Intrinsic excitation-inhibition imbalance in major depressive disorder.
Yao Ge, Lijuan Chen, Yu Shen, Ninghua Li, Bo Liu, Xiaojuan Lv, Yan Bai, Wei Wei, Yaping Wu, Kaixin Li, Mengzhu Wang, Meiyun Wang
Journal of Affective Disorders June 29, 2026 DOI: 10.1016/j.jad.2026.122164 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort with transcriptomic and neurochemical decoding, plus a clinical trial component Peer reviewed |
|---|---|
| Sample size | 254 |
| Population | Patients with major depressive disorder and healthy controls |
| Intervention | Ketamine |
| Topics | Depression Ketamine |
| Keywords | Excitation-inhibition balance Hurst exponent |
| Key findings | Patients with major depressive disorder showed reduced cortical excitation-inhibition balance, measured by the Hurst exponent, which was linked to specific gene expression and neurotransmitter systems, and ketamine increased this balance in treatment-resistant depression. |
Abstract
Major depressive disorder (MDD) ranks among the foremost contributors to disability worldwide, yet its neurophysiological mechanisms remain poorly understood. Excitation-inhibition (E/I) imbalance has been implicated in MDD pathophysiology, but cortex-wide E/I ratio and its molecular substrates in MDD remain unknown. Resting-state functional magnetic resonance imaging data from 254 MDD patients and 451 healthy controls (HCs) across six sites were analyzed. The Hurst exponent, a biophysically confirmed proxy of E/I balance, was estimated using a fractionally integrated process framework. Neurobiological decoding analyses were performed to map the transcriptomic and neurochemical signatures of cortical E/I imbalance in MDD. An independent ketamine clinical trial dataset (32 treatment-resistant depression patients and 21 HCs) was used to examine ketamine-induced changes in cortical E/I balance. Patients with MDD demonstrated significantly reduced Hurst exponent values, predominantly encompassing the parietal and prefrontal-cingulate cortices. Transcriptomic analysis identified enrichment for neuronal structural organization, nucleic acid metabolism, and mitochondrial function, with preferential overlap with excitatory and inhibitory neuron-specific gene sets. Neurochemically, Hurst exponent alterations were spatially associated with GABAergic, opioidergic, serotonergic, and synaptic density distributions. Divergent group-by-treatment effects were observed in the anterior cingulate and medial prefrontal cortices, with ketamine-induced increases in TRD patients. These findings highlight that prefrontal-cingulate E/I imbalance, anchored to specific transcriptional and neurochemical substrates, may underlie the pathophysiology of MDD and the antidepressant effects of ketamine. The Hurst exponent offers a promising neuroimaging approach for probing E/I imbalance and identifying potential treatment targets in depression.
Comparable studies
Other non-randomized and open-label trials on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Rapid Resolution of Suicidal Ideation After a Single Infusion of anN-Methyl-D-Aspartate Antagonist in Patients With Treatment-Resistant Major Depressive Disorder Subjects with DSM-IV-diagnosed treatment-resistant major depressive disorder | 2010 | Open-label trial | n = 33 |
| Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression Adults (≥ 18 years) with treatment-resistant depression | 2020 | Phase 3, open-label, multicenter, long-term study | n = 802 |
| Intravenous arketamine for treatment-resistant depression: open-label pilot study Humans with treatment-resistant depression | 2020 | Open-label pilot trial | n = 7 |
| A Phase 2 Open Label Study of Efficacy, Safety, and Tolerability of SLS-002 (Intranasal Racemic Ketamine) in Adults with MDD at Imminent Risk of Suicide. Hospitalized patients with Major Depressive Disorder and acute suicidal ideation and... | 2024 | Open label study | n = 17 |
| Ketamine Safety and Tolerability in Clinical Trials for Treatment-Resistant Depression Participants with DSM-IV-defined major depressive disorder and treatment-resistant... | 2014 | Pooled analysis of three clinical trials | n = 97 |