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

> **NIH NIH R01** · STATE UNIVERSITY NEW YORK STONY BROOK · 2022 · $752,564

## Abstract

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...

## Key facts

- **NIH application ID:** 10226836
- **Project number:** 5R01MH114972-04
- **Recipient organization:** STATE UNIVERSITY NEW YORK STONY BROOK
- **Principal Investigator:** Christine Delorenzo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $752,564
- **Award type:** 5
- **Project period:** 2018-08-20 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10226836

## Citation

> US National Institutes of Health, RePORTER application 10226836, Role of the metabotropic glutamate receptor subtype 5 in circadian rhythmmisalignment and depression: Implications for treatment (5R01MH114972-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10226836. Licensed CC0.

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