Resting-State Electroencephalogram Complexity Is Associated With Oral Ketamine Treatment Response: A Bayesian Analysis of Lempel-Ziv Complexity and Multiscale Entropy.

Subanesthetic doses of ketamine show promise for treating suicidality, but predictive biomarkers are lacking. This study examined EEG-derived complexity measures—Lempel-Ziv complexity (LZC) and multiscale entropy (MSE)—in 31 participants receiving six weekly oral doses of racemic ketamine (0.5-3 mg/kg). Responders, defined by a ≥50% reduction in Beck Suicide Scale score or a score ≤6, showed elevated baseline eyes-open complexity compared to nonresponders, which decreased from baseline to post-treatment. Elevated baseline eyes-open LZC in responders was localized to the left frontal lobe. EEG complexity metrics may serve as sensitive biomarkers for predicting and evaluating oral ketamine treatment response.

Study at a glance

Abstract

Subanesthetic doses of ketamine are a promising novel treatment for suicidality; however, the evidence for predictive biomarkers is sparse. Recently, measures of complexity, including Lempel-Ziv complexity (LZC) and multiscale entropy (MSE), have been implicated in ketamine's therapeutic action. We evaluated electroencephalogram (EEG)-derived LZC and MSE differences between responders and nonresponders to oral ketamine treatment. A total of 31 participants received six single, weekly (titrated) doses of oral racemic ketamine (0.5-3 mg/kg) and underwent EEG scans at baseline (Week 0), post-treatment (Week 6), and follow-up (Week 10). Resting-state (eyes closed and open) recordings were processed in EEGLAB, and complexity metrics were extracted using the Neurokit2 package. Participants were designated responders or nonresponders by clinical response (Beck Suicide Scale [BSS] score reduction of ≥ 50% from baseline to the respective timepoint or score ≤ 6) and then compared in terms of complexity across resting-state conditions and time. Employing a Bayesian mixed effects model, we found strong evidence that LZC was higher in the eyes-open compared to eyes-closed condition, as were MSE scales 1-3. At a global level, responders displayed elevated eyes-open baseline complexity compared to nonresponders, with these values decreasing from baseline to post-treatment (Week 6) in responders only. Exploratory analyses revealed that the elevated baseline eyes-open LZC in responders was spatially localized to the left frontal lobe (F1, AF3, FC1, and F3). EEG-complexity metrics may be sensitive biomarkers for evaluating and predicting oral ketamine treatment response, with the left prefrontal cortex bein a possible treatment response region.