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Schizophrenia Research

Animal model in schizophrenia research identifies a novel approach for treating cognitive impairments

When neuroscientists co-administered D-serine and a blocker of D-amino acid oxidase (DAAO), which metabolizes and decreases availability of D-serine in the brain, D-serine efficacy increased in the ability to enhance NMDA glutamate receptor function. Enhancing NMDA glutamate receptor function is considered to be a possible treatment for schizophrenia and abnormal behaviors.



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June 9, 2009
Researchers have been seeking a safe and effective way to treat cognitive impairments associated with schizophrenia by enhancing N-methyl-D-aspartate (NMDA) glutamate receptors. Functional deficits in NMDA receptors may contribute to the underlying neurobiology of this disorder. The first generation of studies trying to stimulate NMDA receptors administered large amounts of substances, like glycine or D-serine, which indirectly enhance NMDA receptor function. While there were some positive reports of efficacy, findings across studies were more inconsistent than was hoped.

New approaches following this line of research are just beginning to be tested in patients. For example, several pharmaceutical companies are studying drugs that block the glycine transporter (GlyT1) and thereby raise synaptic glycine levels. A new study in Biological Psychiatry, published by Elsevier, by Dr. Kenji Hashimoto and colleagues may represent a "next step," which is to prevent the inactivation of D-serine by the enzyme D-amino acid oxidase (DAAO). The authors found that this approach enhances the efficacy of D-serine in an animal model for deficits in NMDA glutamate receptor function.

To put it more simply, although D-serine is used as a treatment for schizophrenia, it is metabolized by DAAO, reducing its availability in the brain. So, using an animal model of schizophrenia, these scientists co-administered D-serine and a compound that blocks the effects of DAAO. This increased the levels of D-serine in the mice and therefore its effectiveness in treating the abnormal behaviors in this animal model that may be relevant to schizophrenia.

"We still do not have effective treatments that specifically target the cognitive and functional impairments associated with schizophrenia. These findings are very interesting because there is a continued sense that we have not yet captured the therapeutic promise associated with the glycine site of the NMDA receptor. GlyT1 blockers and DAAO inhibitors may be important new clinical research tools," comments John Krystal, M.D., Editor of Biological Psychiatry.

Further research is still needed to see whether these findings can be extended to humans, but it is hoped that this combination therapy proves to be a novel and effective treatment of schizophrenia.

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Source Information

Neuroscience Article Details:

The article is "Co-Administration of a D-Amino Acid Oxidase Inhibitor Potentiates the Efficacy of D-Serine in Attenuating Prepulse Inhibition Deficits After Administration of Dizocilpine" by Kenji Hashimoto, Yuko Fujita, Mao Horio, Shinsui Kunitachi, Masaomi Iyo, Dana Ferraris, and Takashi Tsukamoto. Authors Hashimoto, Fujita, Horio, and Kunitachi are affiliated with the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. Iyo is from the Department of Psychiatry, Chiba University Graduate School of Medicine, Chiba, Japan. Ferraris and Tsukamoto are with the Eisai Research Institute, Baltimore, Maryland.

The article appears in Biological Psychiatry, Volume 65, Issue 12 (June 15, 2009), published by Elsevier.

The authors' disclosures of financial and conflicts of interests are available in the article. John H. Krystal, M.D. is affiliated with both Yale University School of Medicine and the VA Connecticut Healthcare System and his disclosures of financial and conflicts of interests are available here.

Full text of the article mentioned above is available upon request. Contact Jayne M. Dawkins at [email protected] to obtain a copy or to schedule an interview.

About Biological Psychiatry

This international rapid-publication journal is the official journal of the Society of Biological Psychiatry. It covers a broad range of topics in psychiatric neuroscience and therapeutics. Both basic and clinical contributions are encouraged from all disciplines and research areas relevant to the pathophysiology and treatment of major neuropsychiatric disorders. Full-length and Brief Reports of novel results, Commentaries, Case Studies of unusual significance, and Correspondence and Comments judged to be of high impact to the field are published, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Concise Reviews and Editorials that focus on topics of current research and interest are also published rapidly.

Biological Psychiatry (www.sobp.org/journal) is ranked 4th out of the 95 Psychiatry titles and 16th out of 199 Neurosciences titles on the 2006 ISI Journal Citations Reports® published by Thomson Scientific.

About Elsevier

Elsevier is a world-leading publisher of scientific, technical and medical information products and services. Working in partnership with the global science and health communities, Elsevier's 7,000 employees in over 70 offices worldwide publish more than 2,000 journals and 1,900 new books per year, in addition to offering a suite of innovative electronic products, such as ScienceDirect (http://www.sciencedirect.com/), MD Consult (http://www.mdconsult.com/), Scopus (http://www.info.scopus.com/), bibliographic databases, and online reference works.

Elsevier (http://www.elsevier.com/) is a global business headquartered in Amsterdam, The Netherlands and has offices worldwide. Elsevier is part of Reed Elsevier Group plc (http://www.reedelsevier.com/), a world-leading publisher and information provider. Operating in the science and medical, legal, education and business-to-business sectors, Reed Elsevier provides high-quality and flexible information solutions to users, with increasing emphasis on the Internet as a means of delivery. Reed Elsevier's ticker symbols are REN (Euronext Amsterdam), REL (London Stock Exchange), RUK and ENL (New York Stock Exchange).

Source Information

Source: Elsevier

Contact: Jayne Dawkins www.elsevier.com

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