Elsevier

Brain, Behavior, and Immunity

Volume 43, January 2015, Pages 110-117
Brain, Behavior, and Immunity

A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality

https://doi.org/10.1016/j.bbi.2014.07.012Get rights and content

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 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 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.

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 completed suicide (Harris and Barraclough, 1997).

Patients with depression and suicidality show signs of inflammation 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)-1β (Thomas et al., 2005, Dahl et al., 2014), tumor necrosis factor (TNF)-α (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 psychiatrically healthy individuals upon treatment with interferons (IFNs) (Fragoso et al., 2010, Dieperink et al., 2004). Cerebrospinal fluid (CSF) IL-6 is significantly elevated in suicide attempters (Lindqvist et al., 2009), and post-mortem analysis of brain tissue from suicide victims show microgliosis (Steiner et al., 2008) and increased mRNA for cytokines (Pandey et al., 2012, Tonelli et al., 2008). Interestingly, the degree of inflammation seems to be more pronounced in suicidal patients relative to non-suicidal, depressed patients (Steiner et al., 2008, Janelidze et al., 2011).

Pro-inflammatory cytokines induce the kynurenine pathway of tryptophan degradation, from which several neuroactive compounds are produced (Schwarcz et al., 2012). IFNs are potent inducers of indoleamine 2,3-dioxygenase (IDO-1), regulating the initial step of the kynurenine pathway (Guillemin, 2012a). Kynurenic acid (KYNA] and quinolinic acid (QUIN] are two metabolites produced by this pathway (Fig. 1), both with multiple effects on neuroinflammation and neurotransmission. QUIN is an N-methyl-d-aspartate (NMDA]-receptor agonist, activating receptors containing the NR1 + NR2A and the NR1 + NR2B subunits (de Carvalho et al., 1996, Stone, 1993). QUIN is one-quarter as potent as NMDA, and approximately similarly potent as glutamate and aspartate in stimulating the receptor (Stone and Perkins, 1981) but with considerable differences in sensitivity in different brain areas (Stone, 1993). Specifically, neurons within hippocampus, striatum and neocortex are highly sensitive to QUIN, whereas cerebellar and spinal cord neurons are less sensitive, most likely due to differences in NMDA-receptor configuration (Guillemin, 2012a). Apart from the direct action on the NMDA-receptor, QUIN can also increase glutamate release by neurons, inhibit its uptake by astrocytes and inhibit astroglial glutamine synthetase (see Guillemin, 2012a).

KYNA on the other hand blocks several receptors, i.e. the glycine-site and the glutamate recognition-site of the NMDA receptor, the cholinergic alpha7 nicotinic receptor and, at higher concentrations, α-amino-3-hydroxy-5-metyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. Furthermore, KYNA is known to stimulate the G protein-coupled receptor 35 (GPR35) Stone et al., 2013.

Growing evidence indicates that enhanced NMDA-receptor stimulation participates in the pathophysiology of major depression and suicidality (Serafini et al., 2013, Nowak et al., 1995, Heresco-Levy and Javitt, 1998, Machado-Vieira et al., 2009). In support of this, the NMDA-receptor antagonist ketamine shows remarkable anti-suicidal properties (DiazGranados et al., 2010, Larkin and Beautrais, 2011, Price et al., 2009, Zarate et al., 2012). Connecting the findings of inflammation in suicidal and depressive patients with NMDA-mediated neurotransmission, we recently found increased CSF QUIN, concomitant with elevated CSF levels of IL-6, in suicide attempters (Erhardt et al., 2013). This indicates that the kynurenine pathway is induced in suicidal patients, presumably by an ongoing inflammation in the central nervous system, and that the degree of NMDA-receptor agonism may be increased in these patients. Sublette and coworkers have previously demonstrated that the kynurenine pathway is activated in the peripheral blood of suicide attempters to a higher degree than in non-suicidal depressive patients (Sublette et al., 2011). Moreover, Steiner and colleagues provided evidence of an increased expression of QUIN-reactive microglia cells in the brains of depressed patients who died by suicide (Steiner et al., 2011).

Even if experimental and clinical studies show that inflammatory stimuli are associated with depressive and suicidal symptoms, it is still not known if kynurenine metabolites are causal factors in the underlying pathology. Thus, the aberrations in immune regulation in suicidal patients may be causally related to symptoms, or possibly generated by the suicide attempt per se, constituting an epiphenomenon. Individuals vulnerable to develop suicidality and depression might also have an on-going low-grade inflammation in blood and CSF over time, which could be associated with an increased predisposition to develop symptoms (trait marker), or only exhibit inflammation at specific time-points, related to acute symptoms (state marker).

To further address these important issues, we assessed psychiatric patients for symptom severity over an extended period of time, together with repeated lumbar punctures. The patients were originally enrolled after a suicide attempt and followed for approximately 2 years thereafter. We have previously reported the elevated levels of CSF IL-6 and QUIN at the time-point of the suicide attempt in these patients (Erhardt et al., 2013, Lindqvist et al., 2009). In this study, we repeatedly evaluated depressive symptoms and suicidality over 2 years, along with the analysis of the two key kynurenine metabolites, QUIN and KYNA, in CSF. We hypothesized that increased CSF QUIN and decreased CSF KYNA would be significantly associated with more severe psychiatric symptoms, specifically an increased degree of suicidality and depression, over time in the suicide attempters.

Section snippets

Participants

The study was approved by the Regional Ethical Review Boards in Lund, Linköping and Malmö and carried out in accordance with ‘The code of ethics of the world medical association (Declaration of Helsinki)’. After complete description of the study to the participants, written informed consent was obtained.

All patients were initially enrolled in the study on admission to Lund University Hospital after a suicide attempt and subsequently followed for a maximum of 56 months after the attempt (mean 16 

Sample characteristics

QUIN and KYNA were associated with age and gender, and consequently all statistical models were corrected for these two factors as described in Section 2.7. The samples from the patients had been stored at −80 °C longer than the controls, but there were no storage-time-dependent changes, or trends towards changes, of the metabolite levels (NS for both). Symptom severity, as measured with MADRS and SUAS, fluctuated slightly but remained elevated in the patients over time (Fig. 2). MADRS scores

Discussion

This is the first study to measure the kynurenine pathway metabolites QUIN and KYNA in CSF together with depressive and suicidal symptoms over time in psychiatric patients. We show that CSF QUIN levels remain permanently elevated in patients compared to healthy controls over 2 years after a suicide attempt. CSF QUIN levels were highest at the time of the attempt, decreased over the first year, but remained significantly elevated compared to the healthy controls over time. We also provide

Financial disclosures

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by Michigan State University and Van Andel Research Institute (L.B.), the Swedish Research Council (V.R.) Nos. 2009-4284 and 2011-4787 (L.B.), 2002-5297 and 2008-2922 (L.T-B.), 2009-7052 and 2013-2838 (SE), the Province of Scania clinical state grants (ALF, for L.B. and L.T-B.), The Australian Research Council and the National Health and Medical Research Council, Australia (G.J.G.). The funding sources had no role in the design and conduct of the study; collection,

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