Treatment resistant depression (TRD) is defined as the failure to respond to two adequate antidepressant trials. TRD patients have high levels of psychosocial distress, poor levels of functioning and are at increased risk for suicide. Novel treatment approaches are being developed to address TRD involving both pharmacological and neuromodulation interventions. In this symposium, leaders in the field will outline three strategies for treating depression which has not responded to conventional therapy and contrast the efficacy of these strategies in younger vs. older patients. William McDonald MD (JB Fuqua Professor of Late -Life Depression, Emory University, Atlanta, GA) will provide a brief overview of TRD and moderate the discussion. George Petrides MD (Director of Clinical Trials Operation and Division of ECT, Zucker Hillside Hospital, New York, NY) will discuss recent data from the National Institute of Mental Health sponsored Consortium on ECT Research (CORE) outlining the response of older patients to ultrabrief right unilateral ECT in TRD. He will contrast the response to ECT in older vs, younger patients from the CORE database accumulated over the last 15 years. Collin Reiff MD (Addiction Psychiatrist, New York University Langone Health Center, NY, NY) will discuss his recent review in the American Journal of Psychiatry on Psychedelic and Psychedelic Assisted Psychotherapy and the implications on the treatment of medication resistant depression, including late life mood disorders. The FDA’s breakthrough designation of MDMA for the treatment of PTSD and psilocybin for the treatment of depression reflects the drugs’ potential to treat resistant psychiatric disorders. Psychedelic assisted therapy may play a unique role in late life mood disorders. Finally, Patricio Riva Posse MD (Director of the TRD and Ketamine Clinic, Emory University, Atlanta, GA) will discuss ketamine treatment in resistant depression including a comparison of response rates and safety data on ketamine treatment in older vs. younger patients. He has recently published the largest compilation of safety data for ketamine infusions and he will review a new tool to monitor safety in clinical practice. Dr. Riva Posse is medical director of the Emory TRD program and has enrolled over 1000 patients (100 in his IV ketamine clinic and about half over the age of 60 years) and followed patients through several novel treatments including transcranial magnetic stimulation, ketamine infusion therapy and ECT to start to look at differential response rates.