This study explores the responses to ketamine in patients with treatment-resistant depression (TRD) using a wearable forehead electroencephalography (EEG) device. We recruited 55 outpatients with TRD who were randomized into three approximately equal- sized groups (A: 0.5 mg/kg ketamine; B: 0.2 mg/kg ketamine; and C: normal saline) under double-blind conditions. The ketamine responses were measured by EEG signals and Hamilton Depression Rating Scale (HDRS) scores. At baseline, responders showed a significantly weaker EEG theta power than did non- responders (p < 0.05). Responders exhibited a higher EEG alpha power but lower EEG alpha asymmetry and theta cordance at post-treatment than at baseline (p < 0.05). Furthermore, our baseline EEG predictor classified responders and non-responders with 81.3 9.5% accuracy, 82.1 8.6% sensitivity and 91.9 7.4% specificity. In conclusion, the rapid antidepressant effects of mixed doses of ketamine are associated with prefrontal EEG power, asymmetry and cordance at baseline and early post-treatment changes. The prefrontal EEG patterns at baseline may account for recognizing ketamine effects in advance. Our randomized, double- blind, placebo-controlled study provides information regarding clinical impacts on the potential targets underlying baseline identification and early changes from the effects of ketamine in patients with TRD.