Inclusion Criteria:

• Ability to provide informed consent.
• Current psychiatric inpatient (voluntary only) or outpatient treatment.
• Male or female.
• Age 18-65 years old.
• Meets DSM-5 diagnostic criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder.
• PHQ-9 total score > 15 at screening and at baseline (just prior to first acute phase ketamine infusion).
• Treatment-resistant depression, as defined by failure of at least two previous antidepressant or mood stabilizing treatments within the current depressive episode.Failed antidepressant or mood stabilizing 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).
• 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 induction of perceptual/psychomimetic symptoms, exclusion criteria for this study are as follows:

• Patients with a BMI >40.
• Diagnosis of schizophrenia, schizoaffective 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.
• Currently undergoing ECT, transcranial magnetic stimulation, vagal nerve stimulation, or deep brain stimulation as either an acute or maintenance treatment of depression.
• 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.
• A cannabis use disorder by DSM-5 criteria in partial remission of less than 3 months will be an exclusion from enrollment. Cannabis use disorders in partial remission of at least 3 months will defer this exclusion.
• Any patient-reported abuse or dependence of cannabis within the prior 3 months from date of screening will be an exclusion.
• Any positive urine toxicology screen as part of the screening visit for illicit, non-prescribed, drug use will be an exclusion.
• Any current abuse or dependence of alcohol or drugs (excluding nicotine,caffeine, and cannabis).
  • Note: Persons will be allowed to enroll in this study if their drug or alcohol abuse/dependence is in complete (not partial) and sustained (> 1 year) remission.
• Use of methamphetamine, cocaine, or cannabis. Abuse of stimulant(s) within the prior 12 months.
• Any current abuse or dependence of alcohol or drugs (excluding nicotine. caffeine and cannabis).
  • Note: Persons will be allowed to enroll in this study if their drug or alcohol abuse/dependence is in complete (not partial) and sustained (> 1 year) remission.
• Use of any MAOI is prohibited two weeks prior to administration of study drug; if patients are on an MAOI when enrolled, study drug will not be administered until two weeks off MAOI.
• CYP3A4 inducers carbamazepine and modafinil are prohibited two weeks prior to administration of study drug and at least 24 hours after last dose of study drug.
• Current use of Naltrexone.
• History of traumatic brain injury that resulted in loss of consciousness.
• Developmental delay, mental retardation, 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-5).
• Current or prior clinical treatment by ketamine for depression or prior or current participation in another study of ketamine for depression within the prior 6 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.
• Significant unstable medical condition.
• 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.
• A diagnosis of Complex Regional Pain Syndrome (CRPS).
• Males active in attempting to conceive a child.
• Pregnancy or nursing.
• Prisoners.
• Involuntary psychiatric hospitalization.