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Role of the metabotropic glutamate receptor subtype 5 in circadian rhythmmisalignment and depression: Implications for treatment

Award Number: R01MH114972
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Role of the metabotropic glutamate receptor subtype 5 in circadian rhythmmisalignment and depression: Implications for treatment - In 2011, it was stated: “there appears to be a strong association between the circadian system and mood regulation, although the mechanisms that underlie this association are unclear.” Our exciting preliminary data suggests that the metabotropic glutamate receptor subtype 5 (mGluR5) provides this shared mechanism, and we propose to examine this association in Major Depressive Disorder (MDD). The timing of this proposal is critical, as this highly prevalent, chronic and recurrent disorder is predicted to be the leading cause of global disease burden by the year 2030. Further, conventional MDD treatments have low success rates, potentially because MDD patients experiencing circadian rhythm impairment (which may be a significant subset, as suggested by the high rates of sleep disturbances in MDD) are not optimally treated by conventional therapeutics. Luckily, there are multiple available treatments for such impairment (chronobiotics), with repeatedly demonstrated efficacy, rapidity of action, and lack of side effects. In fact, the rapid antidepressant, ketamine, and the chronobiotic treatment, sleep deprivation, share common mechanisms, including action at mGluR5. Despite these advantageous properties, chronobiotics are significantly underutilized due to: the inability to identify those most likely to respond and a lack of understanding of circadian dysfunction and how it is corrected with treatment. Investigation of mGluR5 may provide this needed information. MGluR5 diurnal variation has been shown in vivo using Positron Emission Tomography (PET) in rodents. We were the first to observe this in humans. Further, mGluR5 dysfunction has been implicated in preclinical and clinical studies of MDD. In this innovative proposal, we take advantage of decades of circadian rhythms research that has provided an effective and feasible method of assessing circadian time. Specifically, the time between the rise of melatonin secretion levels and the midpoint of the sleep/wake cycle is referred to as the phase angle difference (PAD), and is optimally 6 hours in healthy controls. We will assess PAD in 36 MDD and 16 healthy control participants (with equal representation of each sex) to determine whether the magnitude of deviation from optimal PAD is associated with depression severity. We will also quantify mGluR5 using PET at standardized times within the circadian cycle, to confirm the mGluR5-circadian relationship and determine whether improper mGluR5 diurnal variation underlies non-optimal PAD. This will establish, for the first time, the relationship between mGluR5 expression and circadian rhythms in humans (which has implications for diseases beyond MDD and may underlie sex differences in mood and circadian regulation). Finally, we will assess the effect of sleep deprivation therapy on circadian rhythms in depressed and control individuals. This will establish which chronotypes are most amendable to treatment and whether restoration of optimal PAD is required for treatment efficacy. Regardless of outcome, this study will increase our understanding of circadian rhythms (and misalignment) in MDD as well as the mechanism of action of chronobiotic treatments.


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 = $0 )
2025	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	5	4/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	5	4/26/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $752,564 )
2023	2023	THE RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK	W5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	001	5	5/17/2023	NON-COMPETING CONTINUATION	$752,564
2023	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	4	12/15/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $752,564

Issue Date FY: 2022 ( Subtotal = $752,564 )
2022	2022	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	4	8/4/2022	NON-COMPETING CONTINUATION	$752,564
														Subtotal = $752,564

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	001	3	7/9/2021	NON-COMPETING CONTINUATION	$0
2021	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	3	12/23/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $752,564 )
2020	2020	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	3	7/31/2020	NON-COMPETING CONTINUATION	$752,564
														Subtotal = $752,564

Issue Date FY: 2019 ( Subtotal = $752,564 )
2019	2019	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	001	2	5/28/2019	NON-COMPETING CONTINUATION	$752,564
2019	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	1	5/15/2019	NEW	$0
														Subtotal = $752,564

Issue Date FY: 2018 ( Subtotal = $791,878 )
2018	2018	RESEARCH FOUNDATION FOR THE STATE UNIVERSITY OF NEW YORK, THE	WEST 5510 FRANKS MELVILLE MEMORIAL LIBRARY	STONY BROOK	NY	11794	SUFFOLK	USA	Mental Health Research Grants	000	1	8/17/2018	NEW	$791,878
														Subtotal = $791,878

Grand Total All Awards = $3,802,134

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Role of the metabotropic glutamate receptor subtype 5 in circadian rhythmmisalignment and depression: Implications for treatment

Award Number: R01MH114972

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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