A meta-analysis of cytokines in suicidal behavior Ducasse Déborah a,b,c,d,⇑ , Olié Emilie a,b,c,d , Guillaume Sébastien a,b,c,d , Artéro Sylvaine c , Courtet Philippe a,b,c,d a Department of Psychiatric Emergency & Acute Crisis, Lapeyronie Hospital, CHU Montpellier, Montpellier, France b University of Montpellier UM1, Montpellier, France c INSERM U1061, Montpellier, France d Fondamental Foundation, France article info Article history: Received 1 December 2014 Received in revised form 27 January 2015 Accepted 1 February 2015 Available online xxxx Keywords: Suicidal behavior Suicidal ideation Suicidal attempt Cytokine Inflammatory marker Meta-analysis abstract Background: We conducted the first meta-analysis of studies comparing the plasma and CSF concentra- tions of cytokines in suicidal patients vs. non-suicidal patients or healthy controls. Methods: We searched Medline, Web of Science, and PsycINFO from 1965 to November 2014 for relevant studies. Manual searches of references and unpublished data were also included. Suicidal patients included severe suicide ideators and suicide attempters. Results: Eleven articles were available for the meta-analysis, for a total sample size of 494 suicidal patients, 497 non-suicidal patients and 398 healthy controls. Levels of 6 inde- pendent plasma cytokines (IL2, IL6, TNFalpha, IFNgamma, IL4, TGFbeta) were meta-analyzed for plasma studies comparing suicidal vs. both controls. IL8 level was meta-analyzed for cerebrospinal fluid studies comparing suicidal patients with healthy controls. We reported with medium effect size, that suicidal patients had: (1) lower IL2 plasma levels than both non-suicidal patients and healthy controls (medium effect size); (2) lower IL4 and higher TGFbeta plasma levels than healthy controls. Conclusion: Our results promote the hypothesis of altered inflammatory markers in suicidal patients, for both pro-inflammatory (IL2) and anti-inflammatory (IL4 and TGFbeta) cytokines. Ó 2015 Elsevier Inc. All rights reserved. 1. Introduction Suicide is a leading cause of death worldwide (World Health Organization, 2014). Suicidal behavior (SB) refers to a continuum of behaviors from completed suicide to suicidal ideation (O’Carroll et al., 1996). Suicidal behavior disorder has been includ- ed in the DSM-5 as an independent clinical entity (American Psychiatric Association, 2013) due to the large amount of evidence demonstrating its specific pathophysiology. It highlights the need to address suicidal process as a specific condition of study (Aleman and Denys, 2014). Thus, to identify biomarkers will help to enhance our understanding of suicidal pathophysiology (National action alliance for suicide prevention) and improve its prevention. In addition to evidence of inflammatory alterations in major depressive disorder (MDD) (Dowlati et al., 2010; Valkanova et al., 2013), schizophrenia (Potvin et al., 2008) and bipolar disorder (Modabbernia et al., 2013), several lines of evidence support a link between inflammation and SB. First, epidemiological studies have revealed an association between allergy, asthma and suicidality (Goodwin and Eaton, 2005; Postolache et al., 2005; Timonen et al., 2004). Second, clinical case reports have noted emergence of SB in patients treated with cytokines (Baron et al., 1993; Fragoso et al., 2010). Third, increased levels of inflammatory mark- ers (cytokines IL2, IFN gamma, IL4, IL5, IL6, IL10, TNFalpha, IL6, IL8, TGFbeta1, C-reactive protein) in the cerebrospinal fluid (CSF) and plasma have been reported in suicidal patients. Four, postmortem studies are convergent with this hypothesis. Microgliosis has been reported in specific brain regions (i.e., dorsolateral prefrontal cor- tex, anterior cingulate cortex, mediodorsal thalamus) of schizo- phrenic and depressive patients who committed suicide (Schnieder et al., 2014; Steiner et al., 2008; Torres-Platas et al., 2014). Levels of mRNA or proteins expression of interleukin-1b (IL1b), IL4, IL13, IL6, and tumor necrosis factor-alpha (TNFalpha) were higher in orbitofrontal cortex of suicide victims than in sub- jects died of other causes (Pandey et al., 2012; Tonelli et al., 2008). Thus, one could propose that peripheral cytokine changes observed may mirror low-grade inflammation in central nervous system. However, it is still unclear whether central neuroinflammation is primary or whether peripheral inflammation is the precipitating factor of SB. http://dx.doi.org/10.1016/j.bbi.2015.02.004 0889-1591/Ó 2015 Elsevier Inc. All rights reserved. ⇑ Corresponding author at: Department of Psychiatric Emergency & Acute Crisis, Lapeyronie Hospital, Montpellier, France. Tel.: +33 4 67 33 85 81; fax: +33 4 67 33 89 88. E-mail address: d-ducasse@chu-montpellier.fr (D. Déborah). Brain, Behavior, and Immunity xxx (2015) xxx–xxx Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier.com/locate/ybrbi Please cite this article in press as: Déborah, D., et al. A meta-analysis of cytokines in suicidal behavior. Brain Behav. Immun. (2015), http://dx.doi.org/ 10.1016/j.bbi.2015.02.004