A role for inflammatory metabolites as modulators of the glutamate N-methyl-D-aspartate receptor in depression and suicidality Cecilie Bay-Richter a,⇑ , Klas R. Linderholm b , Chai K. Lim c , Martin Samuelsson d , Lil Träskman-Bendz e , Gilles J. Guillemin c , Sophie Erhardt b,1 , Lena Brundin f,g,1 a Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Risskov, Denmark b Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden c Neuroinflammation Group, Australian School of Advanced Medicine, Macquarie University, NSW, Australia d Faculty of Health Sciences, Department of Clinical and Experimental Medicine, Division of Psychiatry, Linköping University, Linköping, Sweden e Department of Clinical Sciences, Section of Psychiatry, Lund University, Lund, Sweden f Division of Psychiatry and Behavioral Medicine, Michigan State University, Grand Rapids, MI, USA g Laboratory of Behavioral Medicine, Van Andel Research Institute, Grand Rapids, MI, USA article info Article history: Received 21 May 2014 Received in revised form 16 July 2014 Accepted 25 July 2014 Available online 12 August 2014 Keywords: Suicide Glutamate Quinolinic acid Kynurenic acid Interleukin-6 Cerebrospinal fluid 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 path- way. 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 mecha- nisms 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 Mont- gomery Åsberg 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 ner- vous 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 vul- nerable 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 support- ing the use of NMDA-receptor antagonists in the treatment of suicidality and depression. Ó 2014 Elsevier Inc. All rights reserved. 1. Introduction Suicide accounts for 1.5% of all deaths and is the tenth leading cause of death worldwide (Heron, 2012). Unfortunately, progress in the prevention of suicide is limited by the large number, high prevalence, and wide distribution of suicide risk factors (Olfson et al., 2014). Moreover, the biological changes associated with symptoms of suicidality are incompletely known and a previous suicide attempt is currently the best predictor of a future com- pleted suicide (Harris and Barraclough, 1997). Patients with depression and suicidality show signs of inflam- mation in peripheral blood as well as within the brain (Dowlati et al., 2010; Valkanova et al., 2013). For example, depressed patients have elevated blood levels of interleukin (IL)-1b (Thomas et al., 2005; Dahl et al., 2014), tumor necrosis factor (TNF)-a (Hestad et al., 2003), IL-8 (Mikova et al., 2001) and IL-6 (Dahl et al., 2014; Berk et al., 1997). Interestingly, several reports have described emerging depression and suicidality in previously http://dx.doi.org/10.1016/j.bbi.2014.07.012 0889-1591/Ó 2014 Elsevier Inc. All rights reserved. ⇑ Corresponding author. Address: Translational Neuropsychiatry Unit, Depart- ment of Clinical Medicine, Aarhus University, Skovagervej 2, 8240 Risskov, Denmark. E-mail address: cbr@clin.au.dk (C. Bay-Richter). 1 Shared senior authorship. Brain, Behavior, and Immunity 43 (2015) 110–117 Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi