People with schizophrenia are characterized by marked cognitive impairments, including abnormalities of attention, processing speed, verbal and visual learning and memory, and working memory. Despite treatment with first or second generation antipsychotics, they continue to exhibit these impairments. The development of effective treatments for the enhancement of cognition remains a central therapeutic challenge. The elucidation of metabolic pathways that are disrupted in schizophrenia provides a novel approach for the identification of new drug development targets. There is emerging evidence to suggest that kynurenine pathway disturbances may be related to schizophrenia pathophysiology. In particular, clinical, genetic, and post-mortem studies have shown that the disruption of key regulatory pathway enzymes results in increased CNS production of kynurenic acid (KYNA), a major tryptophan metabolite. KYNA is a known antagonist of the a7 nicotinic and N-methyl-D-aspartate (NMDA) glutamate receptors. Increased inhibition of these receptors by KYNA is hypothesized to be a critical mechanism in the development ofthe cognitive impairments observed in schizophrenia. The purpose of the current project is to examine the impact of elevated KYNA formation on performance of cognitive tasks hypothesized to be impaired by the actions of KYNA on a7 nicofinic and NMDA receptors. The study design will be a double-blinded, placebo-controlled, cross-over tryptophan challenge study to examine the effect of increased KYNA on neuropsychological test performance;fMRI activation and connectivity at rest and during the performance of a relational memory task;1 H-MRS measures of anterior cingulate/medial prefrontal glutamate;and peripheral markers of the kynurenine pathway, HPA axis and inflammatory system activity. Tryptophan loading will be used to increase KYNA levels. Participants will include people with DSM-5/DSM-IV-TR schizophrenia, schizophreniform, or schizoaffective disorder and healthy controls. The study will provide critical new data on the role of abnormal KYNA metabolism in schizophrenia, markedly enhance our understanding of the pathophysiology of cognitive impairments in schizophrenia, and guide new drug development.

Public Health Relevance

People with schizophrenia are characterized by marked cognitive impairments, for which there are no current effective treatments. These impairments are a major factor in the long-term disability associated with the illness. The elucidation of the causative factors that contribute to these impairments will have a pronounced effect on new drug development for the enhancement of cognitive function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Specialized Center (P50)
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Special Emphasis Panel (ZMH1-ERB-L (01))
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University of Maryland Baltimore
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