Advertisement

Meta-Analysis of Cytokines and Chemokines in Suicidality: Distinguishing Suicidal Versus Nonsuicidal Patients

      Abstract

      Background

      Major psychiatric disorders are associated with inflammation. Aberrant cytokine and chemokine levels have been associated with psychiatric disorders and suicidal behavior. We performed a meta-analysis of cytokine and chemokine levels in patients with versus without suicidality and patients with suicidality versus healthy controls.

      Methods

      We identified articles by searching MEDLINE, PsycINFO, and Thomson Reuters Web of Knowledge databases and the reference lists of identified studies.

      Results

      Study inclusion criteria were met by 18 studies comprising 583 patients with suicidality, 315 patients without suicidality, and 845 healthy control subjects. Levels of interleukin (IL)-1β and IL-6 were significantly increased in blood and postmortem brain samples of patients with suicidality compared with both patients without suicidality and healthy control subjects (p < .05 for each). In vitro IL-2 production by peripheral blood mononuclear cells was significantly decreased in patients with suicidality compared with both patients without suicidality and healthy controls (p < .01 for each). Cerebrospinal fluid levels of IL-8 were significantly decreased in patients with suicidality versus control subjects (p < .05).

      Conclusions

      We found evidence for aberrant cytokine levels in blood, cerebrospinal fluid, and postmortem brain samples of patients with suicidality. Levels of IL-1β and IL-6 were most robustly associated with suicidality, and these cytokines may help distinguish suicidal from nonsuicidal patients. Rigorously designed longitudinal studies are needed to evaluate these associations further.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Biological Psychiatry
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Dowlati Y.
        • Herrmann N.
        • Swardfater W.
        • Liu H.
        • Sham L.
        • Reim E.
        • Lanctot K.L.
        A meta-analysis of cytokines in major depression.
        Biol Psychiatry. 2010; 67: 446-457
        • Miller B.J.
        • Buckley P.
        • Seabolt W.
        • Mellor A.
        • Kirkpatrick B.
        Meta-analysis of cytokine alterations in schizophrenia: Clinical status and antipsychotic effects.
        Biol Psychiatry. 2011; 70: 663-671
        • Munkholm K.
        • Braüner J.V.
        • Kessing L.V.
        • Vinberg M.
        Cytokines in bipolar disorder vs. healthy control subjects: A systematic review and meta-analysis.
        J Psychiatr Res. 2013; 47: 1119-1133
        • Crews F.T.
        • Bechara R.
        • Brown L.A.
        • Guidot D.M.
        • Mandrekar P.
        • Oak S.
        • et al.
        Cytokines and alcohol.
        Alcohol Clin Exp Res. 2006; 30: 720-730
        • Díaz-Marsá M.
        • Macdowell K.S.
        • Guemes I.
        • Rubio V.
        • Carrasco J.L.
        • Leza J.C.
        Activation of the cholinergic anti-inflammatory system in peripheral blood mononuclear cells from patients with borderline personality disorder.
        J Psychiatr Res. 2012; 46: 1610-1617
        • MacDowell K.S.
        • Díaz-Marsá M.
        • Güemes I.
        • Rodríguez A.
        • Leza J.C.
        • Carrasco J.L.
        Inflammatory activation and cholinergic anti-inflammatory system in eating disorders.
        Brain Behav Immun. 2013; 32: 33-39
        • Lindqvist D.
        • Wolkowitz O.M.
        • Mellon S.
        • Yehuda R.
        • Flory J.D.
        • Henn-Haase C.
        • et al.
        Proinflammatory milieu in combat related PTSD is independent of depression and early life stress [published online ahead of print Jun 12].
        Brain Behav Immun. 2014;
        • Stuart M.J.
        • Baune B.T.
        Chemokines and chemokine receptors in mood disorders, schizophrenia, and cognitive impairment: A systematic review of biomarker studies.
        Neurosci Biobehav Rev. 2014; 42: 93-115
        • Baumeister D.
        • Russell A.
        • Pariante C.M.
        • Mondelli V.
        Inflammatory biomarker profiles of mental disorders and their relation to clinical, social and lifestyle factors.
        Soc Psychiatry Psychiatr Epidemiol. 2014; 49: 841-849
        • Tidemalm D.
        • Långström N.
        • Lichtenstein P.
        • Runeson B.
        Risk of suicide after suicide attempt according to coexisting psychiatric disorder: Swedish cohort study with long term follow-up.
        BMJ. 2008; 337: a2205
        • Jones K.A.
        • Thomsen C.
        The role of innate immune system in psychiatric disorders.
        Mol Cell Neurosci. 2013; 53: 52-62
        • Serafini G.
        • Pompili M.
        • Elena Seretti M.
        • Stefani H.
        • Palermo M.
        • Coryell W.
        • Girardi P.
        The role of inflammatory cytokines in suicidal behavior: A systematic review.
        Eur Neuropsychopharmacol. 2013; 23: 1672-1686
        • Bay-Richter C.
        • Linderholm K.R.
        • Lim C.K.
        • Samuelsson M.
        • Träskman-Bendz L.
        • Guillemin G.J.
        • et al.
        A role for inflammatory metabolites as modulators of the glutamate N-methyl-d-aspartate receptor in depression and suicidality [published online ahead of print Aug 12].
        Brain Behav Immun. 2014;
        • Gabbay V.
        • Klein R.G.
        • Guttman L.E.
        • Babb J.S.
        • Alonso C.M.
        • Nishawala M.
        • et al.
        A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression.
        J Child Adolesc Psychopharmacol. 2009; 19: 423-430
        • Grassi-Oliveira R.
        • Brieztke E.
        • Teixeira A.
        • Pezzi J.C.
        • Zanini M.
        • Lopes R.P.
        • Bauer M.E.
        Peripheral chemokine levels in women with recurrent major depression with suicidal ideation.
        Rev Bras Psiquiatr. 2012; 34: 71-75
        • Huang T.
        • Lee C.
        T-helper 1/T-helper 2 cytokine imbalance and clinical phenotypes of acute-phase major depression.
