Effects of an ER Beta Agonist (Lilly Compound LY500307) on Estradiol-Withdrawal-Induced Mood Symptoms in Women With Past Perimenopausal Depression

OBJECTIVE:

During the perimenopause, the incidence of depression increases 1-5 and predicts increased
all-cause and cardiovascular mortality. A role of estradiol withdrawal in the onset of mood
disorders in some perimenopausal women has been suggested indirectly by estradiol s
antidepressant efficacy and safety in perimenopausal depression. Moreover, observational
studies report the emergence of depressive symptoms after the discontinuation of menopausal
hormone therapy (HT) in 5-10% of women. The coincidence of declining ovarian function with
the onset of depression led to the inference that withdrawal from physiologic estradiol
levels underpinned depression during the perimenopause. To test this inference, we undertook
a study to examine the role of estradiol withdrawal in perimenopausal depression. We
evaluated the effects of the acute withdrawal of estradiol therapy in postmenopausal women
with and those without a past perimenopausal depression. Results demonstrated that estradiol
withdrawal induces depressive symptoms in women with a past perimenopausal depression, but
not in those without such a history. This study was the first to provide direct evidence that
estradiol withdrawal is the relevant physiologic trigger for depressive symptoms in women
with this condition. In women with past perimenopausal depression, the recurrence of
depressive symptoms during blinded hormone withdrawal suggests that normal changes in ovarian
estradiol secretion can trigger an abnormal behavioral state in these susceptible women.
These data also suggest that the effects of estradiol withdrawal are processed differently in
some women, presumably by altering the brain network composition or activity that underlies
affective state. In this next protocol, we will examine a possible mechanism mediating the
effects of estradiol- withdrawal on mood symptoms in asymptomatic postmenopausal women with a
past perimenopausal depression. We propose to evaluate the efficacy and safety of a selective
estrogen receptor (ER) beta agonist (Lilly Compound LY500307) to prevent estradiol
withdrawal-induced mood symptoms. The effects of estradiol primarily occur through activation
of two receptor subtypes, often with opposing outcomes: estrogen receptor (ER) alpha, and ER
beta. We focus 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 in animal studies. We propose to employ the selective estrogen
receptor agonist LY500307 under double-blind, placebo controlled conditions to examine the
specific role of estrogen receptor beta in the effects of estrogen withdrawal in women with a
past perimenopause-related depression. Depressive symptoms will be measured with standardized
ratings scales (i.e., Center for Epidemiologic Studies Depression scale (CES-D) and 17-item
Hamilton Rating Scale of Depression (HRSD)). 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:

We propose to employ the selective estrogen receptor agonist LY500307 under double-blind,
placebo controlled conditions to examine the specific role of estrogen receptor beta in the
effects of estrogen withdrawal in women with a past perimenopause-related depression.
Depressive symptoms will be measured with standardized ratings scales (i.e., Center for
Epidemiologic Studies Depression scale (CES-D) and 17-item Hamilton Rating Scale of
Depression (HRSD)). 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.

DESIGN:

We propose to employ the selective estrogen receptor agonist LY500307 under double-blind,
placebo controlled conditions to examine the specific role of estrogen receptor beta in the
effects of estrogen withdrawal in women with a past perimenopause-related depression.
Depressive symptoms will be measured with standardized ratings scales (i.e., Center for
Epidemiologic Studies Depression scale (CES-D) and 17-item Hamilton Rating Scale of
Depression (HRSD)). 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.

- INCLUSION CRITERIA:

1. Women with a past perimenopause-related depression (within 10 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 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 ten years. All women participating in this protocol will have
previously completed the screening protocol # 88-M-0131 during which psychiatric,
medical, and reproductive evaluations will be performed and they will have been
confirmed to be 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.

NIMH employees/staff and their immediate family members will be excluded from the study per
NIMH policy.