Ketamine Alters Electrophysiological Responses to Emotional Faces in Major Depressive Disorder

Abstract

Background: The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action.

Methods: Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data.

Results: In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants.

Limitations: The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings.

Conclusions: Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response.

Clinical trial: Clinicaltrials.gov, NCT#00088699.

Trial registration: ClinicalTrials.gov NCT00088699.

Keywords: depression; emotional face processing; ketamine; magnetoencephalography.

Conflict of interest statement

Declaration of Interests

CAZ is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisometric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. MLF is identified as a co-inventor on a patent application for the use of scopolamine in mood disorders. She has assigned her patent rights to the U.S. government but will share a percentage of any royalties that may be received by the government. MLF is a full-time employee of Janssen Pharmaceuticals of Johnson & Johnson, Inc. All other authors report no biomedical financial interests or potential conflicts of interest.

Copyright © 2020. Published by Elsevier B.V.

Figures

Fig. 1.

Schematic representation of example trials from the emotional evaluation task designed in E-Prime software. Participants completed two blocks of each task condition in which they were shown emotional faces and asked to either identify the emotional valence (happy-neutral or sad-angry; explicit condition) or sex (male or female; implicit condition). Figure adapted from Reed et al., 2019, Supplement.

Fig. 2.

Behavioral results illustrated by plots of marginal means from the linear fixed effects models. A) Diagnosis*valence*task interaction for baseline reaction time. B) Diagnosis*valence*task interaction for baseline percent accuracy. C) Diagnosis*session interaction for ketamine vs. placebo reaction time. D) Diagnosis*session interaction for ketamine vs. placebo percent accuracy. E) Diagnosis*valence*task interaction for ketamine vs. placebo percent accuracy. Error bars represent ±1 standard error of the mean. Abbreviations: MDD: major depressive disorder; HV: healthy volunteers. Positive: happy or neutral faces; Negative: sad or angry faces.

Fig. 3.

Illustrations of the ketamine vs. placebo magnetoencephalography (MEG) results for the A) calcarine, B) left middle occipital, and C) right middle occipital regions. Top: graphic of the anatomically defined regions of interest (ROIs). Middle: Plots of the mean event-related field (ERF) from the ROI, separated by model predictors to illustrate the statistical results. Bottom: Plots of the ERF (M100 for calcarine, M170 for middle occipital) marginal means from each significant result from the linear fixed effects models. Shaded areas on waveform plots represent 95% confidence intervals, and error bars represent ±1 standard error of the mean. Abbreviations: DX: diagnosis; MDD: major depressive disorder; HV: healthy volunteers; KET: ketamine; PLC: placebo; Pos: happy or neutral faces; Neg: sad or angry faces.

Fig. 4.

Illustrations of the ketamine vs. placebo magnetoencephalography (MEG) results for the A) left fusiform and B) right fusiform regions. Top: graphic of the anatomically defined regions of interest (ROI). Middle: Plots of the mean event-related field (ERF) from the ROI, separated by model predictors to illustrate the statistical results. Bottom: Plots of the M170 ERF marginal means from each significant result from the linear fixed effects models. Shaded areas on waveform plots represent 95% confidence intervals, and error bars represent ±1 standard error of the mean. Abbreviations: DX: diagnosis; MDD: major depressive disorder; HV: healthy volunteers; KET: ketamine; PLC: placebo

Fig. 5.

Model predictions of post-infusion event-related field (ERF) amplitudes in participants with major depressive disorder. A) Plot of MADRS*drug*valence interaction for left fusiform M170 log-transformed amplitudes. B) Plot of MADRS*drug interaction for right fusiform M170 log-transformed amplitudes. Shaded areas represent 95% confidence intervals. Negative x-axis values indicate greater antidepressant response. MADRS change scores were mean-centered. Abbreviations: MADRS: Montgomery-Åsberg Depression Rating Scale; Pos: happy or neutral faces; Neg: sad or angry faces.