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Investigating Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine (GO-MARK)

研究氯胺酮抗抑郁反应的谷氨酸和阿片类药物机制 (GO-MARK)

基本信息

批准号：
MR/T028084/1
负责人：
Luke Jelen
金额：
$ 40.4万
依托单位：
King's College London
依托单位国家：
英国
项目类别：
Fellowship
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT028084%2F1
关键词：
Investigating Glutamate Opioid Mechanisms Antidepressant

项目摘要

Depression is a common mental illness and leading cause of disability worldwide. There are significant limitations to currently prescribed antidepressant treatments, including a delay in the onset of action and a substantial number of individuals fail to respond fully, with many demonstrating persistent, treatment-resistant depression. Ketamine is an anaesthetic agent which has shown promise as a novel antidepressant with the potential to overcome these limitations. Rapid reductions in depressive symptoms have been consistently demonstrated following a single sub-anaesthetic ketamine infusion, including in cases of treatment-resistant depression. Ketamine is known to act on a particular subset of receptors in the brain called NMDA receptors, leading to changes in levels of a brain chemical called glutamate. It has been proposed that ketamine's antidepressant effects are caused by an acute 'glutamate surge' after binding to NMDA receptors with accompanying changes in brain connectivity and plasticity. Ketamine also interacts with a number of other sites including opioid receptors. The glutamate theory has recently been challenged with the finding that in patients with treatment-resistant depression, pre-treatment with a drug that blocks the opioid receptor, naltrexone, dramatically reduces the antidepressant effects of ketamine. Despite these theoretical advances, the exact brain mechanisms responsible for the acute antidepressant effects of ketamine have yet to be determined.In this study I aim to test the theory that ketamine causes an acute 'glutamate surge' in individuals with depression that respond to ketamine treatment by using a neuroimaging method that allows measurement of glutamate dynamics. An additional neuroimaging technique will be used to measure changes in brain connectivity before and after ketamine administration to test the prediction that patients who respond to ketamine also show specific changes in brain connectivity. In the study, depressed participants will receive a ketamine infusion on two separate occasions during neuroimaging. Importantly, on one occasion they will first receive treatment with placebo, a tablet that has no active drug effect before the infusion, and on the other they will receive treatment with naltrexone, a drug that blocks opioid effects. This study will help understand if there are changes in brain glutamate and brain connectivity immediately after receiving ketamine and how these changes are related to antidepressant response. Furthermore, it will also help understand the effects of blocking the opioid receptor on any changes in glutamate, brain connectivity or potential antidepressant effects caused by ketamine. This research is important for a number of reasons. Firstly, this study will further our understanding of the processes underlying depression. Secondly, determining the brain changes that are related to antidepressant response will help in identifying markers on brain scans that could be used in the future to help predict which patients with depression will respond to particular treatments, allowing a more personalised treatment approach. Finally, separating and understanding glutamate and opioid mechanisms leading to ketamine's antidepressant effects will help to identify potential novel treatment targets, encouraging the development of new rapid-acting antidepressant treatments in depression.

抑郁症是一种常见的精神疾病，也是世界范围内导致残疾的主要原因。目前处方的抗抑郁药物治疗有很大的局限性，包括起效延迟，相当数量的人没有完全反应，许多人表现出持续性的、治疗抗药性的抑郁症。氯胺酮是一种麻醉剂，已显示出作为一种新型抗抑郁药的前景，有可能克服这些限制。在单次亚麻醉氯胺酮输注后，抑郁症状的迅速减轻一直被证明，包括在治疗难治性抑郁症的病例中。众所周知，氯胺酮作用于大脑中一种名为NMDA受体的特殊受体，导致大脑中一种名为谷氨酸的化学物质的水平发生变化。有人认为，氯胺酮的抗抑郁作用是由于与NMDA受体结合后引起的急性谷氨酸激增，并伴随着大脑连接性和可塑性的变化。氯胺酮还与包括阿片受体在内的许多其他部位相互作用。谷氨酸理论最近受到了挑战，因为研究发现，在难治性抑郁症患者中，预先使用一种阻断阿片受体的药物纳曲酮，可以显著降低氯胺酮的抗抑郁效果。尽管有这些理论上的进展，但氯胺酮急性抗抑郁作用的确切大脑机制尚未确定。在这项研究中，我的目标是通过使用一种能够测量谷氨酸动态的神经成像方法来验证氯胺酮导致对氯胺酮治疗有反应的抑郁症患者的急性谷氨酸激增的理论。另一种神经成像技术将被用来测量服用氯胺酮前后大脑连通性的变化，以测试对氯胺酮有反应的患者也显示出大脑连通性的特定变化的预测。在这项研究中，抑郁的参与者在神经成像期间将在两个不同的场合接受氯胺酮输注。重要的是，在一种情况下，他们将首先接受安慰剂的治疗，这是一种在输液前没有活性药物作用的片剂，而在另一种情况下，他们将接受纳曲酮的治疗，纳曲酮是一种阻断阿片类药物作用的药物。这项研究将有助于了解接受氯胺酮后大脑谷氨酸和大脑连接性是否立即发生变化，以及这些变化与抗抑郁反应之间的关系。此外，它还将有助于了解阻断阿片受体对氯胺酮引起的谷氨酸、大脑连接或潜在的抗抑郁作用的任何变化的影响。这项研究之所以重要，原因有很多。首先，这项研究将进一步加深我们对抑郁症潜在过程的理解。其次，确定与抗抑郁药物反应相关的大脑变化将有助于确定脑部扫描上的标记，这些标记可在未来用于帮助预测哪些抑郁症患者将对特定治疗产生反应，从而实现更个性化的治疗方法。最后，分离和了解谷氨酸和阿片类药物导致氯胺酮抗抑郁作用的机制将有助于确定潜在的新治疗靶点，鼓励开发新的快速有效的抗抑郁药物治疗抑郁症。