Inclusion criteria: 1. patient over 20 years old with depression diagnosed by a psychiatrist and MADRS >= 25 scores; 2. failed to improve by at least optimal dosage of two antidepressants for four weeks and one psychotherapy. Patients and outcome assessors will be blinded from intervention the patients have.

Participants will be randomized into two groups that are intervention (ketamine 0.5 mg/kg IV drip in 40 minutes) and control (midazolam 0.045 mg/kg IV drip in 40 minutes) groups. Participants will administer ketamine/midazolam once daily for three consecutive days. They will be evaluate MADRS changing, vital signs, dissociative symptoms, CGI, and quality of life (EQ-5D-5L) during the treatment, at 1 week and 4 weeks after treatment completion.

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