Effects of a Tissue Selective Estrogen Complex (TSEC) on Depression and the Neural Reward System in the Perimenopause"
Condition: Perimenopausal Disorder; Depression
MeSH terms: Depression; Depressive Disorder
Study type: Interventional
Phase: Phase 4

Summary: 
      Using neuroimaging, the investigator will study the effects of estrogen on mood and brain
      function in perimenopausal women with depression.
    

Detailed description: 
      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).
    

Intervention name(s): Bazedoxifene/Conjugated Estrogen
Intervention type(s): Drug
Intervention description(s): 20 mg bazedoxifene/0.45mg conjugated estrogens tablets
Other intervention name(s): Duavee
Intervention MeSH terms: Bazedoxifene; Estrogens; Estrogens, Conjugated (USP)
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Hormone Replacement Therapy; Estrogen; Depression; Mood Disorders; Estrogen Replacement Therapy; Depressive Disorder; Mental Disorders; Hormones; Physiological effects of drugs; Reproductive Control Agents; Tissue Selective Estrogen Complex