Examining the Effects of Estradiol on Neural and Molecular Response to Reward (PEEPS)

January 24, 2024 updated by: University of North Carolina, Chapel Hill

Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis

This proposal will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis symptoms as well as on brain function using simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR).

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

The transition to menopause (the "perimenopause") is characterized by increased risk for new onset of depression and psychosis. Our work and that of others has demonstrated that a prominent symptom of perimenopausal-onset (PO) depression is anhedonia, contributing significantly to distress and functional impairment. Additionally, the incidence of psychosis in women may increase during this period. Declining or low levels of estradiol, particularly in the late perimenopause, may play a role in the pathogenesis of PO anhedonia and PO psychosis via effects on mesolimbic brain reward circuitry and dopamine (DA) neurotransmission. Preclinical evidence has established that estradiol modulates dopamine systems and reward-related behaviors and estradiol withdrawal evokes loss of dopaminergic functions. Whereas estrogen therapy has shown benefits in reducing mood and psychotic symptoms in perimenopausal women, no study has examined the neural mechanisms underlying such effects in a transdiagnostic sample.

This project will examine the effects of estradiol administration on perimenopausal-onset (PO) anhedonia and psychosis using simultaneous positron emission tomography and functional magnetic resonance imaging (PET-MR). Preliminary data presented here demonstrate that anhedonia is associated with decreased striatal DA release to rewards using PET with the D2/D3 DA receptor antagonist [11C]raclopride; anhedonia and psychosis are characterized by altered striatal activation to rewards using fMRI; estradiol impacts neural responses to rewards in PO anhedonia and PO psychosis; and estradiol improves PO anhedonia and PO psychosis. This project proposes to extend these lines of research by using simultaneous PET-MR to investigate the effects of transdermal estradiol, administered as a mechanistic probe, on PO anhedonia and PO psychosis in a transdiagnostic sample of women using a double-blind between-groups placebo-controlled design. This sample will be enriched for anhedonia (i.e., at least mild anhedonia). Although anhedonia and psychosis will be analyzed dimensionally, our recruitment and stratification strategy will ensure that a range of symptom severities (mild-to-moderate or high PO anhedonia; absent-to-mild or moderate PO psychosis) are equally balanced and randomized to each experimental group (estradiol or placebo). Our central hypotheses are that the mesolimbic DA system is impaired in PO anhedonia and psychosis, that estradiol administration will normalize neural responses to rewards (measured by fMRI) and striatal DA functioning (measured by PET), and that the degree of change in striatal functioning will be associated with the degree of change in PO anhedonia and PO psychosis.

Specific Aim 1 (baseline associations between PO anhedonia, PO psychosis, and PET-MR): Characterize, at baseline, associations between PO anhedonia and PO psychosis symptom severity and reward-related striatal activation measured by fMRI, and tonic and phasic striatal DA activity measured by [11C]raclopride PET.

Specific Aim 2 (estradiol effects on PO anhedonia and PET-MR): Determine the effects of estradiol (vs. placebo) on PO anhedonia and changes in PET-MR metrics related to reward processing.

Specific Aim 3 (estradiol effects on PO psychosis and PET-MR): Determine the effects of estradiol (vs. placebo) on PO psychosis and changes in PET-MR metrics related to reward processing.

This project will improve our understanding of PO anhedonia and psychosis and the mechanisms of action of the effect of estradiol on PO anhedonia and psychosis. This research will provide new mechanistic endpoints to evaluate novel PO anhedonia and psychosis treatments that target the mesolimbic DA system.

