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DepressionPhase 4PEEPSNCT05282277

Examining the Effects of Estradiol on Neural and Molecular Response to Reward

A Phase 4 study testing Transdermal Estradiol, Micronized Progesterone and Raclopride C11 in people with Depression and Psychosis, run by University of North Carolina, Chapel Hill at 1 site in United States.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts
Official record
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Trial 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). Read more about this study

Who is it for?
Ages 45 to 55 years, women only
Conditions the study is for
Depression, Psychosis, Anhedonia
What is being tested?
Transdermal Estradiol, Micronized Progesterone and Raclopride C11
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
103 participants
Where
1 siteUnited States
Study dates
20 Apr 2022to 31 Dec 2026
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 45 to 55 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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

Who cannot join

  • 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.
Show all 40Show fewer
  • 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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Kathryn G Gibson, BS contact

919-966-5243

kathryn_gibson@med.unc.edu

Laura C Lundegard, BA contact

919-966-5243

laura_lundegard@med.unc.edu

United States1 site, 1 recruiting

  • University of North Carolina at Chapel Hill

    Chapel Hill, North Carolina, 27514

    Laura C Lundegard, BA, 919-966-5243, laura_lundegard@med.unc.edu

    Kathryn G Gibson, BS, 919-966-5243, kathryn_gibson@med.unc.edu

    Recruiting

Other trials in United States

About this study

Official title: Examining the Effects of Estradiol on Neural and Molecular Response to Rewards in Perimenopausal-Onset Anhedonia and Psychosis

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).

Read the detailed description

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.

Being tested
Transdermal Estradiol, Micronized Progesterone, Matching Placebo Patch, Raclopride C11
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
Medical subject headings
Depression, Psychotic Disorders, Anhedonia, Mood Disorders, Depressive Disorder

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Transdermal EstradiolDrug

    Also called Climara

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

  • Micronized ProgesteroneDrug

    Also called Prometrium

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

  • Matching Placebo PatchDrug

    Also called Placebo

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

  • Raclopride C11Drug

    Also called [C11]Raclopride

    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.

Study groups in NCT05282277
Study groupRoleWhat they receive
Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, active groupExperimentalParticipants 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.
Receives: Drug: Transdermal Estradiol; Drug: Micronized Progesterone; Drug: Raclopride C11
Perimenopausal women with mild-to-moderate anhedonia + absent-to-mild psychosis, placebo groupExperimentalParticipants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Receives: Drug: Matching Placebo Patch; Drug: Raclopride C11
Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, active groupExperimentalParticipants 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.
Receives: Drug: Transdermal Estradiol; Drug: Micronized Progesterone; Drug: Raclopride C11
Perimenopausal women with mild-to-moderate anhedonia + moderate psychosis, placebo groupExperimentalParticipants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Receives: Drug: Matching Placebo Patch; Drug: Raclopride C11
Perimenopausal women with high anhedonia + absent-to-mild psychosis, active groupExperimentalParticipants 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.
Receives: Drug: Transdermal Estradiol; Drug: Micronized Progesterone; Drug: Raclopride C11
Perimenopausal women with high anhedonia + absent-to-mild psychosis, placebo groupExperimentalParticipants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Receives: Drug: Matching Placebo Patch; Drug: Raclopride C11
Perimenopausal women with high anhedonia + moderate psychosis, active groupExperimentalParticipants 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.
Receives: Drug: Transdermal Estradiol; Drug: Micronized Progesterone; Drug: Raclopride C11
Perimenopausal women with high anhedonia + moderate psychosis, placebo groupExperimentalParticipants will be randomly assigned to receive a matching placebo patch for 3 weeks.
Receives: Drug: Matching Placebo Patch; Drug: Raclopride C11

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Baseline (week 3) to Endpoint (week 7)

Secondary outcomes (3)

  1. 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.

    Measured: Baseline (week 3) to Endpoint (week 7)

  2. 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)

    Measured: Baseline (week 3) to Endpoint (week 7)

  3. 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.

    Measured: Baseline (week 3) to Endpoint (week 7)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted16 Mar 2022
  2. Study start20 Apr 2022
  3. Primary completion31 Dec 2026 (estimated)
  4. Study completion31 Dec 2026 (estimated)

Resources

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
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Model description
Parallel group, randomized placebo-controlled study
Masking
Double blind
Who is masked
Participant, Outcomes assessor
Enrolment
103 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05282277
Sponsor's protocol ID
21-2230
Other IDs
R01MH128238-01
Acronym
PEEPS
Status last verified
Apr 2026
First submitted
7 Mar 2022
Last updated
29 Apr 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
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.

Publications

  • Bromberger JT, Matthews KA, Schott LL, Brockwell S, Avis NE, Kravitz HM, Everson-Rose SA, Gold EB, Sowers M, Randolph JF Jr. Depressive symptoms during the menopausal transition: the Study of Women's Health Across the Nation (SWAN). J Affect Disord. 2007 Nov;103(1-3):267-72. doi: 10.1016/j.jad.2007.01.034. Epub 2007 Feb 28.

