A Phase 4 interventional study of Transdermal Estradiol and Micronized Progesterone in Depression, Psychosis and Anhedonia, sponsored by University of North Carolina, Chapel Hill. Recruiting at 1 site in United States. Open to female participants aged 45 Years to 55 Years. Per ClinicalTrials.gov, last updated 2026-04-29.
Sponsored by University of North Carolina, Chapel Hill · Phase 4, Interventional, and Treatment
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).
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.
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Exclusion Criteria:
Peanut allergy
all reported prescription medications will be reviewed and cleared by a study physician prior to a participant's enrollment;
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
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A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
BMI (body mass index)
Weight in kilograms divided by height in metres squared. Example: 70 kg and 1.75 m gives 70 ÷ (1.75 × 1.75) ≈ 22.9.
What counts as overweight or obesity differs between countries (some use lower cut-offs), so go by the range the study states.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Postmenopausal
Periods have stopped for good: usually no period for 12 months in a row without another medical reason, sometimes confirmed by a blood test (FSH).
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
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 · Drug: Micronized Progesterone · Drug: Raclopride C11
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Matching Placebo Patch · Drug: Raclopride C11
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 · Drug: Micronized Progesterone · Drug: Raclopride C11
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Matching Placebo Patch · Drug: Raclopride C11
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 · Drug: Micronized Progesterone · Drug: Raclopride C11
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Matching Placebo Patch · Drug: Raclopride C11
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 · Drug: Micronized Progesterone · Drug: Raclopride C11
Participants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Drug: Matching Placebo Patch · Drug: Raclopride C11
Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
Also known as: Climara
Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
Also known as: Prometrium
Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
Also known as: Placebo
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.
Also known as: [C11]Raclopride
Changes in Striatal Activation Between Groups during the MID task
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.
Time frame: Baseline (week 3) to Endpoint (week 7)
Changes in PO Psychosis Symptoms following Estradiol Administration Using the BPRS
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.
Time frame: Baseline (week 3) to Endpoint (week 7)
Changes in PO Anhedonia Following Estradiol Administration Using the SHAPS
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)
Time frame: 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.
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.
Time frame: Baseline (week 3) to Endpoint (week 7)
Plan to share: Yes — 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.
Supporting information: Statistical analysis plan, Analytic code
Time frame: Deidentified individual data that supports the results will be shared beginning 18 to 24 months following publication.
Access criteria: Approval from an IRB, IEC, or REB, as applicable and execution of a data use/sharing agreement with UNC.
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Studies of the drugs tested here: Estradiol · Progesterone
University of North Carolina, Chapel Hill →