title: A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality.
abstract: BACKGROUND
  Patients with depression and suicidality suffer from low-grade neuroinflammation. Pro-inflammatory cytokines activate indoleamine 2,3-dioxygenase, an initial enzyme of the kynurenine pathway. This pathway produces neuroactive metabolites, including quinolinic- and kynurenic acid, binding to the glutamate N-methyl-d-aspartate-receptor, which is hypothesized to be part of the neural mechanisms underlying symptoms of depression. We therefore hypothesized that symptoms of depression and suicidality would fluctuate over time in patients prone to suicidal behavior, depending on the degree of inflammation and kynurenine metabolite levels in the cerebrospinal fluid (CSF).
  
  
  METHODS
  We measured cytokines and kynurenine metabolites in CSF, collected from suicide attempters at repeated occasions over 2 years (total patient samples n=143, individuals n=30) and healthy controls (n=36). The association between the markers and psychiatric symptoms was assessed using the Montgomery Asberg Depression Rating Scale and the Suicide Assessment Scale.
  
  
  RESULTS
  Quinolinic acid was increased and kynurenic acid decreased over time in suicidal patients versus healthy controls. Furthermore, we found a significant association between low kynurenic acid and severe depressive symptoms, as well as between high interleukin-6 levels and more severe suicidal symptoms.
  
  
  CONCLUSIONS
  We demonstrate a long-term dysregulation of the kynurenine pathway in the central nervous system of suicide attempters. An increased load of inflammatory cytokines was coupled to more severe symptoms. We therefore suggest that patients with a dysregulated kynurenine pathway are vulnerable to develop depressive symptoms upon inflammatory conditions, as a result the excess production of the NMDA-receptor agonist quinolinic acid. This study provides a neurobiological framework supporting the use of NMDA-receptor antagonists in the treatment of suicidality and depression.
authors.affiliation: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark. Electronic address: cbr@clin.au.dk.
authors.forename: Cecilie
authors.initials: C
authors.lastname: Bay-Richter
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Klas R
authors.initials: KR
authors.lastname: Linderholm
authors.affiliation: Neuroinflammation Group, Australian School of Advanced Medicine, Macquarie University, NSW, Australia.
authors.forename: Chai K
authors.initials: CK
authors.lastname: Lim
authors.affiliation: Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Psychiatry, Linköping University, Linköping, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Samuelsson
authors.affiliation: Department of Clinical Sciences, Section of Psychiatry, Lund University, Lund, Sweden.
authors.forename: Lil
authors.initials: L
authors.lastname: Träskman-Bendz
authors.affiliation: Neuroinflammation Group, Australian School of Advanced Medicine, Macquarie University, NSW, Australia.
authors.forename: Gilles J
authors.initials: GJ
authors.lastname: Guillemin
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Sophie
authors.initials: S
authors.lastname: Erhardt
authors.affiliation: Division of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA; Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA.
authors.forename: Lena
authors.initials: L
authors.lastname: Brundin
mesh_terms: D000328:Adult; D016207:Cytokines / Q000134:cerebrospinal fluid*; D003866:Depressive Disorder / Q000378:metabolism*; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid*; D007736:Kynurenic Acid / Q000134:cerebrospinal fluid; D007737:Kynurenine / Q000134:cerebrospinal fluid; D008297:Male; D008875:Middle Aged; D017378:Quinolinic Acid / Q000134:cerebrospinal fluid; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D059020:Suicidal Ideation; D013406:Suicide, Attempted; D055815:Young Adult
chemical_list: D016207:Cytokines; D016194:Receptors, N-Methyl-D-Aspartate; D007737:Kynurenine; D017378:Quinolinic Acid; D007736:Kynurenic Acid
keywords: Cerebrospinal fluid; Glutamate; Interleukin-6; Kynurenic acid; Quinolinic acid; Suicide