Intravenous Ketamine Plus Neurocognitive Training for Depression

Depression Clinical Trial

Official title:

Testing a Synergistic, Neuroplasticity-Based Intervention for Depressive Neurocognition

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03237286
• Other study ID #: STUDY19040414
• Secondary ID: 1R01MH113857
• Status: Completed
• Phase: Phase 1/Phase 2
• Start date: December 1, 2017
• Est. completion date: October 18, 2022

Study information

• Verified date: February 2024
• Source: University of Pittsburgh
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 154
• Est. completion date: October 18, 2022
• Est. primary completion date: October 18, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

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

Related Conditions & MeSH terms

• Depression
• Depressive Disorder

Intervention

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.

Locations

Country	Name	City	State
United States	Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania

Sponsors (2)

Lead Sponsor	Collaborator
Rebecca Price	National Institute of Mental Health (NIMH)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Neuroplasticity-related Markers in Blood	ketamine metabolite (2R,6R)-HNK concentration levels (range=0-inf; higher score = greater concentration in blood)	40min post-infusion