Effects of neuroactive metabolites of the tryptophan pathway on working memory and cortical thickness in schizophrenia

  • Transl Psychiatry. 2021 Apr 1;11(1):198. doi: 10.1038/s41398-021-01311-z.
Junchao Huang  1 ,  Jinghui Tong  1 ,  Ping Zhang  1 ,  Yanfang Zhou  1 ,  Yimin Cui  2 ,  Shuping Tan  1 ,  Zhiren Wang  1 ,  Fude Yang  1 ,  Peter Kochunov  3 ,  Joshua Chiappelli  3 ,  Baopeng Tian  1 ,  Li Tian  4 ,  Yunlong Tan  5 ,  L Elliot Hong  3
Affiliations
  • 1. Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China.
  • 2. Department of Pharmacy, Peking University First Hospital, Beijing, China.
  • 3. Maryland Psychiatric Research Center, Department of Psychiatry, University of Maryland School of Medicine, Baltimore, MD, USA.
  • 4. Faculty of Medicine, Department of Physiology, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
  • 5. Peking University HuiLongGuan Clinical Medical School, Beijing Huilongguan Hospital, Beijing, China. [email protected].
PMID: 33795641 DOI: 10.1038/s41398-021-01311-z
Abstract

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.

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