There is a tremendous need for improved treatments for schizophrenia (SCZ), especially for its 'negative' symptoms and cognitive deficits. Oxytocin is a reproductive hormone that is also a powerful regulator of brain processes that are very relevant to SCZ. Preliminary research in animals and humans indicate that the oxytocin system may be an auspicious target for developing new SCZ treatments. However, in order for that to occur, a much greater understanding of oxytocin's potential anti-SCZ effects is urgently needed to address inconsistencies and gaps in the existing body of data. Animal studies are an important tool for obtaining information about potential new treatments, but there has been surprisingly little animal research into oxytocin's anti-SCZ potential. The overall aim of this project is to address this critical gap in knowledge. Since it is unclear which specific features f SCZ may be benefited by oxytocin, several experiments have been thoughtfully designed to evaluate its effects in a battery of state-of-the-art animal tests developed to represent the distinct clinical features of SCZ's cognitive and negative symptoms. Other experiments are designed to uncover the biological mechanisms and brain circuits that underlie oxytocin's anti-SCZ effects, something that has not previously been well studied. By testing the effects of long-term oxytocin treatment via the intranasal route, the standard route in human studies, these experiments will provide an understanding of oxytocin's effects that is more relevant to the chronic nature of clinical treatment than the preponderance of previous animal studies on this topic, which have typically examined one-time, peripheral or central oxytocin administration. As it is highly involved in reproductive function, oxytocin's brain effects are likely to differ in maes and females, but animal experiments investigating its SCZ-relevant effects have almost exclusively included only male subjects. By incorporating both female and male animals in experiments, this project will provide much needed information about possible sex differences in oxytocin's anti-SCZ effects. Another important feature of this project is that it will advance the characterization of a promising rat model of relevance to SCZ and facilitate the ultimate assessment of the validity of the tests used to model features of SCZ. This project will greatly expand the current body of scientific knowledge regarding oxytocin's anti-SCZ properties, including important information regarding potential dose-, sex-, and time-dependent aspects of its clinical effects, potential adverse effects, as well as individual characteristics that may hel identify likely responders to oxytocin treatment. These findings will guide future studies in animals and in patients with SCZ, while the findings regarding oxytocin's neurobiological mechanisms will likely guide the design of novel drugs that are based on oxytocin, but that possess improved efficacy and/or safety.

Public Health Relevance

This project will use the most advanced animal models to further investigate promising preliminary findings that the hormone oxytocin is a possible novel treatment for schizophrenia, especially for its most treatment resistant features, the cognitive deficits and the negative symptoms. The brain mechanisms underlying oxytocin's anti- schizophrenia effects, currently unknown, will also be studied. The findings from this project will help advance development of one of the most promising potential new drug candidates for a devastating chronic mental disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Study Section
Biobehavioral Regulation, Learning and Ethology Study Section (BRLE)
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Hillefors, MI
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University of California San Diego
Schools of Medicine
La Jolla
United States
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Shilling, Paul D; Feifel, David (2016) Potential of Oxytocin in the Treatment of Schizophrenia. CNS Drugs 30:193-208
Feifel, D; Shilling, P D; Hillman, J et al. (2015) Peripherally administered oxytocin modulates latent inhibition in a manner consistent with antipsychotic drugs. Behav Brain Res 278:424-8