Intravenous Ketamine Plus Neurocognitive Training for Depression

Phase 1

Completed

Conditions: Depression

Interventions: Drug: Intravenous ketamine
Behavioral: Computer-based Cognitive Training

Registration Number: NCT03237286

Lead Sponsor: Rebecca Price

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 154

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ketamine + Sham Training	Intravenous ketamine	-
Ketamine + Cognitive Training	Computer-based Cognitive Training	-
Saline + Cognitive Training	Computer-based Cognitive Training	-
Ketamine + Cognitive Training	Intravenous ketamine	-

Primary Outcome Measures

Name	Time	Method
Implicit Self-representations	Trajectories from 24 hours through Day 30 post-infusion, Day 5 reported	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)
Montgomery Asberg Depression Scale	Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported	Clinician-rated depression (range: 0-60; higher scores = worse outcome)
Cognitive Flexibility	Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported	Neurocognitive testing via NIH Toolbox DCCS fully-corrected T-scores (range = 0-100; high score=better outcome)
Executive-salience Network Functional Connectivity	Trajectories from 24 hours through Day 30 post-infusion, 24 hours reported	fMRI measure (beta weights where larger beta weight = stronger connectivity)
Quick Inventory of Depressive Symptoms	Trajectories from Day 30 through 12 months post-infusion (naturalistic follow-up), Month 12 reported	Self-reported depression (range: 0-27; higher scores = worse outcome)

Secondary Outcome Measures

Name	Time	Method
Executive-salience Network Functional Connectivity During Resting State	Trajectories from 24 hours through Day 30 post-infusion, 24 hours reported	fMRI measure (beta weights where larger beta weight = stronger connectivity)
Affective Flexibility	Trajectories from 24 hours through Day 30 post-infusion, Day 30 reported	'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)
PROMIS Measures-depression	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported depression T-score range: 0-100 (higher score = worse outcome)
PROMIS Measures-positive Affect	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported positive affect/well-being T-score range: 0-100 (higher score = better outcome)
PROMIS Measures-anger	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anger T-score range: 0-100 (higher score = worse outcome)
PROMIS Measures-anxiety	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anxiety T-score range: 0-100 (higher score = worse outcome)
PROMIS Measures-sleep Disturbance	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported sleep disturbance T-score range: 0-100 (higher score = worse outcome)
PROMIS Measures-cognitive Function	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported cognitive function T-score range: 0-100 (higher score = better outcome)
PROMIS Measures-substance Use	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported substance use Raw score range: 0-35 (higher score = worse outcome)
PROMIS Measures-alcohol	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported alcohol use T-score range: 0-100 (higher score = worse outcome)
Cognitive Triad Inventory	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Negative perceptions of self, future, \& world (range=36-252; higher score = better outcome)
Columbia-Suicide Severity Rating Scale	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Suicidality and patient safety (most severe ideation score, range=0-5; higher score = worse outcome)
WHO Disability Assessment Scale (SR)	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Global functioning (range=0-48; higher score = worse outcome)
Cognitive Flexibility Scale	Trajectories from 24 hours through Month 12 post-infusion, Month 12 reported	Self-reported cognitive flexibility (range=12-72; higher score = better outcome)
Neuroplasticity-related Markers in Blood	40min post-infusion	ketamine metabolite (2R,6R)-HNK concentration levels (range=0-inf; higher score = greater concentration in blood)