Ketamine is emerging as a treatment for difficult-to-treat depression, with its efficacy linked to EEG measures of alertness. This study by Ip and coworkers (2024) explored how brain arousal responds to intravenous ketamine, quantified through EEG vigilance measures. Two cohorts of 24 depressed patients each were examined. A clinical response was defined as a >33% reduction in Montgomery–Åsberg Depression Rating Scale (MADRS) scores 24 h post-infusion. EEG was recorded pre-, start-, end-, and 24 h post-infusion, and the Vigilance Algorithm Leipzig (VIGALL) assessed EEG stages ranging from high vigilance (A1) to low vigilance (B2/3) and sleep onset (C). Ketamine increased low-vigilance stage B1, correlated with serum ketamine levels but independent of clinical response. Responders exhibited a decrease in high-vigilance A1 and an increase in low-vigilance B2/3, observed in both ketamine and placebo conditions. Pretreatment EEG differed between responders and non-responders, with 53% of responders showing high vigilance A1 compared to 21% of non-responders. Logistic regression predicted outcomes with an AUC of 0.7. Pretreatment EEG vigilance stages, particularly A1, may serve as a predictive biomarker for clinical response to ketamine treatment.