        Psychiatry Clin Neurosci. 2007; 61: 415-420
        • Isung J.
        • Aeinehband S.
        • Mobarrez F.
        • Mårtensson B.
        • Nordström P.
        • Asberg M.
        • et al.
        Low vascular endothelial growth factor and interleukin-8 in cerebrospinal fluid of suicide attempters.
        Transl Psychiatry. 2012; 2: e196
        • Isung J.
        • Mobarrez F.
        • Nordström P.
        • Asberg M.
        • Jokinen J.
        Low plasma vascular endothelial growth factor (VEGF) associated with completed suicide.
        World J Biol Psychiatry. 2012; 13: 468-473
        • Janelidze S.
        • Mattei D.
        • Westrin Å.
        • Träskman-Bendz L.
        • Brundin L.
        Cytokine levels in the blood may distinguish suicide attempters from depressed patients.
        Brain Behav Immun. 2011; 25: 335-339
        • Janelidze S.
        • Ventorp F.
        • Erhardt S.
        • Hansson O.
        • Minthon L.
        • Flax J.
        • et al.
        Altered chemokine levels in the cerebrospinal fluid and plasma of suicide attempters.
        Psychoneuroendocrinology. 2013; 38: 853-862
        • Karlović D.
        • Serretti A.
        • Vrkić N.
        • Martinac M.
        • Marčinko D.
        Serum concentrations of CRP, IL-6, TNF-α and cortisol in major depressive disorder with melancholic or atypical feature.
        Psychiatry Res. 2012; 198: 74-80
        • Kim Y.K.
        • Lee S.W.
        • Kim S.H.
        • Shim S.H.
        • Han S.W.
        • Choi S.H.
        • Lee B.H.
        Differences in cytokines between non-suicidal patients and suicidal patients in major depression.
        Prog Neuropsychopharmacol Biol Psychiatry. 2008; 32: 356-361
        • Lee H.Y.
        • Kim Y.K.
        Transforming growth factor-β1 and major depressive disorder with and without attempted suicide: Preliminary study.
        Psychiatry Res. 2010; 178: 92-96
        • Li Z.
        • Qi D.
        • Chen J.
        • Zhang C.
        • Yi Z.
        • Yuan C.
        • et al.
        Venlafaxine inhibits the upregulation of plasma tumor necrosis factor-alpha (TNF-α) in the Chinese patients with major depressive disorder: A prospective longitudinal study.
        Psychoneuroendocrinology. 2013; 38: 107-114
        • Lindqvist D.
        • Janelidze S.
        • Hagell P.
        • Erhardt S.
        • Samuelsson M.
        • Minthon L.
        • et al.
        Interleukin-6 is elevated in the cerebrospinal fluid of suicide attempters and related to symptom severity.
        Biol Psychiatry. 2009; 66: 287-292
        • Lindqvist D.
        • Janelidze S.
        • Erhardt S.
        • Träskman-Bendz L.
        • Engström G.
        • Brundin L.
        CSF biomarkers in suicide attempters—a principal component analysis.
        Acta Psychiatr Scand. 2011; 124: 52-61
        • Mendlovic S.
        • Mozes E.
        • Eilat E.
        • Doron A.
        • Lereya J.
        • Zakuth V.
        • Spirer Z.
        Immune activation in non-treated suicidal major depression.
        Immunol Lett. 1999; 67: 105-108
        • Monfrim X.
        • Gazal M.
        • De Leon P.B.
        • Quevedo L.
        • Souza L.D.
        • Jansen K.
        • et al.
        Immune dysfunction in bipolar disorder and suicide risk: Is there an association between peripheral corticotropin-releasing hormone and interleukin-1β?.
        Bipolar Disord. 2014; 16: 741-747
        • Nassberger L.
        • Traskman-Bendz L.
        Increased soluble interleukin-2 receptor concentrations in suicide attempters.
        Acta Psychiatr Scand. 1993; 88: 48-52
        • O’Donovan A.
        • Rush G.
        • Hoatam G.
        • Hughes B.M.
        • McCrohan A.
        • Kelleher C.
        • et al.
        Suicidal ideation is associated with elevated inflammation in patients with major depressive disorder.
        Depress Anxiety. 2013; 30: 307-314
        • Pandey G.N.
        • Rizavi H.S.
        • Ren X.
        • Fareed J.
        • Hoppensteadt D.A.
        • Roberts R.C.
        • et al.
        Proinflammatory cytokines in the prefrontal cortex of teenage suicide victims.
        J Psychiatr Res. 2012; 46: 57-63
        • Rothenhäusler H.B.
        • Stepan A.
        • Kapfhammer H.P.
        Soluble interleukin 2 receptor levels, temperament and character in formerly depressed suicide attempters compared with normal controls.
        Suicide Life Threat Behav. 2006; 36: 455-466
        • Tonelli L.H.
        • Stiller J.
        • Rujescu D.
        • Giegling I.
        • Schneider B.
        • Maurer K.
        • et al.
        Elevated cytokine expression in the orbitofrontal cortex of victims of suicide.
        Acta Psychiatr Scand. 2008; 117: 198-206
        • Vargas H.O.
        • Nunes S.O.
        • Pizzo de Castro M.
        • Bortolasci C.C.
        • Sabbatini Barbosa D.
        • Kaminami Morimoto H.
        • et al.
        Oxidative stress and lowered total antioxidant status are associated with a history of suicide attempts.
        J Affect Disord. 2013; 25: 923-930
        • DerSimonian R.
        • Laird N.
        Meta-analysis in clinical trials.
        Controlled Clin Trials. 1986; 7: 177-188
        • Hunter J.
        • Schmidt F.
        Fixed effects vs. random effects meta-analysis models: Implications for cumulative research knowledge.
        International Journal of Selection and Assessment. 2000; 8: 275-292
        • Cochran W.B.
        The comparison of percentages in matched samples.
        Biometrika. 1950; 37: 256-266
        • Song F.
        • Sheldon T.A.
        • Sutton A.J.
        • Abrams K.R.
        • Jones D.R.
        Methods for exploring heterogeneity in meta-analysis.
        Eval Health Prof. 2001; 24: 126-151
      1. Higgins JPT, Green S, editors (2011): Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Updated March 2011. 9.7. Sensitivity analyses. The Cochrane Collaboration, 2011. Available at: www.cochrane-handbook.org. Accessed September 2014.

