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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Specialized Center (P50)
Project #
1P50MH103222-01
Application #
8816225
Study Section
Special Emphasis Panel (ZMH1-ERB-L (01))
Project Start
Project End
Budget Start
2014-05-09
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
$480,426
Indirect Cost
$167,445
Name
University of Maryland Baltimore
Department
Type
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Rowland, Laura M; Summerfelt, Ann; Wijtenburg, S Andrea et al. (2016) Frontal Glutamate and γ-Aminobutyric Acid Levels and Their Associations With Mismatch Negativity and Digit Sequencing Task Performance in Schizophrenia. JAMA Psychiatry 73:166-74
Wang, Qi; Chen, Rong; JaJa, Joseph et al. (2016) Connectivity-Based Brain Parcellation: A Connectivity-Based Atlas for Schizophrenia Research. Neuroinformatics 14:83-97
Pershing, Michelle L; Phenis, David; Valentini, Valentina et al. (2016) Prenatal kynurenine exposure in rats: age-dependent changes in NMDA receptor expression and conditioned fear responding. Psychopharmacology (Berl) 233:3725-3735
Chiappelli, Joshua; Shi, Qiaoyun; Kodi, Priyadurga et al. (2016) Disrupted glucocorticoid--Immune interactions during stress response in schizophrenia. Psychoneuroendocrinology 63:86-93
Kochunov, Peter; Ganjgahi, Habib; Winkler, Anderson et al. (2016) Heterochronicity of white matter development and aging explains regional patient control differences in schizophrenia. Hum Brain Mapp 37:4673-4688
Du, Xiaoming; Kochunov, Peter; Summerfelt, Ann et al. (2016) The role of white matter microstructure in inhibitory deficits in patients with schizophrenia. Brain Stimul :
Rowland, L M; Krause, B W; Wijtenburg, S A et al. (2016) Medial frontal GABA is lower in older schizophrenia: a MEGA-PRESS with macromolecule suppression study. Mol Psychiatry 21:198-204
Kochunov, Peter; Thompson, Paul M; Winkler, Anderson et al. (2016) The common genetic influence over processing speed and white matter microstructure: Evidence from the Old Order Amish and Human Connectome Projects. Neuroimage 125:189-97
Keefe, Richard S E; Haig, George M; Marder, Stephen R et al. (2016) Report on ISCTM Consensus Meeting on Clinical Assessment of Response to Treatment of Cognitive Impairment in Schizophrenia. Schizophr Bull 42:19-33
Kochunov, Peter; Rowland, Laura M; Fieremans, Els et al. (2016) Diffusion-weighted imaging uncovers likely sources of processing-speed deficits in schizophrenia. Proc Natl Acad Sci U S A 113:13504-13509

Showing the most recent 10 out of 35 publications