Ketamine has distinct electrophysiological and behavioral effects in depressed and healthy subjects

Introduction

Major depressive disorder (MDD) is commonly resistant to first-line treatments and its neurobiology, as well as the mechanisms of antidepressant drugs, remain incompletely understood. Prior clinical and preclinical work indicates that the NMDA receptor antagonist ketamine produces rapid antidepressant effects in treatment-resistant depression and that enhanced AMPA receptor throughput and synaptic potentiation are important to its action. Acute ketamine administration—and its active metabolite (2R,6R)-hydroxynorketamine—has been associated with increases in gamma-frequency oscillations, a signal thought to reflect the balance of excitation and inhibition in neuronal circuits because gamma depends on both AMPA-mediated excitation and GABAA-mediated inhibition. Disruptions of this inhibition/excitation homeostasis have been implicated in depressive phenotypes in animals and humans, motivating the use of gamma power as a surrogate marker of synaptic homeostasis in clinical investigations of ketamine. This report, drawn from the Ketamine Mechanism of Action (Ket-MOA) study, set out to examine ketamine’s effects on mood and resting-state gamma power in unmedicated, treatment-resistant inpatients with MDD as well as in psychiatrically healthy controls. Nugent and colleagues hypothesised that ketamine would produce sustained increases in gamma power that would correspond to antidepressant improvement. The study therefore measured clinical outcomes and magnetoencephalography (MEG) gamma power at baseline, approximately six to nine hours after infusion, and 11–13 days after infusion to probe both clinical and electrophysiological effects beyond the acute infusion period.