The purpose of this study is to examine the effectiveness of a single infusion of ketamine (KET), to determine which dose is optimal 7 days after infusion using Bayesian Adaptive Randomization, and to learn about how ketamine works in the body and brain in persons with late-life treatment resistant depression.

Primary Aim: To identify the best performing condition across a single intravenous infusion of ketamine (KET) 0.1 mg/kg, KET 0.25 mg/kg, KET 0.50 mg/kg) and midazolam (MID) 0.03 mg/kg on Montgomery-Asberg Depression Rating Scale (MADRS) treatment response (at least a 50% improvement in depression from baseline) 7 days after the infusion in up to 72 Veterans with Late-Life Treatment Resistant Depression (LL-TRD) , using a triple blind (patient, rater, anesthesiologist) Bayesian adaptive randomization design.

Hypothesis 1: Single KET 0.5 mg/kg infusion is superior to KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg measured by the proportion of participants demonstrating > 50% reduction on MADRS scores 7 days post-treatment.

Secondary Aim: To evaluate the durability of day 7 treatment response across 3 sub-anesthetic doses of a single KET (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and MID (0.03 mg/kg) infusion in veterans with LL-TRD during a 4 week follow-up.

Hypothesis 2: a single KET 0.5 mg/kg infusion will be superior to a single infusion of KET 0.1 mg/kg, KET 0.25 mg/kg, and MID 0.03 mg/kg as measured by the proportion of participants demonstrating > 50% reduction on MADRS scores at 28 days post-infusion.

Tertiary Aim: To evaluate the immediate and longer-term safety and tolerability of the most effective KET infusion relative to MID in vets with LL-TRD.

Hypothesis 3: KET infusion at the most effective dose will be safe and well tolerated compared to MID, as assessed by psychoactive and general side effect rating scales during and up to 4 weeks post study infusion.

Exploratory Aims:

1. To measure the effects of the most effective dose of KET relative to MID on neurocognitive performance.
2. To measure the effects the most effective dose of KET relative to MID on peripheral biomarkers of cellular plasticity and inflammation.
3. To measure the effects the most effective dose of KET relative to MID on resting-state quantitative electroencephalography.

Inclusion Criteria:

• Male or female patients, 55 years of age,
• Participants must fulfill DSM 5 criteria for a Major Depressive Episode (Unipolar), based on a structured diagnostic interview, the DSM 5 M.I.N.I. 7.0
• Participants must have a history of at least one previous episode of depression prior to the current episode (recurrent MDD) or have chronic MDD (of at least two years' duration),
• Participants have not responded to two or more adequate trials of FDA-approved antidepressants, determined by Antidepressant Treatment Response Questionnaire (ATRQ) criteria.
• Participants must score 14 or greater on the Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR), and score 27 on the Montgomery Asberg Depression Rating Scale (MADRS),
• Each participant must have a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document.

Exclusion Criteria:

• Patients currently on fluoxetine,
• History of schizophrenia, schizoaffective disorder or any psychotic disorder, or bipolar disorder,
• Documented history of a psychotic disorder in a first-degree relative,
• Current diagnosis of obsessive-compulsive disorder (OCD) or eating disorder [bulimia nervosa or anorexia nervosa],
• Alcohol or substance use [except nicotine] within the preceding 6 months,
• Patients with any clinically significant personality disorder that would, in the investigator's judgment, preclude safe study participation,
• Patients judged to be at serious and imminent suicidal or homicidal risk,
• Serious, unstable medical illnesses including respiratory [obstructive sleep apnea, or history of difficulty with airway management during previous anesthetics], cardiovascular [including ischemic heart disease and uncontrolled hypertension], and neurologic [including history of severe head injury],
• For study entry, patients must be reasonable medical candidates for ketamine or midazolam infusion, as determined by a board-certified physician co-investigator during study Screening,
• Clinically significant abnormal findings of laboratory parameters [including urine toxicology screen for drugs of abuse], physical examination, or ECG,
• Hypertension (systolic BP >160 mm Hg or diastolic BP >90 mm Hg),
• Patients with one or more 11 seizures without a clear and resolved etiology,
• Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening,
• Past intolerance or hypersensitivity to ketamine, or history of recreational use of phencyclidine (PCP) or ketamine,
• Past intolerance or hypersensitivity to midazolam,
• Age-related cognitive decline or mild dementia suggested by a score of < 25 on the Mini-Mental State Examination (MMSE) at Screening,
• Patients taking medications with known activity at the N-methyl-D-aspartate receptor (NMDA) or AMPA glutamate receptor [e.g., riluzole, amantadine, lamotrigine, memantine, topiramate, dextromethorphan, D-cycloserine], or the muopioid receptor,
• Patients taking any of the following medications: St John's Wort, theophylline, tramadol, metrizamide,
• Patients who demonstrate > 25% decrease in depressive symptoms as reflected by the QIDS-SR score from Screening to Randomization,
• Patients who have received electroconvulsive therapy (ECT) in the past 6 months prior to Screening,
• Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive transcranial stimulation (rTMS).

28 days