Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression

Abstract

Traditional antidepressants, which act on the serotonin, dopamine, and norepinephrine systems, require many weeks to produce a therapeutic effect and are not effective for every patient. A sub-anesthetic dose of the anesthetic agent ketamine, a glutamate N-methyl-Daspartate receptor antagonist, has been shown to produce a rapid and robust antidepressant effect in treatment-resistant major depressive disorder (MDD). As depressive symptoms typically return after one week following a single infusion, recent work has begun to focus on methods for prolonging the effects. Repeated infusions on a specific dosing schedule are being explored, however, the early identification of treatment responders and non-responders would be beneficial for optimized treatment selection within this population.The mechanisms underlying ketamine's rapid effects conceivably involve the regulation of altered glutamatergic signaling in MDD, though this is not yet completely understood.Understanding of the central mechanisms mediating ketamine's rapid antidepressant effects may be increased through the use of non-invasive electroencephalographic measures, including resting electroencephalography (EEG) and the mismatch negativity (MMN) event-related potential. These measures have been shown to be altered in depressed individuals and are sensitive to ketamine administration.The primary objectives of this study were to 1) examine acute changes in EEG-and MMN-derived indices, immediately post-and two hours postinfusion, with a sub-anesthetic ketamine dose in comparison to an active placebo (midazolam), and 2) to examine their relationships with early and sustained antidepressant treatment response to ketamine within an eight week clinical trial involving three study phases. IIIKetamine decreased measures of scalp-level alpha and theta resting activity, immediately postinfusion, and increased gamma immediately and two hours postinfusion. An increase in source-localized anterior cingulate activity two hours postinfusion was also observed. Regarding the MMN, ketamine reduced frontal amplitudes as well as theta event-related oscillations and source-localized peak frontal generator activity. Measures of resting theta and change in gamma, as well as left frontal MMN amplitude, theta event-related oscillations, baseline left phase locking factor, and baseline right inferior temporal lobe activity were predictive of decreases in depressive symptoms at both early and sustained treatment time points. Alpha power was predictive of decrease in suicidal ideation, though the relationship with baseline and early change in symptoms was stronger.These findings contribute to our understanding of the role of baseline and ketamineinduced changes in both resting and task-evoked electrophysiological measures, and may have the potential to act as non-invasive biomarkers of antidepressant response prediction to glutamatergic agents. IV PREFACEThis thesis is comprised of manuscripts (Chapters 2-3) which are in preparation for submission for publication in peer-reviewed jo...

Conditioned anti-immobility by ketamine: A comparison to escitalopram and bupropion.

“…First, as expected, repeated exposure to forced swimming increased immobility in rats that were conditioned with SAL in the CS+ (Figure 2B), which is in line with previous studies that employed a repeated swim stress design (Dal-Zotto et al, 2000; Melanson et al, 2021; Mul et al, 2016). Also anticipated was the significant difference between the KET 20 group and all other groups at induction (FSS 1 ), an observation that is consistent with clinical reports of sustained antidepressant activity by KET (de la Salle et al, 2022; Li et al, 2022; Phillips et al, 2019). Importantly, the increase in immobility was not observed in rodents that were exposed to the KET CS+ prior to the last swim (FSS 3 ; Figure 2B), and this occurred in groups conditioned with both KET doses.…”

A Comprehensive Overview of the Role of Visual Cortex Malfunction in Depressive Disorders: Opportunities and Challenges

“…Many studies have shown that ketamine has a rapid and efficient antidepressant effect [80]. A recent metaanalysis has shown that intravenous ketamine has a better antidepressant effect than nasal spray [81].…”

A Predictive Coding Framework for Understanding Major Depression

“…Electrophysiological findings have also demonstrated that ketamine increases the latency of MMN responses in healthy participants ( Umbricht et al, 2000 ; Kreitschmann-Andermahr et al, 2001 ), though its effect on amplitude is stronger than its effect on latency ( Rosburg and Kreitschmann-Andermahr, 2016 ). In the context of the MMN response, ketamine administration was found to reduce frontal MMN amplitudes immediately post-infusion and again at 2 h post-infusion in MDD patients; furthermore, immediate change in MMN amplitude predicted antidepressant response ( de la Salle, 2022 ). In contrast, other studies that used a roving auditory oddball task collected 3–4 h post-ketamine infusion in MDD patients found that ketamine administration increased MMN response, but only when all repetitions of the post-deviant tone were analyzed ( Sumner et al, 2020 ).…”