Abstract
Metabolites of the kynurenine pathway of tryptophan degradation, in particular, the N-Methyl-d-aspartic acid receptor antagonist kynurenic acid (KYNA), are increasingly recognized as primary pathophysiological promoters in several psychiatric diseases. Studies analyzing central KYNA levels from subjects with psychotic disorders have reported increased levels. However, sample sizes are limited and in contrast many larger studies examining this compound in blood from psychotic patients commonly report a decrease. A major question is to what extent peripheral KYNA levels reflect brain KYNA levels under physiological as well as pathophysiological conditions. Here we measured KYNA in plasma from a total of 277 subjects with detailed phenotypic data, including 163 BD subjects and 114 matched healthy controls (HCs), using an HPLC system. Among them, 94 BD subjects and 113 HCs also had CSF KYNA concentrations analyzed. We observe a selective increase of CSF KYNA in BD subjects with previous psychotic episodes although this group did not display altered plasma KYNA levels. In contrast, BD subjects with ongoing depressive symptoms displayed a tendency to decreased plasma KYNA concentrations but unchanged CSF KYNA levels. Sex and age displayed specific effects on KYNA concentrations depending on if measured centrally or in the periphery. These findings implicate brain-specific regulation of KYNA under physiological as well as under pathophysiological conditions and strengthen our previous observation of CSF KYNA as a biomarker in BD. In summary, biomarker and drug discovery studies should include central KYNA measurements for a more reliable estimation of brain KYNA levels.
Highlights
Increased concentration of kynurenic acid (KYNA), a neuroactive end-product of the kynurenine pathway of tryptophan degradation[1], has repeatedly been observed in cerebrospinal fluid (CSF) and postmortem brain tissue of subjects with schizophrenia or bipolar disorder[2,3,4,5,6,7,8,9]
Peripheral and central KYNA levels in bipolar disorder and healthy controls Peripheral KYNA levels in patients with BD and HCs were measured in plasma from a total of 277 subjects (114 HCs and 163 subjects with either BD type I [n = 93] or II [n = 70])
Among HCs we observed a positive correlation between age and plasma levels of KYNA, while plasma KYNA levels were unaffected by age in BD
Summary
Increased concentration of kynurenic acid (KYNA), a neuroactive end-product of the kynurenine pathway of tryptophan degradation[1], has repeatedly been observed in cerebrospinal fluid (CSF) and postmortem brain tissue of subjects with schizophrenia or bipolar disorder[2,3,4,5,6,7,8,9]. Based on limited sample sizes, CSF levels of KYNA in BD subjects, as well as IL-1β levels, have been reported to be selectively increased in subjects with a history of psychotic episodes[5,6,9], and linked to persistent set-shifting impairment[6]. In line with these clinical associations, rodent studies have confirmed that KYNA causes disruption of pre-pulse inhibition[13], as well as behavioral responses analogous to impaired set-shifting ability[14].
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