Inclusion Criteria:
For inclusion in this study, the following will be required:
* Ability to provide informed consent;
* Current psychiatric inpatient (voluntary only) or outpatient treatment;
* Male or female;
* Age 18-65 years;
* Meets diagnostic criteria for major depressive disorder/bipolar depression without psychotic features per the SCID DSM-IV-TR;
* PHQ-9 total score ≥ 15 at screening and at baseline (just prior to first acute phase ketamine infusion);
* Treatment-resistant depression (TRD), as defined by failure of at least two previous antidepressant treatments within the current depressive episode. Failed antidepressant treatments can include pharmacotherapy for depression at an adequate dose for at least 8 weeks, or an acute series of at least 6 administrations of electroconvulsive therapy (ECT) or an acute series of Transcranial magnetic stimulation (TMS);
* Ability to pass a comprehension assessment test related to effects of ketamine and trial objectives and criteria.
Exclusion Criteria: Based on ketamine's known difficulties with the induction of perceptual/psychomimetic symptoms, the exclusion criteria for this study will be as follows:
* Inability to speak English
* Patients with a BMI \>40.
* Any current psychiatric diagnosis other than anxiety disorders needing concurrent antidepressant therapy
* Personality disorder being the primary diagnosis
* Diagnosis of schizophrenia, schizoaffective disorder, post-traumatic stress disorder, or active psychotic symptoms;
* Ongoing prescription of \> 4 mg lorazepam equivalents (total) daily, or morning dosing of any benzodiazepine at the time of assessment;
* Medications known to affect glutamate (i.e., riluzole, carbamazepine) or GABA (zaleplon, zolpidem, zopiclone, valproate, gabapentin, pregabalin, tiagabine, and vigabatrin) are prohibited within two weeks prior to administration of study drug;
* Antidepressant Monoamine Oxidase Inhibitors (MAOIs) are prohibited two weeks prior to the administration of the study drug.
* CYP3A4 inducers carbamazepine and modafinil are prohibited within two weeks prior to administration of the study drug and at least 24 hours after the last dose of study drug.
* Currently undergoing TMS, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression;
* ECT in the past 12 months;
* Any active or unstable medical condition judged by the study psychiatrist as conferring too great a level of medical risk to allow inclusion in the study;
* Use of methamphetamine, cocaine, or cannabis. Abuse of stimulant(s) within the prior 12 months;
* Any current substance use disorder (excluding nicotine and caffeine). Note: Persons will be allowed to enroll in this study if their substance use is in complete (not partial) and sustained (\> 1 year) remission;
* History of traumatic brain injury that resulted in loss of consciousness;
* Developmental delay, intellectual disability, or intellectual disorder;
* Clinical or self-reported diagnosis of delirium, encephalopathy, or related clinical diagnosis within the prior 12 months;
* Cognitive disorder (mild and major categories, per DSM-);
* Received ketamine treatment for depression within the prior 2 months;
* History of either poor antidepressive response to or poor tolerability of ketamine (any route of administration) when previously administered for treating symptoms of depression;
* History of hypothyroidism unless taking a stable dose of thyroid medication and asymptomatic for 6 months;
* Hepatic insufficiency (2.5 X ULN for AST or ALT) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver;
* Gastroesophageal reflux disease
* A diagnosis of Complex Regional Pain Syndrome (CRPS);
* Pregnancy, or nursing;
* History of claustrophobia
* Any contraindication to MRI safety questionnaire