    PubMed 17331589

  • Freeman EW, Sammel MD, Boorman DW, Zhang R. Longitudinal pattern of depressive symptoms around natural menopause. JAMA Psychiatry. 2014 Jan;71(1):36-43. doi: 10.1001/jamapsychiatry.2013.2819.

    PubMed 24227182

  • Maki PM, Kornstein SG, Joffe H, Bromberger JT, Freeman EW, Athappilly G, Bobo WV, Rubin LH, Koleva HK, Cohen LS, Soares CN. Guidelines for the Evaluation and Treatment of Perimenopausal Depression: Summary and Recommendations. J Womens Health (Larchmt). 2019 Feb;28(2):117-134. doi: 10.1089/jwh.2018.27099.mensocrec. Epub 2018 Sep 5.

    PubMed 30182804

  • Frokjaer VG. Pharmacological sex hormone manipulation as a risk model for depression. J Neurosci Res. 2020 Jul;98(7):1283-1292. doi: 10.1002/jnr.24632. Epub 2020 May 12.

    PubMed 32399989

  • Schiller CE, Johnson SL, Abate AC, Schmidt PJ, Rubinow DR. Reproductive Steroid Regulation of Mood and Behavior. Compr Physiol. 2016 Jun 13;6(3):1135-60. doi: 10.1002/cphy.c150014.

    PubMed 27347888

  • Dichter GS, Damiano CA, Allen JA. Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings. J Neurodev Disord. 2012 Jul 6;4(1):19. doi: 10.1186/1866-1955-4-19.

    PubMed 22958744

  • Nusslock R, Alloy LB. Reward processing and mood-related symptoms: An RDoC and translational neuroscience perspective. J Affect Disord. 2017 Jul;216:3-16. doi: 10.1016/j.jad.2017.02.001. Epub 2017 Feb 4.

    PubMed 28237133

  • Macoveanu J, Meluken I, Chase HW, Phillips ML, Kessing LV, Siebner HR, Vinberg M, Miskowiak KW. Reduced frontostriatal response to expected value and reward prediction error in remitted monozygotic twins with mood disorders and their unaffected high-risk co-twins. Psychol Med. 2021 Jul;51(10):1637-1646. doi: 10.1017/S0033291720000367. Epub 2020 Mar 2.

    PubMed 32115012

  • Guffanti G, Kumar P, Admon R, Treadway MT, Hall MH, Mehta M, Douglas S, Arulpragasam AR, Pizzagalli DA. Depression genetic risk score is associated with anhedonia-related markers across units of analysis. Transl Psychiatry. 2019 Sep 19;9(1):236. doi: 10.1038/s41398-019-0566-7.

    PubMed 31537779

  • Kumar P, Goer F, Murray L, Dillon DG, Beltzer ML, Cohen AL, Brooks NH, Pizzagalli DA. Impaired reward prediction error encoding and striatal-midbrain connectivity in depression. Neuropsychopharmacology. 2018 Jun;43(7):1581-1588. doi: 10.1038/s41386-018-0032-x. Epub 2018 Feb 26.

    PubMed 29540863

  • Treadway MT, Zald DH. Reconsidering anhedonia in depression: lessons from translational neuroscience. Neurosci Biobehav Rev. 2011 Jan;35(3):537-55. doi: 10.1016/j.neubiorev.2010.06.006. Epub 2010 Jul 11.

    PubMed 20603146

  • Willner P, Scheel-Kruger J, Belzung C. The neurobiology of depression and antidepressant action. Neurosci Biobehav Rev. 2013 Dec;37(10 Pt 1):2331-71. doi: 10.1016/j.neubiorev.2012.12.007. Epub 2012 Dec 19.

    PubMed 23261405

  • Pizzagalli DA. Depression, stress, and anhedonia: toward a synthesis and integrated model. Annu Rev Clin Psychol. 2014;10:393-423. doi: 10.1146/annurev-clinpsy-050212-185606.

    PubMed 24471371

  • Hamilton JP, Sacchet MD, Hjornevik T, Chin FT, Shen B, Kampe R, Park JH, Knutson BD, Williams LM, Borg N, Zaharchuk G, Camacho MC, Mackey S, Heilig M, Drevets WC, Glover GH, Gambhir SS, Gotlib IH. Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent 11C-raclopride positron emission tomography and functional magnetic resonance imaging investigation. Transl Psychiatry. 2018 Nov 30;8(1):264. doi: 10.1038/s41398-018-0316-2.

    PubMed 30504860

  • Treadway MT. The Neurobiology of Motivational Deficits in Depression--An Update on Candidate Pathomechanisms. Curr Top Behav Neurosci. 2016;27:337-55. doi: 10.1007/7854_2015_400.

    PubMed 26475160

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Transdermal Estradiol, Micronized Progesterone and Raclopride C11 in people with Depression and Psychosis, 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 8 inclusion and 40 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 Apr 2026. 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 Kathryn G Gibson, BS (919-966-5243, kathryn_gibson@med.unc.edu), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Changes in Striatal Activation Between Groups during the MID task (time frame: Baseline (week 3) to Endpoint (week 7)). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05282277, which also lists 155 linked publications.

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 Apr 2026.

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