Ketamine Treatment for PTSD and MDD in TBI

• IV ketamine (Drug): Subjects will receive a single infusion of racemic ketamine at 0.5mg/kg for 40 minutes twice a week for 3 weeks.
• Midazolam (Drug): Subjects will receive a single infusion of midazolam at 0.045mg/kg for 40 minutes twice a week for 3 weeks.

Primary outcomes

• Change in Severity of Depressive Symptoms [3 weeks]: Total score on the Montgomery- Åsberg Depression Rating Scale , a semi- structured 10-item scale. Range 0-60. Higher values represent worse outcomes. The total score is obtained by summing the severity score of each item.

Secondary outcomes

• Change in Severity of Post-traumatic Stress Disorder (PTSD) Symptoms [3 weeks]: Total score on the PTSD Checklist for DSM-5 (PCL-5), a 20-item self-report measure that assesses the 20 DSM-5 symptoms of PTSD. The total score is obtained by summing the score of each item.

Sex: All, ages: 18 Years to 75 Years

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)