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

2011年，有人指出："昼夜节律系统和情绪之间似乎有很强的联系 监管，尽管这种关联的机制尚不清楚。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）提供了这种共享机制， 我们建议在重度抑郁症（MDD）中检查这种关联。这一提议的时机是 至关重要，因为这种高度流行的慢性和复发性疾病预计将成为全球疾病的主要原因。 到2030年的疾病负担。此外，常规MDD治疗的成功率较低，潜在地 因为经历昼夜节律损害的MDD患者（其可能是重要的子集， 由MDD中睡眠障碍的高发生率所暗示）并不是常规治疗的最佳选择。 治疗学幸运的是，有多种可用的治疗这种损害（生物钟）， 反复证明了疗效、作用迅速且无副作用。实际上，快速抗抑郁药， 氯胺酮和时间生物素治疗，睡眠剥夺，共享共同的机制，包括行动， mGluR5。尽管有这些有利的性质，但生物钟显著地未被充分利用，这是由于： 无法识别那些最有可能做出反应的人，缺乏对昼夜节律功能障碍及其如何影响的理解， 通过治疗得到纠正。对mGluR5的研究可以提供这一所需的信息。MGluR5昼夜变化 在啮齿动物中使用正电子发射断层扫描（PET）已经显示出体内变化。我们是第一个 在人类身上观察到这一点。此外，mGluR5功能障碍已经涉及在临床前和临床研究中， MDD。在这个创新的建议中，我们利用了几十年的昼夜节律研究， 提供了一种有效可行的评估昼夜节律时间的方法。具体来说， 睡眠/觉醒周期的中点被称为相位角 差异（PAD），并且在健康对照中最佳为6小时。我们将评估36例MDD患者和16例健康患者的PAD 控制参与者（每种性别的代表性相同），以确定偏差的幅度是否 最佳PAD与抑郁严重程度相关。我们还将使用PET定量mGluR5， 昼夜节律周期内的标准化时间，以确认mGluR5-昼夜节律关系并确定 不适当的mGluR5昼夜变化是否是非最佳PAD的基础。这将首次确立 mGluR5表达与人类昼夜节律之间的关系（这对 MDD以外的疾病，可能是情绪和昼夜节律调节的性别差异的基础）。最后我们将 评估睡眠剥夺治疗对抑郁症患者和对照组患者昼夜节律的影响。这 将确定哪些时间类型最适合治疗，以及最佳PAD的恢复是否 治疗效果所需。无论结果如何，这项研究将增加我们对昼夜节律的理解， MDD中的节律（和失调）以及时间生物素治疗的作用机制。

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.