Over the past few years since I started working with patients with major depression I have noticed an alarming number that have had a poor response to monotherapy antidepressants. What is the best pharmacological approach to treating treatment-resistant depression? DEBORAH ANTAI-OTONG RESPONDS: Treatment-resistant depression (TRD) is a relatively common, yet chronic, complicated, and disabling illness despite the broad range of treatment options available for depression. It is generally unrecognized and undertreated. Growing data challenge monotherapy antidepressant treatment as the sole option for depressed patients.