Biomarkers of ketamine's antidepressant effect: a clinical review of genetics, functional connectivity, and neurophysiology

Abstract

Major depressive disorder (MDD) is one of the leading causes of morbidity and all-cause mortality (including suicide) worldwide, and, unfortunately, first-line monoaminergic antidepressants and evidence-based psychotherapies are not effective for all patients. Subanesthetic doses of the N-methyl-D-aspartate receptor antagonists and glutamate modulators ketamine and S-ketamine have rapid and robust antidepressant efficacy in such treatment-resistant depressed patients (TRD). Yet, as with all antidepressant treatments including electroconvulsive therapy (ECT), not all TRD patients adequately respond, and we are presently unable to a priori predict who will respond or not respond to ketamine. Therefore, antidepressant treatment response biomarkers to ketamine have been a major focus of research for over a decade. In this article, we review the evidence in support of treatment response biomarkers, with a particular focus on genetics, functional magnetic resonance imaging, and neurophysiological studies, i.e. electroencephalography and magnetoencephalography. The studies outlined here lay the groundwork for replication and dissemination.

Keywords: electroencephalography; functional magnetic resonance imaging; genetics; glutamate; ketamine; magnetoencephalography; major depressive disorder; treatment resistant depression.

Figure 1.

Brain regions implicated in the antidepressant response to ketamine and their emotional processing correlates. Sagittal (a) and lateral (b) views of the brain outlining the main emotional functions of regions implicated in ketamine’s antidepressant efficacy.

Figure 2.

Common functional connectivity pathways implicated in ketamine’s antidepressant response. Functional connections outlined here are referenced throughout this review and have been found to be correlated with ketamine’s antidepressant effect. The relationship of the connection to antidepressant response is indicated by the line type, where a solid straight line corresponds to increased connectivity, a dotted line represents decreased connectivity, and a coiled line signifies mixed reports, i.e. some studies with increased and others with decreased connectivity in this circuit. A “halo” effect represents global brain connectivity (GBC), where the strength of the connectivity of the prefrontal cortex and caudate with the rest of the brain is related to antidepressant response. The laterality of these regions were mixed across the studies, except for the left amygdala, which was consistently reported. As alluded to above, there is a broad range of heterogeneity, i.e. task used, time of measurement (in relation to ketamine administration), and functional analysis methodology. CC: cingulate cortex, ACC: anterior cingulate cortex, PFC: prefrontal cortex.