Recruiting

Estradiol

Sponsor:

University of North Carolina, Chapel Hill

Code:

NCT05282277

Conditions

Depression

Psychosis

Anhedonia

Eligibility Criteria

Sex: Female

Age: 45 - 55

Healthy Volunteers: Not accepted

Interventions

Transdermal Estradiol

Micronized Progesterone

Matching Placebo Patch

Raclopride C11

Study Details

Brief summary:

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).

Conditions

Depression

Psychosis

Anhedonia

Study ID

NCT05282277

Start date

Apr 20, 2022

Status verified date

Apr, 2026

Completion date

Dec 31, 2026

Anticipated

Primary completion date

Dec 31, 2026

Anticipated

Eligibility Criteria

Eligibility Criteria

Sex: Female

Age: 45 - 55

Healthy Volunteers: Not accepted

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 Design

Enrollment

103 participants

Anticipated

Allocation

Randomized

Intervention Model

Parallel Assignment

Primary purpose

Treatment

Interventions and Outcome Measures

Arms

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.

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.

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.

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.

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.

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.

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.

experimental: Perimenopausal women with high anhedonia + moderate psychosis, placebo group

Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.

Interventions

Transdermal Estradiol

Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.

Micronized Progesterone

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

Matching Placebo Patch

Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks

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.

Primary outcome measure

  • Changes in Striatal Activation Between Groups during the MID task [ Time Frame: Baseline (week 3) to Endpoint (week 7) ]

Central Contacts and Locations

Central contacts

Kathryn G Gibson, BS

919-966-5243kathryn_gibson@med.unc.edu

Laura C Lundegard, BA

919-966-5243laura_lundegard@med.unc.edu

Locations

University of North Carolina at Chapel Hill

Recruiting

Chapel Hill, North Carolina, United States, 27514

Contacts

Laura C Lundegard, BA

919-966-5243laura_lundegard@med.unc.edu

Kathryn G Gibson, BS

919-966-5243kathryn_gibson@med.unc.edu

More Information

Sponsor

University of North Carolina, Chapel Hill

Last update posted

Apr 29, 2026

Last verified

Apr, 2026

Keywords

  • Reproductive Affective Disorder
  • Anhedonia
  • Perimenopause
  • Estrogen
  • Hormone Replacement Therapy
  • Mood Disorders
  • Estradiol Treatment
  • Sex Steroids
  • Psychosis Symptoms
  • Depressive Disorders
  • Estradiol
  • Hormones
  • Reward Activation
  • Reproductive Control Agents

Trial information was received from ClinicalTrials.gov and was last updated on 2026-09-09. This information was provided to ClinicalTrials.gov by University of North Carolina, Chapel Hill on 2026-04-29.