Functional Neuroimaging of the Enhanced Antidepressant Efficacy of Ketamine in a Biologically-Enriched Subgroup

Inclusion Criteria: 1. 18 to 55 years of age. 2. A level of understanding sufficient to agree to all required tests and examinations, sign an informed consent document and verify understanding by a score greater than or equal to 90% on the consent quiz. 3. Diagnostic and Statistical Manual-4th Edition-Text Revision (DSM-IV-TR)) diagnosis of major depressive disorder (MDD), single-episode (296.30) or recurrent (296.20) without psychotic features based on clinical assessment and confirmed by a Structured Clinical Interview for the DSM-IV- Patient Version (SCID-P). Subjects must be experiencing a current major depressive episode of at least 2 weeks duration. 4. Past failure of greater than or equal to one standard antidepressant trial based on the Antidepressant Treatment History Form (ATHF). 5. MADRS score greater than or equal to 20 at baseline and the day of ketamine infusion.

Exclusion Criteria: 1. Inadequate knowledge of family mental and substance use history, e.g. adoption. 2. Current psychotic features or prior diagnosis of a DSM-IV-TR psychotic spectrum disorder, e.g. schizophrenia, schizoaffective disorder, bipolar I disorder with psychotic features, MDD with psychotic features, or bipolar disorder, e.g. bipolar I disorder without psychotic features, bipolar II disorder and bipolar disorder not otherwise specified (NOS). 3. Current/active DSM-IV-TR substance use disorder (except for caffeine or nicotine dependence). 4. Pregnant or nursing women or women of childbearing potential not using at least one medically accepted means of contraception (to include oral, injectable, or implant birth control, condom or diaphragm with spermicide, intrauterine devices (IUD), tubal ligation, abstinence or partner with vasectomy). 5. Serious, unstable medical conditions/problems including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic disease, e.g. uncontrolled asthma, uncontrolled hyper/hypothyroidism or active cancer. 6. Presence of any medical illness likely to alter brain morphology and/or physiology (e.g., hypertension, diabetes) even if controlled by medications. 7. Clinically significant abnormal laboratory tests. 8. Subjects with one or more seizures without clear and resolved etiology and head injury with loss of consciousness for \> 5 minutes or requiring hospitalization. 9. Treatment with psychiatric medications, e.g. selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, benzodiazepines and antipsychotics, at least two weeks of study phase II. 10. Treatment with fluoxetine within 5 weeks of study phase II. 11. Treatment with device-based treatment for depression, e.g. electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS) and vagal nerve stimulation (VNS), within 4 weeks of study phase II. 12. Lifetime history of deep brain stimulation. 13. Treatment with any disallowed concomitant medications. 14. Positive HIV test 15. Presence of ferromagnetic implants, e.g, heart pacemaker or aneurysm clip, or other contraindications to magnetic resonance imaging (MRI), e.g. claustrophobia or hearing loss. 16. Clinically-significant anatomical brain abnormalities detected on routine brain MRI. 17. Subjects who, in the investigator's judgment, pose a current serious suicidal or homicidal risk, or who have a MADRS item 10 score of greater than or equal to 4. 18. A current NIMH employee/staff or their immediate family member (N.B. former exclusion criteria likely to be no longer relevant at the University of Iowa Health Care). 19. Currently engaged in an evidence-based structured psychotherapy for mood and/or anxiety disorders, e.g. cognitive-behavioral therapy (CBT) or interpersonal psychotherapy (IPT). Additionally, the investigators may exclude or terminate any patient for clinical reasons.