Perimenopausal Effects of Estradiol on Reward Responsiveness
Condition: Perimenopausal 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 either with or without depression.
    

Detailed description: 
      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.
    

Intervention name(s): Estradiol; Progesterone
Intervention type(s): Drug; Drug
Intervention description(s): Participants will receive transdermal estradiol (100μg/day) for 3 weeks; Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Other intervention name(s): Transdermal estradiol; Climara; Prometrium; Micronized progesterone
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Progesterone
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Reproductive Affective Disorder; Depression; Perimenopause; Estrogen; Estradiol treatment; Mood Disorders; Estrogen Replacement Therapy; Sex Steroids; Depressive disorder; Mental Disorders; Estradiol; Hormones; Physiological effects of drugs; Reproductive Control Agents