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1/2 Neurodevelopmental and clinical trajectories of youth at risk for bipolar I disorder

Award Number: R01MH125886
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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1/2 Neurodevelopmental and clinical trajectories of youth at risk for bipolar I disorder - Program Director/Principal Investigator (Last, First, Middle): Strakowski, Stephen M. ABSTRACT Although bipolar I disorder is a dynamic condition expressing a wide range of affective, cognitive and neurovegetative symptoms, it is defined by the occurrence of mania. Mania typically first emerges in adolescence and young adulthood, and it is a strongly predictive phenotype. Moreover, the early course of bipolar I disorder is progressive, as euthymic periods shorten over time. Additionally, bipolar I disorder is strongly familial with heritability rates approaching 85%. A family history of bipolar I disorder increases risk for mania as well as a number of other psychiatric conditions, including suicidal behaviors and reward hypersensitivity. Together, these characteristics suggest that bipolar I disorder results from an inherited failure during adolescence to develop healthy neural systems that modulate mood and behavioral activation. Complicating the inherited risk is that people with a family history of bipolar disorder also report higher rates of early life adversity than the general population. Early life adversity is associated with lifelong elevated rates of depression, anxiety and substance use disorders, impaired risk-reward processing, and suicide. Consequently, during development individuals with a familial risk for bipolar I disorder may be exposed to a dual risk, i.e. an inherited vulnerability and environmental early-life stress. How these risks interact to impact brain development and subsequent outcomes in these individuals is not known. Mood and risk-reward behaviors are managed by intersecting ventral prefrontal networks. These networks undergo substantial development in the transition from adolescence to young adulthood (when bipolar I disorder emerges) in which maturation of prefrontal networks leads to adaptive adult emotional regulation and risk-reward processing. Abnormalities in these networks are commonly described in both bipolar disorder and in response to early life adversity, with many shared characteristics. With these considerations in mind, we hypothesize that heritability for bipolar I disorder interacts with early life adversity to synergistically disrupt healthy ventral prefrontal network development during adolescence, underlying a cumulative increased risk for developing mania and other conditions more common in bipolar families. To test this hypothesis, over a four-year interval we will assess trajectories in ventral prefrontal network connectivity in youth at-familial-risk for bipolar I disorder compared to those without this risk, and the interaction with or without early life trauma, to determine whether these risks cumulatively lead to increasing emergence of: 1) mood symptoms and syndromes, 2) substance misuse, 3) suicidal behaviors, and 4) approach motivation hypersensitivity. These results can inform future approaches to prevent illness onset and progression in individuals at risk for or early in the course of bipolar disorder. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page


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: 2025 ( Subtotal = $938,141 )
2025	2025	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	000	5	6/3/2025	NON-COMPETING CONTINUATION	$938,141
														Subtotal = $938,141

Issue Date FY: 2024 ( Subtotal = $938,141 )
2024	2024	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	000	4	6/7/2024	NON-COMPETING CONTINUATION	$938,141
														Subtotal = $938,141

Issue Date FY: 2023 ( Subtotal = $811,720 )
2023	2023	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	000	3	5/30/2023	NON-COMPETING CONTINUATION	$811,720
														Subtotal = $811,720

Issue Date FY: 2022 ( Subtotal = $831,458 )
2022	2022	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	001	2	6/30/2022	NON-COMPETING CONTINUATION	$831,458
2022	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	000	1	6/29/2022	NEW	$0
														Subtotal = $831,458

Issue Date FY: 2021 ( Subtotal = $731,135 )
2021	2021	UNIVERSITY OF TEXAS AT AUSTIN	110 INNER CAMPUS DR MN 13	AUSTIN	TX	78712	TRAVIS	USA	Mental Health Research Grants	000	1	7/28/2021	NEW	$731,135
														Subtotal = $731,135

Grand Total All Awards = $4,250,595

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1/2 Neurodevelopmental and clinical trajectories of youth at risk for bipolar I disorder

Award Number: R01MH125886

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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