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).