Major depressive disorder (MDD) is highly prevalent and frequently disabling. Only about 30% of patients respond to a first-line antidepressant treatment, and around 30% of patients are classified as “treatment-resistant” after failing to respond to multiple adequate trials. While most antidepressants target monoaminergic targets, ketamine is an N-methyl-D-aspartate (NMDA) antagonist that has shown rapid antidepressant effects when delivered intravenously or intranasally. While there is evidence that ketamine exerts its effects via enhanced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) throughput, its mechanism for relieving depressive symptoms is largely unknown. This study acquired resting-state magnetoencephalography (MEG) recordings after both Ketamine online and placebo infusions and investigated functional connectivity using a multilayer amplitude-amplitude correlation technique spanning the canonical frequency bands. Twenty-four healthy volunteers (VHS) and 27 unmedicated participants with MDD took part in a double-blind, placebo-controlled, crossover trial of 0.5 mg/kg IV ketamine. The order of infusion was randomized, and participants crossed over to receive the second infusion after two weeks. The results indicated widespread ketamine-induced reductions in connectivity in the alpha and beta bands that did not correlate with the magnitude of antidepressant response. In contrast, the magnitude of ketamine’s antidepressant effects in MDD participants was associated with cross-frequency connectivity for delta-alpha and delta-gamma bands, with VHS and ketamine non-responders showing connectivity, decreases post-ketamine and ketamine responders demonstrating small increases in connectivity. These results may indicate functional subtypes of MDD and also suggest that neural responses to ketamine are fundamentally different between responders and non-responders.
Major depressive disorder (MDD) affects up to 20% of people at some point across their lifespan and is associated with significantly increased morbidity and mortality. Yet MDD remains difficult to treat; most conventional antidepressant medications take weeks to achieve their maximum effects, and only 30% of those with MDD respond to a first-line antidepressant (1). In contrast, the N-methyl-D-aspartate (NMDA) antagonist ketamine, a racemic mixture of ketamine’s R- and S-isomers, has rapid antidepressant effects when delivered via either infusion or nasal spray. Notably, the discovery of ketamine’s antidepressant properties and the subsequent FDA approval of esketamine (the S-isomer of ketamine) in March 2019 represents the first novel target for MDD since the development of selective serotonin reuptake inhibitors (SSRIs). Nevertheless, relatively little is known about how ketamine exerts its antidepressant effects. Evidence suggests that ketamine binds to receptors on both excitatory glutamatergic pyramidal neurons as well as inhibitory gamma-aminobutyric acid (GABA)-interneurons. This leads to disinhibition of the pyramidal neurons, resulting in a glutamate surge in the synapse and enhanced α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) throughput, leading to downstream changes that enhance synaptic plasticity.
The present study acquired MEG recordings in both VHS and individuals with MDD 6 to 9 h post-ketamine and placebo infusions in a double-blind, placebo-controlled, crossover trial. The study sought to characterize changes in connectivity induced by ketamine infusion using a multi-layer network approach (29) that examined band-limited amplitude envelope correlations within and between the canonical frequency bands delta, theta, alpha, beta, and gamma. Based on prior literature, we expected to see reductions in alpha- and beta-band connectivity following ketamine versus placebo infusions in the three core networks central to the pathophysiology of MDD: the DMN, the central executive network (CEN), and the salience network (SN). The study also examined how changes in connectivity are related to antidepressant response to ketamine in participants with MDD. This study is unique in its inclusion of both unmedicated MDD participants and VHS, its use of placebo-controlled infusions, and its use of MEG to enable spatial localization of connectivity changes.