Project Summary

John W. Newcomer, M.D. (Independent Investigator 2001) of Washington University, notes that schizophrenia is widely viewed as a neurodevelopmental disorder, increasing interest in prevention strategies that could interrupt abnormalities in brain development. Various lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction (NRH) in the brain may play an important role in the pathogenesis of schizophrenia, including the production of psychotic and cognitive symptoms by NMDA antagonist drugs.  At this time the most promising approach for blocking NRH-induced circuit disinhibition is alpha-2 adrenergic receptor agonists. These agents can block NRH-induced neuropathological changes, cognitive and behavioral effects in animals, and NRH-induced psychosis in humans. Based on their favorable safety profile and their activity against NRH-induced effects in adults, alpha-2 adrenergic receptor agonists offer advantages for use in children. Key issues though concerning safety and effectiveness still need to be addressed in pediatric populations. The FDA-approved NMDA antagonist drug, ketamine, is rapidly becoming widely used in children for sedation during painful therapeutic procedures such as fracture reductions.  Agitation and psychosis have complicated the use of ketamine in children, as in adults. In addition to the schizophrenia-related interest in this area, there is a pressing clinical need for prevention therapies that could be used along with ketamine to block NRH-induced psychosis. Anesthesiologists have begun to use alpha-2 adrenergic agonists for preventing ketamine-induced cardiac stimulation and psychosis in adults. However, there is no currently available data addressing the efficacy and safety of alpha-2 adrenergic agonists in blocking NRH-induced psychosis in children. This project will test the efficacy and safety of the alpha-2 adrenergic agonist, dexmedetomidine, for preventing NRH-induced psychosis and memory impairment in otherwise healthy children undergoing forearm fracture reductions during ketamine treatment. Confirmation that alpha-2 adrenergic agonists can block NRH-induced psychosis and memory impairment in children would provide further clinical evidence for a strategy to prevent mental symptoms and pathophysiological consequences of NRH, which may occur early in life and give rise to the later development of schizophrenia.

Program Area: SCHIZOPHRENIA/PSYCHOTIC DISORDERS\Schizophrenia\First-Episode Psychosis\Pharmacology

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