Intravenous Ketamine Plus Neurocognitive Training for Depression

This study has two aims: 1) to characterize the effects of intravenous ketamine on neurocognitive markers in depressed patients; 2) to test the efficacy of a synergistic intervention for depression combining intravenous ketamine with neurocognitive training. Three of the primary outcomes listed (fMRI functional connectivity; Implicit Association Test; cognitive flexibility testing) pertain to Aim 1. For Aim 2, one primary clinical outcome (MADRS, a clinician-administered measure of depression severity) pertains to the acute (30-day) phase, while the QIDS (a self-report measure of depression severity) becomes the primary clinical outcome during the 12-month naturalistic follow-up.

This study measures clinical and mechanistic outcome trajectories following ketamine (with or without adjunctive neurocognitive training) measured over an acute (30-day) period; and subsequently (for a subset of measures) over a 12-month naturalistic follow-up period.

NOTE: Corrections have been made to the "Time Frame" entries for all primary/secondary outcomes after identifying errors stemming from the study team's misunderstanding of the "Time Frame" query. Initially, the "Time Frame" query was misinterpreted to mean the range (minimum to maximum) length of the time interval over which any given assessment visit might query symptoms, and were therefore assigned erroneous values ("1 day to 2 weeks"; "1 day to lifetime") reflecting the time interval(s) queried by the instrument (e.g. at the +24 hours timepoint, symptoms are queried over a 1-day interval; at other assessment points, they could be queried over a 2-week interval for some measures, or over the entire lifetime for other measures). After recognizing this misinterpretation, the values have been adjusted to accurately reflect the a priori analytic plan.

Eligibility Criteria:
Inclusion Criteria:

Participants will:

1. be between the ages of 18 and 60 years,
2. have not responded to one or more adequate trials of FDA-approved antidepressants within the current depressive episode, determined by Antidepressant Treatment History Form
3. score ≥ 25 on the Montgomery Asberg Depression Rating Scale (MADRS)
4. 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
5. possess a level of understanding sufficient to agree to all tests and examinations required by the protocol and must sign an informed consent document
6. 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:

1. Presence of lifetime bipolar, psychotic, or autism spectrum; current problematic substance use (e.g., substance use disorder); or lifetime recreational ketamine or PCP use
2. Use of a Monoamine Oxidase Inhibitor (MAOI) within the previous 2 weeks
3. 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.
4. Current pregnancy or breastfeeding, or failure to engage in an effective birth control strategy throughout the duration of the study
5. Acute suicidality or other psychiatric crises requiring treatment escalation.
6. Changes made to treatment regimen within 4 weeks of baseline assessment
7. Reading level \<6th grade
8. 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.
9. Clinically significant abnormal findings of laboratory parameters \[including urine toxicology screen for drugs of abuse\], physical examination, or ECG.
10. 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.
11. Patients with one or more seizures without a clear and resolved etiology.
12. Patients starting hormonal treatment (e.g., estrogen) in the 3 months prior to Screening. Birth control is not an exclusion.
13. Past intolerance or hypersensitivity to ketamine or midazolam.
14. 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.
15. Patients taking any of the following medications: St John's Wort, theophylline, tramadol, metrizamide
16. Patients who have received ECT in the past 6 months prior to Screening.
17. Patients currently receiving treatment with vagus nerve stimulation (VNS) or repetitive transcranial stimulation (rTMS).
18. Patients taking benzodiazepines (within 8 hours of infusion) or GABA agonists