Oxytocin Add-on Study for Stable Anxiety Patients

Anxious patients treated with even the best currently available anti-anxiety drugs continue
to experience significant symptoms.

A variety of basic science, animal studies, and human studies support the idea that the
neuropeptide oxytocin may be effective against anxiety in humans. For example, plasma
oxytocin levels may function as an index of central serotonin (5-HT) function in human
subjects, and serotonin is well-known to be involved in clinical anxiety disorders. Since
oxytocin is released directly from limbic-hypothalamic cells, this response presumably
represents a direct central assessment of 5-HT response in limbic-hypothalamus (Lee 2003).
In animal models, Ring 2006 examined the effects of oxytocin on both behavioral and
autonomic parameters of the anxiety response in male mice using three pharmacologically
validated preclinical models of anxiety: the four-plate test (FPT), elevated zero maze
(EZM), and stress-induced hyperthermia (SIH). The results from this study provide specific
behavioral and autonomic evidence of anxiolytic-like effects for oxytocin. In primates,
Emiliano et al 2007 found support for the idea that that SSRIs' therapeutic effects on
social affiliation and anxiety may be mediated in part through components of the oxytocin
system. Human studies include Kosfeld et al (2005), who demonstrated that oxytocin
administered intranasally to healthy human subjects in a double-blind, placebo controlled
study increased levels of trust. As well, Kirsch et al (2005) showed that intranasal
oxytocin reduced activation of brain circuits involved in fear in human subjects. Finally,
Scantamburlo (2007) showed a significant negative correlation between oxytocin and the
scored symptoms depression and anxiety. These studies clearly suggest the potential utility
of OTR agonism as a therapeutically relevant mechanism of action for novel anxiolytics in
both sexes.

Each subject will be enrolled for 6 week treatment period after a screening phase. Study
procedures involve weekly clinic visits as an outpatient. Forty patients will be randomly
assigned to either 40 International Units (IU) oxytocin twice daily or vehicle placebo.
After 3 weeks, treatments will be crossed over such that subjects that received oxytocin
will receive placebo and vice versa. The study ratio is 1:1. Dose of oxytocin is based upon
previous studies in humans showing improvement in psychiatric populations related changes in
behavior and brain function (Kosfeld et al, 2005; Kirsch 2005; Heinrich M 2003).

The total study duration for each individual subject will be approximately 7 weeks, which
includes up to 21-day screening/wash-out period, a baseline (randomization) visit, three
week treatment period, 1 week washout, baseline, and three weeks cross over treatment.

Inclusion Criteria:

1. A diagnosis of Generalized Anxiety Disorder (GAD), Social Anxiety Disorder (SAD),
Post-traumatic stress disorder, or Anxiety Disorder NOS, confirmed by a
semi-structured interview with the Structured Clinical Interview for DSM-IV Axis
Disorders-Modified-Patient Edition (SCID).

2. HAM-A total score ≥15 with Item 1 (anxious mood) and Item 2 (tension) scores ≥2 at
randomization.

3. Have a Clinical Global Impressions-Severity (CGI-S) scale score of at least 4
(moderately ill) at baseline;

4. Must be able to communicate effectively with the investigator and study coordinator
and have the ability to provide informed consent.

5. Must demonstrate an acceptable degree of compliance with medication and procedures
in the opinion of the investigator

6. Adult men or women, 18 years of age or older.

7. Laboratory results, including serum chemistries, hematology, and urinalysis, must
show no clinically significant abnormalities (clinically significant is defined as
laboratory values requiring acute medical intervention, indicating a serious medical
illness, or requiring further medical evaluation in the judgment of the
investigator). In addition, there must be no clinical information that, in the
judgment of a physician, should preclude a subjects' participation at study entry.

8. Must be able to use nasal spray

9. Must be able to communicate effectively with the investigator and study coordinator.

10. Patients may be taking a variety of medications for anxiety at the time of
enrollment, or may be receiving no medication treatment, but must be stable on their
particular regiment for 3 weeks. If the subject is in the process of changing
medications, enrollment will be deferred

Exclusion Criteria:

1. Are pregnant or are breastfeeding

2. A urine drug screen at screening that is positive for recent use of illegal drugs or
alcohol

3. Any active medical condition that in the opinion of the investigator will interfere
with the objectives of the study

4. For any reason the investigator considers the subject to be an unsuitable candidate
to receive Oxytocin or believes the subject would be non-compliant with taking the
study drug or study procedures.

5. Subjects with a score greater than 1 on question #3 "Suicide". suicidal is excluded.

6. Subjects with a total score greater than 17 on the 21 item scale, HAMD, are excluded
from participating.

7. Subjects with a diagnosis of Obsessive Compulsive Disorder, a psychotic disorder,
bipolar disorder, or with substance abuse or dependence in the prior 6 months will be
excluded.