Reduction of kynurenic acid to quinolinic acid ratio in both the depressed and remitted phases of major depressive disorder

Highlights

• There was no significant difference in CRP and IL-1RA across groups.

• There was no significant difference in activation of the kynurenine pathway (KYN/TRP).

• Depressed and remitted subjects show reduced kynurenic acid: quinolinic acid ratio.

• An abnormality in kynurenine metabolism may persistent in fully-remitted patients.

• Our data raise questions concerning the optimal treatment of remitted individuals.

Abstract

Low-grade inflammation is characteristic of a subgroup of currently depressed patients with major depressive disorder (dMDD). It may lead to the activation of the kynurenine-metabolic pathway and the increased synthesis of potentially neurotoxic metabolites such as 3-hydroxykynurenine (3HK) and quinolinic acid (QA), relative to kynurenic acid (KynA). Nevertheless, few studies have examined whether abnormalities in this pathway are present in remitted patients with MDD (rMDD). Here we compared the serum concentrations of kynurenine metabolites, measured using high performance liquid chromatography with tandem mass spectrometry, across 49 unmedicated subjects meeting DSM-IV-TR criteria for MDD, 21 unmedicated subjects meeting DSM-IV-TR criteria for rMDD, and 58 healthy controls (HCs). There was no significant group difference in the concentrations of the individual kynurenine metabolites, however both the dMDD group and the rMDD group showed a reduction in KynA/QA, compared with the HCs. Further, there was an inverse correlation between KynA/QA and anhedonia in the dMDD group, while in the rMDD group, there was a negative correlation between lifetime number of depressive episodes and KynA/QA as well as a positive correlation between the number of months in remission and KynA/QA. Our results raise the possibility that a persistent abnormality exists within the kynurenine metabolic pathway in MDD that conceivably may worsen with additional depressive episodes. The question of whether persistent abnormalities in kynurenine metabolism predispose to depression and/or relapse in remitted individuals remains unresolved.

Introduction

Circulating biomarkers of inflammation such as C-reactive protein (CRP) and pro-inflammatory cytokines such as IL-1β and IL-6 have been reported to be elevated in individuals with major depressive disorder (MDD) (Howren et al., 2009). Cytokines and other inflammatory molecules may directly affect neurophysiological function, mood, and emotion (Miller et al., 2013). However, inflammation may also affect mood and behavior indirectly by activating the tryptophan degrading enzyme, indoleamine 2,3 dioxygenase (IDO), increasing the formation of neuroactive kynurenine-pathway metabolites, including kynurenic acid (KynA), 3-hydroxykynurenine (3HK), and quinolinic acid (QA) (Dantzer et al., 2011).

Kynurenine is metabolized along two main branches to form either KynA or alternatively, 3HK, 3-hydroxyanthrallic acid (3-HAA), and QA (Fig. S1). Both the preclinical literature and human studies of known inflammatory and/or neurodegenerative disorders have led to the hypothesis that microglial-derived 3HK and QA are neurotoxic while astrocyte-derived KynA is neuroprotective (Amaral et al., 2013, Myint and Kim, 2003, Stone et al., 2012). While this model is likely overly simplistic, our previous results showing reductions in KynA/3HK and/or KynA/QA in depressed patients with MDD (Savitz et al., 2015) and bipolar disorder (BD) (Savitz et al., 2014a) along with positive correlations between KynA/3HK and/or KynA/QA and hippocampal volume in the MDD and BD groups, are arguably consistent with this model.

Few studies have measured both KynA and QA-pathway metabolites in the same depressed subjects with primary MDD. Our previous reports of mood disorder-associated reductions in KynA/3HK and/or KynA/QA are partially consistent with two studies that found reductions in KynA in groups of depressed patients compared with healthy controls (Maes et al., 2011, Myint et al., 2007), and an ex vivo study of skin fibroblasts derived from BD subjects that reported disproportionate elevations in 3HK relative to KynA after stimulation with pro-inflammatory cytokines (Johansson et al., 2013). Moreover, (Bay-Richter et al., 2015) recently reported persistent decreases in KynA and increases in QA in the cerebrospinal fluid of predominantly depressed subjects up to 2 years after a suicide attempt.

A question that has to our knowledge, not been addressed in the literature is whether the putative depression-associated changes in kynurenine metabolism are temporally restricted to the depressive episode or whether these abnormalities are present both within and between episodes, constituting a trait-like abnormality. Here we present preliminary data suggesting the existence of a sustained abnormality in the kynurenine metabolic pathway in MDD.