Ketamine as a Rapid Treatment for Post-traumatic Stress Disorder (PTSD)

PTSD is a debilitating anxiety disorder characterized by intrusive re-experiences of the
traumatic events, avoidance of situations and stimuli that could serve as reminders of these
events, and feeling jumpy or easily startled. Patients with PTSD are often also depressed,
and many have significant memory impairments. Existing drug treatments are unsuccessful in a
majority of patients, especially in those with combat-related PTSD.

Our aim is to test the effectiveness of a potential new drug for PTSD, ketamine. For many
years, intravenous ketamine has been extensively used for anesthesia. More recently, using
doses lower than those used in anesthesia, a single ketamine infusion was shown to rapidly
reduce depressed mood as well as anxiety in patients with severe depression. Some clinical
evidence of potential efficacy in depressed patients with co-morbid PTSD also exists.

Adverse effects in these studies have been limited to feeling intoxicated and having
increased blood pressure during the infusion.

In the present study, we expect a single ketamine infusion to reduce core PTSD symptoms. In
addition, in those patients with PTSD who are depressed, we expect ketamine to reduce
depressed mood.

Finally, ketamine is known to impair memory function temporarily. We will also test if the
extent of ketamine-induced memory impairment during the infusion can predict how well people
do after the infusion. Forty patients with PTSD (with and without combat-related trauma
histories) will be tested, using a design that will compare the effectiveness of intravenous
ketamine to that of midazolam, another anesthetic drug without any known long-term effects on
anxiety, depressed mood, and memory function. If ketamine is found to have the expected
effects, future studies may explore additional benefits of repeated infusions and / or
alternatives to intravenous drug administration. Our study may contribute to improved
function of patients with PTSD by providing a new means to rapidly treat their debilitating
symptoms.

Inclusion Criteria:

- Men or women, 21-55 years of age;

- Participants must have a level of understanding sufficient to agree to all tests and
examinations required by the protocol and must sign a written informed consent
document;

- Participants must fulfill DSM-IV criteria for current civilian or combat-related PTSD,
based on clinical assessment by a study psychiatrist and on the CAPS (score must be at
least 50 at screening and prior to each infusion - this is done to ensure at least
moderate severity and to safeguard against high placebo response rates); additionally,
clinicians will use clinical judgment to assess if patients are symptomatic enough to
receive each infusion

- Women must be using a medically accepted reliable means of contraception (if using an
oral contraceptive medication, they must also be using a barrier contraceptive) or not
be of childbearing potential (i.e., surgically sterile, postmenopausal for at least
one year);

- Women of childbearing potential must have a negative pregnancy test at screening and
pre-infusion;

- Participants must be able to identify a family member, physician, or friend (i.e.
someone who knows them well) who will participate in a Treatment Contract (and e.g.
contact the study physician on their behalf in case manic symptoms or suicidal
thoughts develop).

Exclusion Criteria:

- Women who plan to become pregnant, are pregnant or are breast-feeding (because the
medical risk of using ketamine during pregnancy and breast-feeding is unknown);

- Serious, unstable medical illnesses such as hepatic, renal, gastroenterologic,
respiratory, cardiovascular, endocrinologic, neurologic, immunologic, or hematologic
disease (including gastro-esophageal reflux disease, obstructive sleep apnea, history
of difficulty with airway management during previous anesthetics, ischemic heart
disease and uncontrolled hypertension, and history of severe head injury);

- Clinically significant abnormal findings of laboratory parameters, physical
examination, or ECG;

- Patients with uncorrected hypothyroidism or hyperthyroidism;

- Hormonal treatment (e.g., estrogen) started in the 3 months prior to the first
infusion day;

- Use of evidence-based individual psychotherapy (such as prolonged exposure) and other
non-pharmacological treatments during the study;

- Histories of autism, mental retardation, pervasive developmental disorders, or
Tourette's syndrome;

- History of one or more seizures without a clear and resolved etiology;

- History of (hypo)mania;

- Past or current presence of psychotic symptoms, or diagnosis of a lifetime psychotic
disorder including schizophrenia or schizoaffective disorder;

- Drug or alcohol abuse or dependence within the preceding 3 months (given that this
might otherwise contribute to their symptoms, however, a rather narrow time period was
chosen such as to allow participation by individuals with a history of substance abuse
or dependence problems that could be secondary to their PTSD, and to more closely
approximate patients seen in real-world settings);

- Previous recreational use of ketamine or PCP;

- Current diagnosis of bulimia nervosa or anorexia nervosa;

- Diagnosis of schizotypal or antisocial personality disorder (since these are known to
reduce the possibility of study completion; other Axis II diagnoses will be allowed);

- Patients judged clinically to be at serious and imminent suicidal or homicidal risk.

- A blood pressure of one reading over 160/90 or two separate readings over 140/90 at
screen or baseline visits.