Infections, Anti-infective Agents, and Risk of Deliberate Self-harm and Suicide in a Young Cohort: A Nationwide Study

  • Helene Gjervig Hansen
    Address correspondence to Helene Gjervig Hansen, M.D., Mental Health Centre Copenhagen, Kildegårdsvej 28, DK-2900 Hellerup, Capital Region of Denmark, Denmark.
    Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Danish Research Institute for Suicide Prevention, Mental Health Centre Copenhagen, Copenhagen, Denmark
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  • Ole Köhler-Forsberg
    Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Psychosis Research Unit, Aarhus University Hospital, Risskov, Denmark
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  • Liselotte Petersen
    National Centre for Register-based Research, Aarhus University, Aarhus, Denmark

    Centre for Integrated Register-based Research at Aarhus University, Aarhus, Denmark

    iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
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  • Merete Nordentoft
    Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Danish Research Institute for Suicide Prevention, Mental Health Centre Copenhagen, Copenhagen, Denmark

    iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, Aarhus, Denmark
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  • Teodor T. Postolache
    University of Maryland School of Medicine, Baltimore, Maryland

    Rocky Mountain Mental Illness Research, Education and Clinical Center for Suicide Prevention, Denver, Colorado

    The Military and Veteran Microbiome Consortium for Research and Education, Denver, Colorado
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  • Annette Erlangsen
    Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark

    Danish Research Institute for Suicide Prevention, Mental Health Centre Copenhagen, Copenhagen, Denmark

    Institute of Regional Health Research, University of Southern Denmark, Odense, Denmark
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  • Michael E. Benros
    Mental Health Centre Copenhagen, Copenhagen University Hospital, Copenhagen, Denmark
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Published:November 21, 2018DOI:



      Evidence links infections to mental disorders and suicidal behavior. However, knowledge is sparse regarding less severe infections, anti-infective treatment, and deliberate self-harm. Using nationwide Danish longitudinal registers, we estimated associations between infections treated with anti-infective agents and infections requiring hospitalization with the risk of deliberate self-harm.


      A total of 1.3 million people born between 1977 and 2002 were followed during the period from 1995 to 2013. In total, 15,042 individuals were recorded with deliberate self-harm (92% had been treated with anti-infective agents and 19% had been hospitalized for infections) and 114 died by suicide (64% had been treated with anti-infective agents and 13% had been hospitalized for infections). Hazard rate ratios were obtained while adjusting for age, gender, calendar period, education, hospitalizations with infections, prescribed anti-infective agents during childhood, parental mental disorders, and parental deliberate self-harm.


      Individuals with infections treated with anti-infective agents had an increased risk of deliberate self-harm with a hazard rate ratio of 1.80 (95% confidence interval = 1.68–1.91). The associations fitted a dose–response relationship (p < .001) and remained significant up to 5 years after last infection. An additive effect was found for individuals with an additional hospitalization for infections with an increased hazard rate ratio of 3.20 (95% confidence interval = 2.96–3.45) for deliberate self-harm.


      An increased risk of deliberate self-harm was found among individuals with infections treated with anti-infective agents in temporal and dose–response associations. These results add to the growing literature on a possible link between infections and the pathophysiological mechanisms of suicidal behavior.


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      1. World Health Organization (2014): Preventing suicide: A global imperative. Available at: Published 2014. Accessed December 2, 2015.

