Estrogen Receptor Beta and Mood

NCT03689543 | Completed Phase 2 Results FDA Drug

• 2 other identifiers: 18014418-M-0144
• Study Type: interventional
• Target: 74
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Our previous studies have found that women who had depression during the perimenopause may have mood symptoms again if they stop estrogen therapy. Estrogen acts in the brain and other tissues by binding to estrogen receptors. There are two main types of estrogen receptors. They are estrogen receptor alpha and beta. Several studies have shown that estrogen receptor beta may play an important role in anxiety- and depressive-like behaviors in animals. Objectives: To examine a possible mechanism mediating the effects of estradiol-withdrawal on mood symptoms in asymptomatic postmenopausal women with a past perimenopausal depression. To evaluate the efficacy and safety of a selective estrogen receptor (ER) beta agonist (Lilly Compound LY500307) to prevent estradiol withdrawal-induced mood symptoms. Eligibility: Healthy, non-depressed postmenopausal women, ages 45 to 65, with a well-documented past perimenopause-related depression (within 12 years) and whose mood systems got better with estradiol Design: Participants will be screened with: Medical history Physical exam Blood tests Psychiatric interview Gynecological exam

• Participants able to get pregnant must use effective barrier birth control throughout the study.
• During the first 3 weeks, participants will wear an estrogen patch. It is 1x2 inches and will be replaced every 3 days.
• For the next 3 weeks, participants will take 3 study capsules every morning. They will not know if they get the study drug or placebo.
• Some participants will also take a progesterone-like drug for 1 week at the end of the medication phase of the study.
• Participants will have 9 one-hour study visits. They will have blood samples and vital signs taken. They will answer questions about mood and behavior symptoms.
• Participants will keep a daily log of these symptoms.
• Participants will have 2 transvaginal ultrasounds. A probe is temporarily placed 2-3 inches into the vaginal canal and sound waves are used to create pictures of the lining of the uterus.
• Participants will have a final visit 4 weeks after stopping the study drug. They will answer questions about mood and side effects.

Conditions

Perimenopause-Related Depression

Keywords

Perimenopause-related depression

Outcome Measures

Primary Outcomes (2)

• Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score

  Center for Epidemiologic Studies-Depression (CES-D) Scale is a 20-item questionnaire that asks participants to rate how often over the past week they experienced symptoms associated with depression. Each item is rated from 0 to 3 (0 = Rarely or None of the Time, 1 = Some or Little of the Time, 2 = Moderately or Much of the time, 3 = Most or Almost All the Time). Total scores range from 0 to 60, with high scores indicating greater depressive symptoms. CES-D scores \>8 and \<16 is consistent with subsyndromal depression. CES-D scores \> 16 are consistent with clinically significant depressive symptoms of at least moderate severity. Participants completed the CES-D at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).

  Baseline, then weekly through end of week six

• Hamilton Rating Scale of Depression (HRSD) Mean Total Score

  The Hamilton Rating Scale of Depression (HRSD) is a 21-item scale used by clinicians to assess the severity of depressive symptoms administered through a structured interview. The HRSD contains 21 items, but four questions are not added to the numerical total score. The first 17 items are scored on a 3 (0-2) or 5 (0-4) point scale, with total score range between 0 and 52. Higher score indicates greater depressive symptom. Scores of 0-7 are considered normal, 8-16 suggest mild depression, 17-23 moderate depression and scores over 24 are indicative of severe depression. Participants completed the HRSD at baseline and every week for six weeks during each of the study phases (open label estradiol patch, double blind placebo or LY500307 compound). Analysis was calculated as the mean of scores for baseline (week 0) and weekly through week six (6).

  Baseline, then weekly through end of week six

Study Arms (3)

Arm 1: High dose LY500307 compound

EXPERIMENTAL

Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received LY500307 compound 75mg orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.

Drug: Estradiol; Drug: ER Beta Agonist; Drug: Provera

Arm 2: Low dose LY500307 compound

ACTIVE COMPARATOR

Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received a combination of LY500307 compound 25mg and placebo orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.

Drug: Estradiol; Drug: ER Beta Agonist; Other: Placebo; Drug: Provera

Arm 3: Placebo

PLACEBO COMPARATOR

Female participants received open label estradiol 0.1mg transdermal patch per day for three weeks. Then participants received placebo orally once per day for three weeks under double blind conditions. Participants with a uterus received Provera 5mg orally once a day for one week after completion of randomization.

