Perimenopausal Effects of Estradiol on Reward Responsiveness

Despite decades of research, affective disorders are prevalent and associated with
significant morbidity and mortality. Unraveling the pathophysiology of affective disorders
has been uniquely challenging because depressive syndromes are heterogeneous and have diverse
etiologies. Thus, past studies aimed at identifying neural and genetic biomarkers that would
improve the prediction of susceptibility, course of illness, and treatment response have
yielded inconsistent results. The investigator proposes to address this problem by studying
perimenopausal major depressive disorder (MDD), a depression subtype with a specific
endocrine trigger (i.e., ovarian hormone withdrawal). Evidence supporting ovarian hormone
withdrawal as a trigger for affective dysfunction in perimenopausal MDD includes the
following: perimenopausal women show a temporal association between ovarian hormone
withdrawal and the onset of mood symptoms; treatment with estrogen reduces mood symptoms; and
blinded estradiol withdrawal re-precipitates depression in women with a history of
perimenopausal MDD (manuscript in preparation). Focusing on perimenopausal MDD, a more
homogeneous subtype with a specific endocrine trigger, will increase the likelihood of
identifying meaningful neurobiological markers.One of the most powerful tools for
understanding the neural mediators of MDD is brain imaging. Prior research suggests that the
frontostriatal reward system is regulated by estradiol and implicated in MDD. However, neural
mechanisms of perimenopausal MDD have never been studied. We will assess the neural reward
system in perimenopausal women with and without MDD using functional magnetic resonance
imaging (fMRI) at baseline and following estradiol treatment. The central hypothesis is that
the neural reward system is hypoactive in perimenopausal MDD, and the antidepressant effects
of a three-week transdermal estradiol intervention will be mediated by increased activity in
the neural reward system, assessed using fMRI. The investigator will test the hypothesis by
executing the following aims:

Aim 1: To measure the frontostriatal response to reward in perimenopausal MDD and test the
effects of estradiol on neural activation in perimenopausal women. The investigator will use
fMRI at baseline and following estradiol treatment in women with and without MDD to probe
frontostriatal reward circuitry.

Aim 2: To quantify motivated behavior at baseline and following estradiol administration in
perimenopausal women with and without MDD. Motivated behavior will be operationally defined
as the response latency to reward versus non-reward during the fMRI reward task.

Aim 3: To measure the psychological correlates of the frontostriatal response to reward in
women with perimenopausal MDD at baseline and following estradiol administration. Depressive
symptoms will be assessed at baseline and following estradiol administration.

The results will provide critical information about the neuroendocrine pathophysiology of
perimenopausal depression and may subsequently contribute to the development of novel
pharmacologic interventions.

Inclusion Criteria:

1. Perimenopause Status: We will employ the Stages of Reproductive Aging Workshop (STRAW)
criteria70 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 final menstrual period (FMP).
We will enroll women who have ≥ 2 skipped cycles and an interval of amenorrhea ≥ 60
days, consistent with the late menopause transition (stage -1), and who demonstrate an
FSH level > 25 IU/mL. Because extremes of body weight (BMI < 18 or > 30 kg/m2) or a
history of chronic menstrual cycle irregularity can contribute to inaccurate
reproductive staging, these will serve as additional exclusion criteria;

2. MDD Group Eligibility Criterion: current diagnosis of MDD with an onset associated
with menstrual cycle irregularity, and no history of psychiatric illness during the 2
years before the onset of the current depressive episode as determined by the
Structure Clinical Interview for DSM-IV-TR (Diagnostic and Statistical Manual-4-Text
Revision) for Axis I Disorders (SCID);

3. Control Group Eligibility Criterion: absence of any past or present psychiatric
disorder as assessed by the SCID.

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)*;

2. pregnant, breastfeeding or trying to conceive;

3. FMP more than 12 months prior to enrollment;

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;

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**;

22. heart or kidney disease**;

23. liver disease;

24. cerebrovascular disease (stroke);

25. first degree relative with history of heart attack or stroke;

26. current cigarette smoking;

27. current suicidal ideation or psychosis;

28. past suicide attempts or psychotic episodes requiring hospitalization;

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

30. recurrent depression (i.e., more than 1 prior episode, not including episodes with
postpartum onset)

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

32. self-reported claustrophobia

33. peanut allergy

- all reported prescription medications will be reviewed and cleared by a study
physician prior to a participant's enrollment; **participants will be given the
opportunity to describe these conditions in the online screening survey. Reported
conditions that are acute in nature and/or benign will be reviewed by a study
physician and exclusions will be decided case-by-case. All chronic conditions
will be exclusionary.