Ketamine alters the aperiodic EEG exponent in major depression: implications for cortical E/I balance and treatment prediction.
Yujuan Liu, Xiaorong Liu, Sebastian Olbrich, Chong-Leong Lao, Haoyun Zhang, Martin Brunovský, Cheng-Teng Ip
Therapeutic Advances in Psychopharmacology 2026 DOI: 10.1177/20451253261462240 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Placebo-controlled, single-blind, one-arm, fixed-sequence design without randomization trial Peer reviewed |
|---|---|
| Sample size | 24 |
| Population | Patients with major depressive disorder, most meeting criteria for treatment-resistant depression |
| Intervention | Intravenous ketamine infusion |
| Dose | 0.54 mg/kg over 30 min |
| Duration | 24 hours post-infusion |
| Topics | Ketamine Depression Esketamine |
| Keywords | E/i balance EEG Aperiodic exponent Biomarker |
| Key findings | Ketamine significantly reduced the aperiodic exponent across the scalp, and higher pretreatment occipital aperiodic exponents predicted better antidepressant response. |
Abstract
Ketamine has emerged as a promising rapid-acting antidepressant for treatment-resistant depression (TRD), yet its mechanisms of action and reliable biomarkers of treatment response remain poorly understood. Recent evidence suggests that the aperiodic exponent (1/f slope) of electroencephalography (EEG) power spectra reflects cortical excitation-inhibition balance (EIB), offering a potential non-invasive marker of treatment outcomes. Our study investigated whether subanesthetic ketamine modulates the EEG aperiodic exponent in patients with major depressive disorder (MDD), most of whom met criteria for TRD. We also examined whether pretreatment aperiodic exponent predicts antidepressant response. A placebo-controlled, single-blind, one-arm, fixed-sequence design without randomization trial of intravenous ketamine infusion in patients with MDD. Twenty-four MDD patients underwent both placebo and ketamine (0.54 mg/kg over 30 min) infusions. Resting-state EEG was recorded pre-, start-, end-, and 24 h post-infusion. Aperiodic exponent (1-40 Hz) was extracted using spectral parameterization. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale, with responders defined as ⩾33% symptom reduction 24 h post-infusion. Meta-analysis revealed substantial heterogeneity in ketamine's effect on aperiodic exponents. In our cohort, ketamine significantly reduced the aperiodic exponent across the scalp. Notably, responders exhibited higher pretreatment occipital aperiodic exponents than non-responders. A steeper pretreatment 1/f slope in the occipital region predicted better treatment outcomes. Subanesthetic ketamine alters cortical aperiodic dynamics in MDD, potentially reflecting EIB modulation. The EEG aperiodic exponent, particularly in occipital regions, may serve as a useful biomarker for predicting antidepressant response to ketamine. However, our meta-analysis underscores the complexity and variability of the EEG aperiodic exponent. Future large-scale, multimodal studies are needed to validate and expand on these findings. EudraCT Number: 2013-000952-17 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-000952-17/CZ).