Intervention: Ketamine
Trial phase: Phase 4
ATC code: N01AX03 | N01AX14 | N06AX27
SMILES: CNC1(c2ccccc2Cl)CCCCC1=O
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 75
Group description: Subjects will receive three IV Ketamine Hydrochloride infusions (0.5 mg/kg, infused over 100 minutes) and measure their depressive symptom responses. Biomarkers will be developed using blood samples from study subjects, taken prior to (predictive biomarkers) and following ketamine treatment (change biomarkers).

Ketamine Hydrochloride: Subjects will receive three IV ketamine infusions at 0.5 mg/kg, infused over 100 minutes.
Eligibility criteria:
Inclusion criteria:

Ability to provide informed consent
Current psychiatric inpatient (voluntary only) or outpatient treatment
Meets Diagnostic and Statistical Manual of Mental Disorders (DSM-5) diagnostic criteria for major depressive disorder, bipolar I disorder, or bipolar II disorder
Patient Health Questionnaire (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:

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
Use or abuse of methamphetamine, cocaine, cannabis, or stimulants (prescribed and illicit) within the past 12 months
Any current abuse or dependence of alcohol or drugs (excluding nicotine and caffeine) 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
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)
Prior 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 upper limit of normal (ULN) for aspartate aminotransferase (AST) or ALT) within 1 year of consent, past liver transplant recipient, and/or clinical diagnosis of cirrhosis of the liver
Pregnancy, or nursing
Prisoners
Involuntary psychiatric hospitalization