Longitudinal Association Between Depression and Inflammatory Markers: Results From the Netherlands Study of Depression and Anxiety



      While cross-sectional associations of inflammatory markers interleukin-6 (IL-6) and C-reactive protein with major depressive disorder are well established, evidence for longitudinal associations mostly comes from studies on depression symptoms, not diagnoses. This study examined cross-sectional and bidirectional longitudinal associations between depression diagnosis and symptoms in an adult sample over a 6-year period.


      Data were obtained from the baseline (n = 2416) and 2- and 6-year follow-up assessments (n = 1925 and n = 1924, respectively) of the Netherlands Study of Depression and Anxiety. C-reactive protein and IL-6 were assessed at each wave, as were the Composite International Diagnostic Interview and Inventory of Depressive Symptomatology. Linear mixed models and generalized estimating equation models with a binomial distribution were used to study longitudinal associations between depression and inflammation and vice versa.


      There was a consistent cross-sectional association between current depressive disorder (vs. no current disorder) and symptoms with IL-6 across all follow-up measurements (Cohen’s ddepression diagnosis = 0.06, p = .017; Bstandardized Inventory of Depressive Symptomatology = 0.029, SE = 0.011, p = .008). In longitudinal analyses, higher IL-6 levels predicted subsequent chronic course in those with a diagnosis at baseline in women but not in men (odds ratiowomen = 1.13, 95% confidence interval = 1.04–1.23), and both depressive disorder and high severity predicted higher IL-6 levels at the subsequent follow-up (p values < .01). In contrast, C-reactive protein was not associated with current depression in cross-sectional and longitudinal analyses.


      In this longitudinal study, cross-sectional and bidirectional longitudinal associations were found between depression and IL-6 levels. This underlines the importance of targeting inflammation pathways in the treatment of major depressive disorder. IL-6 could be a potential marker for patient profiling in personalized medicine approaches.


