VA Aripiprazole vs Esketamine for Treatment Resistant Depression

Inclusion Criteria: * DSM-5 diagnosis of current episode of major depressive disorder (MDE, single or recurrent, non-psychotic) by MINI * TRD defined as at least 2 failed trials of antidepressants (adequate dose and duration) including the current episode and another during last 2 years * Current QIDS-C16 score of \> 14 * Currently on an antidepressant medication at stable dose for at least 6 weeks without adequate improvement * Ages 18-74 years old at the time of randomization Exclusion Criteria: * Lifetime history of bipolar disorder, schizophrenia, schizoaffective disorder, or other psychotic disorder * Presence of psychotic features in the current MDE * Lifetime history of major neurocognitive disorder or any diagnosed neurodegenerative or neurodevelopmental disorder * Current evidence of cognitive dysfunction based on MoCA score \< 24 * Hypersensitivity to ESK or ketamine * History of aneurysmal vascular disease or arteriovenous malformation * History of intracerebral hemorrhage * Uncontrolled hypertension (systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg, unless cleared by the patient's primary care physician) * History of significant cardiovascular disease, including recent myocardial infarction (within last 12 months), unstable angina, or chronic heart failure * History of interstitial or ulcerative cystitis * Any current unstable medical condition that in the opinion of the investigator would place the patient at increased risk, including hepatic, respiratory, immunological, cardiovascular, endocrine, or renal disease * Imminent need for psychiatric hospitalization * History of moderate or severe SUD in last 6 months will be excluded, not including cannabis, tobacco, and caffeine * Women who are pregnant, lactating, or planning to become pregnant or those of childbearing potential who are sexually active but unwilling to use a contraceptive * Unable to provide informed consent * Current treatment with any antipsychotic * Prior antidepressant treatment with ketamine or ESK within the current episode/past two years * Prior antidepressant treatment with ARI at an FDA-approved dose for at least 6 weeks within the past 2 years * Lifetime history of ketamine use disorder * History of drug induced leukopenia For women of childbearing potential, pregnancy will be excluded prior to randomization and counseling on potential risks of taking ESK or ARI during pregnancy will be provided.