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

NCT ID: NCT06610305

Last Updated: 2025-10-29

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-09-02
• Study Completion Date: 2028-06-01

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

Detailed Description

Potential participants will first be screened over the phone to assess health history (including mental health) and reproductive status. Those who meet inclusion/exclusion criteria will be invited to an in-person enrollment session. At enrollment, consent will be obtained and participants will complete a structured interview and a series of questionnaires. Interested participants will be educated on the use of smartphone-based ecological momentary assessment (EMA) surveys, which will be used to complete daily mood ratings over the course of the study.

Following enrollment, women will complete daily mood ratings for one menstrual cycle using EMA; this is called the "prospective-assessment" phase. Those who meet our predetermined mood criteria during prospective assessment will move into a one-cycle lead-in phase of the study, where they will continue daily EMA; for those who do not, study participation will conclude. Participants will complete a single in-person visit during the lead-in phase, at which they will be randomized to one of two conditions within the randomized crossover design; they will also complete an acute stress task and computer tasks while EEG is recorded.

During the intervention phase, the first condition will receive transdermal estradiol (E2) (0.1mg/d)+oral progesterone (P4) (200mg/d) during the luteal phase of cycle 1 of the intervention phase (third cycle overall), and placebo (transdermal+oral) during the luteal phase of cycle 3 of the intervention phase (fifth cycle overall); the second will receive placebo during the luteal phase of intervention cycle 1, and transdermal E2+oral P4 during the luteal phase of intervention cycle 3. Cycle 2 will be a washout for both conditions (mood assessment only, without hormone collection or labs). During cycles 1 and 3, every-other-day urine samples will be collected for estradiol and progesterone metabolites and daily anhedonia symptoms will be assessed. Women will also complete two lab sessions tied to the mid-follicular and late luteal phases, as determined by a fixed time window relative to ovulation. At each lab session, EEG will be recorded during computer tasks that probe reward sensitivity, responses from which will serve as our primary outcome measure.

Conditions

Major Depressive Disorder

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: OTHER
• Blinding Strategy: TRIPLE

Study Groups

Estradiol+Progesterone, then Placebo

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

Group Type: EXPERIMENTAL

Transdermal estradiol

Intervention Type: DRUG

0.1 mg/day delivered via weekly patch

Progesterone

Intervention Type: DRUG

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

Transdermal placebo patch

Intervention Type: DRUG

Once weekly via transdermal patch

placebo capsule

Intervention Type: DRUG

Twice daily via oral capsule

Placebo, then Estradiol+Progesterone

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)

Group Type: EXPERIMENTAL

Transdermal estradiol

Intervention Type: DRUG

0.1 mg/day delivered via weekly patch

Progesterone

Intervention Type: DRUG

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

Transdermal placebo patch

Intervention Type: DRUG

Once weekly via transdermal patch

placebo capsule

Intervention Type: DRUG

Twice daily via oral capsule

Interventions

Transdermal estradiol

0.1 mg/day delivered via weekly patch

Intervention Type: DRUG

Progesterone

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

Intervention Type: DRUG

Transdermal placebo patch

Once weekly via transdermal patch

Intervention Type: DRUG

placebo capsule

Twice daily via oral capsule

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• 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

Exclusion Criteria

• 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

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

Chris Sikes-Keilp, MD

Role: PRINCIPAL_INVESTIGATOR

University of North Carolina, Chapel Hill

Locations

University of North Carolina, Chapel Hill

Chapel Hill, North Carolina, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Study Coordinator

Role: CONTACT

pearstudy@unc.edu

(919) 445-6814

Facility Contacts

Study Coordinator

Role: primary

pearstudy@unc.edu

(919) 445-6814

Other Identifiers

1R01MH122446

Identifier Type: NIH

Identifier Source: secondary_id

View Link

24-1715

Identifier Type: -

Identifier Source: org_study_id