Intravenous Ketamine Plus Neurocognitive Training for Depression

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.

• Intravenous ketamine (Drug): Intravenous ketamine is given at a subanesthetic dose, which previous research suggests is safe and efficacious for rapid relief from depression.
• Computer-based Cognitive Training (Behavioral): 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 outcomes

• 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)
• 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)
• 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)
• 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)
• 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 outcomes

• 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-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-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-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-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)

Sex: All, ages: 18 Years to 60 Years

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

Participant flow

Outcome results

• Montgomery Asberg Depression Scale (Primary), Mean, score on a scale: Ketamine + Cognitive Training 19.72 +/- 10.20; Ketamine + Sham Training 22.87 +/- 11.63; Saline + Cognitive Training 23.51 +/- 9.66 (p .0004)
• Executive-salience Network Functional Connectivity (Primary), Mean, beta weights: Ketamine + Cognitive Training 0.55 +/- 0.11; Ketamine + Sham Training 0.59 +/- 0.11; Saline + Cognitive Training 0.57 +/- 0.10
• Implicit Self-representations (Primary), Mean, factor score: Ketamine + Cognitive Training -.16 +/- 1.00; Ketamine + Sham Training 0.15 +/- 1.03; Saline + Cognitive Training 0.03 +/- 0.97
• Cognitive Flexibility (Primary), Mean, score on a scale: Ketamine + Cognitive Training 54.51 +/- 13.33; Ketamine + Sham Training 49.34 +/- 12.48; Saline + Cognitive Training 53.25 +/- 12.98
• Quick Inventory of Depressive Symptoms (Primary), Mean, score on a scale: Ketamine + Cognitive Training 10.77 +/- 6.84; Ketamine + Sham Training 12.03 +/- 5.94; Saline + Cognitive Training 10.42 +/- 4.38
• Executive-salience Network Functional Connectivity During Resting State (Secondary), Mean, beta weights: Ketamine + Cognitive Training 0.53 +/- 0.10; Ketamine + Sham Training 0.50 +/- 0.09; Saline + Cognitive Training 0.51 +/- 0.12
• Affective Flexibility (Secondary), Mean, Z-score: Ketamine + Cognitive Training -.18 +/- 1.71; Ketamine + Sham Training -.07 +/- 1.52; Saline + Cognitive Training 0.26 +/- 1.62
• PROMIS Measures-depression (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 58.97 +/- 12.15; Ketamine + Sham Training 61.01 +/- 9.54; Saline + Cognitive Training 57.13 +/- 9.57
• PROMIS Measures-anxiety (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 58.07 +/- 9.42; Ketamine + Sham Training 62.49 +/- 9.26; Saline + Cognitive Training 57.88 +/- 8.87
• PROMIS Measures-anger (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 50.27 +/- 13.03; Ketamine + Sham Training 54.21 +/- 10.44; Saline + Cognitive Training 49.59 +/- 10.23
• PROMIS Measures-positive Affect (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 44.12 +/- 7.72; Ketamine + Sham Training 44.02 +/- 7.76; Saline + Cognitive Training 45.98 +/- 7.60
• PROMIS Measures-sleep Disturbance (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 53.06 +/- 9.91; Ketamine + Sham Training 53.78 +/- 8.63; Saline + Cognitive Training 51.41 +/- 10.29
• PROMIS Measures-cognitive Function (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 43.61 +/- 9.54; Ketamine + Sham Training 39.19 +/- 8.07; Saline + Cognitive Training 44.87 +/- 8.81
• PROMIS Measures-substance Use (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 3.00 +/- 5.22; Ketamine + Sham Training 2.32 +/- 5.09; Saline + Cognitive Training 3.03 +/- 5.94
• PROMIS Measures-alcohol (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 46.29 +/- 8.56; Ketamine + Sham Training 47.82 +/- 5.35; Saline + Cognitive Training 47.25 +/- 7.04
• Cognitive Triad Inventory (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 133.89 +/- 35.15; Ketamine + Sham Training 126.00 +/- 39.02; Saline + Cognitive Training 138.97 +/- 28.50
• Columbia-Suicide Severity Rating Scale (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 0.70 +/- 1.14; Ketamine + Sham Training 1.30 +/- 1.24; Saline + Cognitive Training 1.10 +/- 1.29
• WHO Disability Assessment Scale (SR) (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 10.58 +/- 9.28; Ketamine + Sham Training 15.75 +/- 10.87; Saline + Cognitive Training 12.64 +/- 10.72
• Cognitive Flexibility Scale (Secondary), Mean, score on a scale: Ketamine + Cognitive Training 52.64 +/- 8.82; Ketamine + Sham Training 50.82 +/- 10.81; Saline + Cognitive Training 51.20 +/- 10.46
• Neuroplasticity-related Markers in Blood (Secondary), Mean, ng/mL: Ketamine + Cognitive Training 26.94 +/- 11.59; Ketamine + Sham Training 27.35 +/- 11.76

Adverse events

Time frame: 4 hours

Other adverse events by term

• Results publication: Hossein S, Woody ML, Panny B, Spotts C, Wallace ML, Mathew SJ, Howland RH, Price RB. Functional connectivity subtypes during a positive mood induction: Predicting clinical response in a randomized controlled trial of ketamine for treatment-resistant depression. J Psychopathol Clin Sci. 2025 Apr;134(3):228-238. doi: 10.1037/abn0000951. Epub 2024 Sep 23. PMID 39311825
• Results publication: Price RB, Wallace ML, Mathew SJ, Howland RH. One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression: A Secondary Analysis of a Randomized Clinical Trial. JAMA Netw Open. 2023 May 1;6(5):e2312434. doi: 10.1001/jamanetworkopen.2023.12434. PMID 37155171
• Results publication: 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. PMID 33271040

• Study Protocol and Statistical Analysis Plan (PDF, 2020-08-07)

NIH grants: R01MH113857