Acute subanesthetic ketamine-induced effects on the mismatch negativity and their relationship to early and sustained treatment response in major depressive disorder.

A sub-anesthetic dose of ketamine, an NMDAR antagonist, produces rapid antidepressant effects in treatment-resistant major depressive disorder. In 24 patients, ketamine reduced frontal mismatch negativity (MMN) amplitude, theta event-related oscillations, and source-localized frontal generator activity immediately and 2 hours after infusion, compared to midazolam. Larger reductions in MMN measures, particularly left frontal amplitude and theta oscillations, correlated with and predicted greater early and sustained symptom improvement on the Montgomery-Åsberg Depression Rating Scale. Baseline phase-locking factor also predicted sustained response. The findings suggest that acute NMDAR blockade reduces frontal MMN, and that MMN indices may serve as non-invasive biomarkers for predicting antidepressant response to glutamatergic agents.

Study at a glance

Abstract

A sub-anesthetic dose of ketamine, an N-methyl-D-aspartate receptor (NMDAR) antagonist, produces robust antidepressant effects in treatment-resistant major depressive disorder (MDD). The mismatch negativity (MMN) is reliant on glutamatergic neurotransmission and reduced by NMDAR antagonists. The MMN may characterise the neural mechanisms underlying ketamine's effects. This study examined the acute effects of ketamine and midazolam on the MMN and its relationship to early and sustained decreases in depressive symptoms. Treatment-resistant MDD patients (N = 24), enrolled in a multi-phase clinical ketamine trial, received two intravenous infusions within an initial double-blind crossover phase: ketamine (0.5 mg/kg) and midazolam (30 μg/kg). Three recordings were carried out per session (pre-, immediately post- and 2 h post-infusion). Peak MMN amplitude (μV), latency (ms), theta event-related oscillations (EROs), theta phase locking factor (PLF) and source-localised MMN generator activity were assessed. Relationships between changes in MMN indices and early (Phase 1: double-blind, cross-over phase) and sustained (Phases 2, 3: open-label repeated and maintenance phases, respectively) changes in depressive symptoms (Montgomery-Åsberg Depression Rating Scale score) were examined. Ketamine reduced frontal MMN amplitudes, theta ERO immediately post- and 2 h post-infusion and source-localised peak MMN frontal generator activity. Select baseline and ketamine-induced MMN decreases correlated and predicted greater early (left frontal MMN decreases in amplitude and theta ERO, baseline left PLF) and sustained (baseline left PLF, right inferior temporal activity) symptom reductions. Acute NMDARs blockade reduced frontal MMN, with larger MMN reductions predicting greater symptom improvement. The MMN may serve as a non-invasive biomarker predicting antidepressant response to glutamatergic agents.