Ketamine alters the aperiodic EEG exponent in major depression: implications for cortical E/I balance and treatment prediction.

Ketamine, a rapid-acting antidepressant for treatment-resistant depression, may work by altering the brain's excitation-inhibition balance, measurable via the aperiodic exponent of EEG power spectra. In a placebo-controlled trial of 24 patients with major depressive disorder, ketamine infusion significantly reduced the aperiodic exponent across the scalp. Patients who responded to treatment had steeper pretreatment occipital aperiodic exponents, which predicted better outcomes. A meta-analysis within the study revealed substantial variability in ketamine's effect on this measure. The occipital aperiodic exponent may serve as a biomarker for predicting antidepressant response, but further large-scale studies are needed.

Study at a glance

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).