patch and placebo tablets for eight weeks		Raloxifene (Evista) 60 mg per day and placebo skin patch for eight weeks		Rimostil (phytoestrogen) 1000mg twice a day and placebo skin patch for eight weeks
All Cause Mortality
	Estradiol		Placebo		Raloxifene		Rimostil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Estradiol		Placebo		Raloxifene		Rimostil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/17 (0%)		0/19 (0%)		0/16 (0%)		0/11 (0%)
Other (Not Including Serious) Adverse Events
	Estradiol		Placebo		Raloxifene		Rimostil
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/17 (5.9%)		2/19 (10.5%)		1/16 (6.3%)		0/11 (0%)
Immune system disorders
Allergic reaction	0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/11 (0%)
Musculoskeletal and connective tissue disorders
Chest wall pain	0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/11 (0%)
Pain in extremity	0/17 (0%)		0/19 (0%)		1/16 (6.3%)		0/11 (0%)
Reproductive system and breast disorders
Breast pain	0/17 (0%)		1/19 (5.3%)		0/16 (0%)		0/11 (0%)
Skin and subcutaneous tissue disorders
Rash maculo-papular	1/17 (5.9%)		0/19 (0%)		0/16 (0%)		0/11 (0%)

Limitations/Caveats

Two participants signed the consent but were not started (did not meet inclusion criteria.) Early termination of Rimostil treatment arm limits the generalizability of treatment response in this arm.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.