Ketamine for Treatment Resistant Late-Life Depression

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).