Study Type

Interventional

Enrollment (Estimated)

103

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

45 years to 55 years (Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria:

  • Provision of signed and dated informed consent form
  • Stated willingness to comply with all study procedures, lifestyle considerations, and availability for the duration of the study
  • 44-55 years old unmedicated perimenopausal women who have ≥ 2 skipped menstrual cycles, amenorrhea ≥ 60 days, corresponding to the late menopause transition (Stages of Reproductive Aging Workshop (STRAW stage -1).
  • Anhedonia or psychosis symptoms that began during the period of menstrual irregularity.
  • Clinician's Global Impression Scale-Severity score (CGI-S) > 3 to confirm a clinically impaired sample.
  • Anhedonia severity inclusion criteria and stratification: All participants will have Snaith-Hamilton Pleasure Scale (SHAPS) scores > 20 consistent with the NIMH Fast-Fail Trial for Mood and Anxiety Disorders, corresponding to clinically impairing anhedonia.
  • Psychosis severity inclusion criteria and stratification: Participants will be stratified according to scores on the psychotic subscale of the Brief Psychiatric Rating Scale (BPRS)
  • Willingness to adhere to the estradiol regimen

Exclusion Criteria:

  • Pregnancy; allergies to any active or inactive ingredients in the Climara® patch or Prometrium®.
  • BMI < 18 or > 35 kg/m^2
  • A history of chronic menstrual cycle irregularity, meaning > 1 year without menses
  • MR contraindications: Metal in the body, dental work other than fillings or gold, tattoos, metal injury, any other implant unless they are 100% plastic.
  • PET contradictions: participation in >1 research study in the past 12 months that included ionizing radiation exceeding 3 rem to the whole body (e.g., PET, CT). Standard of care imaging is not exclusionary.
  • The use of psychotropics or hormonal preparations.
  • History of psychiatric illness during the 2 years before the onset of perimenopause.
  • History of chronic, recurrent mood or psychotic disorders (i.e., more than one non-reproductive-related mood episode prior to the perimenopausal index episode).
  • A history of mood episodes requiring hospitalization.
  • Current mania;
  • Depressive episode(s) within 2 years of enrollment not associated with the transition to menopause;
  • A history of suicide attempts within the last year or current active suicidal ideation with intent and plan.
  • Neurological conditions (e.g., history of seizure or TBI)
  • Brain stimulation treatment in the past six months.
  • Endometriosis;
  • First degree relative with premenopausal breast cancer or breast cancer presenting in both breasts or multiple family members (greater than three relatives) with postmenopausal breast cancer.
  • Current medication use (i.e., current psychotropics, current anti-hypertensives, current statins, current 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)*;
  • Pregnant, breastfeeding or trying to conceive;
  • Last menstrual period more than 12 months prior to enrollment;
  • History of undiagnosed vaginal bleeding;
  • Undiagnosed enlargement of the ovaries;
  • Polycystic ovary syndrome;
  • History of breast or ovarian cancer;
  • First degree relative with ovarian cancer;
  • Abnormal finding in a provider breast exam and/or mammogram;
  • Known carrier of BRCA1 or 2 mutation;
  • Porphyria;
  • Malignant melanoma;
  • Hodgkin's disease;
  • Recurrent migraine headaches that are preceded by aura;
  • Gallbladder or pancreatic disease**;
  • Heart or kidney disease**;
  • Liver disease;
  • cerebrovascular disease (stroke);
  • First degree relative with history of heart attack or stroke;
  • Current nicotine use;
  • Self-reported claustrophobia

  • 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. For those where it is deemed that an exclusion does not apply, primary analyses will not be affected, but exploratory analyses will be conducted excluding these individuals

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, active group
Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.
Drug: Transdermal Estradiol
Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
Other Names:
  • Climara
Drug: Micronized Progesterone
Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Other Names:
  • Prometrium
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Experimental: Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, placebo group
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Drug: Matching Placebo Patch
Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
Other Names:
  • Placebo
Experimental: Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, active group
Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.
Drug: Transdermal Estradiol
Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
Other Names:
  • Climara
Drug: Micronized Progesterone
Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Other Names:
  • Prometrium
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Experimental: Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, placebo group
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Drug: Matching Placebo Patch
Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
Other Names:
  • Placebo
Experimental: Perimenopausal women with high anhedonia + absent-to-mild psychosis, active group
Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.
Drug: Transdermal Estradiol
Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
Other Names:
  • Climara
Drug: Micronized Progesterone
Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Other Names:
  • Prometrium
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Experimental: Perimenopausal women with high anhedonia + absent-to-mild psychosis, placebo group
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Drug: Matching Placebo Patch
Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
Other Names:
  • Placebo
Experimental: Perimenopausal women with high anhedonia + moderate psychosis, active group
Participants will be randomly assigned to take 100 μg/day of transdermal estradiol for 3 weeks followed by 1 week of combined 100 μg/day of transdermal estradiol and 200 mg/day progesterone.
Drug: Transdermal Estradiol
Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
Other Names:
  • Climara
Drug: Micronized Progesterone
Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Other Names:
  • Prometrium
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Experimental: Perimenopausal women with high anhedonia + moderate psychosis, placebo group
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Raclopride C11
All Participants will receive two PET-MR scans using [11C]raclopride IV as the tracer. The first scan will occur at baseline and the second at post treatment after 3 weeks.
Other Names:
  • [C11]Raclopride
Drug: Matching Placebo Patch
Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
Other Names:
  • Placebo