        • Fedyszyn I.E.
        • Erlangsen A.
        • Hjorthøj C.
        • Madsen T.
        • Nordentoft M.
        Repeated suicide attempts and suicide among individuals with a first emergency department contact for attempted suicide.
        J Clin Psychiatry. 2016; 77: 832-840
        • Carroll R.
        • Metcalfe C.
        • Gunnell D.
        Hospital presenting self-harm and risk of fatal and non-fatal repetition: Systematic review and meta-analysis.
        PLoS One. 2014; 9: e89944
        • Geulayov G.
        • Ferrey A.
        • Casey D.
        • Wells C.
        • Fuller A.
        • Bankhead C.
        • et al.
        Relative toxicity of benzodiazepines and hypnotics commonly used for self-poisoning: An epidemiological study of fatal toxicity and case fatality.
        J Psychopharmacol. 2018; 32: 654-662
        • Hawton K.
        • van Heeringen K.
        Lancet. 2009; 373: 1372-1381
        • Erlangsen A.
        • Appadurai V.
        • Wang Y.
        • Turecki G.
        • Mors O.
        • Werge T.
        • et al.
        Genetics of suicide attempts in individuals with and without mental disorders: A population-based genome-wide association study.
        Mol Psychiatry. 2018; ([published online ahead of print Aug 16])
        • Brundin L.C.
        • Grit J.
        Ascertaning whether suicides are caused by infections.
        JAMA Psychiatry. 2016; 73: 895-896
        • 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
        • Steiner J.
        • Bielau H.
        • Brisch R.
        • Danos P.
        • Ullrich O.
        • Mawrin C.
        • et al.
        Immunological aspects in the neurobiology of suicide: Elevated microglial density in schizophrenia and depression is associated with suicide.
        J Psychiatr Res. 2008; 42: 151-157
        • 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
        • 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
        • 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
        • 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
        • 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
        • Black C.
        • Miller B.J.
        Meta-analysis of cytokines and chemokines in suicidality: Distinguishing suicidal versus nonsuicidal patients.
        Biol Psychiatry. 2015; 78: 28-37
        • Ducasse D.
        • Olié E.
        • Guillaume S.
        • Artéro S.
        • Courtet P.
        A meta-analysis of cytokines in suicidal behavior.
        Brain Behav Immun. 2015; 46: 203-211
        • Cryan J.F.
        • O’Mahony S.M.
        The microbiome-gut-brain axis: From bowel to behavior.
        Neurogastroenterol Motil. 2011; 23: 187-192
        • Mayer E.A.
        • Knight R.
        • Mazmanian S.K.
        • Cryan X.J.F.
        • Tillisch K.
        Gut microbes and the brain : Paradigm shift in neuroscience.
        J Neurosci. 2014; 34: 15490-15496
        • Lund-Sørensen H.
        • Benros M.E.
        • Madsen T.
        • Sørensen H.J.
        • Eaton W.W.
        • Postolache T.T.
        • et al.
        A nationwide cohort study of the association between hospitalization with infection and risk of death by suicide.
        JAMA Psychiatry. 2016; 73: 912-919
        • Okusaga O.
        • Yolken R.H.
        • Langenberg P.
        • Arling T.A.
        • Dickerson F.B.
        • Scrandis D.A.
        • et al.
        Association of seropositivity for influenza and coronaviruses with history of mood disorders and suicide attempts.
        J Affect Disord. 2011; 130: 220-225
        • Zhang Y.
        • Träskman-Bendz L.
        • Janelidze S.
        • Langenberg P.
        • Saleh A.
        • Constantine N.
        • et al.
        Toxoplasma gondii immunoglobulin G antibodies and nonfatal suicidal self-directed violence.
        J Clin Psychiatry. 2012; 73: 1069-1076
        • Yagmur F.
        • Yazar S.
        • Temel H.O.
        • Cavusoglu M.
        May Toxoplasma gondii increase suicide attempt? Preliminary results in Turkish subjects.
        Forensic Sci Int. 2010; 199: 15-17
