Ovarian Hormone Withdrawal, Anhedonia, and Reward Sensitivity in Women With Premenstrual Exacerbations of Depression

NCT06610305 | Recruiting Phase 4 FDA Drug

• 2 other identifiers: 24-17151R01MH122446
• Study Type: interventional
• Target: 75
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical trial is to learn how hormonal changes over the menstrual cycle affect mood symptoms in reproductive-aged women with depression that worsens during the premenstrual period. The main questions it aims to answer are:

• -How do fluctuations in estradiol and progesterone across the menstrual cycle affect the ability to experience pleasure and the neural sensitivity to reward in hormone-sensitive, depressed women? And consequently, how does stabilizing the luteal phase decline in estrogen and progesterone (using estradiol patches and progesterone pills) affect these changes? Participants will:
• Receive hormones followed by placebo, or vice versa, for a total of four weeks across three menstrual cycles
• Complete daily mood ratings
• Collect home urine samples for hormone testing
• Complete five biobehavioral testing sessions during which neural responses are recorded (via electroencephalography, or EEG) during an acute stress task and computer tasks

Conditions

Major Depressive Disorder

Keywords

depression; hormone; premenstrual; estrogen; progesterone; perimenstrual

Outcome Measures

Primary Outcomes (2)

• Dimensional Anhedonia Rating Scale (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)

  Measures several domains of hedonic function, including desire, motivation, effort, and consummatory pleasure, across various contexts. 17 items, max score 68, higher scores indicate greater anhedonia.

  3 menstrual cycles (each cycle approximately 28 days in duration)

• Reward Positivity (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)

  An EEG event-related potential reflecting sensitivity to positive feedback.

  Over the course of 2 menstrual cycles (~28 days each), EEG will be collected four times on four separate days: twice during the late luteal phase (11-14 days following ovulation), and twice during the mid follicular phase (23-25 days following ovulation)

Secondary Outcomes (2)

• Daily Record of Severity of Problems (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)

  5 menstrual cycles (each cycle approximately 28 days in duration)

• Inventory for Depression and Anxiety Symptoms (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)

  Over the course of 2 menstrual cycles (~28 days each), IDAS will be collected 4 times on 4 separate days: twice during the late luteal phase (11-14 days following ovulation), and twice during the mid follicular phase (23-25 days following ovulation)

Study Arms (2)

Estradiol+Progesterone, then Placebo

EXPERIMENTAL

Two weeks of luteal phase transdermal estradiol (0.1mg/day)+oral progesterone (200 mg/day) during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal/oral placebo

Drug: Transdermal estradiol; Drug: Progesterone; Drug: Transdermal placebo patch; Drug: placebo capsule

Placebo, then Estradiol+Progesterone

EXPERIMENTAL

Two weeks of luteal phase transdermal/oral placebo during the first intervention cycle, followed by a one cycle washout, followed by two weeks of luteal phase transdermal estradiol (0.1 mg/day)+oral progesterone (200 mg/day)

Drug: Transdermal estradiol; Drug: Progesterone; Drug: Transdermal placebo patch; Drug: placebo capsule

Interventions

Transdermal estradiol DRUG

0.1 mg/day delivered via weekly patch

Estradiol+Progesterone, then Placebo; Placebo, then Estradiol+Progesterone

Progesterone DRUG

100 mg twice daily (200 mg/day total) administered via oral capsule

Estradiol+Progesterone, then Placebo; Placebo, then Estradiol+Progesterone

Transdermal placebo patch DRUG

Once weekly via transdermal patch

Estradiol+Progesterone, then Placebo; Placebo, then Estradiol+Progesterone

placebo capsule DRUG

Twice daily via oral capsule

Estradiol+Progesterone, then Placebo; Placebo, then Estradiol+Progesterone

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Biologically female and between the ages of 18-45 years (45 set as upper limit to avoid endocrine changes associated with perimenopause).
• Self-reported regular menstrual cycles between 25 and 35 days.
• A previous diagnosis of major depressive disorder, with self-reported premenstrual worsening of symptoms.
• If the woman has children, she must be at least 1 year postpartum.
• English-speaking

You may not qualify if:

• Pregnant, breastfeeding, or trying to become pregnant. Pregnancy status will be confirmed using a urine pregnancy test at the enrollment visit and again at the first visit of the second condition. Women will be instructed to use a barrier method of birth control during the study.
• Taking any form of exogenous hormones or IUD, and must have ended previous use of hormonal preparations at least one month prior to the study. Women who were previously taking oral contraceptives or other hormonal medications must have one normal menstrual cycle (menstrual period) prior to enrollment in the study.
• BMI less than 18 or greater than 29.
• A personal history of any chronic medical condition that could confound the experimental protocol, including but not limited to metabolic or autoimmune disease, epilepsy, endometriosis, cancer, diabetes, cardiovascular, gastrointestinal, hepatic, renal, pulmonary disease, migraine with aura, hypertension, Parkinson's disease, chronic pain, and thromboembolic events.
• A family history indicative of increased risk of breast cancer or thromboembolic disorders.
• Current cigarette smoking.
• A history of mania, psychosis, or substance use disorder.
• Any recent history (last 12 months) of active suicidal ideation, or suicide attempt within the last 5 years.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead
• National Institute of Mental Health (NIMH): collaborator

Study Sites (1)

University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, 27707, United States

RECRUITING

MeSH Terms

Conditions

Depressive Disorder, Major; Depression

Interventions

Progesterone

Condition Hierarchy (Ancestors)

Depressive Disorder; Mood Disorders; Mental Disorders; Behavioral Symptoms; Behavior

Intervention Hierarchy (Ancestors)

Pregnenediones; Pregnenes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Corpus Luteum Hormones; Gonadal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progesterone Congeners; Gonadal Steroid Hormones

Study Officials

• Chris Sikes-Keilp, MD

  University of North Carolina, Chapel Hill

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Study Coordinator

CONTACT

(919) 445-6814; pearstudy@unc.edu

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 17, 2024
• First Posted: September 24, 2024
• Study Start: September 2, 2024
• Primary Completion (Estimated): June 1, 2028
• Study Completion (Estimated): June 1, 2028
• Last Updated: October 29, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)