Effects of a Tissue Selective Estrogen Complex (TSEC) on Depression and the Neural Reward System in the Perimenopause"

Despite decades of clinical research, depression continues to affect 20.9 million Americans
each year and remains the leading cause of disability worldwide. Women are twice as likely as
men to experience depression, and depression symptoms are particularly common during periods
of hormone change. Depression risk increases 14-fold in the two years surrounding menopause,
suggesting that hormone changes may cause depression during this time. Past research has
shown that estrogen, in particular, plays an important role in depression during the
transition to menopause ("the perimenopause") for the following reasons: 1) depression begins
when estrogen levels plummet, 2) estrogen therapy reduces depression symptoms, and 3) when
perimenopausal women who were treated with estrogen are taken off of estrogen (without their
knowledge), their depression returns. Despite clear evidence that estrogen plays a role in
depression during the perimenopause (DPM), the investigators don't know how estrogen affects
the brain, which is important for developing effective medications to treat DPM and also for
determining which patients are most likely to benefit from medication that replaces the
estrogen lost during menopause (estrogen replacement therapy).

The investigator received a grant from the National Institutes of Health, which received
preliminary support from the Foundation of Hope, to characterize the effect of estrogen
replacement therapy on the brain in women with DPM and women without depression ("controls").
The brain pathway affected most by depression is the neural reward circuit, which consists of
a number of different brain regions that act in concert to determine a person's response to
rewards. Activity in the neural reward circuit depends on estrogen levels and is reduced in
people with depression. The investigator's NIH-funded study will be the first to examine how
the neural reward circuit is affected by DPM and estrogen replacement therapy. While estrogen
replacement therapy acts as an antidepressant, many women elect not to take estrogen and many
physicians discourage its use because of the risk of long-term negative health effects,
including breast and uterine cancer. A new FDA-approved compound, Duavee, combines estrogen
with another medication, bazedoxifene, which protects against breast and uterine cancer while
reducing hot flashes. Duavee may therefore be more acceptable to women with DPM and their
doctors than estrogen replacement therapy. However, the effects of Duavee on depression and
the neural reward circuit have never been tested, and one can't infer that estrogen will have
the same antidepressant effects in the presence of bazedoxifene (which partially blocks the
effects of estrogen in certain tissues).

The purpose of the proposed project is to 1) test the antidepressant effects of Duavee, and
2) quantify the effects of Duavee on the neural reward circuit. The investigators expect that
Duavee will reduce symptoms of depression and increase activity in the neural reward circuit.
In this study, the investigators will recruit medically healthy, unmedicated women with DPM
and administer Duavee for 3 weeks (a duration that has been shown in previous studies of
estrogen replacement to be sufficient for treating depression). Eligibility will be assessed
by an initial telephone screen and confirmed by a gynecologic exam, laboratory testing, and
an interview about their current and past depression symptoms. Only women with depression
that began during the menopause transition (i.e., when they started skipping periods) will be
enrolled. Both before and after treatment, women will have a fMRI brain scan to determine the
effects of the medication on the neural reward circuit. During the 3-week treatment, women
will come into the clinic to have their blood drawn, refill their medication, and answer
questions about their mood and menopause symptoms.This study is important because untreated
DPM contributes to cardiac deaths. Many women are afraid to use estrogen replacement therapy
because of the long-term risk of cancer and yet refuse to take antidepressants for fear of
side effects and stigma. Because Duavee addresses the main potential problems of estrogen
replacement therapy, this research stands to revolutionize treatment for DPM. The use of
estrogen replacement therapy to treat DPM is a relatively new area of research and one of
great importance given the large and increasing number of women who enter the perimenopause
each year and are potentially at risk for depression. Women with DPM seek treatment from
gynecologists, psychiatrists, and general practitioners, yet there is neither consensus nor
practical guidelines for preventing and treating DPM.

Specific Aims: The investigators currently are assessing the neural reward system in subjects
with perimenopausal major depressive disorder (PM-MDD) and those without depression
("controls") using functional magnetic resonance imaging (fMRI) at baseline and following
estrogen replacement therapy (ERT). The Foundation of Hope (FOH) award will allow us to add a
Tissue Selective Estrogen Complex (TSEC) treatment condition in a separate group of PM-MDD.
The investigators' central hypothesis is that the neural reward system is hypoactive in
PM-MDD, and the antidepressant effects of a three-week TSEC intervention will be associated
with increased activity in the neural reward system, assessed using functional magnetic
resonance imaging (fMRI). The investigators will test the hypothesis by executing the
following aims: Aim 1: Determine the extent to which TSEC reduces anhedonia and other
depressive symptoms in PM-MDD. Anhedonia and other depressive symptoms will be assessed at
baseline and following TSEC administration. The investigators also will compare the effects
of TSEC and ERT in PM-MDD. Hypothesis 1: Women PM-MDD will report a significant reduction in
depressive symptoms following TSEC administration, and the degree of symptom improvement will
be associated with the change in frontostriatal responsivity to reward. Aim 2: Quantify the
effect of TSEC on the neural reward system in PM-MDD. The investigators will use fMRI at
baseline and following TSEC treatment in PM-MDD to probe frontostriatal reward circuitry. The
investigator will also compare the effects of TSEC and ERT in PM-MDD. Hypothesis 2: PM-MDD
will show increased activation of the frontostriatal circuit in response to reward following
TSEC administration (compared with baseline).

