Oxytocin Add on Study for Stable Schizophrenic Patients

Schizophrenia patients treated with even the best currently available antipsychotic drugs
continue to experience significant symptoms. There is a strong need for better treatments
including treatments that can safely be given as adjunct to current antipsychotics in order
to improve overall efficacy of treatment.

Oxytocin is a neurohypophyseal peptide best known for its role as a neurohormone involved in
parturition and lactation. In addition to these well established peripheral effects, there
is a compelling body of converging evidence indicating that oxytocin plays a critical role
in the regulation of a number of diverse centrally-mediated behavioral and cognitive
processes that are highly relevant to Schizophrenia, including social attachment and memory
, (see Argiolas and Gessa 1990; McCarthy and Aaltemus 1997).Furthermore, several lines of
research suggest that oxytocin receptors may be an important target for development of novel
treatments for schizophrenia. Oxytocin and its receptors exist in several areas of the brain
which have been heavily implicated in the pathophysiology of schizophrenia, such as the
nucleus accumbens and the hippocampus, (Van Leeuwan et al 1985). Oxytocin administered
peripherally inhibits dopamine transmission in the mesolimbic pathway (Sarnyai 1992) et al,
1990). Antipsychotics have been found to elevate the secretion of oxytocin in rats
(Uvnas-Moberg et al 1992a) suggesting that endogenous oxytocin may play a role in the
therapeutic effects of antipsychotic drugs.

Each subject will be enrolled for 6 week treatment period after a screening phase Study
procedure involves weekly clinic visits as an outpatient. Forty patients will be randomly
assigned to either 40 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 schizophrenia 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 7-day screening period, a baseline (randomization) visit, three week
treatment period, 1 week washout, baseline, and three weeks cross over treatment.

Inclusion Criteria:

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

2. Meet DSM-IV criteria for Schizophrenia.

3. Women of childbearing potential must test negative for pregnancy at the time of
enrollment based on urine pregnancy test and agree to use a reliable method of birth
control during the study.

4. Must be on a therapeutic dose of an atypical antipsychotic medication (examples but
not limited to Clozapine Olanzapine, Risperidone, Ziprasidone, Aripiprazole,
Seroquel) with no major dose changes for at least 4 weeks.

5. A minimum PANSS total score of 55 at screening and baseline and a score of at least
4 (moderate) on the subscale of the PANSS (suspiciousness/persecution) at screening.

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

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

8. Must be able to use nasal spray.

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

Exclusion Criteria:

Subjects will be excluded from the study of they meet any of the following criteria:

1. Are pregnant or are breastfeeding (negative pregnancy test at screening).

2. A urine drug screen performed at screening must not show evidence of recent use of
drugs of abuse.

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

4. Are unsuitable in any way to participate in this study, in the opinion of the
investigator.

5. Another current DSM-IV diagnosis other than Schizophrenia.

Permitted:

Subjects on one SSRI, and/or sleep medication (diphenhydramine, zolpidem, zaleplon, or
diazepam), at a reasonable dose, as judged by the investigator, is permitted in this
study.