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

• 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;
• 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 Structured Clinical Interview for DSM-IV-TR (Diagnostic and Statistical Manual-4-Text Revision) for Axis I Disorders (SCID);
• 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:

• 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)*;
• pregnant, breastfeeding or trying to conceive;
• FMP more than 12 months prior to enrollment;
• history of undiagnosed vaginal bleeding;
• undiagnosed enlargement of the ovaries;
• polycystic ovary syndrome;
• history of breast or ovarian cancer;
• first degree relative with ovarian cancer;
• first degree relative with premenopausal onset or bilateral breast cancer;
• 2+ first degree relatives with breast cancer (regardless of onset);
• 3+ relatives with postmenopausal breast cancer;
• abnormal finding in a provider breast exam and/or mammogram;
• known carrier of BRCA1 or 2 mutation;
• endometriosis;
• blood clots in the legs or lungs;
• porphyria;
• diabetes mellitus;
• malignant melanoma;
• Hodgkin's disease;
• recurrent migraine headaches that are preceded by aura;
• gallbladder or pancreatic disease**;
• heart or kidney disease**;
• liver disease;
• cerebrovascular disease (stroke);
• first degree relative with history of heart attack or stroke;
• current cigarette smoking;
• current suicidal ideation or psychosis;
• past suicide attempts or psychotic episodes requiring hospitalization;
• chronic depression (i.e., episode(s) lasting 3+ years);
• recurrent depression (i.e., more than 1 prior episode, not including episodes with postpartum onset)
• depressive episode(s) within 2 years of enrollment;
• self-reported claustrophobia
• 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.