Acute subanesthetic ketamine-induced effects on the mismatch negativity and their relationship to early and sustained treatment response in major depressive disorder.
Sara de la Salle, Jennifer L Phillips, Pierre Blier, Verner J Knott
Journal of psychopharmacology (Oxford, England) February 26, 2025 DOI: 10.1177/02698811251319456 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Randomized controlled trial Double-blind Open-label Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Treatment-resistant major depressive disorder patients |
| Interventions | Ketamine Midazolam |
| Dose | 0.5 mg/kg ketamine, 30 μg/kg midazolam |
| Topics | Depression Ketamine Esketamine |
| Keywords | Cortical source density Event-related oscillations Midazolam Mismatch negativity Treatment response Depression treatment Ketamine therapy Neuroscience research Clinical trials |
| Citations | 3 |
| Key findings | Ketamine-induced reductions in frontal MMN amplitude, theta oscillations, and generator activity predicted greater early and sustained antidepressant symptom improvement. |
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.
Comparable studies
Other randomized controlled trials on ketamine for depression, most cited first.