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

Study Details

Locations

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

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