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A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality
Aarhus University, Denmark.
Karolinska Institute, Sweden.
Macquarie University, Australia.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Region Östergötland, Närsjukvården i centrala Östergötland, Psykiatriska kliniken. Linköpings universitet, Medicinska fakulteten.
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2015 (Engelska)Ingår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 43, s. 110-117Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Background: Patients with depression and suicidality suffer from low-grade neuroinflammation. Proinflammatory 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. (C) 2014 Elsevier Inc. All rights reserved.

Ort, förlag, år, upplaga, sidor
ACADEMIC PRESS INC ELSEVIER SCIENCE , 2015. Vol. 43, s. 110-117
Nyckelord [en]
Suicide; Glutamate; Quinolinic acid; Kynurenic acid; Interleukin-6; Cerebrospinal fluid
Nationell ämneskategori
Medicinska och farmaceutiska grundvetenskaper
Identifikatorer
URN: urn:nbn:se:liu:diva-121771DOI: 10.1016/j.bbi.2014.07.012ISI: 000360592700015PubMedID: 25124710OAI: oai:DiVA.org:liu-121771DiVA, id: diva2:859346
Anmärkning

Funding Agencies|Michigan State University; Van Andel Research Institute; Swedish Research Council [2009-4284, 2011-4787, 2002-5297, 2008-2922, 2009-7052, 2013-2838]; Province of Scania clinical state grants (ALF); Australian Research Council; National Health and Medical Research Council, Australia

Tillgänglig från: 2015-10-06 Skapad: 2015-10-05 Senast uppdaterad: 2018-01-11

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Samuelsson, Martin

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Avdelningen för neuro- och inflammationsvetenskapPsykiatriska klinikenMedicinska fakulteten
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Brain, behavior, and immunity
Medicinska och farmaceutiska grundvetenskaper

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