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A Confirmatory Efficacy Trial of Engaging a Novel Sleep/Circadian Rhythm Target as Treatment for Depression in Adolescents

Award Number: R01MH129558
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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A Confirmatory Efficacy Trial of Engaging a Novel Sleep/Circadian Rhythm Target as Treatment for Depression in Adolescents - Project Summary Major Depressive Disorder (MDD) in adolescence is associated with significant psychosocial impairment, health problems, school failure, and suicidality. Many youth remain substantially symptomatic despite receiving current first-line treatments, underscoring the need for novel, modifiable targets to improve depression treatment outcomes. Between 60-81% of adolescents suffering from MDD have evening circadian preference (ECP), defined as the behavioral predilection for later sleep and wake timing. ECP is associated with increased MDD severity, poor antidepressant response, recurrent MDD episodes, and increased suicidality. In an initial efficacy study among 42 youth with MDD and ECP, an evidence based cognitive-behavioral sleep therapy, the Transdiagnostic Sleep and Circadian Intervention (TranS-C), resulted in improved depression trajectories for one year compared to an active control. The therapeutic effect of TranS-C on MDD was mediated by increasing the time from when subjects have onset of melatonin release in dim light in the evening (dim light melatonin onset [DLMO], the gold standard objective measurement of biological circadian rhythm timing) and average wake time. This measure of the alignment between the timing of circadian biology and behavior is commonly employed in circadian rhythm research and referred to as the phase angle difference (PAD) between DLMO and waketime (PADDLMO WAKETIME). Initial efficacy study data suggests that 90% of youth with ECP and MDD have a short PADDLMO WAKETIME that will be lengthened by TranS-C. Building on our initial efficacy study, we propose a sufficiently powered confirmatory efficacy trial to confirm that TranS-C will lengthen PADDLMO WAKETIME and thereby improve depression in adolescents with ECP, MDD and short PADDLMO WAKETIME. Following the Experimental Therapeutics Approach, we propose a blinded randomized controlled trial of TranS-C in 200 adolescents with MDD, ECP, and short PADDLMO WAKETIME to confirm target engagement (lengthening PADDLMO WAKETIME) and whether engaging this target has a therapeutic effect on MDD. Adolescents will receive 8 weeks of TranS-C or a credible comparator condition (Psychoeducation). If successful this study will provide a low stigma, safe, data driven precision medicine approach, for improving MDD for adolescents with MDD, ECP and short PADDLMO WAKETIME, a large, underserved, and vulnerable sub-group. It will also establish short PADDLMO WAKETIME as a new target for the development of other novel antidepressant therapies.


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 = $778,871 )
2026	2026	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Mental Health Research Grants	001	4	4/10/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$778,871
2026	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	3	4/8/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $778,871

Issue Date FY: 2025 ( Subtotal = $636,291 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	3	3/19/2025	NON-COMPETING CONTINUATION	$636,291
														Subtotal = $636,291

Issue Date FY: 2024 ( Subtotal = $746,141 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	000	2	3/1/2024	NON-COMPETING CONTINUATION	$671,526
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Mental Health Research Grants	001	2	8/14/2024	NON-COMPETING CONTINUATION	$74,615
														Subtotal = $746,141

Issue Date FY: 2023 ( Subtotal = $766,514 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Mental Health Research Grants	000	1	3/8/2023	NEW	$766,514
														Subtotal = $766,514

Grand Total All Awards = $2,927,817

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A Confirmatory Efficacy Trial of Engaging a Novel Sleep/Circadian Rhythm Target as Treatment for Depression in Adolescents

Award Number: R01MH129558

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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