Gamma oscillations as a prognostic marker for ketamine therapy in treatment resistant depression - Project Summary Treatment-resistant depression (TRD) is a significant public health issue and the leading cause of disability in young and middle-age adults. The FDA's approval of esketamine nasal spray for TRD and the rapid proliferation of clinics providing ketamine (KET) has markedly increased numbers of patients receiving these interventions. However, we lack valid and reliable biological or clinical markers that predict treatment success for an initial course of KET therapy. Electroencephalography (EEG) gamma band power is a neurophysiological measure of cortical excitability and synaptic potentiation. These processes are implicated in KET’s mechanism as a NMDA receptor channel antagonist, making gamma power a candidate biomarker. The broad, long-term objective of this R21 application is to optimize the rational selection of patients with TRD who benefit from rapid-acting antidepressant therapies such as KET or esketamine. To achieve this goal, we examine gamma band potentiation (KET induced power increase) in treatment-seeking TRD patients (N=60) scheduled to receive an induction course of KET therapy (twice weekly infusions for 4 weeks) from a partner community-based clinic. To examine gamma potentiation, we conduct a pharmaco-EEG challenge entailing a fixed-order infusion of saline followed by KET while recording resting-state and evoked gamma oscillatory activity. To characterize the unique effects of psychotropic medication resistance, we include an age- and sex-matched major depressive disorder (MDD) group (N=20), and an age- and sex-matched healthy control (HC) group (N=20). In AIM 1, we examine baseline patterns of gamma band power and potentiation in TRD patients compared to MDD and HCs. We hypothesize that patients with depression (TRD/MDD) will have lower baseline gamma power than HCs, and that patients with TRD will show greater gamma potentiation in response to KET, compared to non-treatment resistant MDD patients and HCs. In AIM 2, we determine the relevance of gamma band potentiation to the antidepressant mechanism of action of KET for TRD patients who receive an induction course of KET therapy. We hypothesize that greater reduction in depressive symptoms during the induction phase of KET therapy is associated with a higher level of gamma potentiation in response to the first infusion of KET. An innovative exploratory aim is to investigate the stability of gamma band potentiation at the midpoint of the KET induction course of treatment and its relationship with clinical outcomes. This project is significant because the current trial-and-error approach to TRD therapeutics highlights the urgent need for personalized care. Our study’s potential to efficiently capture gamma dynamics across a spectrum of depressed patients provides strong innovation. Finally, this project is impactful because, if successful, it provides a compelling rationale for a larger prospective investigation of gamma dynamics as a moderator of outcome to varied TRD therapies which impact the balance of cortical excitation and inhibition.
