Inclusion Criteria:  over 20 years old depression was diagnosed by a psychiatrist and having MADRS >= 25 depression treated with 2 optimal dosage of antidepressants for 4 weeks and one psychotherapy stable dosage of current medications for 4 weeks fluently Thai  Exclusion Criteria:  secondary depression PTSD current pregnancy history of increased intracranial hemorrhage, increased intracranial pressure, severe head injury, abnormal thyroid function, angina, heart failure, arrhythmia, aneurysm, uncontrolled hypertension, chronic lower tract respiratory disease, myasthenia gravis, glaucoma, dementia, acute porphyria, or cystitic (within 3 months prior to recruitment) allergy to ketamine or midazolam history of substance use disorder within 1 year prior to recruitment history of psychosis within 3 months history of bipolar disorder BMI over 35 frail medical condition currently ECT or TMS