Inclusion Criteria:  age 18-65 years meeting DSM-V criteria for major depressive disorder a pretreatment score ≥17 on HDRS-17 meeting criteria for TRD, defined as having had at least two adequate dose-duration antidepressant medication failures in the current depressive episode. current treatment drugs were stably used for at least 4 weeks  Exclusion Criteria:  MDD with psychosis, e.g., bipolar disorder, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, panic disorder, et al Drug, tobacco or alcohol abuse active suicidal intention previous administration of NMDA receptor antagonists (e.g., ketamine) previous (<6 weeks prior) or ongoing treatment with electroconvulsive therapy (ECT) or transcranial magnetic stimulation (TMS) pregnancy or breastfeeding morbidly obese, BMI>35kg/m2 other diseases that could interfere with the results