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. 2022 Mar:101:136-145.
doi: 10.1016/j.bbi.2022.01.002. Epub 2022 Jan 6.

Peripheral and central kynurenine pathway abnormalities in major depression

Elisabeth R Paul  1 , Lilly Schwieler  2 , Sophie Erhardt  2 , Sandra Boda  3 , Ada Trepci  2 , Robin Kämpe  1 , Anna Asratian  4 , Lovisa Holm  4 , Adam Yngve  1 , Robert Dantzer  5 , Markus Heilig  6 , J Paul Hamilton  7 , Martin Samuelsson  6
Affiliations

Peripheral and central kynurenine pathway abnormalities in major depression

Elisabeth R Paul et al. Brain Behav Immun. 2022 Mar.

Abstract

Considerable data relate major depressive disorder (MDD) with aberrant immune system functioning. Pro-inflammatory cytokines facilitate metabolism of tryptophan along the kynurenine pathway (KP) putatively resulting in reduced neuroprotective and increased neurotoxic KP metabolites in MDD, in addition to modulating metabolic and immune function. This central nervous system hypothesis has, however, only been tested in the periphery. Here, we measured KP-metabolite levels in both plasma and cerebrospinal fluid (CSF) of depressed patients (n = 63/36 respectively) and healthy controls (n = 48/33). Further, we assessed the relation between KP abnormalities and brain-structure volumes, as well as body mass index (BMI), an index of metabolic disturbance associated with atypical depression. Plasma levels of picolinic acid (PIC), the kynurenic/quinolinic acid ratio (KYNA/QUIN), and PIC/QUIN were lower in MDD, but QUIN levels were increased. In the CSF, we found lower PIC in MDD. Confirming previous work, MDD patients had lower hippocampal, and amygdalar volumes. Hippocampal and amygdalar volumes were correlated positively with plasma KYNA/QUIN ratio in MDD patients. BMI was increased in the MDD group relative to the control group. Moreover, BMI was inversely correlated with plasma and CSF PIC and PIC/QUIN, and positively correlated with plasma QUIN levels in MDD. Our results partially confirm previous peripheral KP findings and extend them to the CSF in MDD. We present the novel finding that abnormalities in KP metabolites are related to metabolic disturbances in depression, but the relation between KP metabolites and depression-associated brain atrophy might not be as direct as previously hypothesized.

Keywords: Brain volumetry; Central nervous system; Cerebrospinal fluid; Inflammation; Kynurenine pathway; Major depressive disorder; Structural magnetic resonance imaging.

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Conflict of interest statement

Conflict of interest

Ms Paul, Dr Schwieler, Ms Boda, Ms Trepci, Mr Kämpe, Ms Asratian, Dr Holm, Mr Yngve, Dr Hamilton, and Dr Samuelsson declare no potential conflict of interest. Dr Erhardt discloses grant support from AstraZeneca and Jansen Pharmaceuticals as principal investigator and has been a speaker for Roche Pharmaceuticals, AstraZeneca, Eli Lilly, Orion Corporation Orion Pharma and Bristol Myers Squibb, none of which are relevant to the presented work. Dr Dantzer discloses an honorarium from Compass Pathways not related to the presented work. Dr Heilig has received consulting fees, research support or other compensation from Indivior, Camurus, BrainsWay, Aelis Farma, and Janssen Pharmaceuticals, none of which are relevant to the presented work.

Figures

Figure 1.
Figure 1.
A) Scatterplots and boxplots showing the distributions of kynurenine metabolite levels (nM) that differed significantly between patients with major depressive disorder (green) and healthy controls (blue). 1) plasma picolinic acid 2) plasma quinolinic acid, 3) plasma kynurenic / quinolinic acid ratio, 4) plasma picolinic / quinolinic ratio, and 5) cerebrospinal fluid (CSF) picolinic acid; B) Median and interquartile range (IQR) of all kynurenine pathway metabolites levels in plasma and CSF of major depressive disorder (MDD) and healthy control (HC) participants. P-values are based on Mann-Whitney U tests. NAM: nicotinamide, PIC: picolinic acid, QUIN: quinolinic acid, KYNA: kynurenic acid, KYN: L-kynurenine, 3-HK: 3-hydroxy-kynurenine. CSF: cerebrospinal fluid 1p <.05
Figure 2.
Figure 2.
Scatterplots showing distributions of BMI versus A) plasma picolinic acid, B) plasma quinolinic acid, C) plasma kynurenic /quinolinic acid ratio, D) plasma picolinic / quinolinic ratio, and E) cerebrospinal fluid picolinic acid. Spearman rho values with one-sided and two-sided significance levels shown. PIC: picolinic acid, QUIN: quinolinic acid, and KYNA: kynurenic acid
Figure 3.
Figure 3.
Correlations between all plasma and CSF kynurenine pathway metabolites in A) major depressive disorder and B) healthy controls. C) Peripheral to central correlations on a per metabolite basis and corresponding one- and two-sided p-values. NAD: nicotinamide, PIC: picolinic acid, QUIN: quinolinic acid, KYNA: kynurenic acid, KYN: L-kynurenine, 3-HK: 3-hydroxy-kynurenine. 1 p <.05, Ϯ = replication of Haroon et al
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