Project 4

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Project 4: Kynurenic Acid in Schizophrenia: A Tryptophan Challenge Study

Research Summary

People with schizophrenia show marked cognitive deficits, including abnormalities of attention, processing speed, verbal and visual learning and memory, and working memory. These impairments persist despite treatment with first or second generation antipsychotic drugs. Interventions leading to cognitive enhancement therefore remain a central therapeutic challenge.

Emerging evidence suggests an etiologically relevant role of disturbances in the kynurenine pathway of tryptophan degradation, leading to enhanced formation of kynurenic acid in the brain. Kynurenic acid is a known antagonist of ?7 nicotinic and NMDA receptors, and increased inhibition of these receptors is hypothesized to be a critical mechanism in the development of cognitive impairments in schizophrenia.

The project is designed to investigate the impact of elevated kynurenic acid formation on the performance of cognitive tasks that are hypothesized to be linked to alpha-7 nicotinic and NMDA receptor function.

A double-blinded, placebo-controlled, cross-over tryptophan challenge study will examine the effect of increased kynurenic acid on

1. neuropsychological test performance;
2. fMRI activation and connectivity at rest and during the performance of a relational memory task;
3. 1H-MRS measures of anterior cingulate/medial prefrontal glutamate; and
4. peripheral markers of the kynurenine pathway, HPA axis and inflammatory system activity. 

Participants will include people with DSM-5/DSM-IV-TR schizophrenia, schizophreniform or schizoaffective disorder, and healthy controls.