The goal of this clinical trial is to examine the use of sedative ketamine to treat depression and post-traumatic stress disorder (PTSD) in Veterans with mild to moderate traumatic brain injury (TBI). The main questions it aims to answer are:

• Efficacy of ketamine to reduce symptoms of depression and/or PTSD
• Safety of ketamine to treat depression and/or PTSD in TBI Participants will be randomly assigned to receive either ketamine or midazolam (active placebo) twice a week for 3 weeks. During participation, subjects will be interviewed, have lab tests, and complete rating scales, and questionnaires.

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 TBI mild-moderate that is ≥12 weeks post-injury (chronic period) that met at minimum the 2021 VA/DoD Clinical Practice Guideline for the Management and Rehabilitation of Post-Acute Mild Traumatic Brain Injury (i.e., new onset or worsening of at least one of the following clinical signs immediately following the event: loss or decreased of consciousness, period of posttraumatic amnesia, period of being dazed and confused, and neurologic deficits).
• Lifetime history of treatment resistance to at least one adequate trial of an antidepressant as determined by the Massachusetts General Hospital Antidepressant Treatment History Questionnaire (MGH-ATRQ).
• FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin, or clonidine with stable treatment, as determined by the study clinician, for at least 4 weeks prior to randomization. Following randomization, changes to doses may be allowable at the investigator's discretion

Exclusion Criteria:

• Ketamine treatment within the last 6 months

  • Lifetime history of psychosis-related disorder, current episode of mania/hypomania/mixed assessed by the Mini-International Neuropsychiatric Interview (MINI 7.0 for DSM-5).
  • History of penetrating head wounds or severe traumatic brain injury (Glasgow Coma Scale <9; loss of consciousness >24hr; post-traumatic amnesia>7 days).
  • Severe substance and/or alcohol use disorder (DSM-5-TR) within six months of initial assessment; presence of illicit drugs (except cannabis) by positive urine toxicology at screening.
  • Intellectual disability or pervasive developmental disorder; dementia of any type.
  • Any disorder that, based on the Principal Investigator's judgement, would increase risk (e.g., unstable cardiac conditions) or protocol adherence (e.g., severe personality disorder).
  • For women: pregnancy (confirmed by lab test), initiation of female hormonal treatments within 3 months of screening, or inability/ unwillingness to use a medically accepted contraceptive method during the study. Women who are surgically sterile or have been post-menopausal for at least 1 year will not be excluded
  • At screening, resting blood pressure (sitting or supine) lower than 90/60 or higher than 150/90, or resting heart rate lower than 45/min or higher than 100/min.
  • Imminent risk of suicidal/homicidal ideation and/or behavior with intent and/or plan.
  • Concurrent participation in a cognitive rehabilitation program, however patient will have a TBI clinician involved in directed services.
  • Subjects on a prohibited medication: monoamine oxidase inhibitors, memantine, long acting benzodiazepines (i.e., Chlordiazepoxide, Diazepam, Flurazepam)