Clinical TrialParallelTreatment-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).

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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

1 sessions
40 min each

Integration

0 sessions

Therapeutic Protocol

Manualized psychotherapy included

Study Arms & Interventions

Ketamine + Cognitive Training

experimental

IV ketamine (0.5 mg/kg over 40 minutes) plus active computer-based automated self-association training (ASAT), delivered twice daily for 4 days starting 24 hours after infusion.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single infusion• 1 doses total

    Subanesthetic intravenous ketamine infusion over 40 minutes.

  • Compound
    via Other• twice daily for 4 consecutive days• 8 doses total

    Active automated self-association training (ASAT), up to 20 minutes per session.

Ketamine + Sham Training

active comparator

IV ketamine (0.5 mg/kg over 40 minutes) plus sham computer-based training, delivered twice daily for 4 days starting 24 hours after infusion.

Interventions

  • Ketamine0.5 mg/kg
    via IV• single infusion• 1 doses total

    Subanesthetic intravenous ketamine infusion over 40 minutes.

  • Compound
    via Other• twice daily for 4 consecutive days• 8 doses total

    Sham computer-based training with no positive or self-referential stimuli.

Saline + Cognitive Training

inactive

IV saline placebo (50 mL 0.9% sodium chloride over 40 minutes) plus active computer-based ASAT, delivered twice daily for 4 days starting 24 hours after infusion.

Interventions

  • Placebo50 ml
    via IV• single infusion• 1 doses total

    Intravenous saline placebo over 40 minutes.

  • Compound
    via Other• twice daily for 4 consecutive days• 8 doses total

    Active automated self-association training (ASAT), up to 20 minutes per session.

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

Study Protocol, Arms & Participants

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Study Details

Locations

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

Related Publications

Open AccessindividualPrimary

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

This double-blind, placebo-controlled study (n=154) of ketamine (35mg/70kg) (or placebo) with (and without) positive self-regard training (automated self-association training) finds that the combination can extend the positive antidepressant (MADRS) effects of ketamine, whilst the effects of ketamine alone was not distinguishable from placebo 30 days later.

Published
Journal
American Journal of Psychiatry
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.
Open AccessindividualLong-term follow-up

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

This secondary analysis of a randomised clinical trial examines whether automated self‑association training prolongs the antidepressant effect of a single intravenous ketamine infusion in patients with treatment‑resistant depression, reporting outcomes over a one‑year follow‑up.

Published
Journal
JAMA Network Open
Authors
Price, R., Wallace, M. L., Mathew, S. J., Howland, R. H.
Open AccessindividualSecondary analysis

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

In a randomized trial of 98 treatment‑resistant depressed adults, a single intravenous ketamine infusion produced 24‑hour decreases in gray‑matter DTI mean diffusivity in prefrontal and limbic regions that correlated with larger improvements in depression scores, with left BA10 and left amygdala effects driven mainly by ketamine and right BA10 effects seen across groups, while hippocampal changes showed an opposite pattern on the MADRS. These findings suggest the acute antidepressant effects of ketamine are partly mediated by rapid neuroplasticity detectable with DTI.

Published
Journal
Translational Psychiatry
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.
Open AccessindividualPrimary

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

This randomised controlled trial (n=116) investigated the psychological mechanisms of ketamine's antidepressant effects. Participants receiving ketamine reported significantly heightened feelings of awe compared to those receiving a placebo. Awe experiences, as measured by the Awe Experience Scale (AWE-S), mediated depression outcomes (% improvement in MADRS scores) at multiple time points (24 hours and 5, 12, 21, and 30 days) post-infusion, indicating a potential role of awe in ketamine's therapeutic efficacy for depression.

Published
Journal
Biological Psychiatry
Authors
Aepfelbacher, J., Panny, B., Price, R.

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