Substance P Antagonist in the Treatment of Posttraumatic Stress Disorder

Posttraumatic Stress Disorder (PTSD) is a common chronic anxiety disorder that is often
debilitating and follows exposure to an overwhelming traumatic event. The burden of PTSD on
individuals and society is significant. The majority of PTSD sufferers also meet the
diagnostic criteria for several other psychiatric disorders and many attempt suicide. Despite
the devastating impact of PTSD on the lives of millions worldwide, little is known about the
etiology or pathophysiology of this disorder. Although disruptions in the
hypothalamic-pituitary adrenal (HPA) Axis, noradrenergic, serotonergic systems have been
proposed as neurobiological substrates in the development of PTSD, the exact underpinnings of
the neurobiology of PTSD remain to be fully elucidated.

PTSD is responsive to treatment with selective serotonin reuptake inhibitors, but response
rates rarely exceed 60%, and even fewer patients (20%-30%) experience improvement that could
be characterized as remission. Thus, there is a clear need to develop novel and improved
therapeutics for PTSD. A growing body of preclinical evidence suggests that activation of the
Substance P (SP) and its receptor NK1 is anxiogenic and that NK1 antagonists, upon chronic
administration, exert significant dampening (albeit complex) effects on the SP-NP system.
Furthermore, several stress paradigms are believed to exert many of their deleterious effects
on hippocampal structures via enhancement of SP-NK1 system. Overall, excess activity of the
SP-NK1 system stands as a prime candidate for involvement in the pathophysiology of anxiety
disorders such as PTSD.

In this study, we propose to investigate the potential antianxiety efficacy of the highly
specific NK1 antagonist GR205171 in PTSD. Furthermore, we propose to, in a preliminary
fashion, longitudinally investigate whether neuroendocrine surrogate markers are predictive
of treatment response.

This is an 8-week double-blind placebo-controlled study that will examine the efficacy and
safety of an NK1 antagonist in patients with PTSD.

Patients, ages 18 to 65 years with a diagnosis of PTSD, will in this pilot study be
randomized to double-blind treatment to receive either the NK1 antagonist, GR205171 (5
mg/day) or placebo for a period of 8 weeks.

Approximately 52 patients will enter the study to obtain 40 subjects who complete the 8 weeks
of acute NK1 antagonist treatment.

- INCLUSION CRITERIA:

Subjects may be included in the study only if they meet all of the following criteria:

1. Male or female subjects, 18 to 65 years.

2. Female subjects of childbearing potential must be using a medically accepted means of
contraception.

3. Each subject must have a level of understanding sufficient to agree to all required
tests and examinations and sign an informed consent document.

4. A negative urine toxicology.

5. Subjects must fulfill the criteria for PTSD as defined in DSM-IV (309.81), which
should be the primary diagnosis. Diagnoses are based on clinical assessment and
confirmed by structured diagnostic interview SCID-P.

6. Duration of illness of PTSD for at least 3 months.

7. Subjects must have an initial score at Visit 1 and Visit 2 of at least 50 on the CAPS
for PTSD Studies.

8. Subjects must not have a decrease in the total score of CAPS of greater than 25%
during washout (between Visits 1 and 2).

EXCLUSION CRITERIA:

Subjects will be excluded from the study for any of the following reasons:

1. Presence of psychotic features.

2. Participation in a clinical trial of another investigational drug within 1 month (30
days) prior to study entry (Visit 1).

3. Female subjects who are either pregnant or nursing.

4. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory,
cardiovascular (including ischemic heart disease), endocrinologic, neurologic,
immunologic, or hematologic disease.

5. Subjects with uncorrected hypothyroidism or hyperthyroidism.

6. Previous treatment with NK1 receptor antagonist.

7. DSM-IV substance abuse or dependence within the past 90 days.

8. Treatment with an injectable depot neuroleptic within less than one dosing interval
between depot neuroleptic injections prior to Visit 2.

9. Treatment with a reversible MAOI, guanethidine, or guanadrel within 1 week or with
fluoxetine within 6 weeks prior to Visit 2.

10. Treatment with any other concomitant medication with primarily CNS activity.

11. Treatment with clozapine or ECT within 12 weeks prior to Visit 2.

12. Current diagnosis of schizophrenia or other psychotic disorder, bipolar disorder,
other Axis I disorder (except for major depressive disorder, dysthymia and other
anxiety disorders that followed exposure to the trauma) as defined in the DSM-IV.

13. Patients who are currently at high risk for homicide or suicide, a score greater than
4 on item 10 of the MADRS.

14. Current or planned litigation regarding the traumatic event.

Patients will not be allowed to receive structured psychotherapy during the trial.