Perimenopause-Related Depression
Conditions
Keywords
Perimenopause-related depression
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.
Detailed description
OBJECTIVE: Depression risk increases during the perimenopause, and depression is cited as a primary reason for resuming menopausal hormone therapy (HT). Community-based epidemiologic studies document a 1.5-3 fold greater risk of first onset and recurrent depressions in women during the perimenopause compared with those who are premenopausal (or who are several years postmenopausal). Observational studies report the emergence of depressive symptoms after the discontinuation of HT in 5-10% of women. The role of estradiol (E2) - either declining or low levels - in the precipitation of perimenopausal depression (PMD) is unknown, largely due to the associational and indirect nature of the evidence linking ovarian function and depression. In study 03-M-0175, our results demonstrated that estradiol withdrawal was associated with a significant increase in depressive symptoms in those women with a past depression during the perimenopause. Of note, the effects of estradiol primarily occur through activation of two receptor subtypes, often with opposing outcomes: estrogen receptor (ER) alpha, and ER beta. Therefore, in this protocol, we examined the ability of a selective ER beta agonist (LY500307) to prevent estradiol withdrawal- induced mood symptoms in women with past perimenopausal depression. We focused on ER beta because the beta estrogen receptor is reported to mediate the effects of estradiol on the serotonergic system and mediate the antidepressant-like effects of estradiol in the forced-swim test. Moreover, selective agonists of estrogen receptor beta have been demonstrated to attenuate the behavioral and hypothalamic-pituitary-adrenal (HPA) axis response to stress. Our objective is to examine the specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a past perimenopause-related depression. Results of this study will determine the role of ER beta in estradiol withdrawal-induced mood symptoms and can provide preliminary data to support the efficacy and safety of this compound as a treatment for depression during the perimenopausal transition. STUDY POPULATION: 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: The medication phase of this study is a seven-week randomized, double blind, placebo controlled study and there is a four week follow-up evaluation phase to monitor all women for the emergence of adverse effects post-medication exposure. Participants will have weekly outpatient visits, weekly blood draws and will also complete daily symptom rating scales. The study involves a three week baseline phase in which all women receive open label (OL) estradiol therapy (ET) at a dose of 100 micrograms per day by transdermal skin patch, after which all women receive three weeks of double blind (DB) medication (i.e., LY500307 \[at a daily dose of either 25 mg or 75 mg\] or placebo). All participants will receive three capsules of LY500307 or placebo each morning consisting of the following formulations: 1) women randomized to 75 mg LY500307 will receive three capsules each containing 25 mg LY500307; 2) women randomized to 25 mg LY500307 will receive one capsule containing 25 mg LY500307 and two capsules of placebo; and 3) women randomized to placebo will receive three capsules each containing placebo. Then, in non-menstruating women (i.e., the absence of reported menstrual bleeding of greater than 1-2 days during the double blind phase of this study), the double blind phase will be followed by one week of Provera to precipitate a progestin-induced menses. The week of Provera is not a research-related intervention but is clinically-indicated to induce endometrial shedding that will eliminate potentially abnormal endometrial tissue consequent to the three weeks of unopposed estradiol exposure.
Interventions
DRUGEstradiol
Estradiol patch 0.1 mg transdermal every three days for three weeks
DRUGER Beta Agonist
Lilly Compound LY500307, a selective estrogen receptor (ER) beta agonist
OTHERPlacebo
Placebo orally once daily
DRUGProvera
Provera 5 mg orally once a day for one week after completion of randomization
Sponsors
National Institute of Mental Health (NIMH)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Age 45 to 65 3. 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). 4. Subjects must have consent capacity
Exclusion criteria
The following conditions will constitute contraindications to participate in this protocol: 1. Any current Axis 1 psychiatric illness or any clinically significant sleep disorder; 2. Women with histories of hormone replacement therapy-induced dysphoria due to either the estrogen or the progesterone components of their hormone replacement; 3. Past history of major depression with suicidal ideation; 4. History of ischemic cardiac disease, pulmonary embolism, or thrombophlebitis; 5. Renal disease; hepatic dysfunction; history of cholecystitis; hypertension; 6. Women with a history of carcinoma of the breast or any undiagnosed breast nodule/mass; 7. Women with a history of uterine cancer, ill-defined pelvic lesions, particularly undiagnosed ovarian enlargement, undiagnosed vaginal bleeding; 8. Pregnant women; sexually active women will be required to employ barrier contraceptive methods; 9. Cerebrovascular disease (stroke); 10. Recurrent migraine headaches; 11. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Baseline, then weekly through end of week six | 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). |
| Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Baseline, then weekly through end of week six | 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). |
Countries
United States
Participant flow
Pre-assignment details
of the 74 participants consented to study, 19 participants failed screening and nine (9) dropped out prior to randomization
Participants by arm
| Arm | Count |
|---|---|
| Arm 1: High Dose LY500307 Compound 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. | 15 |
| Arm 2: Low Dose LY500307 Compound 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. | 15 |
| Arm 3: Placebo 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. | 16 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 |
Baseline characteristics
| Characteristic | Arm 1: High Dose LY500307 Compound | Arm 2: Low Dose LY500307 Compound | Arm 3: Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 15 Participants | 15 Participants | 16 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 15 Participants | 12 Participants | 13 Participants | 40 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 1 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 11 Participants | 12 Participants | 36 Participants |
| Sex: Female, Male Female | 15 Participants | 15 Participants | 16 Participants | 46 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 46 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 42 |
| other Total, other adverse events | 6 / 46 | 3 / 15 | 2 / 15 | 1 / 16 | 3 / 42 |
| serious Total, serious adverse events | 0 / 46 | 0 / 15 | 0 / 15 | 0 / 16 | 0 / 42 |
Outcome results
Primary
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).
