Intensive 7-day Treatment for PTSD Combining Ketamine With Exposure Therapy

Based on the current research findings on the therapeutic effectiveness of trauma focus
psychotherapy and of ketamine, combining the two treatments may yield a promising new rapid
7-day treatment for PTSD. As PTSD symptoms' structure is comprised of several unique clusters
which include re-experiencing, avoidance, numbing/depression and hypervigilance the
investigators hypothesize that by combining Ketamine with prolonged exposure (PE) the
investigators can address these symptoms clusters more effectively. This treatment has the
potential to produce a significant therapeutic effect that otherwise would take months to
occur by tapping on the enhanced neuroplasticity and the antidepressant effect of ketamine
(which lasts between 24hrs to 7 days), to promote rapid changes in learning and memory using
prolonged exposure therapy within this unique "window of opportunity".

During the first visit participants will undergo a clinical interview to establish a PTSD
diagnosis and other eligibility criteria. If found eligible participants will be invited to
take part in this 7-day rapid treatment trial for PTSD.

On the first therapy visits, participants will be educated about the psychological treatment
that will be provided and the potential benefit of ketamine to enhance the psychotherapy
outcomes.

On the second day of the study, participants will receive an infusion of ketamine and will
undergo an magnetic resonance imaging (MRI) scan and will receive the second psychotherapy
session.

On days 3-6 participants will attend a 60-90 minutes psychotherapy session to address their
PTSD symptoms.

Day 7 will include another MRI scan and the last psychotherapy session.

Participants will be asked to come back for a follow up evaluation of their PTSD symptoms 30
and 90 days post discharge.

Inclusion Criteria:

- Male or female between the ages of 21-55 years. This age range was chosen to fit with
prior samples in which no adverse effects of ketamine have been observed. Adults in
the 18-20 ranges have been eliminated because previous experience indicates that they
often lack the maturity to participate effectively in similar protocols. Females will
be included if they are not pregnant and agreed to utilize a medically accepted birth
control method (to include oral, injectable, or implant birth control, condom,
diaphragm with spermicide, intrauterine device, tubal ligation, abstinence, or partner
with vasectomy) or if post-menopausal for at least 1 year, or surgically sterile.

- Able to provide written informed consent according to Yale HIC guidelines.

- Able to read and write English as a primary language.

- Diagnosis of PTSD, as determined by the Clinician Administered PTSD Scale (CAPS-5)
(Weathers et al., 2013).

- Must have a score of 50 or higher on the Clinician-Administered PTSD Scale (CAPS-5) at
screening.

- No more than mild Traumatic Brain Injury (TBI) according to a modified version of the
Brief TBI Screen (Schwab, et al., 2006).

- Must not have a medical/neurological problem or use medication that would render
ketamine unsafe by history or medical evaluation.

Exclusion Criteria:

- Patients with a diagnostic history of bipolar disorder, schizophrenia or
schizoaffective disorder or currently exhibiting psychotic features as determined by
the Structured Clinical Interview for DSM (SCID) (First, et al. 2010); dementia or
suspicion thereof, are excluded. Other DSM Axis I disorders are permitted as long as
they are not considered primary disorders.

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

- Serious suicide or homicide risk, as assessed by evaluating clinician; A serious
suicide risk will be considered an inability to control suicide attempts, imminent
risk of suicide in the investigator's judgment, or a history of serious suicidal
behavior, which is defined using the Columbia-Suicide Severity Rating Scale (C-SSRS)
(Posner et al., 2011) as either (1) one or more actual suicide attempts in the 3 years
before study entry with the lethality rated at 3 or higher, or (2) one or more
interrupted suicide attempts with a potential lethality judged to result in serious
injury or death.

- Substance abuse or dependence during the 6 months prior to screening as determined by
the Structured Clinical Interview for DSM (SCID).

- Any significant history of serious medical or neurological illness.

- Any signs of major medical or neurological illness on examination or as a result of
electrocardiogram (ECG) screening or laboratory studies.

- Lifetime history of psychoactive substance or alcohol dependence or substance or
alcohol abuse (other than nicotine or caffeine abuse), or drinking more than 5
drinks/week during the last year.

- Abnormality on physical examination. A subject with a clinical abnormality may be
included only if the study physician considers the abnormality will not introduce
additional risk factors and will not interfere with the study procedure.

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

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

- Positive HIV or Hepatitis B tests. This test will take place at the screening visit.
Subjects will be invited back to the Yale Depression Research Program either for their
next study visit or for a HIV/Hep debriefing session. A study physician will inform
them in person of the results. They will be given access to counselling and advised of
the appropriate next steps.

- Has received either prescribed or over-the-counter (OTC) centrally active medicine or
herbal supplements within 60 days of enrollment into the study. Subjects who have
taken OTC medication or herbal supplements may still be entered into the study, if, in
the opinion of the principal/co-investigator, the medication received will not
interfere with the study procedures or compromise safety.

- Any history indicating learning disability, mental retardation, or attention deficit
disorder.

- Known sensitivity to ketamine.

- Body circumference of 52 inches or greater.

- Body weight of 250 pounds or greater.

- History of claustrophobia.

- Presence of cardiac pacemaker or other electronic device or ferromagnetic metal
foreign bodies in vulnerable positions as assessed by a standard pre-MRI screening
questionnaire.

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

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