        • Arling T.A.
        • Yolken R.H.
        • Lapidus M.
        • Langenberg P.
        • Dickerson F.B.
        • Zimmerman S.A.
        • et al.
        Toxoplasma gondii antibody titers and history of suicide attempts in patients with recurrent mood disorders.
        J Nerv Ment Dis. 2009; 197: 905-908
        • Okusaga O.
        • Langenberg P.
        • Sleemi A.
        • Vaswani D.
        • Giegling I.
        • Hartmann A.M.
        • et al.
        Toxoplasma gondii antibody titers and history of suicide attempts in patients with schizophrenia.
        Schizophr Res. 2011; 133: 150-155
        • Pedersen M.G.
        • Mortensen P.B.
        • Norgaard-Pedersen B.
        • Postolache T.T.
        Toxoplasma gondii infection and self-directed violence in mothers.
        Arch Gen Psychiatry. 2012; 69: 1123-1130
        • Kohler O.
        • Petersen L.
        • Mors O.
        • Mortensen P.B.
        • Yolken R.H.
        • Gasse C.
        • et al.
        Exposure to anti-infective agents and the risk of severe mental disorders—A nationwide study.
        Acta Psychiatr Scand. 2017; 22: 14-15
        • Nielsen P.R.
        • Benros M.E.
        • Mortensen P.B.
        Hospital contacts with infection and risk of schizophrenia: A population-based cohort study with linkage of Danish national registers.
        Schizophr Bull. 2014; 40: 1526-1532
        • Benros M.E.
        • Nielsen P.R.
        • Nordentoft M.
        • Eaton W.W.
        • Dalton S.O.
        • Mortensen P.B.
        Autoimmune diseases and severe infections as risk factors for schizophrenia: A 30-year population-based register study.
        Am J Psychiatry. 2011; 168: 1303-1310
        • Benros M.E.
        • Waltoft B.L.
        • Nordentoft M.
        • Ostergaard S.D.
        • Eaton W.W.
        • Krogh J.
        • et al.
        Autoimmune diseases and severe infections as risk factors for mood disorders: A nationwide study.
        JAMA Psychiatry. 2013; 70: 812-820
        • Blomström A.
        • Karlsson H.
        • Svensson A.
        • Frisell T.
        • Lee B.K.
        • Dal H.
        • et al.
        Hospital admission with infection during childhood and risk for psychotic illness—A population-based cohort study.
        Schizophr Bull. 2013; 40: 1-8
        • Wium-Andersen M.K.
        • Ørsted D.D.
        • Nielsen S.F.
        • Nordestgaard B.G.
        Elevated C-reactive protein levels, psychological distress, and depression in 73,131 individuals.
        JAMA Psychiatry. 2013; 70: 176-184
        • Khandaker G.M.
        • Pearson R.M.
        • Zammit S.
        • Lewis G.
        • Jones P.B.
        Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life.
        JAMA Psychiatry. 2014; 71: 1121-1128
        • Janelidze S.
        • Brundin L.
        Inflammation in suicidality: Implications for novel treatment options.
        Mod Trends Pharmacopsychiatry. 2013; 28: 188-202
        • Miná V.A.L.
        • Lacerda-Pinheiro S.F.
        • Maia L.C.
        • Pinheiro R.F.F.
        • Meireles C.B.
        • de Souza S.I.R.
        • et al.
        The influence of inflammatory cytokines in physiopathology of suicidal behavior.
        J Affect Disord. 2015; 172: 219-230
        • Serafini G.
        • Pompili M.
        • Elena Seretti M.
        • Stefani H.
        • Palermo M.
        • Coryell W.
        • et al.
        The role of inflammatory cytokines in suicidal behavior: A systematic review.
        Eur Neuropsychopharmacol. 2013; 23: 1672-1686
        • Brundin L.
        • Erhardt S.
        • Bryleva E.Y.
        • Achtyes E.D.
        • Postolache T.T.
        The role of inflammation in suicidal behaviour.
        Acta Psychiatr Scand. 2015; 132: 192-203
        • Batty G.D.
        • Bell S.
        • Stamatakis E.
        • Kivimäki M.
        Association of systemic inflammation with risk of completed suicide in the general population.
        JAMA Psychiatry. 2016; 73: 993-995
        • 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.
        Brain Behav Immun. 2015; 43: 110-117