Time frame: Baseline, then weekly through end of week six
Population: All participants who were randomized to arms in the study. One participant dropped out at week 5 therefore did not complete week 6 questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 1 | 9.43 Units on a scale | Standard Deviation 7.11 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 4 | 5.60 Units on a scale | Standard Deviation 5.45 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 3 | 3.47 Units on a scale | Standard Deviation 4.09 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Baseline | 12.96 Units on a scale | Standard Deviation 9.06 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 6 | 8.40 Units on a scale | Standard Deviation 11.19 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 5 | 7.47 Units on a scale | Standard Deviation 11.36 |
| Arm 1: High Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 2 | 4.27 Units on a scale | Standard Deviation 4.22 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 3 | 4.13 Units on a scale | Standard Deviation 3.87 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Baseline | 18.02 Units on a scale | Standard Deviation 11.27 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 1 | 10.67 Units on a scale | Standard Deviation 8.01 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 2 | 5.60 Units on a scale | Standard Deviation 4.7 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 4 | 5.27 Units on a scale | Standard Deviation 5.08 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 5 | 5.47 Units on a scale | Standard Deviation 5.18 |
| Arm 2: Low Dose LY500307 Compound | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 6 | 6.00 Units on a scale | Standard Deviation 6.37 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 4 | 5.19 Units on a scale | Standard Deviation 7.2 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 1 | 5.38 Units on a scale | Standard Deviation 6.83 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 6 | 9.93 Units on a scale | Standard Deviation 9.32 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 5 | 8.25 Units on a scale | Standard Deviation 9.55 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 3 | 2.25 Units on a scale | Standard Deviation 2.82 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Week 2 | 3.44 Units on a scale | Standard Deviation 3.83 |
| Arm 3: Placebo | Center for Epidemiologic Studies-Depression (CES-D) Scale Mean Total Score | Baseline | 11.53 Units on a scale | Standard Deviation 9.03 |
Primary
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).
Time frame: Baseline, then weekly through end of week six
Population: All participants who were randomized to arms in the study. One participant dropped out at week 5 therefore did not complete week 6 questionnaire.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 1 | 3.87 Units on a scale | Standard Deviation 4.1 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 4 | 2.93 Units on a scale | Standard Deviation 3.28 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 3 | 0.87 Units on a scale | Standard Deviation 1.06 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Baseline | 5.78 Units on a scale | Standard Deviation 4.84 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 6 | 5.52 Units on a scale | Standard Deviation 7.17 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 5 | 4 Units on a scale | Standard Deviation 7.03 |
| Arm 1: High Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 2 | 1.93 Units on a scale | Standard Deviation 1.94 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 3 | 0.73 Units on a scale | Standard Deviation 0.7 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Baseline | 5.92 Units on a scale | Standard Deviation 3.45 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 1 | 2.87 Units on a scale | Standard Deviation 2.92 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 2 | 1 Units on a scale | Standard Deviation 1.31 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 4 | 3.07 Units on a scale | Standard Deviation 3.37 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 5 | 3.6 Units on a scale | Standard Deviation 3.76 |
| Arm 2: Low Dose LY500307 Compound | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 6 | 3.8 Units on a scale | Standard Deviation 3.67 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 4 | 2.94 Units on a scale | Standard Deviation 2.79 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 1 | 2.63 Units on a scale | Standard Deviation 3.07 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 6 | 4.87 Units on a scale | Standard Deviation 4.69 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 5 | 5.25 Units on a scale | Standard Deviation 5.52 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 3 | 0.69 Units on a scale | Standard Deviation 0.79 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Week 2 | 0.69 Units on a scale | Standard Deviation 0.95 |
| Arm 3: Placebo | Hamilton Rating Scale of Depression (HRSD) Mean Total Score | Baseline | 3.59 Units on a scale | Standard Deviation 2.81 |