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

Официальное название

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

Обзор

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).

Подробное описание

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.

Вмешательства

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

Первичные конечные точки

• Changes in Striatal Activation Between Groups during the MID task [Срок оценки: Baseline (week 3) to Endpoint (week 7)]

Вторичные конечные точки (3)

• Changes in PO Psychosis Symptoms following Estradiol Administration Using the BPRS [Срок оценки: Baseline (week 3) to Endpoint (week 7)]
• Changes in PO Anhedonia Following Estradiol Administration Using the SHAPS [Срок оценки: 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. [Срок оценки: Baseline (week 3) to Endpoint (week 7)]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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.
• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 1 центр

• University of North Carolina at Chapel Hill — Chapel Hill

Публикации

• 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 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. PMID 32115012

Идентификаторы

NCT: NCT05282277 · 21-2230 · R01MH128238-01

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