Effects of a Tissue Selective Estrogen Complex (TSEC) on Depression and the Neural Reward System in the Perimenopause
Owing largely to a steep drop in estrogen production, perimenopausal women are 14 times more likely to experience symptoms of depression than premenopausal women. While estrogen therapy can alleviate symptoms of depression, it’s also associated with an increased risk of breast and uterine cancer, and so many women decline it. However, a promising new FDA-approved drug bolsters estrogen while mitigating cancer risks. Researchers will test this drug’s capacity to alleviate depression in women whose symptoms have manifested with the onset of menopause.
Crystal Schiller, Ph.D.
Need/Problem: The risk for developing depression increases 14-fold during the transition to menopause. Despite evidence that estrogen plays a role in depression during menopause, the use of estrogen replacement therapy remains controversial, in part, because of the long-term health risks, including breast and uterine cancer. A new FDA-approved estrogen compound, Duavee, protects against breast and uterine, but it is unclear whether it will improve mood.
Grant Summary: The purpose of this grant is to test the effects of Duavee on mood and the brain circuits implicated in depression.
Goals & Projected Outcomes: The outcome of this research will be increased knowledge of the use of estrogen to treat depression that occurs during the transition to menopause. We will compare the effects of Duavee on depression and the brain to the effects of estrogen replacement therapy, which will provide the first opportunity to determine whether Duavee can be used to treat depression and change activity in the brain circuits involved in depression. This research will also provide information essential for 1) identifying which patients will benefit most from hormone therapies and 2) developing new medications for depression during the transition to menopause. We expect to use the results of this research to conduct future clinical trials aimed at developing new safe and effective medications for depression during the menopause transition.
Grant Details: 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), we 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).
I recently 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. My 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. We expect that Duavee will reduce symptoms of depression and increase activity in the neural reward circuit.
In this study, we 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 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.