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. 2016 Aug 2;6(8):e865.
doi: 10.1038/tp.2016.133.

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation

L Brundin  1 , C M Sellgren  2   3   4 , C K Lim  5 , J Grit  1 , E Pålsson  6 , M Landén  6 , M Samuelsson  2   7 , K Lundgren  7 , P Brundin  1 , D Fuchs  8 , T T Postolache  9   10 , L Traskman-Bendz  11 , G J Guillemin  5   12 , S Erhardt  2
Affiliations

An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation

L Brundin et al. Transl Psychiatry. .

Abstract

Emerging evidence suggests that inflammation has a key role in depression and suicidal behavior. The kynurenine pathway is involved in neuroinflammation and regulates glutamate neurotransmission. In the cerebrospinal fluid (CSF) of suicidal patients, levels of inflammatory cytokines and the kynurenine metabolite quinolinic acid (QUIN), an N-methyl-d-aspartate receptor agonist, are increased. The enzyme amino-β-carboxymuconate-semialdehyde-decarboxylase (ACMSD) limits QUIN formation by competitive production of the neuroprotective metabolite picolinic acid (PIC). Therefore, decreased ACMSD activity can lead to excess QUIN. We tested the hypothesis that deficient ACMSD activity underlies suicidal behavior. We measured PIC and QUIN in CSF and plasma samples from 137 patients exhibiting suicidal behavior and 71 healthy controls. We used DSM-IV and the Montgomery-Åsberg Depression Rating Scale and Suicide Assessment Scale to assess behavioral changes. Finally, we genotyped ACMSD tag single-nucleotide polymorphisms (SNPs) in 77 of the patients and 150 population-based controls. Suicide attempters had reduced PIC and a decreased PIC/QUIN ratio in both CSF (P<0.001) and blood (P=0.001 and P<0.01, respectively). The reductions of PIC in CSF were sustained over 2 years after the suicide attempt based on repeated measures. The minor C allele of the ACMSD SNP rs2121337 was more prevalent in suicide attempters and associated with increased CSF QUIN. Taken together, our data suggest that increased QUIN levels may result from reduced activity of ACMSD in suicidal subjects. We conclude that measures of kynurenine metabolites can be explored as biomarkers of suicide risk, and that ACMSD is a potential therapeutic target in suicidal behavior.

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Conflict of interest statement

SE reports having received lecture fees from Roche and an independent research grant from AstraZeneca. ML declares that over the past 36 months, he has received lecture honoraria from Biophausia Sweden, Servier Sweden, AstraZeneca and served at advisory board for Lundbeck pharmaceuticals. MS has received lecture honoraria from GlaxoSmithKline during the past 36 months. PB has received commercial support as a consultant from Renovo Neural, Roche, Teva Pharmaceutical Industries, Lundbeck A/S, AbbVie, ClearView Healthcare, FCB Health, IOS Press Partners and Capital Technologies. In addition, he has received commercial support for grants/research from Renovo and Teva/Lundbeck. BL has ownership interests in Acousort AB and Parkcell AB. SMC reports having received lecture fees from AstraZeneca and Roche. GJG, LB, SE and CKL have filed provisional patent P31294PC00 related to the findings in this article. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
A simplified diagram of the kynurenine pathway. ACMSD, amino-β-carboxymuconate-semialdehyde-decarboxylase; HAAO, hydroxyanthranilate 3,4-dioxygenase; IDO, indoleamine 2,3-dioxygenases; KAT, kynurenine aminotransferases; KMO, kynurenine 3-monooxygenases; KYNU, kynureninase; NAD, nicotinamide adenine dinucleotide; QPRT, quinolinate phosphoribosyltransferase; TDO, tryptophan 2,3-dioxygenase.
Figure 2
Figure 2
Kynurenine metabolites in the cerebrospinal fluid (CSF) of suicide attempters and healthy controls. (a) CSF picolinic acid (PIC). (b) CSF picolinic acid/quinolinic (PIC/QUIN) acid ratio. (c) CSF kynurenine/tryptophan ratio (KYN/TRP). (d) CSF PIC in suicide attempters over time compared with a single time point measured in control subjects. PIC was lower in suicide attempters than in healthy controls and did not fluctuate over time. (a–d) **P<0.01; ***P<0.001 suicide attempters vs controls. All values represent mean (+s.e.m.).
Figure 3
Figure 3
Kynurenine metabolites in the plasma of suicide attempters and healthy controls. (a) Plasma picolinic acid (PIC). (b) Plasma quinolinic acid (QUIN). (c) Plasma PIC/QUIN ratio. (d) Plasma kynurenine/tryptophan ratio. (a–d) *P<0.05; ***P<0.001 suicide attempters versus controls. All values represent mean (+s.e.m.).
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