Intravenous Ketamine Plus Neurocognitive Training for Depression

• ClinicalTrials.gov Identifier: NCT03237286
• Recruitment Status: Completed
• First Posted: August 2, 2017
• Last Update Posted: December 8, 2022
• Sponsor: Rebecca Price
• Collaborator: National Institute of Mental Health (NIMH)
• Information provided by (Responsible Party): Rebecca Price, University of Pittsburgh

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Depression	Drug: Intravenous ketamine; Behavioral: Computer-based Cognitive Training	Phase 1; Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 154 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition
• Actual Study Start Date: December 1, 2017
• Actual Primary Completion Date: October 18, 2022
• Actual Study Completion Date: October 18, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Ketamine + Cognitive Training	Drug: Intravenous ketamine; Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.; Behavioral: Computer-based Cognitive Training; 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.
Sham Comparator: Ketamine + Sham Training	Drug: Intravenous ketamine; Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.
Placebo Comparator: Saline + Cognitive Training	Behavioral: Computer-based Cognitive Training; 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.

Outcome Measures

Primary Outcome Measures :

1. Montgomery Asberg Depression Scale [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   Clinician-rated depression (range: 0-60; higher scores = worse outcome)
2. Executive-salience network functional connectivity [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   fMRI measure (beta weights where larger beta weight = stronger connectivity
3. Implicit self-representations [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   Implicit Association Test "D-score" (performance-based measure; range = -inf-inf; high score=worse outcome)
4. Cognitive Flexibility [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   Neurocognitive testing via NIH Toolbox DCCS fully-corrected T-scores (range = 0-100; high score=better outcome)
5. Quick Inventory of Depressive Symptoms [ Time Frame: Trajectories from Day 30 through 12 months post-infusion (naturalistic follow-up) ]
   Self-reported depression (range: 0-27; higher scores = worse outcome)

Secondary Outcome Measures :

1. Neural activation and connectivity patterns [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   MRI measures in prefrontal cortex, hippocampus, amygdala (range: -inf-inf; high score=greater connectivity)
2. Affective flexibility/inhibition [ Time Frame: Trajectories from 24 hours through Day 30 post-infusion ]
   Neurocognitive testing via Affective Go/No-Go task (range: -inf-inf; high score=better performance)
3. PROMIS measures-depression [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported depression T-score range: 0-100 (higher score = worse outcome)
4. PROMIS measures-anxiety [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anxiety T-score range: 0-100 (higher score = worse outcome)
5. PROMIS measures-anger [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anger T-score range: 0-100 (higher score = worse outcome)
6. PROMIS measures-positive affect [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported positive affect/well-being T-score range: 0-100 (higher score = better outcome)
7. PROMIS measures-sleep disturbance [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported sleep disturbance T-score range: 0-100 (higher score = worse outcome)
8. PROMIS measures-cognitive function [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported cognitive function T-score range: 0-100 (higher score = better outcome)
9. PROMIS measures-substance use [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
   Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported substance use T-score range: 0-100 (higher score = worse outcome)
10. PROMIS measures-alcohol [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
    Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported alcohol use T-score range: 0-100 (higher score = worse outcome)
11. Cognitive Triad Inventory [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
    Negative perceptions of self, future, & world (range=12-84; higher score = better outcome)
12. Columbia-Suicide Severity Rating Scale [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
    Suicidality and patient safety (most severe ideation score, range=0-5; higher score = worse outcome)
13. WHO Disability Assessment Scale (SR) [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
    Global functioning (range=0-48; higher score = better outcome)
14. Cognitive Flexibility Scale [ Time Frame: Trajectories from 24 hours through Month 12 post-infusion ]
    Self-reported cognitive flexibility (range=12-72; higher score = better outcome)
15. Neuroplasticity-related markers in blood [ Time Frame: Trajectories from 40min through Day 5 post-infusion ]
    ketamine, ketamine metabolites, BDNF, inflammatory markers (range=0-inf; higher score = greater concentration in blood)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, Pennsylvania

Western Psychiatric Institute and Clinic

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Rebecca Price

National Institute of Mental Health (NIMH)

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Price RB, Panny B, Degutis M, Griffo A. Repeated measurement of implicit self-associations in clinical depression: Psychometric, neural, and computational properties. J Abnorm Psychol. 2021 Feb;130(2):152-165. doi: 10.1037/abn0000651. Epub 2020 Dec 3.

• Responsible Party: Rebecca Price, Assistant Professor of Psychiatry, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT03237286
• Other Study ID Numbers: STUDY19040414; 1R01MH113857 ( U.S. NIH Grant/Contract )
• First Posted: August 2, 2017
• Last Update Posted: December 8, 2022
• Last Verified: December 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We will comply with all NIMH guidelines regarding data repository/sharing.
• Time Frame: We will comply with all NIMH guidelines regarding data repository/sharing.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Rebecca Price, University of Pittsburgh:

depression; ketamine; neurocognitive; fMRI; cognitive training

Additional relevant MeSH terms:

Depression; Depressive Disorder; Behavioral Symptoms; Mood Disorders; Mental Disorders; Ketamine; Analgesics; Sensory System Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Anesthetics, Dissociative; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Central Nervous System Depressants; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action