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.

Investigating the Effects of Auditory and Vibrotactile Rhythmic Sensory Stimulation on Depression: An EEG Pilot Study

“…Another notable effect of RSS was an increase in prefrontal gamma power that was greater in the responders than in the nonresponders. The use of gamma activity as a biomarker of treatment response in depression is an emerging topic [23,57,58]. It has been shown that different classes of antidepressant drugs have distinct effects on gamma oscillations, whereby serotonin-boosting antidepressants (e.g., citalopram and fluoxetine) suppress gamma, while noradrenergic drugs and ketamine increase gamma activity [59][60][61][62][63][64].…”

Intrinsic Connectivity Networks of Glutamate-Mediated Antidepressant Response: A Neuroimaging Review

“…Existing literature reviews in the field of glutamatergic ICNs support the notion that glutamate-based therapies act on several brain networks, leading to a rapid antidepressant response ( 38 , 326 , 327 ). As discussed by Alario and Niciu ( 326 ), further research exploring how glutamate-based therapies for depression, such as ketamine, have long-lasting effects with short-term connectivity changes is needed.…”

“…Existing literature reviews in the field of glutamatergic ICNs support the notion that glutamate-based therapies act on several brain networks, leading to a rapid antidepressant response ( 38 , 326 , 327 ). As discussed by Alario and Niciu ( 326 ), further research exploring how glutamate-based therapies for depression, such as ketamine, have long-lasting effects with short-term connectivity changes is needed. The promising findings that exist to date suggest the importance of coordinating the timing of study and neuroimaging procedures in a way that is physiologically appropriate to capture acute vs. delayed effects of glutamate-based therapies within affected ICNs ( 326 ).…”

“…As discussed by Alario and Niciu ( 326 ), further research exploring how glutamate-based therapies for depression, such as ketamine, have long-lasting effects with short-term connectivity changes is needed. The promising findings that exist to date suggest the importance of coordinating the timing of study and neuroimaging procedures in a way that is physiologically appropriate to capture acute vs. delayed effects of glutamate-based therapies within affected ICNs ( 326 ). Future research may also employ long-term follow-ups to generate an understanding of how such delayed effects occur at a physiological level and provide insight into sustainable long-term changes in brain connectivity following therapeutics that target the glutamate system.…”

An Integrative Approach to Ketamine Therapy May Enhance Multiple Dimensions of Efficacy: Improving Therapeutic Outcomes With Treatment Resistant Depression

“…One of the relevant impacts of ketamine's AMPA stimulation, the downstream enhancement of neurotropic factors such as BDNF and the resulting synaptogenesis, is a normalization of connectivity within and between multiple brain areas. For example, there is evidence that in certain conditions, with appropriate ketamine dosage, and at certain times post-treatment remitters showed temporary normalization ( 106 ) in global brain connectivity (GBC) between salience networks and the default mode network (DMN) ( 85 ); and between the dorsal caudate and the ventrolateral PFC ( 18 ); normalized connectivity between the amygdala and the subgenual anterior cingulate cortex (sgACC) ( 107 ); between the posterior cingulate and the right posterior insula; between left and right primary somatosensory cortex, between left frontal cortex and left primary somatosensory cortex ( 108 ), and between anterior insula to anterior cingulate ( 109 ); normalized global grain connectivity with global signal regression (GBCr) in the PFC ( 110 ), cerebellum, caudate, and insula ( 111 ); normalized connectivity in the sensorimotor and salience networks ( 112 ), in the parahippocampal gyrus, cingulate gyri, left medial and middle frontal gyri, and precuneus ( 113 ), in the right caudate ( 114 ), and in the sgACC ( 115 ).…”