Perimenopausal Effects of Estradiol on Reward Responsiveness

NCT ID: NCT02255175

Last Updated: 2019-11-12

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 64 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2015-10-01
• Study Completion Date: 2018-10-17

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.

Conditions

Perimenopausal Depression

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

Estradiol

Intervention Type: DRUG

Participants will receive transdermal estradiol (100μg/day) for 3 weeks

Progesterone

Intervention Type: DRUG

Participants will receive an additional week of combined estradiol and micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.

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.

Group Type: ACTIVE_COMPARATOR

Estradiol

Intervention Type: DRUG

Participants will receive transdermal estradiol (100μg/day) for 3 weeks

Progesterone

Intervention Type: DRUG

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

Estradiol

Participants will receive transdermal estradiol (100μg/day) for 3 weeks

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

Transdermal estradiol; Climara; Prometrium; Micronized progesterone

Eligibility Criteria

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.

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.

• Minimum Eligible Age: 44 Years
• Maximum Eligible Age: 55 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: Yes

Sponsors

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

NIH

Sponsor Role: collaborator

National Institute of Mental Health (NIMH)

NIH

Sponsor Role: collaborator

University of North Carolina, Chapel Hill

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Crystal Schiller, PhD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina at Chapel Hill Psychiatry Department

Locations

University of North Carolina

Chapel Hill, North Carolina, United States

Countries

United States

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

K12HD001441-15

Identifier Type: NIH

Identifier Source: secondary_id

View Link

K23MH105569-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

13-3572

Identifier Type: -

Identifier Source: org_study_id