Drug: Estradiol; Other: Placebo; Drug: Provera

Interventions

Estradiol DRUG

Estradiol patch 0.1 mg transdermal every three days for three weeks

Arm 1: High dose LY500307 compound; Arm 2: Low dose LY500307 compound; Arm 3: Placebo

ER Beta Agonist DRUG

Lilly Compound LY500307, a selective estrogen receptor (ER) beta agonist

Also known as: LY500307

Arm 1: High dose LY500307 compound; Arm 2: Low dose LY500307 compound

Placebo OTHER

Placebo orally once daily

Arm 2: Low dose LY500307 compound; Arm 3: Placebo

Provera DRUG

Provera 5 mg orally once a day for one week after completion of randomization

Arm 1: High dose LY500307 compound; Arm 2: Low dose LY500307 compound; Arm 3: Placebo

Eligibility Criteria

• Age: 45 Years - 65 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Women with a past perimenopause-related depression (within 12 years). The diagnosis of perimenopause-related depression will be based on a history of a past depressive episode (major or minor depression confirmed by Structured Clinical Interview for Diagnostic and Statistical Manual (DSM)-V (SCID)) at midlife in association with menstrual cycle irregularity (and possibly hot flushes and/or vaginal dryness) and in whom menopausal hormone therapy was reported to improve their depression at any time within the prior twelve years. All women participating in this protocol will be screened with psychiatric, medical, and reproductive evaluations to confirm they are in good medical health.
• Age 45 to 65
• Medication free (including no mood stabilizers, no sleep medication) except for the following: women on menopausal hormone therapy who will discontinue these medications at the start of this study and have their hormone therapy replaced with estradiol 100mcg per day (as described below), women who are on stable doses of thyroid replacement for at least six months prior to study enrollment, or women who occasionally take non-steroidal anti-inflammatory drugs \[NSAIDs\] or allergy medications (although we will ask women to minimize the use of these medications during the study).
• Subjects must have consent capacity

You may not qualify if:

• The following conditions will constitute contraindications to participate in this protocol:
• Any current Axis 1 psychiatric illness or any clinically significant sleep disorder;
• Women with histories of hormone replacement therapy-induced dysphoria due to either the estrogen or the progesterone components of their hormone replacement;
• Past history of major depression with suicidal ideation;
• History of ischemic cardiac disease, pulmonary embolism, or thrombophlebitis;
• Renal disease; hepatic dysfunction; history of cholecystitis; hypertension;
• Women with a history of carcinoma of the breast or any undiagnosed breast nodule/mass;
• Women with a history of uterine cancer, ill-defined pelvic lesions, particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding;
• Pregnant women; sexually active women will be required to employ barrier contraceptive methods;
• Cerebrovascular disease (stroke);
• Recurrent migraine headaches;
• Women who have had a hysterectomy before one year after their last menstrual period.
• National Institute of Mental Health (NIMH) employees/staff and their immediate family members will be excluded from the study per NIMH policy.

Sponsors & Collaborators

• National Institute of Mental Health (NIMH): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Cohen LS, Soares CN, Vitonis AF, Otto MW, Harlow BL. Risk for new onset of depression during the menopausal transition: the Harvard study of moods and cycles. Arch Gen Psychiatry. 2006 Apr;63(4):385-90. doi: 10.1001/archpsyc.63.4.385.

  PMID: 16585467 BACKGROUND

• Freeman EW, Sammel MD, Lin H, Nelson DB. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry. 2006 Apr;63(4):375-82. doi: 10.1001/archpsyc.63.4.375.

  PMID: 16585466 BACKGROUND

• Freeman EW. Associations of depression with the transition to menopause. Menopause. 2010 Jul;17(4):823-7. doi: 10.1097/gme.0b013e3181db9f8b.

  PMID: 20531231 BACKGROUND

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Interventions

Estradiol; erteberel; Medroxyprogesterone Acetate

Intervention Hierarchy (Ancestors)

Estrenes; Estranes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Estradiol Congeners; Gonadal Steroid Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Medroxyprogesterone; Hydroxyprogesterones; Progesterone; Pregnenediones; Pregnenes; Pregnanes

Results Point of Contact

• Title: Dr. Peter Schmidt
• Organization: National Institute of Mental Health

peterschmidt@mail.nih.gov

+1 301 496 6120

Study Officials

• Peter J Schmidt, M.D.

  National Institute of Mental Health (NIMH)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2018
• First Posted: September 28, 2018
• Study Start: May 23, 2019
• Primary Completion: September 9, 2024
• Study Completion: September 9, 2024
• Last Updated: September 16, 2025
• Results First Posted: September 16, 2025

Record last verified: 2025-08-15

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF
• Time Frame: Starting 24 months after final publication
• Access Criteria: Data will be shared with dbGaP, BTRIS and NIMH Data Archive as determined by the Principal Investigator.

Locations

US (1)