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Perimenopausal Effects of Estradiol on Reward Responsiveness (PEERS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02255175
Recruitment Status : Completed
First Posted : October 2, 2014
Results First Posted : November 12, 2019
Last Update Posted : November 12, 2019
Sponsor:
Collaborators:
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Information provided by (Responsible Party):
University of North Carolina, Chapel Hill

Brief Summary:
Using neuroimaging, the investigator will study the effects of estrogen on mood and brain function in perimenopausal women either with or without depression.

Condition or disease Intervention/treatment Phase
Perimenopausal Depression Drug: Estradiol Drug: Progesterone Phase 4

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Effects of Estradiol on Neural Reward System and Depression in the Perimenopause
Study Start Date : October 1, 2015
Actual Primary Completion Date : October 17, 2018
Actual Study Completion Date : October 17, 2018


Arm Intervention/treatment
Experimental: Perimenopausal women, depressed
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.
Drug: Estradiol
Participants will receive transdermal estradiol (100μg/day) for 3 weeks
Other Names:
  • Transdermal estradiol
  • Climara

Drug: Progesterone
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 Names:
  • Prometrium
  • Micronized progesterone

Active Comparator: Perimenopausal women, non-depressed
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.
Drug: Estradiol
Participants will receive transdermal estradiol (100μg/day) for 3 weeks
Other Names:
  • Transdermal estradiol
  • Climara

Drug: Progesterone
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 Names:
  • Prometrium
  • Micronized progesterone




Primary Outcome Measures :
  1. Caudate Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment [ Time Frame: Pre-treatment (visit 3) ]
    Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.

  2. Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment [ Time Frame: Pre-treatment (visit 3) ]
    Nucleus Accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.

  3. Putamen Signal Intensity in Response to Reward During the MID fMRI Task at Pre-treatment [ Time Frame: Pre-treatment (visit 3) ]
    Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups at pre-treatment.

  4. Caudate Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment. [ Time Frame: Post-treatment (visit 6) ]
    Caudate reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.

  5. Nucleus Accumbens (NAcc) Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment. [ Time Frame: Post-treatment (visit 6) ]
    Nucleus accumbens (NAcc) reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.

  6. Putamen Signal Intensity in Response to Reward During the MID fMRI Task Following Estradiol Treatment. [ Time Frame: Post-treatment (visit 6) ]
    Putamen reactivity to reward during the Monetary Incentive Delay (MID) task was measured between the two groups. During MID the task, participants respond to "win" trials by pressing a button on a button box in the MRI as quickly as possible when the see a target. Reactivity is measured by examining participant's change in blood-oxygen-level dependent (BOLD) (i.e., measurement of oxygen level that is carried to neurons by red blood cells since areas of the brain that are thought to be more "active" or involved in certain tasks require more oxygen) in response to a stimulus of interest (win trials) versus non-stimulus (non-win trials). Percent signal change in BOLD activation between monetary reward versus non-reward is the outcome of interest. Percent signal change is then compared between the two groups following treatment.


Secondary Outcome Measures :
  1. Response Latency to Reward During the MID fMRI Task at Pre-treatment [ Time Frame: Pre-treatment (visit 3) ]
    Time (ms) between stimulus and response will be measured during the Monetary Incentive Delay (MID) task during the win trials. During MID the task, participants need to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI.

  2. Response Latency to Reward During the MID fMRI Task Following Estradiol Treatment [ Time Frame: Post-treatment (visit 6) ]
    Time (ms) between stimulus and response will be measured during reward trials of the Monetary Incentive Delay (MID) task. During MID the task, participants need to select the correct response during "win" and "lose" conditions by pressing a button on a button box in the MRI.

  3. Change in Inventory of Depression and Anxiety Symptoms (IDAS) Dysphoria Scores [ Time Frame: Assessed at pre- and post-treatment (visits 3 and 6) ]
    The Dysphoria Scale of the Inventory of Depression and Anxiety Symptoms (IDAS) will be used to assess the change in depressive symptom severity. The IDAS Dysphoria Scale consists of 10 items and uses a 5-point Likert-type scale, ranging from 1 to 5 with 1 indicating "not at all" and 5 indicating "extremely". As such, the range of possible scores is 10 to 50. The Dysphoria scale includes items assessing feelings of depression, inadequacy, psychomotor agitation, guilt, discouragement, anhedonia, poor concentration, difficulty with decision-making, psychomotor retardation, and worry. Higher scores indicate worse depression symptoms.



Information from the National Library of Medicine

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Layout table for eligibility information
Ages Eligible for Study:   44 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. 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;
  2. 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);
  3. 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:

  1. 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)*;
  2. pregnant, breastfeeding or trying to conceive;
  3. FMP more than 12 months prior to enrollment;
  4. history of undiagnosed vaginal bleeding;
  5. undiagnosed enlargement of the ovaries;
  6. polycystic ovary syndrome;
  7. history of breast or ovarian cancer;
  8. first degree relative with ovarian cancer;
  9. first degree relative with premenopausal onset or bilateral breast cancer;
  10. 2+ first degree relatives with breast cancer (regardless of onset);
  11. 3+ relatives with postmenopausal breast cancer;
  12. abnormal finding in a provider breast exam and/or mammogram;
  13. known carrier of BRCA1 or 2 mutation;
  14. endometriosis;
  15. blood clots in the legs or lungs;
  16. porphyria;
  17. diabetes mellitus;
  18. malignant melanoma;
  19. Hodgkin's disease;
  20. recurrent migraine headaches that are preceded by aura;
  21. gallbladder or pancreatic disease**;
  22. heart or kidney disease**;
  23. liver disease;
  24. cerebrovascular disease (stroke);
  25. first degree relative with history of heart attack or stroke;
  26. current cigarette smoking;
  27. current suicidal ideation or psychosis;
  28. past suicide attempts or psychotic episodes requiring hospitalization;
  29. chronic depression (i.e., episode(s) lasting 3+ years);
  30. recurrent depression (i.e., more than 1 prior episode, not including episodes with postpartum onset)
  31. depressive episode(s) within 2 years of enrollment;
  32. self-reported claustrophobia
  33. 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02255175


Locations
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United States, North Carolina
University of North Carolina
Chapel Hill, North Carolina, United States, 27514
Sponsors and Collaborators
University of North Carolina, Chapel Hill
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Mental Health (NIMH)
Investigators
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Principal Investigator: Crystal Schiller, PhD University of North Carolina at Chapel Hill Psychiatry Department
  Study Documents (Full-Text)

Documents provided by University of North Carolina, Chapel Hill:
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Responsible Party: University of North Carolina, Chapel Hill
ClinicalTrials.gov Identifier: NCT02255175    
Other Study ID Numbers: 13-3572
K12HD001441-15 ( U.S. NIH Grant/Contract )
K23MH105569-01A1 ( U.S. NIH Grant/Contract )
First Posted: October 2, 2014    Key Record Dates
Results First Posted: November 12, 2019
Last Update Posted: November 12, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by University of North Carolina, Chapel Hill:
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
Additional relevant MeSH terms:
Layout table for MeSH terms
Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Estradiol 3-benzoate
Estradiol 17 beta-cypionate
Estradiol
Polyestradiol phosphate
Progesterone
Estrogens
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Contraceptive Agents
Reproductive Control Agents
Contraceptive Agents, Female
Progestins