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        • Howren M.B.
        • Lamkin D.M.
        • Suls J.
        Associations of depression with C-reactive protein, IL-1, and IL-6: A meta-analysis.
        Psychosom Med. 2009; 71: 171-186
        • Dowlati Y.
        • Herrmann N.
        • Swardfager W.
        • Liu H.
        • Sham L.
        • Reim E.K.
        • Lanctot K.L.
        A meta-analysis of cytokines in major depression.
        Biol Psychiatry. 2010; 67: 446-457
        • Liu Y.
        • Ho R.C.-M.
        • Mak A.
        Interleukin (IL)-6, tumour necrosis factor alpha (TNF-α) and soluble interleukin-2 receptors (sIL-2R) are elevated in patients with major depressive disorder: A meta-analysis and meta-regression.
        J Affect Disord. 2012; 139: 230-239
        • Jansen R.
        • Penninx B.W.J.H.
        • Madar V.
        • Xia K.
        • Milaneschi Y.
        • Hottenga J.J.
        • et al.
        Gene expression in major depressive disorder.
        Mol Psychiatry. 2016; 21: 339-347
        • Mostafavi S.
        • Battle A.
        • Zhu X.
        • Potash J.B.
        • Weissman M.M.
        • Shi J.
        • et al.
        Type I interferon signaling genes in recurrent major depression: Increased expression detected by whole-blood RNA sequencing.
        Mol Psychiatry. 2014; 19: 1267-1274
        • Leday G.G.R.
        • Vértes P.E.
        • Richardson S.
        • Greene J.R.
        • Regan T.
        • Khan S.
        • et al.
        Replicable and coupled changes in innate and adaptive immune gene expression in two case-control studies of blood microarrays in major depressive disorder.
        Biol Psychiatry. 2018; 83: 70-80
        • 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
        • Sproston N.R.
        • Ashworth J.J.
        Role of C-reactive protein at sites of inflammation and infection.
        Front Immunol. 2018; 9: 754
        • Raison C.L.
        • Capuron L.
        • Miller A.H.
        Cytokines sing the blues: Inflammation and the pathogenesis of depression.
        Trends Immunol. 2006; 27: 24-31
        • Raison C.L.
        • Miller A.H.
        The evolutionary significance of depression in pathogen host defense (PATHOS-D).
        Mol Psychiatry. 2013; 18: 15-37
        • Valkanova V.
        • Ebmeier K.P.
        • Allan C.L.
        CRP, IL-6 and depression: A systematic review and meta-analysis of longitudinal studies.
        J Affect Disord. 2013; 150: 736-744
        • Smith K.J.
        • Au B.
        • Ollis L.
        • Schmitz N.
        The association between C-reactive protein, interleukin-6 and depression among older adults in the community: A systematic review and meta-analysis.
        Exp Gerontol. 2018; 102: 109-132
        • Pasco J.A.
        • Nicholson G.C.
        • Williams L.J.
        • Jacka F.N.
        • Henry M.J.
        • Kotowicz M.A.
        • et al.
        Association of high-sensitivity C-reactive protein with de novo major depression.
        Br J Psychiatry. 2010; 197: 372-377
        • Copeland W.E.
        • Shanahan L.
        • Worthman C.
        • Angold A.
        • Costello E.J.
        Cumulative depression episodes predict later C-reactive protein levels: A prospective analysis.
        Biol Psychiatry. 2012; 71: 15-21
        • 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: A population-based longitudinal study.
        JAMA Psychiatry. 2014; 71: 1121-1128
        • Glaus J.
        • von Känel R.
        • Lasserre A.M.
        • Strippoli M.-P.F.
        • Vandeleur C.L.
        • Castelao E.
        • et al.
        Mood disorders and circulating levels of inflammatory markers in a longitudinal population-based study.
        Psychol Med. 2018; 48: 961-973
        • Lamers F.
        • Hoogendoorn A.W.
        • Smit J.H.
        • Van Dyck R.
        • Zitman F.G.
        • Nolen W.A.
        • Penninx B.W.J.H.
        Socio-demographic and psychiatric determinants of attrition in the Netherlands Study of Depression and Anxiety (NESDA).
        Compr Psychiatry. 2012; 53: 63-70
        • Penninx B.W.J.H.
        • Beekman A.T.F.
        • Smit J.H.
        • Zitman F.G.
        • Nolen W.A.
        • Spinhoven P.
        • et al.
        The Netherlands Study of Depression and Anxiety (NESDA): Rationale, objectives and methods.
        Int J Methods Psychiatr Res. 2008; 17: 121-140
        • World Health Organization
        CIDI-Auto, Version 2.1: Administrator’s Guide.
        World Health Organization, Sydney, New South Wales, Australia1997
        • Vogelzangs N.
        • Duivis H.E.
        • Beekman A.T.F.
        • Kluft C.
        • Neuteboom J.
        • Hoogendijk W.
        • et al.
        Association of depressive disorders, depression characteristics and antidepressant medication with inflammation.
        Transl Psychiatry. 2012; 2: e79
        • Verduijn J.
        • Milaneschi Y.
        • Schoevers R.A.
        • van Hemert A.M.
        • Beekman A.T.F.
        • Penninx B.W.J.H.
        Pathophysiology of major depressive disorder: Mechanisms involved in etiology are not associated with clinical progression.
        Transl Psychiatry. 2015; 5: e649
        • Rush A.J.
        • Gullion C.M.
        • Basco M.R.
        • Jarrett R.B.
        • Trivedi M.H.
        The Inventory of Depressive Symptomatology (IDS): Psychometric properties.
        Psychol Med. 1996; 26: 477-486
        • Babor T.F.
        • Kranzler H.R.
        • Lauerman R.J.
        Early detection of harmful alcohol consumption: Comparison of clinical, laboratory, and self-report screening procedures.
        Addict Behav. 1989; 14: 139-157
        • Twisk J.
        Applied Multilevel Analysis: A Practical Guide for Medical Researchers.
        Cambridge University Press, Cambridge, UK2006
