EEG vigilance and response to oral prolonged-release ketamine in treatment-resistant depression – A double-blind randomized validation study

Treatment-resistant depression (TRD) is associated with reduced quality of life and elevated mortality, posing a major challenge to psychiatric care. After non-response to conventional treatments, next-level interventions such as (es)ketamine are recommended, though remission rates remain variable. Identifying reliable markers of treatment response is therefore critical. Recent evidence suggests that a higher percentage of electroencephalography (EEG) vigilance stage A1 is associated with response to intravenous ketamine in major depression. We aimed to corroborate this finding in TRD patients from a recent phase-2 randomized controlled trial of oral prolonged-release ketamine. An algorithm classified vigilance stages in 21 10-minute resting-state EEG recordings. While no significant response × treatment interaction emerged for percentage of vigilance stage A1, a small-scale meta-analysis showed a significant pooled mean difference between ketamine responders and non-responders. Applying a previously proposed A1 cutoff (43 %) yielded chance-level prediction accuracy in the combined ketamine group, but 75 % accuracy in the 240 mg subgroup. Moreover, responders to 240 mg ketamine exhibited a significantly more stable vigilance over time compared to non-responders. Although further validation in a larger sample is warranted, these findings support the clinical value of EEG vigilance as a predictive biomarker for treatment outcomes in depression.