Serum kynurenic acid is reduced in affective psychosis

Abstract

A subgroup of individuals with mood and psychotic disorders shows evidence of inflammation that leads to activation of the kynurenine pathway and the increased production of neuroactive kynurenine metabolites. Depression is hypothesized to be causally associated with an imbalance in the kynurenine pathway, with an increased metabolism down the 3-hydroxykynurenine (3HK) branch of the pathway leading to increased levels of the neurotoxic metabolite, quinolinic acid (QA), which is a putative N-methyl-d-aspartate (NMDA) receptor agonist. In contrast, schizophrenia and psychosis are hypothesized to arise from increased metabolism of the NMDA receptor antagonist, kynurenic acid (KynA), leading to hypofunction of GABAergic interneurons, the disinhibition of pyramidal neurons and striatal hyperdopaminergia. Here we present results that challenge the model of excess KynA production in affective psychosis. After rigorous control of potential confounders and multiple testing we find significant reductions in serum KynA and/or KynA/QA in acutely ill inpatients with major depressive disorder (N=35), bipolar disorder (N=53) and schizoaffective disorder (N=40) versus healthy controls (N=92). No significant difference was found between acutely ill inpatients with schizophrenia (n=21) and healthy controls. Further, a post hoc comparison of patients divided into the categories of non-psychotic affective disorder, affective psychosis and psychotic disorder (non-affective) showed that the greatest decrease in KynA was in the affective psychosis group relative to the other diagnostic groups. Our results are consistent with reports of elevations in proinflammatory cytokines in psychosis, and preclinical work showing that inflammation upregulates the enzyme, kynurenine mono-oxygenase (KMO), which converts kynurenine into 3-hydroxykynurenine and quinolinic acid.

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

“…8,[13][14][15][16] Studies in peripheral blood could not find differences in KYNA levels between patients with mania and healthy controls 17 or showed decreased KYNA levels in affective psychosis. 18 Findings in bipolar depression are similar to those in MDD. Savitz 19 found a decreased neuroprotective ratio KYNA/QA in patients with bipolar depression, but no differences in absolute kynurenine metabolite levels.…”

“…As in schizophrenia, elevated KYNA levels have been found in CSF, postmortem brain, and fibroblast cultures of patients with BD, and are mainly associated with a history of mania or psychosis . Studies in peripheral blood could not find differences in KYNA levels between patients with mania and healthy controls or showed decreased KYNA levels in affective psychosis . Findings in bipolar depression are similar to those in MDD.…”

Role of Microbiota and Tryptophan Metabolites in the Remote Effect of Intestinal Inflammation on Brain and Depression

“…Depression is believed to arise from the excessive production of the neurotoxic quinolinic acid together with a reduction in kynurenic acid [54]. Reduced levels of kynurenic acid have been correlated with severe depressive and suicidal symptoms [55,56], and decreased blood levels of this molecule has been detected in the patients with major depressive disorder [57]. Quinolinic acid is a neurotoxic agent, and its production is significantly enhanced by proinflammatory cytokines through their stimulation of the rate limiting step enzyme in the quinolinic acid pathway, kynurenine-3-monooxygenase (KMO) enzyme [58,59].…”

Regulation of proinflammatory monocyte activation by the kynurenine–AhR axis underlies immunometabolic control of depressive behavior in mice

“…However, the mechanism by which Kyn is causally associated with the etiology of depression and related mental deficits is not fully understood. There is evidence that expression of Kyn in the brain elicits oxidative stress and suppresses neurogenesis by generating the neurotoxic metabolite quinolinic acid (10, 11). Although the neurotoxicity‐based view has a rationale, the putative involvement of nonneuronal mechanisms has received little attention.…”