# The Effects of Kynurenine Aminotransferase Inhibition in People with Schizophrenia

> **NIH NIH P50** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $603,309

## Abstract

PROJECT SUMMARY
There is converging evidence to suggest that kynurenine pathway disturbances may be related to the
pathophysiology of schizophrenia. In particular, clinical, genetic, and post-mortem studies suggest that the
disruption of key regulatory pathway enzymes results in increased CNS production of kynurenic acid (KYNA); a
known antagonist of ±-7 nicotinic and N-Methyl-D-aspartate (NMDA) glutamate receptors. The KYNA
antagonism of these receptors is hypothesized to be a critical mechanism in the development of the cognitive
impairments observed in schizophrenia. In our previous work, we demonstrated that increased KYNA
(following tryptophan (TRYP) challenge) impaired learning on verbal and visual memory tests in healthy
controls. In addition, we found that increased KYNA decreased whole brain and frontal cortical gray matter
cerebral blood flow (CBF) in people with schizophrenia; importantly, lower resting CBF is related to poorer
cognitive function in schizophrenia. Furthermore, we identified a subgroup of people with schizophrenia with
elevated serum KYNA levels, who were characterized by higher BPRS total, positive symptom, and thought
disorder factor scores; and who exhibited a significant worsening of their performance on a sustained attention
task following TRYP, but not placebo, administration. Finally, we recently reported that higher circulating KYNA
correlates with lower brain glutamate in humans and present preliminary evidence that higher brain KYNA is
associated with lower white matter fractional anisotropy. The convergence of these results provides further
support for the hypothesis that increased KYNA is related to the pathophysiology of cognitive impairments in
schizophrenia. The proposed study is designed to examine whether NAC blocks the adverse effects of
increased KYNA on selected measures of brain function, structure, chemistry, and behavior through KAT II
inhibition. The study will be a double-blind, placebo-controlled, randomized cross-over challenge study, in
which people with schizophrenia are pretreated with either high-dose NAC, 140 mg/kg up to a maximum of 15
g, or placebo, then receive TRYP, 6 gms. We will collect baseline and post-treatment clinical, cognitive,
electrophysiological, laboratory, and neuroimaging measures. We will examine whether NAC compared to
placebo blocks the peripheral conversion of kynurenine to KYNA; attenuates the effects of TRYP on ASL CBF
measures; and increases diffusion weighted imaging (DWI) indices of white matter integrity; ERP
interhemispheric transfer; and MRS glutamate measures. We will also examine whether the NAC effects on
the above neuroimaging measures are related to changes in cognitive measures of attention, verbal and visual
memory, and working memory. Finally, we will examine if baseline serum KYNA levels and/or PBMC
kynurenine 3-monooxygenase (KMO) activity are related to the effects of NAC on the proposed outcome
measures. The demonstration that NAC reverses the ad...

## Key facts

- **NIH application ID:** 10016398
- **Project number:** 5P50MH103222-07
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** ROBERT W BUCHANAN
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $603,309
- **Award type:** 5
- **Project period:** 2014-05-09 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10016398

## Citation

> US National Institutes of Health, RePORTER application 10016398, The Effects of Kynurenine Aminotransferase Inhibition in People with Schizophrenia (5P50MH103222-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10016398. Licensed CC0.

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