LAUSR

A number of tryptophan metabolites known to be neuroactive have been examined for their potential associations with cognitive deficits in schizophrenia. Among these metabolites, kynurenic acid (KYNA), 5-hydroxyindole (5-HI), and quinolinic acid (QUIN) are documented in their diverse effects on α-7 nicotinic acetylcholine receptor (α7nAChR) and/or N -methyl-D-aspartate receptor (NMDAR), two of the receptor types thought to contribute to cognitive impairment in schizophrenia. In this study, serum levels of KYNA, 5-HI, and QUIN were measured in 195 patients with schizophrenia and in 70 healthy controls using liquid chromatography-tandem mass spectrometry; cognitive performance in MATRICS Consensus Cognitive Battery and cortical thickness measured by magnetic resonance imaging were obtained. Patients with schizophrenia had significantly lower serum KYNA ( p  < 0.001) and QUIN ( p  = 0.02) levels, and increased 5-HI/KYNA ( p  < 0.001) and QUIN/KYNA ratios ( p  < 0.001) compared with healthy controls. Multiple linear regression showed that working memory was positively correlated with serum 5-HI levels ( t  = 2.10, p  = 0.04), but inversely correlated with KYNA concentrations ( t  = −2.01, p  = 0.05) in patients. Patients with high 5-HI and low KYNA had better working memory than other subgroups ( p  = 0.01). Higher 5-HI levels were associated with thicker left lateral orbitofrontal cortex ( t  = 3.71, p  = 2.94 × 10 −4 ) in patients. The different effects of 5-HI and KYNA on working memory may appear consistent with their opposite receptor level mechanisms. Our findings appear to provide a new insight into the dynamic roles of tryptophan pathway metabolites on cognition, which may benefit novel therapeutic development that targets cognitive impairment in schizophrenia.