Ketamine for Treatment Resistant Late-Life Depression

Primary Aim: To identify and evaluate the durability of benefit of the best performing of 3
sub-anesthetic doses of a single ketamine (0.1 mg/kg, 0.25 mg/kg, and 0.50 mg/kg) and
midazolam (MID) (0.03 mg/kg) infusion in up to 72 Veterans with Late-Life Treatment Resistant
Depression (LL-TRD).

Hypothesis 1: the durability of benefit of a single KET 0.5 mg/kg infusion is superior to
(0.1 mg/kg, 0.25 mg/kg, and MID 0.03 mg/kg) time to relapse as measured by repeated
measurements using the Montgomery-Asberg Depression Rating Scale (MADRS) during a four-week,
post-infusion follow-up.

Secondary Aim: To evaluate and compare the antidepressant efficacy of the best performing of
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 vets with LL-TRD, using a triple blind (patient, rater, anesthesiologist)
Bayesian adaptive randomization design.

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 72-hour post-infusion.

Tertiary Aim: To evaluate the immediate and longer-term safety and tolerability of the most
effective KET infusion (0.5 mg/kg) relative to MID (0.03 mg/kg) in vets with LL-TRD.

Hypothesis 3: KET infusion at the most effective dose (0.5 mg/kg) 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 (0.50 mg/kg) relative to MID
(0.03 mg/kg) on neurocognitive performance.

2. To measure the effects the most effective dose of KET (0.50 mg/kg) relative to MID (0.03
mg/kg) on peripheral biomarkers of cellular plasticity and inflammation.

3. To measure the effects the most effective dose of KET (0.50 mg/kg) relative to MID (0.03
mg/kg) 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).