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Using allopregnanolone to probe behavioral and neurobiological mechanisms that underlie depression in women across perimenopausal stage

Award Number: R01MH128617
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Using allopregnanolone to probe behavioral and neurobiological mechanisms that underlie depression in women across perimenopausal stage - PROJECT SUMMARY Women are twice as likely as men to develop depression, and among some women, reproductive transitions trigger unique hormonal risks for reproductive-endocrine mood disorders. Changing reproductive steroid dynamics contribute female-specific endocrine risk factors in postpartum depression (PPD), premenstrual dysphoric disorder (PMDD), and perimenopausal depression (PeriDep). However, PeriDep lags far behind PPD and PMDD, each of which has FDA-approved therapies that leverage the reproductive endocrine changes underlying hormonally-linked depression. For example, the neurosteroid allopregnanolone (ALLO) in its proprietary form brexanolone has proven antidepressant efficacy for PPD. Endogenous ALLO levels decline after delivery, as women traverse menopause, and are lower in women with than without depression. Despite parallels to PPD, and despite the large population potentially affected by PeriDep—approximately 5.4 million women are perimenopausal annually—the contributions of ALLO to PeriDep have not been investigated. Key pilot data show a protective benefit of the ALLO precursor progesterone (P4) in PeriDep and that P4 correlates with advantageous neuroprotective, inflammatory, and neurophysiologic sleep profiles, all known ALLO targets. Thus, this project will use a mechanistic placebo-controlled trial to uncover the behavioral and neurobiological mechanisms through which ALLO exerts its therapeutic effects in women with PeriDep. Specifically, the project will examine key mechanistic targets underlying depression to include behavioral (Aim 1a: rumination, negative attentional bias), circuit-based (Aim 1b: functional connectivity within default mode network and between default mode and salience networks), molecular (Aim 2a: circulating and magnetic resonance spectroscopy neurotrophic and pro-inflammatory molecules), and physiological (Aim 2b: sleep EEG wake after sleep onset) outcomes. Eighty women with mild to severe PeriDep will be randomized to double-blinded placebo or ALLO administered as a 60-hour brexanolone infusion, stratified by early vs. late perimenopausal status. Analyses will test the acute (immediately post-treatment) and durable (30-days post-treatment) effects of ALLO on each of the selected mechanistic outcomes, mirroring the efficacy and biological data in human and animal models of PPD. Results will be integrated (Aim 3) to determine how each mechanistic outcome mediates ALLO’s effect on global measures of depression severity and to examine modification by depression illness course and early vs. late perimenopausal status. This innovative project pairing a mechanistic intervention with robust behavioral and neurobiological outcomes will exploit mechanistic pathways underlying the role of ALLO in PeriDep and translate findings to identify novel therapeutic targets that are specific for PeriDep.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	3	9/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $924,035 )
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	3	1/15/2025	NON-COMPETING CONTINUATION	$785,431
2025	2025	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	002	3	9/23/2025	NON-COMPETING CONTINUATION	$138,604
2025	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	10/24/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $924,035

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	1/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $925,688 )
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	001	2	1/19/2023	NON-COMPETING CONTINUATION	$92,569
2023	2023	BRIGHAM & WOMENS HOSPITAL INC	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	2	12/8/2022	NON-COMPETING CONTINUATION	$833,119
														Subtotal = $925,688

Issue Date FY: 2022 ( Subtotal = $947,753 )
2022	2022	BRIGHAM AND WOMEN'S HOSPITAL, INC., THE	75 FRANCIS ST	BOSTON	MA	02115	SUFFOLK	USA	Mental Health Research Grants	000	1	1/27/2022	NEW	$947,753
														Subtotal = $947,753

Grand Total All Awards = $2,797,476

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Using allopregnanolone to probe behavioral and neurobiological mechanisms that underlie depression in women across perimenopausal stage

Award Number: R01MH128617

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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