de la Salle Sara, Phillips Jennifer L, Blier Pierre, Knott Verner
University of Ottawa Institute of Mental Health Research at the Royal, Ottawa, ON, Canada.
School of Psychology, University of Ottawa, Ottawa, ON, Canada.
J Psychopharmacol. 2025 Jun;39(6):577-592. doi: 10.1177/02698811251319456. Epub 2025 Feb 26.
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 ( = 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.
亚麻醉剂量的氯胺酮，一种N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂，在难治性重度抑郁症（MDD）中产生强大的抗抑郁作用。失配负波（MMN）依赖于谷氨酸能神经传递，并被NMDAR拮抗剂降低。MMN可能表征氯胺酮作用的神经机制。
本研究考察了氯胺酮和咪达唑仑对MMN的急性影响及其与抑郁症状早期和持续减轻的关系。
参加多阶段氯胺酮临床研究的难治性MDD患者（n = 24）在初始双盲交叉阶段接受两次静脉输注：氯胺酮（0.5mg/kg）和咪达唑仑（30μg/kg）。每次输注进行三次记录（输注前、输注后即刻和输注后2小时）。评估MMN峰值幅度（μV）、潜伏期（ms）、θ事件相关振荡（ERO）、θ锁相因子（PLF）和源定位的MMN发生器活动。考察MMN指标变化与抑郁症状（蒙哥马利-阿斯伯格抑郁评定量表评分）早期（第1阶段：双盲交叉阶段）和持续（第2、3阶段：分别为开放标签重复和维持阶段）变化之间的关系。
氯胺酮降低了前额叶MMN幅度、输注后即刻和输注后2小时的θ ERO以及源定位的MMN前额叶发生器峰值活动。特定的基线和氯胺酮诱导的MMN降低相关，并预测更大程度的早期（左侧前额叶MMN幅度和θ ERO降低、基线左侧PLF）和持续（基线左侧PLF、右侧颞下回活动）症状减轻。
急性NMDAR阻断降低了前额叶MMN，MMN降低幅度越大，症状改善越明显。MMN可能作为预测对谷氨酸能药物抗抑郁反应的非侵入性生物标志物。