        • Sterne J.A.C.
        • Egger M.
        Funnel plots for detecting bias in meta-analysis: Guidelines on choice of axis.
        J Clin Epidemiol. 2001; 54: 1046-1055
        • Egger M.
        • Davey Smith G.
        • Schneider M.
        • Minder C.
        Bias in meta-analysis detected by a simple, graphical test.
        BMJ. 1997; 315: 629-634
        • StataCorp
        Stata Statistical Software: Release 10.
        StataCorp LP, College Station, TX2007
        • O’Connor M.
        • Bower J.E.
        • Cho H.J.
        • Creswell J.D.
        • Dimitrov S.
        • Hamby M.E.
        • et al.
        To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers.
        Brain Behav Immun. 2009; 23: 887-897
        • Sullivan K.E.
        • Cutilli J.
        • Piliero L.M.
        • Ghavimi-Alagha D.
        • Starr S.E.
        • Campbell D.E.
        • Douglas S.D.
        Measurement of cytokine secretion, intracellular protein expression, and mRNA in resting and stimulated peripheral blood mononuclear cells.
        Clin Diagn Lab Immunol. 2000; 7: 920-924
        • Scheller J.
        • Chalaris A.
        • Schmidt-Arras D.
        • Rose-John S.
        The pro- and anti-inflammatory properties of the cytokine interleukin-6.
        Biochim Biophys Acta. 2011; 1813: 878-888
        • Nordentoft M.
        • Mortensen P.
        • Pedersen C.
        Absolute risk of suicide after first hospital contact in mental disorder.
        Arch Gen Psychiatry. 2011; 68: 1058-1064
        • Dieperink E.
        • Willenbring M.
        • Ho S.B.
        Neuropsychiatric symptoms associated with hepatitis C and interferon alpha: A review.
        Am J Psychiatry. 2000; 157: 867-876

      Linked Article

      • Cytokines as Suicide Risk Biomarkers
        Biological PsychiatryVol. 78Issue 1
        • Preview
          Suicide is a major public health problem as about 40,000 people die by suicide in the United States annually. Prevention and treatment of suicidal behavior are therefore very important. The major problem in the prevention of suicide is early identification and treatment of suicide-prone patients. Suicide is a multifactorial problem involving clinical, genetic, and neurobiological risk factors. The identification of risk factors that could accurately predict completed suicide has been investigated by many researchers.
        • Full-Text
        • PDF