Enhancing Week-long Psychological Treatment for PTSD With Ketamine

Inclusion Criteria:

• Male or female between the ages of 21-70 years. This age range was chosen to fitwith prior samples in which no adverse effects of ketamine have been observed.Adults in the 18-20 ranges have been eliminated because previous experienceindicates that they often lack the maturity to participate effectively in similarprotocols. Females will be included if they are not pregnant and agreed to utilize amedically accepted birth control method (to include oral, injectable, or implantbirth control, condom, diaphragm with spermicide, intrauterine device, tuballigation, abstinence, or partner with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.

• Must not have a medical/neurological problem or use medication that would renderketamine unsafe by history or medical evaluation.

• Diagnosis of chronic PTSD with a score of 25 or higher (i.e. severe PTSD) on theClinician-Administered PTSD Scale (CAPS-5) at screening. PTSD symptoms must havepersisted for >1 year post-trauma exposure to meet the DSM-5 definition of chronic.

• Subjects on FDA-approved antidepressant, trazodone, atypical neuroleptic, prazosin,or clonidine may enter the study if they have been on a stable treatment, asdetermined by the study clinician, for at least 4 weeks prior to randomization.Following randomization, small changes to doses may be allowable at the PI'sdiscretion.

• Able to provide written informed consent.

• Able to read and write English.

Exclusion Criteria:

• Patients with a diagnostic history of borderline personality disorder, obsessivecompulsive disorder, schizophrenia or schizoaffective disorder or currentlyexhibiting psychotic features as determined by the Structured Clinical Interview forDSM (SCID); dementia or suspicion thereof, are excluded. Patients with history ofbipolar disorder will be included only if they have not experienced a manic orhypomanic episode in the 30 days prior to enrollment. Other DSM Axis I disorders arepermitted as long as they are not considered primary disorders.

• Patients with a history of antidepressant-induced hypomania or mania as determinedby open-ended psychiatric interview.

• Current, ongoing serious suicidal risk as assessed by evaluating investigator basedon the Columbia-Suicide Severity Rating Scale (C-SSRS).

• Moderate severity or greater Substance Use Disorder (excepting Alcohol and MarijuanaUse Disorder) during the 3 months prior to randomization, as determined by theSCID.Alcohol or Marijuana Use Disorder may be allowed based on the judgment of studyphysician/APRN/clinician that patients can remain sober for all study visits.

• Subjects on a prohibited medication (see Table 1). Patients will not be taken offmedication for the purpose of this study.

• History of traumatic brain injury (TBI) with loss of consciousness for more than 24hours or posttraumatic amnesia for more than 7 days may be considered if the traumaoccurred more than 1 year ago, and no more than minimal symptoms have persisted overthe past year.

• Positive pregnancy test at screening or prior to any study drug infusion.

• Breathalyzer showing an alcohol level > 0% at screening, or at the discretion of theinvestigator, prior to any study drug infusion.

• Resting blood pressure lower than 90/60 or higher than 150/90, or resting heart ratelower than 45/min or higher than 100/min.

• Any significant history of serious medical or neurological illness.

• Any signs of major medical or neurological illness on examination or as a result ofECG screening or laboratory studies.

• Abnormality on physical examination. A subject with a clinical abnormality may beincluded only if the study physician considers the abnormality will not introduceadditional risk factors and will not interfere with the study procedure.

• A positive pre-study (screening) urine drug screen or, at the study physician'sdiscretion on any drug screens given before the scans.

• Pregnant or lactating women or a positive urine pregnancy test for women ofchild-bearing potential at screening or prior to any imaging day.

• Any history indicating learning disability or mental retardation.

• Known sensitivity to ketamine.

• Body circumference of 52 inches or greater.

• Body weight of 350 pounds or greater.

• History of claustrophobia.

• Presence of cardiac pacemaker or other electronic device or ferromagnetic metalforeign bodies in vulnerable positions as assessed by a standard pre-MRI screeningquestionnaire.

• Donation of blood in excess of 500 mL within 56 days prior to dosing.

• History of sensitivity to heparin or heparin-induced thrombocytopenia.

• Active engagement in trauma-focused CBT (TF cognitive-behavioral therapy) or anyevidence-based PTSD psychotherapy (CPT, PE, EMDR) initiated within the past 3 months (continuation of established maintenance supportive therapy will be permitted

• Enrollment in another research study testing an experimental/clinical/behavioralintervention intended to affect symptoms initiated within the last 2 months, orintended enrollment within the next 3 months

Table 1. Concomitant Treatments that are prohibited

MAOIs: 4-weeks off medication prior to randomization is required.

Memantine: 4-weeks of medication prior to randomization is required.

Long Acting Benzodiazepines -Chlordiazepoxide, Diazepam, Flurazepam: 2-weeks off medication prior to randomization is required.

Notes: As above, individuals who have used any of the prohibited medications within the "weeks off" time period will not be eligible for the study. Use of sedatives, hypnotics, benzodiazepines, sedating antihistamines or other psychotropic medications are not permitted within 8 hours of treatment sessions; except - at the discretion of the investigator - for medications that will result in discontinuation/withdrawal symptoms or that may alter the risk benefit ratio.