Intravenous Ketamine Plus Neurocognitive Training for Depression

Study Overview
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Brief Summary
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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.

Official Title
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Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition

Conditions
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Depression

Intervention / Treatment
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* Drug: Intravenous ketamine
* Behavioral: Computer-based Cognitive Training


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ketamine + Cognitive Training<br> | Drug: Intravenous ketamine<br>* Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.<br>Behavioral: Computer-based Cognitive Training<br>* Computer-based Cognitive Training will be delivered following intravenous ketamine to test whether learning during a post-ketamine window of opportunity might extend relief from depression.<br>|
| Sham Comparator: Ketamine + Sham Training<br> | Drug: Intravenous ketamine<br>* Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.<br>|
| Placebo Comparator: Saline + Cognitive Training<br> | Behavioral: Computer-based Cognitive Training<br>* Computer-based Cognitive Training will be delivered following intravenous ketamine to test whether learning during a post-ketamine window of opportunity might extend relief from depression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Montgomery Asberg Depression Scale | Clinician-rated depression (range: 0-60; higher scores = worse outcome) | Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported | 
| Executive-salience Network Functional Connectivity | fMRI measure (beta weights where larger beta weight = stronger connectivity) | Trajectories from 24 hours through Day 30 post-infusion, 24 hours reported | 
| Implicit Self-representations | Implicit Association Test composite difference score (performance-based measure; range = -inf-inf; high score=worse outcome; negatively signed value indicates associating oneself more strongly with positive than negative attributes) | Trajectories from 24 hours through Day 30 post-infusion, Day 5 reported | 
| Cognitive Flexibility | Neurocognitive testing via NIH Toolbox DCCS fully-corrected T-scores (range = 0-100; high score=better outcome) | Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported | 
| Quick Inventory of Depressive Symptoms | Self-reported depression (range: 0-27; higher scores = worse outcome) | Trajectories from Day 30 through 12 months post-infusion (naturalistic follow-up), Month 12 reported | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Executive-salience Network Functional Connectivity During Resting State | fMRI measure (beta weights where larger beta weight = stronger connectivity) | Trajectories from 24 hours through Day 30 post-infusion, 24 hours reported | 
| Affective Flexibility | 'D-Prime' discrimination Z-score measured via accuracy of responses during the Affective Go/No-Go task (range: -inf-inf; high score=better performance; Z-score of 0=the sample mean) | Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported | 
| PROMIS Measures-depression | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported depression T-score range: 0-100 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-anxiety | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anxiety T-score range: 0-100 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-anger | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anger T-score range: 0-100 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-positive Affect | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported positive affect/well-being T-score range: 0-100 (higher score = better outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-sleep Disturbance | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported sleep disturbance T-score range: 0-100 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-cognitive Function | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported cognitive function T-score range: 0-100 (higher score = better outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-substance Use | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported substance use Raw score range: 0-35 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| PROMIS Measures-alcohol | Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported alcohol use T-score range: 0-100 (higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| Cognitive Triad Inventory | Negative perceptions of self, future, & world (range=36-252; higher score = better outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| Columbia-Suicide Severity Rating Scale | Suicidality and patient safety (most severe ideation score, range=0-5; higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| WHO Disability Assessment Scale (SR) | Global functioning (range=0-48; higher score = worse outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| Cognitive Flexibility Scale | Self-reported cognitive flexibility (range=12-72; higher score = better outcome) | Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported | 
| Neuroplasticity-related Markers in Blood | ketamine metabolite (2R,6R)-HNK concentration levels (range=0-inf; higher score = greater concentration in blood) | 40min post-infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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depression, ketamine, neurocognitive, fMRI, cognitive training