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

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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.