Project Summary/Abstract Among all medical, mental health and substance related disorders, Major Depressive Disorder (MDD) is the leading cause disease burden worldwide; MDD is a major cause of suffering and disability for those receiving their care from the Veterans Health Administration (VHA). Current treatments have limited effectiveness as only about 30% of patients achieve remission with the first antidepressant treatment. By regulatory convention, the term treatment-resistant depression (TRD) is used when a depressed patient has not responded to two or more adequate treatment trials in the current episode. So defined, patients with TRD account for a disproportionately large share of treatment resources and, despite such efforts, are at the highest risk to become chronically ill, develop a complicating substance abuse disorder and/or die by suicide. The CSP 576, VA Augmentation and Switching Treatments for Improving Depression Outcomes (VAST-D), showed that adjunctive aripiprazole resulted in a significantly greater likelihood of remission as compared to switching to bupropion. Secondary analyses of VAST-D demonstrated that the advantage of adjunctive aripiprazole among 12-week remitters was sustained across up to six months of therapy and was evident whether or not patients had co-occurring PTSD. In 2019 the U.S. Food and Drug Administration (FDA) reviewed intranasal esketamine as a new therapy for treatment of TRD. The safety and efficacy of esketamine was evaluated in a series of phase III studies that ultimately led to the FDA approval of esketamine (Spravato) for the treatment of TRD in adults. The proposed study will be an open-label, parallel-group, randomized clinical trial of up to 6 months treatment of adjunctive intranasal esketamine vs. adjunctive aripiprazole in Veterans with TRD. This study will assess the efficacy, safety, and acceptability of adjunctive intranasal esketamine in direct comparison to adjunctive aripiprazole for therapy of TRD. The primary hypothesis is that participants receiving adjunctive intranasal esketamine will be significantly more likely to achieve remission after six weeks of treatment as compared to those who receive adjunctive aripiprazole. Depressive symptoms will be assessed by independent evaluators without knowledge of treatment assignment using the Quick Inventory of Depressive Symptomatology clinician rating (QIDS-C), which is a well-validated tool that commonly and is easily translated across other depression inventory scales. The study is powered to be able to detect an absolute difference in remission rates of 10% or larger at 6 weeks. Secondary outcomes of interest include symptom reduction across 6 months of randomized therapy, side effects and other tolerability indices, suicidality, and measures of quality of life and cost-effectiveness.