Ketamine Treatment for PTSD and MDD in TBI
Randomised, quadruple-blind, parallel Phase II trial (n=40) comparing IV ketamine 0.5 mg/kg vs midazolam 0.045 mg/kg twice weekly for 3 weeks in Veterans with mild–moderate TBI and comorbid PTSD and MDD to evaluate efficacy and safety.
Detailed Description
This parallel, randomised, quadruple-blind Phase II study will compare racemic IV ketamine 0.5 mg/kg to active comparator midazolam 0.045 mg/kg administered twice weekly for three weeks (six 40-minute infusions) in Veterans with chronic mild–moderate traumatic brain injury and comorbid PTSD and major depressive disorder.
Outcomes include change in PTSD and depression symptom scales, safety and tolerability in the TBI population, laboratory tests, interviews, and standard questionnaires assessed during treatment and follow-up.
Study Protocol
Preparation
Dosing
Integration
Study Arms & Interventions
Ketamine
experimentalIV ketamine 0.5 mg/kg twice weekly for 3 weeks (6 infusions).
Interventions
- Ketamine0.5 mg/kgvia IV• twice weekly• 6 doses total
Infusion over 40 minutes
Midazolam
active comparatorIV midazolam 0.045 mg/kg twice weekly for 3 weeks (6 infusions).
Interventions
- Placebo0.045 mg/kgvia IV• twice weekly• 6 doses total
Midazolam 0.045 mg/kg IV infusion over 40 minutes (active comparator)
Participants
Inclusion Criteria
- Inclusion Criteria:
- Willingness/able to sign informed consent.
- Able to read and write in English.
- Male or female Veterans aged 18-55 years old.
- Remote history of mild–moderate TBI ≥12 weeks post-injury meeting 2021 VA/DoD guideline criteria (e.g., loss/decreased consciousness, post-traumatic amnesia, dazed/confused period, neurologic deficits).
- Lifetime history of treatment resistance to at least one adequate antidepressant trial (MGH-ATRQ).
- On stable FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin, or clonidine for ≥4 weeks prior to randomization (dose changes after randomization may be allowable per investigator).
Exclusion Criteria
- Exclusion Criteria:
- Ketamine treatment within the last 6 months.
- Lifetime history of psychosis-related disorder; current episode of mania/hypomania/mixed (MINI 7.0 for DSM-5).
- History of penetrating head wounds or severe TBI (Glasgow Coma Scale <9; loss of consciousness >24 hr; post-traumatic amnesia >7 days).
- Severe substance and/or alcohol use disorder within 6 months; positive urine toxicology for illicit drugs (except cannabis) at screening.
- Intellectual disability, pervasive developmental disorder, or dementia.
- Any disorder that increases risk (e.g., unstable cardiac conditions) or impairs protocol adherence (e.g., severe personality disorder) per PI judgement.
- For women: pregnancy, initiation of female hormonal treatments within 3 months, or inability/unwillingness to use accepted contraception (surgically sterile or post-menopausal ≥1 year not excluded).
- Screening vitals outside limits: resting BP <90/60 or >150/90 mmHg, HR <45 or >100 bpm.
- Imminent risk of suicidal/homicidal ideation and/or behaviour with intent and/or plan.
- Concurrent participation in a cognitive rehabilitation programme (TBI clinician involvement allowed).
- Prohibited medications: MAOIs, memantine, long-acting benzodiazepines (e.g., chlordiazepoxide, diazepam, flurazepam).