Peripheral and central levels of kynurenic acid in bipolar disorder subjects and healthy controls

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.

A mood state‐specific interaction between kynurenine metabolism and inflammation is present in bipolar disorder

“…As shown earlier by the same group, history of psychosis was related to a significant increase in central KYNA levels, which was not reflected in plasma levels. Similar to our results, depressive symptoms were associated with decreased KYNA levels in both plasma and CSF (the levels were however not correlated) . The correlation of central and peripheral QA levels has not yet been studied.…”

“…Although only prescribed in a small subgroup, valproate was associated with low levels of almost all kynurenine metabolites. A negative correlation between valproate and peripheral KYNA has been shown before, although again in a small subgroup . This repeated observation underlines the need for further investigation on the effect of psychopharmacological treatment on biological markers.…”

“…Although we observe a weak inverse correlation between KYNA levels and HDRS scores, our data strongly suggest a decreased kynurenine metabolism downstream the astrocytic branch in both euthymic and non‐euthymic patients. This decrease in KYNA contrasts with previous reports in CSF and postmortem brain tissue where increased KYNA levels in patients with BD were related to manic episodes and psychotic symptoms . In line with our findings, studies using peripheral blood samples showed unchanged or decreased KYNA levels in patients with a history of mania or psychosis .…”

“…TRP, KYN, and 3‐HK easily cross the BBB by active transport, but passage of QA and KYNA is more difficult . A recent study by Sellgren et al in a large sample of patients with BD and healthy controls, could not show a relevant correlation between CSF and plasma KYNA levels. As shown earlier by the same group, history of psychosis was related to a significant increase in central KYNA levels, which was not reflected in plasma levels.…”

“…Savitz found a decreased neuroprotective ratio KYNA/QA in patients with bipolar depression, but no differences in absolute kynurenine metabolite levels. Decreased KYNA and increased neurotoxic ratios also have been reported in euthymic to mild depressive patients with BD . A recent meta‐analysis on kynurenine metabolites in mood disorders found no significant differences between patients with BD and controls, but included a limited number of studies with high heterogeneity.…”