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Intravenous Ketamine Plus Neurocognitive Training for Depression

Primary Purpose

Depression

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Intravenous ketamine
Computer-based Cognitive Training
Sponsored by
Rebecca Price
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Depression focused on measuring depression, ketamine, neurocognitive, fMRI, cognitive training

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Western Psychiatric Institute and Clinic

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Sham Comparator

Placebo Comparator

Arm Label

Ketamine + Cognitive Training

Ketamine + Sham Training

Saline + Cognitive Training

Arm Description

Outcomes

Primary Outcome Measures

Montgomery Asberg Depression Scale
Clinician-rated depression (range: 0-60; higher scores = worse outcome)
Executive-salience network functional connectivity
fMRI measure (beta weights where larger beta weight = stronger connectivity
Implicit self-representations
Implicit Association Test "D-score" (performance-based measure; range = -inf-inf; high score=worse outcome)
Cognitive Flexibility
Neurocognitive testing via NIH Toolbox DCCS fully-corrected T-scores (range = 0-100; high score=better outcome)
Quick Inventory of Depressive Symptoms
Self-reported depression (range: 0-27; higher scores = worse outcome)

Secondary Outcome Measures

Neural activation and connectivity patterns
MRI measures in prefrontal cortex, hippocampus, amygdala (range: -inf-inf; high score=greater connectivity)
Affective flexibility/inhibition
Neurocognitive testing via Affective Go/No-Go task (range: -inf-inf; high score=better performance)
PROMIS measures-depression
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported depression T-score range: 0-100 (higher score = worse outcome)
PROMIS measures-anxiety
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anxiety T-score range: 0-100 (higher score = worse outcome)
PROMIS measures-anger
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anger T-score range: 0-100 (higher score = worse outcome)
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)
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)
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)
PROMIS measures-substance use
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported substance use T-score range: 0-100 (higher score = worse outcome)
PROMIS measures-alcohol
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported alcohol use T-score range: 0-100 (higher score = worse outcome)
Cognitive Triad Inventory
Negative perceptions of self, future, & world (range=12-84; higher score = better outcome)
Columbia-Suicide Severity Rating Scale
Suicidality and patient safety (most severe ideation score, range=0-5; higher score = worse outcome)
WHO Disability Assessment Scale (SR)
Global functioning (range=0-48; higher score = better outcome)
Cognitive Flexibility Scale
Self-reported cognitive flexibility (range=12-72; higher score = better outcome)
Neuroplasticity-related markers in blood
ketamine, ketamine metabolites, BDNF, inflammatory markers (range=0-inf; higher score = greater concentration in blood)

Full Information

First Posted
July 28, 2017
Last Updated
December 7, 2022
Sponsor
Rebecca Price
Collaborators
National Institute of Mental Health (NIMH)
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1. Study Identification

Unique Protocol Identification Number
NCT03237286
Brief Title
Intravenous Ketamine Plus Neurocognitive Training for Depression
Official Title
Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition
Study Type
Interventional

2. Study Status

Record Verification Date
December 2022
Overall Recruitment Status
Completed
Study Start Date
December 1, 2017 (Actual)
Primary Completion Date
October 18, 2022 (Actual)
Study Completion Date
October 18, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Rebecca Price
Collaborators
National Institute of Mental Health (NIMH)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. 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.
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Depression
Keywords
depression, ketamine, neurocognitive, fMRI, cognitive training

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
154 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Ketamine + Cognitive Training
Arm Type
Experimental
Arm Title
Ketamine + Sham Training
Arm Type
Sham Comparator
Arm Title
Saline + Cognitive Training
Arm Type
Placebo Comparator
Intervention Type
Drug
Intervention Name(s)
Intravenous ketamine
Intervention Description
Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.
Intervention Type
Behavioral
Intervention Name(s)
Computer-based Cognitive Training
Intervention Description
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.
Primary Outcome Measure Information:
Title
Montgomery Asberg Depression Scale
Description
Clinician-rated depression (range: 0-60; higher scores = worse outcome)
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
Executive-salience network functional connectivity
Description
fMRI measure (beta weights where larger beta weight = stronger connectivity
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
Implicit self-representations
Description
Implicit Association Test "D-score" (performance-based measure; range = -inf-inf; high score=worse outcome)
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
Cognitive Flexibility
Description
Neurocognitive testing via NIH Toolbox DCCS fully-corrected T-scores (range = 0-100; high score=better outcome)
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
Quick Inventory of Depressive Symptoms
Description
Self-reported depression (range: 0-27; higher scores = worse outcome)
Time Frame
Trajectories from Day 30 through 12 months post-infusion (naturalistic follow-up)
Secondary Outcome Measure Information:
Title
Neural activation and connectivity patterns
Description
MRI measures in prefrontal cortex, hippocampus, amygdala (range: -inf-inf; high score=greater connectivity)
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
Affective flexibility/inhibition
Description
Neurocognitive testing via Affective Go/No-Go task (range: -inf-inf; high score=better performance)
Time Frame
Trajectories from 24 hours through Day 30 post-infusion
Title
PROMIS measures-depression
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported depression T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-anxiety
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anxiety T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-anger
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported anger T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-positive affect
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported positive affect/well-being T-score range: 0-100 (higher score = better outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-sleep disturbance
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported sleep disturbance T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-cognitive function
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported cognitive function T-score range: 0-100 (higher score = better outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-substance use
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported substance use T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
PROMIS measures-alcohol
Description
Patient-Reported Outcomes Measurement Information System (PROMIS) measure: Self-reported alcohol use T-score range: 0-100 (higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
Cognitive Triad Inventory
Description
Negative perceptions of self, future, & world (range=12-84; higher score = better outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
Columbia-Suicide Severity Rating Scale
Description
Suicidality and patient safety (most severe ideation score, range=0-5; higher score = worse outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
WHO Disability Assessment Scale (SR)
Description
Global functioning (range=0-48; higher score = better outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
Cognitive Flexibility Scale
Description
Self-reported cognitive flexibility (range=12-72; higher score = better outcome)
Time Frame
Trajectories from 24 hours through Month 12 post-infusion
Title
Neuroplasticity-related markers in blood
Description
ketamine, ketamine metabolites, BDNF, inflammatory markers (range=0-inf; higher score = greater concentration in blood)
Time Frame
Trajectories from 40min through Day 5 post-infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Facility Information:
Facility Name
Western Psychiatric Institute and Clinic
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
We will comply with all NIMH guidelines regarding data repository/sharing.
IPD Sharing Time Frame
We will comply with all NIMH guidelines regarding data repository/sharing.
Citations:
PubMed Identifier
33271040
Citation
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.
Results Reference
derived

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Intravenous Ketamine Plus Neurocognitive Training for Depression

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