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in Striatal Activation Between Groups during the MID task
Time Frame: Baseline (week 3) to Endpoint (week 7)
Characterize reward-related striatal activation measured by fMRI using the Monetary Incentive Delay (MID) task to elicit blood-oxygen-level dependent (BOLD) responses. 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) response to win trials versus non-win trials. Reactivity is then compared between the two groups.
Baseline (week 3) to Endpoint (week 7)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in PO Psychosis Symptoms following Estradiol Administration Using the BPRS
Time Frame: Baseline (week 3) to Endpoint (week 7)
Determine the effects of estradiol (vs. placebo) on PO psychosis symptoms using the Brief Psychiatric Rating Scale (BPRS).The BPRS is an 18-item clinician rated psychosis measure that examines the severity of psychotic symptoms. Individuals with psychotic major depression typically have BPRS positive symptom subscale scores 7-11, and a score of 6 best differentiates psychotic MDD from nonpsychotic MDD.
Baseline (week 3) to Endpoint (week 7)
Changes in PO Anhedonia Following Estradiol Administration Using the SHAPS
Time Frame: Baseline (week 3) to Endpoint (week 7)
Determine the effects of estradiol (vs. placebo) on PO anhedonia symptoms using the Snaith-Hamilton Pleasure Scale (SHAPS). The SHAPS is a 14-item self-rated anhedonia scale. Items are comprised of statements that participants rate as "strongly disagree" (1), "disagree" (2), "agree" (3), or "strongly agree" (4). The lowest possible score is 14, the highest possible score is 56 (greatest anhedonia)
Baseline (week 3) to Endpoint (week 7)
Change in striatal phasic DA release and background DA tone to rewards measured by [11C]raclopride PET using the Monetary Incentive Delay (MID) task.
Time Frame: Baseline (week 3) to Endpoint (week 7)
Binding potential changes due to DA release and competition will be determined using a dynamic occupancy model. We will use baseline nondisplaceable binding potential (BPND) and change in BPND following task onset (ΔBPND%) to determine differences between groups in terms of the baseline (tonic) state and the activation (phasic) state.
Baseline (week 3) to Endpoint (week 7)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

University of North Carolina, Chapel Hill

Collaborators

National Institute of Mental Health (NIMH)

Investigators

  • Principal Investigator: Crystal E Schiller, PhD, UNC School of Medicine - Department of Psychiatry
  • Principal Investigator: Gabriel Dichter, PhD, UNC School of Medicine - CIDD

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

April 20, 2022

Primary Completion (Estimated)

December 31, 2026

Study Completion (Estimated)

December 31, 2026

Study Registration Dates

First Submitted

March 7, 2022

First Submitted That Met QC Criteria

March 7, 2022

First Posted (Actual)

March 16, 2022

Study Record Updates

Last Update Posted (Estimated)

January 25, 2024

Last Update Submitted That Met QC Criteria

January 24, 2024

Last Verified

January 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 21-2230
  • R01MH128238-01 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.

IPD Sharing Time Frame

Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication.

IPD Sharing Access Criteria

Approval from an IRB, IEC, or REB, as applicable and execution of a data use/sharing agreement with UNC.

IPD Sharing Supporting Information Type

  • SAP
  • ANALYTIC_CODE

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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