        • Erhardt S.
        • Lim C.K.
        • Linderholm K.R.
        • Janelidze S.
        • Lindqvist D.
        • Samuelsson M.
        • et al.
        Connecting inflammation with glutamate agonism in suicidality.
        Neuropsychopharmacology. 2013; 38: 743-752
        • Sublette M.E.
        • Galfalvy H.C.
        • Fuchs D.
        • Lapidus M.
        • Grunebaum M.F.
        • Oquendo M.A.
        • et al.
        Plasma kynurenine levels are elevated in suicide attempters with major depressive disorder.
        Brain Behav Immun. 2011; 25: 1272-1278
        • Brundin L.
        • Sellgren C.M.
        • Lim C.K.
        • Grit J.
        • Pålsson E.
        • Landén M.
        • et al.
        An enzyme in the kynurenine pathway that governs vulnerability to suicidal behavior by regulating excitotoxicity and neuroinflammation.
        Transl Psychiatry. 2016; 6: e865
        • Pedersen C.B.
        The Danish Civil Registration System.
        Scand J Public Health. 2011; 39: 22-25
        • Lynge E.
        • Sandegaard J.L.
        • Rebolj M.
        The Danish National Patient Register.
        Scand J Public Health. 2011; 39: 30-33
        • Mors O.
        • Perto G.P.
        • Mortensen P.B.
        The Danish Psychiatric Central Research Register.
        Scand J Public Health. 2011; 39: 54-57
        • Ferrer M.
        • Méndez-García C.
        • Rojo D.
        • Barbas C.
        • Moya A.
        Antibiotic use and microbiome function.
        Biochem Pharmacol. 2017; 134: 114-126
        • Schizophrenia Working Group of the Psychiatric Genomoics Consortium
        Biological insights from 108 schizophrenia-associated genetic loci.
        Nature. 2014; 511: 421-427
        • Püntener U.
        • Booth S.G.
        • Perry V.H.
        • Teeling J.L.
        Long-term impact of systemic bacterial infection on the cerebral vasculature and microglia.
        J Neuroinflammation. 2012; 9: 146
        • Nørgaard H.C.B.
        • Søndergaard Pedersen H.
        • Fenger-Grøn M.
        • Mors O.
        • Nordentoft M.
        • Vestergaard M.
        • et al.
        Increased use of primary care during 6 years of prodromal schizophrenia.
        Acta Psychiatr Scand. 2016; 134: 225-233
        • Erlangsen A.
        • Fedyszyn I.
        Danish nationwide registers for public health and health-related research.
        Scand J Public Health. 2015; 43: 333-339
        • Kardas P.
        • Devine S.
        • Golembesky A.
        • Roberts C.
        A systematic review and meta-analysis of misuse of antibiotic therapies in the community.
        Int J Antimicrob Agents. 2005; 26: 106-113
        • Benros M.E.
        • Pedersen M.G.
        • Rasmussen H.
        • Eaton W.W.
        • Nordentoft M.
        • Mortensen P.B.
        A nationwide study on the risk of autoimmune diseases in individuals with a personal or a family history of schizophrenia and related psychosis.
        Am J Psychiatry. 2014; 171: 218-226
        • Morthorst B.R.
        • Soegaard B.
        • Nordentoft M.
        • Erlangsen A.
        Incidence rates of deliberate self-harm in Denmark 1994-2011: A nationwide register study.
        Crisis. 2016; 37: 256-264

      Linked Article

      • Infections, Anti-infective Medications, and Suicidal Behavior: An Association Bearing Further Investigation
        Biological PsychiatryVol. 85Issue 9
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          Deliberate self-harm, encompassing suicide attempts, completed suicides, and nonsuicidal self-injurious behavior, is a global public health problem with a particularly strong impact on the world’s youth and young adults. In the United States, suicide is the third leading cause of death among children 10 to 14 years of age and the second leading cause of death among adolescents and adults 15 to 34 years of age (1). Suicide attempts far outnumber completed suicides, and the personal, social, and economic costs of suicidal behavior are staggering.
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