Table 1.

Inclusion and Exclusion criteria.

Inclusion criteria

•Age ≥55 years •Current MDE (Unipolar) based on the MINI 7.0 •History of ≥1 previous episode of depression prior to the current episode (recurrent MDD) or chronic MDD (of at least two years' duration) •Failure to respond to ≥ 2 adequate trials of FDA-approved antidepressants determined by the ATRQ criteria •QIDS-SR ≥14 •MADRS ≥ 27 •CGI-S ≥ 4 •Able to understand and sign informed consent

Exclusion criteria

•Currently taking fluoxetine •History of bipolar disorder, schizophrenia, schizoaffective disorder or any psychotic disorder •Documented history of a psychotic disorder in a first-degree relative •Current diagnosis of OCD or eating disorder •Alcohol or substance use disorder (except nicotine) within the preceding 3 months •Clinically significant personality disorder that would, in the investigator's judgment, preclude safe study participation •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] •Clinically significant abnormal findings of laboratory parameters [including urine ECG, toxicology screen for drugs of abuse], physical examination, or ECG •Hypertension (systolic BP > 160 mm Hg or diastolic BP > 90 mm Hg) •Participants with one or more seizures without a clear and resolved etiology •Participants starting hormonal treatment in the 3 months prior to Screening •Past intolerance or hypersensitivity to ketamine, or history of recreational use of PCP or ketamine •Past intolerance or hypersensitivity to midazolam •MMSE < 25 at Screening, suggesting age-related cognitive decline or mild dementia •Ongoing use of medications with known activity at the NMDA or AMPA glutamate receptor [e.g., riluzole, amantadine, lamotrigine, memantine, topiramate, dextromethorphan, D-cycloserine], or the mu-opioid receptor •Ongoing use of the following medications: St John's Wort, theophylline, tramadol, metrizamide •Decrease of >25% in depressive symptoms as reflected by the QIDS-SR score from Screening to Randomization •ECT treatment within 6 months prior to Screening •Current VNS or rTMS therapy

MINI Mini-International Neuropsychiatric Interview.

ATRQ Antidepressant Treatment Response Questionnaire.

QIDS-SR Quick Inventory of Depressive Symptomatology-Self Report.

MADRS Montgomery Asberg Depression Rating Scale.

CGI-S Clinical Global Impression-Severity.

MMSE Mini-Mental State Examination.

NMDA N-methyl-D-aspartate.

AMPA Alpha-Amino-3-Hydroxy-5-Methyl-4-Isoxazole Propionic Acid.

ECT Electroconvulsive Therapy.

VNS Vagus nerve stimulation.

rTMS Repetitive transcranial stimulation.