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

代谢型谷氨酸受体亚型 5 在昼夜节律失调和抑郁中的作用：对治疗的影响

• 批准号: 9766372
• 负责人: Christine Delorenzo
• 金额: $ 75.26万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-20 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766372
• 关键词: Acute; Affect; Aftercare; Antidepressive Agents; Area; Biological; Biological Markers; Chronic; Circadian Dysregulation; Circadian Rhythms; Clinical Research; Cues; Data; Depressed mood; Disease; Diurnal Rhythm; Ensure; Female; Functional disorder; Glutamate Receptor; Hamilton Rating Scale for Depression; Hour; Human; Hydrocortisone; Imaging Techniques; Impairment; Individual; Investigation; Ketamine; Light; Link; Major Depressive Disorder; Measures; Melatonin; Mental Depression; Metabotropic Glutamate Receptors; Methods; Molecular; Mood Disorders; Moods; Neurotransmitters; Outcome Study; Participant; Patients; Pattern; Periodicity; Phase; Positioning Attribute; Positron-Emission Tomography; Predisposition; Property; Recurrence; Regulation; Reporting; Reproducibility; Research; Rodent; Role; Severities; Sex Differences; Sleep; Sleep Deprivation; Sleep Wake Cycle; Sleep disturbances; Standardization; System; Therapeutic; Time; Tracer; Treatment Efficacy; Variant; Wakefulness; Woman; base; burden of illness; circadian; circadian regulation; cohort; disorder control; experience; in vivo; innovation; male; men; mood regulation; patient subsets; preclinical study; receptor density; restoration; sex; side effect; success; therapy development; time interval

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.

在2011年说：“昼夜节律与情绪之间似乎有很强的联系 调节，尽管这种关联是基础的机制尚不清楚。”我们令人兴奋的初步数据 表明代谢型谷氨酸受体亚型5（MGLUR5）提供了这种共同的机制，并且 我们建议检查主要抑郁症（MDD）的这种关联。该提议的时机是 至关重要的，因为预计这种高度普遍，慢性和复发性障碍是全球的主要原因 到2030年，伯恩疾病伯宁。此外，常规MDD治疗的成功率较低，可能 因为MDD患者患有昼夜节律障碍（这可能是重要的子集） 由MDD中高睡眠障碍率提出的建议未经常规治疗 治疗。幸运的是，有多种可用的治疗方法用于这种损害（Chronobiotics）， 反复表现出有效性，行动速度和缺乏副作用。实际上，快速抗抑郁药， 氯胺酮和经纪幼体治疗，睡眠剥夺，共享共同的机制，包括在 mglur5。尽管具有这些优势，但由于： 无法识别最有可能做出反应的人，并且对昼夜节律障碍缺乏了解 通过治疗纠正。对MGLUR5的调查可能会提供此必需的信息。 mglur5 diurnal 使用啮齿动物中的正电子发射断层扫描（PET）在体内显示了变异。我们是第一个 在人类中观察到这一点。此外，在临床前和临床研究中暗示了MGLUR5功能障碍 MDD。在这项创新的建议中，我们利用了数十年的昼夜节律研究的优势 提供了一种评估昼夜节时间的有效且可行的方法。具体而言，上升之间的时间 褪黑激素分泌水平和睡眠/唤醒周期的中点称为相角 差异（PAD），在健康对照中最佳6小时。我们将评估36 MDD和16个健康状态的PAD 控制参与者（每个性别的同等表示），以确定出发的幅度是否 从最佳垫子中与抑郁严重程度有关。我们还将使用pet at At量化mglur5 昼夜节律内的标准化时间，以确认mglur5-circadian关系并确定 MGLUR5昼夜变化不当是非最佳垫的基础。这将首次建立 Mglur5表达与人类昼夜节律之间的关系（这对 超越MDD的疾病，可能是情绪和昼夜节律调节的性别差异的基础）。最后，我们会的 评估睡眠剥夺治疗对抑郁症和控制个体昼夜节律的影响。这 将确定哪些计时型最适合治疗以及最佳垫的恢复是否为 需要治疗效率。无论结果如何，这项研究都会增加我们对昼夜节律的理解 MDD中的节奏（和未对准）以及成年生物处理的作用机理。