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Perimenopausal Effects of Estradiol on Reward Responsiveness (PEERS)

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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

Tracking Information
First Submitted Date  ICMJE September 29, 2014
First Posted Date  ICMJE October 2, 2014
Results First Submitted Date  ICMJE September 25, 2019
Results First Posted Date  ICMJE November 12, 2019
Last Update Posted Date November 12, 2019
Study Start Date  ICMJE October 1, 2015
Actual Primary Completion Date October 17, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 21, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: September 29, 2014)
Change in frontostriatal reactivity to reward during the MID fMRI task [ Time Frame: 3 weeks ]
The Monetary Incentive Delay (MID)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 21, 2019)
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 29, 2014)
  • Change in neural connectivity measured during resting-state fMRI [ Time Frame: 3 weeks ]
    Resting state scans will be conducted at the beginning and end of each fMRI session
  • Change in response latency to reward versus non-reward during the MID fMRI task [ Time Frame: Assessed at baseline and at week 3 ]
    The Monetary Incentive Delay (MID) Task
  • Change in Inventory of Depression and Anxiety Symptoms (IDAS) scores [ Time Frame: Assessed at baseline and at week 3 ]
  • Change in the Positive and Negative Affect Schedule (PANAS) [ Time Frame: Assessed at baseline and at week 3 ]
  • Change in Mood and Anxiety Symptom Questionnaire--Anhedonic Depression subscale (MASQ-AD) [ Time Frame: Assessed at baseline and at week 3 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures
 (submitted: September 29, 2014)
Change in Hamilton Rating Scale for Depression (HRSD) scores [ Time Frame: Assessed at baseline and at week 3 ]
 
Descriptive Information
Brief Title  ICMJE Perimenopausal Effects of Estradiol on Reward Responsiveness
Official Title  ICMJE Effects of Estradiol on Neural Reward System and Depression in the Perimenopause
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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 4
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Perimenopausal Depression
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Estradiol
    • Drug: 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.
    Interventions:
    • Drug: Estradiol
    • Drug: Progesterone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 21, 2019)
64
Original Estimated Enrollment  ICMJE
 (submitted: September 29, 2014)
50
Actual Study Completion Date  ICMJE October 17, 2018
Actual Primary Completion Date October 17, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: Female
Ages  ICMJE 44 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02255175
Other Study ID Numbers  ICMJE 13-3572
K12HD001441-15 ( U.S. NIH Grant/Contract )
K23MH105569-01A1 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party University of North Carolina, Chapel Hill
Study Sponsor  ICMJE University of North Carolina, Chapel Hill
Collaborators  ICMJE
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
  • National Institute of Mental Health (NIMH)
Investigators  ICMJE
Principal Investigator: Crystal Schiller, PhD University of North Carolina at Chapel Hill Psychiatry Department
PRS Account University of North Carolina, Chapel Hill
Verification Date November 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP