Dataset Information

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

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-?-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.

SUBMITTER: Brundin L

PROVIDER: S-EPMC5022080 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Brundin L L Sellgren C M CM Lim C K CK Grit J J Pålsson E E Landén M M Samuelsson M M Lundgren K K Brundin P P Fuchs D D Postolache T T TT Traskman-Bendz L L Guillemin G J GJ Erhardt S S

Translational psychiatry 20160802 8

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 competitiv ...[more]

PMID: 27483383

Similar Datasets

Project description:Suicidal behavior constitutes a major public health problem. Based on the stress-diathesis model, biological correlates of a diathesis might help to predict risk after stressor-exposure. Structural changes in cortical and subcortical areas and their connections have increasingly been linked with the diathesis. The current study identified structural network changes associated with a diathesis using a whole-brain approach by examining the structural connectivity between regions in euthymic suicide attempters (SA). In addition, the association between connectivity measures, clinical and genetic characteristics was investigated. We hypothesized that SA showed lower connectivity strength, associated with an increased severity of general clinical characteristics and an elevated expression of short alleles in serotonin polymorphisms. Thirteen euthymic SA were compared with fifteen euthymic non-attempters and seventeen healthy controls (HC). Clinical characteristics and three serotonin-related genetic polymorphisms were assessed. Diffusion MRI together with anatomical scans were administered. Preprocessing was performed using Explore DTI. Whole brain tractography of the diffusion-weighted images was followed by a number of streamlines-weighted network analysis using NBS. The network analysis revealed decreased connectivity strength in SA in the connections between the left olfactory cortex and left anterior cingulate gyrus. Furthermore, SA had increased suicidal ideation, hopelessness and self-reported depression, but did not show any differences for the genetic polymorphisms. Finally, lower connectivity strength between the right calcarine fissure and the left middle occipital gyrus was associated with increased trait anxiety severity (rs = -0.78, p < 0.01) and hopelessness (rs = -0.76, p < 0.01). SA showed differences in white matter network connectivity strength associated with clinical characteristics. Together, these variables could play an important role in predicting suicidal behavior.

Project description:Background and aimsWe investigated kynurenine pathway (KP) metabolites levels and their association with suicidal ideation in patients with treatment-resistant depression (TRD) and elevated peripheral inflammation. The effect of antidepressant augmentation with minocycline on KP metabolites was tested.MethodsWe analysed data from MINocycline in DEPression, a 4-week, randomized, placebo controlled (1:1) trial of minocycline added to antidepressant treatment in 39 TRD patients (n = 18 minocycline; n = 21 placebo) with C-reactive protein (CRP) ⩾1 mg/L. At baseline and at week 4, we collected data on suicidality (Beck Depression Inventory) and blood samples to measure inflammatory markers and KP metabolites. We tested (1) the association of KP metabolites ratios with inflammatory markers and suicidal ideation at baseline and (2) the role of suicidality and treatment (minocycline vs placebo) in affecting KP changes over time.ResultsAt baseline, kynurenine/tryptophan (KYN/TRP) ratio positively correlated with high-sensitivity CRP (Spearman's ρ = 0.35, p = 0.02) and IL-10, (ρ = 0.41, p = 0.009); and tumour necrosis factor was positively correlated with quinolinic acid/3-hydroxykynurenine ratio (ρ = 0.55, p < 0.001). Moreover, participants with suicidal ideation showed higher levels of KYN/TRP (U = 143.000, p = 0.02) than those without suicidal ideation. There was no significant effect of minocycline on KP metabolites changes from baseline to week 4. However, in the minocycline group, the number of participants with suicidal thoughts decreased from 44.4% (8/18) to 22.2% (4/18).ConclusionIncreased KP neurotoxic metabolites are associated with elevated peripheral inflammation in depressed individuals, particularly in those with suicidal ideation. Targeting KP in this population could be a potential effective personalized approach. Whether this includes minocycline should be investigated in future larger trials.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets