Major Depressive DisorderPhase 4PEARNCT06610305
Ovarian Hormone Withdrawal, Anhedonia, and Reward Sensitivity in Women With Premenstrual Exacerbations of Depression
A Phase 4 study testing Transdermal estradiol and Progesterone in people with Major Depressive Disorder, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 45 years, women only
- Conditions the study is for
- Major Depressive Disorder
- What is being tested?
- Transdermal estradiol and Progesterone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 75 participants
- Where
- 1 siteUnited States
- Study dates
- 2 Sep 2024to 1 Jun 2028
- Phase
- Phase 4
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 45 years
- Women only
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
United States1 site, 1 recruiting
- Recruiting
University of North Carolina, Chapel Hill
Chapel Hill, North Carolina, 27707
Study Coordinator, (919) 445-6814, pearstudy@unc.edu
About this study
Official title: Ovarian Hormone Withdrawal, Anhedonia, and Reward Sensitivity in Women With Premenstrual Exacerbations of Depression: A Crossover Randomized Controlled Trial
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?
Read more
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
Read the 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
- Being tested
- Transdermal estradiol, Progesterone, Transdermal placebo patch, placebo capsule
- Keywords
- depression, hormone, premenstrual, estrogen, progesterone, perimenstrual
- Medical subject headings
- Depressive Disorder, Major, Depression
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Transdermal estradiolDrug
0.1 mg/day delivered via weekly patch
ProgesteroneDrug
100 mg twice daily (200 mg/day total) administered via oral capsule
Transdermal placebo patchDrug
Once weekly via transdermal patch
placebo capsuleDrug
Twice daily via oral capsule
| Study group | Role | What they receive |
|---|---|---|
| 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 Receives: 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) Receives: Drug: Transdermal estradiol; Drug: Progesterone; Drug: Transdermal placebo patch; Drug: placebo capsule |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: 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)
Measures daily symptom burden used for the evaluation and diagnosis of menstrual-related mood disorders. The items measure symptoms related to core emotional disturbance, including depression, anxiety, irritability, and mood lability, as well as secondary symptoms such as concentration, energy, appetite, sleep, and physical symptoms and interference from symptoms overall. 24 items, scale range 24-144, higher scores indicate greater symptoms.
Measured: 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)
Measures depressive and anxiety symptoms within 10 different subdomains: Suicidality, Lassitude, Insomnia, Appetite Loss, Appetite Gain, Ill Temper, Well-Being, Panic, Social Anxiety, and Traumatic Intrusions. 64 items, scale range 64-320, higher scores indicate greater symptoms
Measured: 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)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Sep 2024
- Study start2 Sep 2024
- Primary completion1 Jun 2028 (estimated)
- Study completion1 Jun 2028 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Major Depressive DisorderStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 75 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Responsible party
- Sponsor
- Investigators
- Chris Sikes-Keilp, MD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT06610305
- Sponsor's protocol ID
- 24-1715
- Other IDs
- 1R01MH122446
- Acronym
- PEAR
- Status last verified
- Oct 2025
- First submitted
- 17 Sep 2024
- Last updated
- 29 Oct 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 29 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Ovarian Hormone Withdrawal, Anhedonia, and Reward Sensitivity in Women With Premenstrual Exacerbations of Depression: A Crossover Randomized Controlled Trial
- ClinicalTrials.gov ID
- NCT06610305
- Acronym / sponsor ID
- PEAR / 24-1715
- Conditions
- Major Depressive Disorder
- Keywords
- depression, hormone, premenstrual, estrogen, progesterone, perimenstrual
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Recruiting
- Enrolment
- 75 participants (estimated)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Institute of Mental Health (NIMH)
- Study start
- 2 Sep 2024 (actual)
- Primary completion
- 1 Jun 2028 (estimated)
- Study completion
- 1 Jun 2028 (estimated)
- First posted
- 24 Sep 2024 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Estradiol+Progesterone, then Placebo | Experimental | Drug: Transdermal estradiol, Drug: Progesterone, Drug: Transdermal placebo patch, Drug: placebo capsuleTwo 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 |
| Placebo, then Estradiol+Progesterone | Experimental | Drug: Transdermal estradiol, Drug: Progesterone, Drug: Transdermal placebo patch, Drug: placebo capsuleTwo 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) |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- Female only
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (8 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Transdermal estradiol0.1 mg/day delivered via weekly patch | Drug | Estradiol+Progesterone, then Placebo, Placebo, then Estradiol+Progesterone |
| Progesterone100 mg twice daily (200 mg/day total) administered via oral capsule | Drug | Estradiol+Progesterone, then Placebo, Placebo, then Estradiol+Progesterone |
| Transdermal placebo patchOnce weekly via transdermal patch | Drug | Estradiol+Progesterone, then Placebo, Placebo, then Estradiol+Progesterone |
| placebo capsuleTwice daily via oral capsule | Drug | Estradiol+Progesterone, then Placebo, Placebo, then Estradiol+Progesterone |
Primary outcome
Dimensional Anhedonia Rating Scale (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)
Time frame: 3 menstrual cycles (each cycle approximately 28 days in duration)
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.
Reward Positivity (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)
Time frame: 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)
An EEG event-related potential reflecting sensitivity to positive feedback.
2 secondary outcomes
Daily Record of Severity of Problems (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase)
Time frame: 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)
Time frame: 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)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Oct 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Chris Sikes-Keilp, MD principal investigator
University of North Carolina, Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Transdermal estradiol and Progesterone in people with Major Depressive Disorder, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 29 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Study Coordinator ((919) 445-6814, pearstudy@unc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Dimensional Anhedonia Rating Scale (Luteal Phase Stabilized vs Luteal Phase Unstabilized Hormones vs Follicular Phase) (time frame: 3 menstrual cycles (each cycle approximately 28 days in duration)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Oct 2025.