Skip to content

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)

Read Full Text
Relevant Not relevant

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).

Comparable studies

Other randomized controlled trials on ketamine for depression, most cited first.

Study Year Design Participants
Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial Patients with treatment-resistant major depression experiencing a major depressive episode 2013 Randomized controlled trial n = 73
Efficacy and Safety of Flexibly Dosed Esketamine Nasal Spray Combined With a Newly Initiated Oral Antidepressant in Treatment-Resistant Depression: A Randomized Double-Blind Active-Controlled Study Adults with moderate to severe nonpsychotic depression and a history of nonresponse to... 2019 Phase 3, double-blind, active-controlled, multicenter randomized controlled trial n = 227
Efficacy of Esketamine Nasal Spray Plus Oral Antidepressant Treatment for Relapse Prevention in Patients With Treatment-Resistant Depression Adults with treatment-resistant depression who achieved stable remission or stable... 2019 Phase 3, multicenter, double-blind, randomized withdrawal study n = 297
Efficacy and Safety of Intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression Adults with DSM-IV-TR diagnosis of major depressive disorder and history of inadequate... 2017 Phase 2, double-blind, doubly randomized, delayed-start, placebo-controlled study n = 67
Efficacy and Safety of Intranasal Esketamine for the Rapid Reduction of Symptoms of Depression and Suicidality in Patients at Imminent Risk for Suicide: Results of a Double-Blind, Randomized, Placebo-Controlled Study Depressed patients at imminent risk for suicide 2018 Randomized controlled trial n = 68

Citations in the library

Cites 9

and 4 more in the library

Related reading

Explore topics

Ketamine Depression Esketamine

By condition and practice

Ketamine for depression