Clinical TrialTreatment-Resistant Depression (TRD)KetamineKetaminePlaceboCompleted

Intravenous Ketamine Plus Neurocognitive Training for Depression

Randomized, parallel-group study (n=154 actual) testing intravenous subanesthetic ketamine with or without adjunctive computer-based cognitive training for treatment-resistant depression; mechanistic outcomes (fMRI, IAT, cognitive flexibility) and clinical outcomes (MADRS acute; QIDS over 12-month follow-up).

Target Enrollment
154 participants
Study Type
Phase I/II interventional
Design
Randomized, quadruple Blind

Detailed Description

This randomized, quadruple-masked, parallel-group trial examines whether pairing subanesthetic intravenous ketamine with computer-based cognitive training extends antidepressant effects compared with ketamine with sham training and saline with training.

Aim 1 focuses on mechanistic outcomes (fMRI functional connectivity, Implicit Association Test, cognitive flexibility), and Aim 2 assesses clinical efficacy with MADRS during the acute 30-day phase and QIDS across a 12-month naturalistic follow-up.

Study Protocol

Preparation

sessions

Dosing

sessions

Integration

sessions

Therapeutic Protocol

Manualized psychotherapy included

Study Arms & Interventions

Ketamine + Cognitive Training

experimental

IV subanesthetic ketamine combined with computer-based cognitive training delivered post-infusion.

Interventions

  • Ketamine
    via IV• as per protocol

    Subanesthetic intravenous ketamine infusion (dose per protocol).

  • Compound
    via Other• multiple sessions

    Computer-based cognitive training delivered following infusion.

Ketamine + Sham Training

active comparator

IV ketamine with sham cognitive training comparator.

Interventions

  • Ketamine
    via IV• as per protocol

    Subanesthetic intravenous ketamine infusion (dose per protocol).

  • Compound
    via Other• multiple sessions

    Sham computer-based training.

Saline + Cognitive Training

inactive

IV saline placebo with computer-based cognitive training.

Interventions

  • Placebo
    via IV• as per protocol

    Intravenous saline placebo.

  • Compound
    via Other• multiple sessions

    Computer-based cognitive training delivered following infusion.

Participants

Ages
18 – 60
Sexes
Male & Female

Inclusion 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

  • 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 mu-opioid 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

Primary Results(4 publications)

Participants

N = 154Mean age: 33.5–34.7 across armsB. et al. 2022 →
N = 154Mean age: 34.3 across armsR. et al. 2023 →
N = 31J. et al. 2023 →
N = 193Mean age: 33–34 across armsJ. et al. 2024 →

Response Rates

≥50% reduction from preinfusion MADRS baseline score

28/53(52.8%)·B. et al. 2022 →
13/51(25.5%)·B. et al. 2022 →

MADRS score ≤9 (remission)

15/53(28.3%)·B. et al. 2022 →
2/51(3.9%)·B. et al. 2022 →

Adverse Events (from all publications)

Arm / GroupnAny TEAESevereSeriousDiscont.
Ketamine + Cognitive Trainingexperimental53———1(1.9%)
Ketamine + Sham Trainingactive_comparator50———0(0.0%)
Saline + Cognitive Traininginactive51———2(3.9%)
Ketamine + Cognitive Trainingexperimental53————
Ketamine + Sham Trainingactive_comparator50————
Saline + Cognitive Traininginactive51————
Ketamine + Cognitive Trainingexperimental—————
Ketamine + Sham Trainingactive_comparator—————
Saline + Cognitive Traininginactive—————
Ketamine + Cognitive Trainingexperimental40————
Ketamine + Sham Trainingactive_comparator37————
Saline + Cognitive Traininginactive39————

* 1 participant withdrew due to scheduling and travel constraints (per CONSORT diagram). Safety data details are in the online supplement (Table S2).

* One patient in this arm had an infusion discontinued after ~2/3 dose at patient request, but this is not explicitly categorized as a TEAE discontinuation in the summary text.

* 2 participants withdrew: 1 to pursue open label/community ketamine treatment and 1 due to scheduling/travel constraints; 1 participant was withdrawn due to repeated nonadherence (per CONSORT diagram).

* No summary safety data (TEAEs, SAEs, discontinuations due to AEs) were reported for this arm.

* The n=40 represents the subset included in current analyses after excluding 13 participants who completed infusion prior to addition of AWE measure. Safety data (TEAEs) not explicitly summarized in the provided text/tables.

* The n=37 represents the intent-to-treat subset for the ketamine+sham ASAT group. Safety data (TEAEs) not explicitly summarized in the provided text/tables.

* The n=39 represents the intent-to-treat subset for the saline group. Safety data (TEAEs) not explicitly summarized in the provided text/tables.

Study Details

Locations

Western Psychiatric Institute and Clinic — Pittsburgh, Pennsylvania, United States

Related Publications

A Novel, Brief, Fully Automated Intervention to Extend the Antidepressant Effect of a Single Ketamine Infusion: A Randomized Clinical Trial

Published
Authors
Price, R. B., Spotts, C., Panny, B., Griffo, A., Degutis, M., Cruz, N., Bell, E., Do-Nguyen, K., Wallace, M. L., Mathew, S. J., Howland, R. H.

One-Year Outcomes Following Intravenous Ketamine Plus Digital Training Among Patients with Treatment-Resistant Depression

Published
Authors
Price, R., Wallace, M. L., Mathew, S. J., Howland, R. H.

Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression

Published
Authors
Kopelman, J., Keller, T. A., Panny, B., Griffo, A., Degutis, M., Spotts, C., Cruz, N., Bell, E., Do-Nguyen, K., Wallace, M. L., Mathew, S. J., Howland, R. H., Price, R. B.

Experiences of Awe Mediate Ketamine's Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression

Published
Authors
Aepfelbacher, J., Panny, B., Price, R.

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