Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine

Abstract

The neural mechanisms underlying the antidepressant effects of ketamine are not fully understood. Beyond N-methyl-D-aspartate (NMDA) glutamate receptor antagonism, ketamine interacts with the opioid system, potentially modulating its antidepressant efficacy. This thesis aims to elucidate potential opioidergic mechanisms contributing to ketamine’s antidepressant effects, within a clinical context. Specifically, it explores ketamine's acute impact on brain glutamatergic measures, cerebral blood flow (CBF), and functional connectivity in adults with major depressive disorder (MDD) and investigates whether pre-treatment with the opioid receptor antagonist, naltrexone, influences these neuroimaging measures or ketamine's antidepressant effects.

The GO-MARK study (investigating Glutamate and Opioid Mechanisms of Antidepressant Response to Ketamine) was a randomised, double-blind, crossover design with two treatment conditions: oral placebo or oral naltrexone 50 mg, preceding a ketamine infusion (0.5mg/kg, 40 minutes) during neuroimaging in 26 adults with MDD. Depressive symptoms were rated before each infusion and at post-infusion day one using the clinician rated Montgomery– Åsberg Depression Rating Scale (MADRS). Neuroimaging methods consisted of: (1) Functional magnetic resonance spectroscopy (1H-fMRS), to measure dynamic anterior cingulate cortex (ACC) glutamate measures during ketamine administration, compared to a pre-infusion baseline; (2) Arterial spin labelling (ASL) scans to measure changes in CBF during ketamine administration compared to a pre-infusion baseline; and (3) Resting state functional MRI (rsfMRI) scans to measure functional brain connectivity changes immediately aber the ketamine infusion, compared to a pre-infusion baseline.

Naltrexone pre-treatment significantly attenuated reductions in MADRS scores at day one post-ketamine infusion. Ketamine induced an acute increase in ACC glutamatergic activity, which was significantly reduced by naltrexone. Although ketamine induced significant focal increases in CBF in a frontal cluster, encompassing the subgenual, pregenual, and dorsal ACC, these changes were not significantly affected by naltrexone. Spatially, CBF changes induced by ketamine correlated with mu-opioid, glutamatergic, and gamma-aminobutyric acid (GABA)ergic systems, while the spatial distribution of the interaction effect of naltrexone on ketamine-induced CBF changes was linked to mu-opioid and GABAergic systems. For the rsfMRI, naltrexone did not significantly impact ketamine-induced connectivity changes in predefined seeds, with ketamine demonstrating significant main effects on functional connectivity across multiple seeds. Notably, baseline subgenual ACC (sgACC) CBF and sgACC— amygdala connectivity changes post-ketamine predicted day one antidepressant effects for the placebo plus ketamine condition, whereas naltrexone pre-treatment disrupted these relationships.

This thesis offers clinical evidence supporting the role of the opioid system in the acute antidepressant response to ketamine, one day post-administration. It also provides initial mechanistic insights into both opioidergic and non-opioidergic neural mechanisms that may mediate ketamine's antidepressant effects. Future research should further explore the interaction between glutamatergic and opioidergic systems to clarify their combined or independent roles in the antidepressant effects of ketamine and other treatments.

Date of Award	1 May 2024
Original language	English
Awarding Institution	King's College London
Supervisor	Mitul Mehta (Supervisor), Allan Young (Supervisor) & James Stone (Supervisor)