NCT05282277

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

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

• Status: Recruiting
• Phase: Phase 4
• Study type: Interventional
• Enrollment: 103 (estimated)
• Sponsor: University of North Carolina, Chapel Hill · Academic / Other
• Sex: Female
• Age: 45 Years – 55 Years
• Healthy volunteers: Not accepted

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).

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.

Conditions

• Depression
• Psychosis
• Anhedonia

Interventions

Type	Name	Description
DRUG	Transdermal Estradiol	Participants will be randomized to receive transdermal estradiol (100μg/day) patch for 3 weeks.
DRUG	Micronized Progesterone	Participants will receive an additional week of micronized progesterone (200 mg/day) at the end of the study to precipitate menstruation.
DRUG	Matching Placebo Patch	Participants will be randomized to receive a transdermal estradiol-matching placebo patch for 3 weeks
DRUG	Raclopride C11	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.

Timeline

• Start date: 2022-04-20
• Primary completion: 2026-12-31
• Completion: 2026-12-31
• First posted: 2022-03-16
• Last updated: 2025-02-26

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study