Inclusion Criteria:

- The investigators will employ the Stages of Reproductive Aging Workshop (STRAW)
criteria to confirm perimenopausal status. The stages are primarily based on the
characteristics of the menstrual cycle and secondarily on follicle stimulating hormone
(FSH) levels. The anchor for the staging system is the last menstrual period (LMP).
The investigators will enroll women who have > 2 skipped cycles with an interval of
amenorrhea > 60 days and FSH values > 14, consistent with the late menopause
transition (stage-1)*. Women who have taken oral contraceptives continuously for
relief of perimenopausal symptoms will be exempt from our LMP criteria, and their
perimenopausal status will be determined by FSH alone. Because extremes of body weight
(BMI < 18 or > 35 kg/m2) or a history of chronic menstrual cycle irregularity can
contribute to inaccurate reproductive staging, these will serve as additional
exclusion criteria.

Current diagnosis of MDD with an onset associated with menstrual cycle irregularity.
Present or past mania, psychosis, suicide attempts, and alcohol or drug dependence, and
current substance abuse, as determined by the Structure Clinical Interview for The
Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
(DSM-IV-TR) for Axis I Disorders (SCID) are exclusionary.

* Per the STRAW criteria, FSH values are highly variable in the late menopausal transition
(stage -1), and clinicians should "carefully evaluate the appropriate FSH value, depending
on the assay they use" (Harlow et al, 2012). For nearly two years following the LMP, FSH
values can fluctuate between levels characteristic of the early reproductive years and
levels characteristic of menopause (Hale et al, 2014). McLendon Labs at the University of
North Carolina at Chapel Hill (UNC) uses an FSH assay that defines levels consistently
above ? 21.5 IU/mL as post-menopausal (McLendon Labs, 2016). As FSH values do not stabilize
at consistently high levels until post-menopause, the investigators are setting our minimum
required FSH value at > 14 IU/mL to carefully select for women in the perimenopause
transition.

Exclusion Criteria:

- Patients will not be permitted to enter this protocol if they have any of the
following:

1. current medication use (i.e., psychotropics, anti-hypertensives, statins,
hormonal preparations, or frequent use of anti-inflammatory agents (> 10
times/month)). Women will be allowed to enroll who take medications without known
mood effects (e.g. stable thyroid hormone replacement and occasional (< 5
times/month) use of Ambien);

- all reported prescription medications will be reviewed and cleared by a
study physician prior to a participant's enrollment;

2. pregnant, breastfeeding or trying to conceive;

3. LMP more than 12 months prior to enrollment;

- women who have recently taken oral contraceptives continuously for relief of
perimenopausal symptoms will be exempt from the final menstrual period (FMP)
criteria, and instead, the presence of menstrual irregularity prior to the
use of oral contraceptives and elevated FSH will be used to determine their
perimenopausal status;

4. history of undiagnosed vaginal bleeding;

5. undiagnosed enlargement of the ovaries;

6. polycystic ovary syndrome;

7. history of breast or ovarian cancer;

8. first degree relative with ovarian cancer;

9. first degree relative with premenopausal onset or bilateral breast cancer;

10. 2+ first degree relatives with breast cancer (regardless of onset);

11. 3+ relatives with postmenopausal breast cancer;

12. abnormal finding in a provider breast exam and/or mammogram;

- participants will be given the opportunity to describe these conditions in
the online screening survey. Reported conditions that were acute in nature
and have resolved completely (as indicated by the medical record or
follow-up testing) and/or benign will be reviewed by a study physician prior
to enrollment. All chronic conditions will be exclusionary.

13. known carrier of BRCA1 or 2 mutation;

14. endometriosis;

15. blood clots in the legs or lungs;

16. porphyria;

17. diabetes mellitus;

18. malignant melanoma;

19. Hodgkin's disease;

20. recurrent migraine headaches that are preceded by aura;

21. gallbladder or pancreatic disease;

- participants will be given the opportunity to describe these conditions in
the online screening survey. Reported conditions that were acute in nature
and have resolved completely (as indicated by the medical record or
follow-up testing) and/or benign will be reviewed by a study physician prior
to enrollment. All chronic conditions will be exclusionary.

22. heart or kidney disease;

- participants will be given the opportunity to describe these conditions in
the online screening survey. Reported conditions that were acute in nature
and have resolved completely (as indicated by the medical record or
follow-up testing) and/or benign will be reviewed by a study physician prior
to enrollment. All chronic conditions will be exclusionary.

23. liver disease;

24. cerebrovascular disease (stroke);

25. current cigarette smoking;

26. current suicidal ideation, mania, psychosis, or alcohol/drug abuse/dependence;

27. past suicide attempts, mania, alcohol/drug dependence, or psychotic episodes;

28. chronic depression (i.e., episode(s) lasting 3+ years);

29. depressive episode(s) within 2 years of enrollment;

30. self-reported claustrophobia;

31. peanut allergy;

32. HIV/AIDS