Intravenous Ketamine Plus Neurocognitive Training for Depression

Inclusion Criteria

Participants will:

• be between the ages of 18 and 60 years,
• have not responded to one or more adequate trials of FDA-approved antidepressants within the current depressive episode, determined by Antidepressant Treatment History Form
• score ≥ 25 on the Montgomery Asberg Depression Rating Scale (MADRS)
• score >1SD above the normative mean on the Cognitive Triad Inventory "self" subscale *OR* <1SD below the normative mean on the Rosenberg self-esteem scale
• possess a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document
• agree to sign a release of information (ROI), identifying another individual [friend, family member, etc.] as a contact person while the patient is enrolled in the study.

Exclusion Criteria

• Presence of lifetime bipolar, psychotic, or autism spectrum; current problematic substance use (e.g., substance use disorder); or lifetime recreational ketamine or PCP use
• Use of a Monoamine Oxidase Inhibitor (MAOI) within the previous 2 weeks
• Failure to meet standard MRI inclusion criteria: those who have cardiac pacemakers, neural pacemakers, cochlear implants, metal braces, or other non-MRI-compatible metal objects in their body, especially in the eye. Dental fillings do not present a problem. Plastic or removable dental appliances do not require exclusion. History of significant injury or surgery to the brain or spinal cord that would impair interpretation of results.
• Current pregnancy or breastfeeding, or failure to engage in an effective birth control strategy throughout the duration of the study
• Acute suicidality or other psychiatric crises requiring treatment escalation.
• Changes made to treatment regimen within 4 weeks of baseline assessment
• Reading level <6th grade
• For study entry, patients must be reasonable medical candidates for ketamine infusion, as determined by a board-certified physician co-investigator during study screening. 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] will be exclusions.
• Clinically significant abnormal findings of laboratory parameters [including urine toxicology screen for drugs of abuse], physical examination, or ECG.
• Uncontrolled or poorly controlled hypertension, as determined by a board-certified physician co-investigator's review of vitals collected during screening and any other relevant medical history/records.
• Patients with one or more seizures without a clear and resolved etiology.
• Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening. Birth control is not an exclusion.
• Past intolerance or hypersensitivity to ketamine or midazolam.
• Patients taking medications with known activity at the 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 have received ECT in the past 6 months prior to Screening.
• Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive transcranial stimulation (rTMS).
• Patients taking benzodiazepines (within 8 hours of infusion) or GABA agonists