        • Galic S.
        • Oakhill J.S.
        • Steinberg G.R.
        Adipose tissue as an endocrine organ.
        Mol Cell Endocrinol. 2010; 316: 129-139
        • Felger J.C.
        • Haroon E.
        • Patel T.A.
        • Goldsmith D.R.
        • Wommack E.C.
        • Woolwine B.J.
        • et al.
        What does plasma CRP tell us about peripheral and central inflammation in depression?.
        Mol Psychiatry. 2018; ([published online ahead of print Jun 12])
        • Kim Y.
        • Noren Hooten N.
        • Dluzen D.F.
        • Martindale J.L.
        • Gorospe M.
        • Evans M.K.
        Posttranscriptional regulation of the inflammatory marker C-reactive protein by the RNA-binding protein HuR and microRNA 637.
        Mol Cell Biol. 2015; 35: 4212-4221
        • Horn S.R.
        • Long M.M.
        • Nelson B.W.
        • Allen N.B.
        • Fisher P.A.
        • Byrne M.L.
        Replication and reproducibility issues in the relationship between C-reactive protein and depression: A systematic review and focused meta-analysis.
        Brain Behav Immun. 2018; 73: 85-114
        • Lima B.B.
        • Hammadah M.
        • Wilmot K.
        • Pearce B.D.
        • Shah A.
        • Levantsevych O.
        • et al.
        Posttraumatic stress disorder is associated with enhanced interleukin-6 response to mental stress in subjects with a recent myocardial infarction.
        Brain Behav Immun. 2019; 75: 26-33
        • Marsland A.L.
        • Walsh C.
        • Lockwood K.
        • John-Henderson N.A.
        The effects of acute psychological stress on circulating and stimulated inflammatory markers: A systematic review and meta-analysis.
        Brain Behav Immun. 2017; 64: 208-219
        • Strawbridge R.
        • Arnone D.
        • Danese A.
        • Papadopoulos A.
        • Herane Vives A.
        • Cleare A.J.
        Inflammation and clinical response to treatment in depression: A meta-analysis.
        Eur Neuropsychopharmacol. 2015; 25: 1532-1543
        • Chamberlain S.R.
        • Cavanagh J.
        • de Boer P.
        • Mondelli V.
        • Jones D.N.C.
        • Drevets W.C.
        • et al.
        Treatment-resistant depression and peripheral C-reactive protein.
        Br J Psychiatry. 2019; 214: 11-19
        • Uher R.
        • Tansey K.E.
        • Dew T.
        • Maier W.
        • Mors O.
        • Hauser J.
        • et al.
        An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline.
        Am J Psychiatry. 2014; 171: 1278-1286
        • Vogelzangs N.
        • Beekman A.T.
        • van Reedt Dortland A.K.
        • Schoevers R.A.
        • Giltay E.J.
        • de Jonge P.
        • Penninx B.W.
        Inflammatory and metabolic dysregulation and the 2-year course of depressive disorders in antidepressant users.
        Neuropsychopharmacology. 2014; 39: 1624-1634
        • Kohler O.
        • Benros M.E.
        • Nordentoft M.
        • Farkouh M.E.
        • Iyengar R.L.
        • Mors O.
        • Krogh J.
        Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: A systematic review and meta-analysis of randomized clinical trials.
        JAMA Psychiatry. 2014; 17: 1381-1391
        • Galatzer-Levy I.R.
        • Bryant R.A.
        636,120 Ways to have posttraumatic stress disorder.
        Perspect Psychol Sci. 2013; 8: 651-662
        • Lamers F.
        • Milaneschi Y.
        • de Jonge P.
        • Giltay E.J.
        • Penninx B.W.J.H.
        Metabolic and inflammatory markers: Associations with individual depressive symptoms.
        Psychol Med. 2018; 48: 1102-1110
        • Rethorst C.D.
        • Moynihan J.
        • Lyness J.M.
        • Heffner K.L.
        • Chapman B.P.
        Moderating effects of moderate-intensity physical activity in the relationship between depressive symptoms and interleukin-6 in primary care patients.
        Psychosom Med. 2011; 73: 265-269
        • Jha M.K.
        • Minhajuddin A.
        • Gadad B.S.
        • Greer T.
        • Grannemann B.
        • Soyombo A.
        • et al.
        Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial.
        Psychoneuroendocrinology. 2017; 78: 105-113
        • Raison C.L.
        • Rutherford R.E.
        • Woolwine B.J.
        • Shuo C.
        • Schettler P.
        • Drake D.F.
        • et al.
        A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: Role of baseline inflammatory biomarkers.
        JAMA Psychiatry. 2013; 70: 31-41
        • Sun Y.
        • Wang D.
        • Salvadore G.
        • Hsu B.
        • Curran M.
        • Casper C.
        • et al.
        The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman’s disease.
        Brain Behav Immun. 2017; 66: 156-164
        • Lamers F.
        • de Jonge P.
        • Nolen W.A.
        • Smit J.H.
        • Zitman F.G.
        • Beekman A.T.
        • Penninx B.W.
        Identifying depressive subtypes in a large cohort study: Results from the Netherlands Study of Depression and Anxiety (NESDA).
        J Clin Psychiatry. 2010; 71: 1582-1589
        • Levitan R.D.
        • Davis C.
        • Kaplan A.S.
        • Arenovich T.
        • Phillips D.I.
        • Ravindran A.V.
        Obesity comorbidity in unipolar major depressive disorder: Refining the core phenotype.
        J Clin Psychiatry. 2012; 73: 1119-1124
        • Jha M.K.
        • Wakhlu S.
        • Dronamraju N.
        • Minhajuddin A.
        • Greer T.L.
        • Trivedi M.H.
        Validating pre-treatment body mass index as moderator of antidepressant treatment outcomes: Findings from CO-MED trial.
        J Affect Disord. 2018; 234: 34-37
        • Uher R.
        • Mors O.
        • Hauser J.
        • Rietschel M.
        • Maier W.
        • Kozel D.
        • et al.
        Body weight as a predictor of antidepressant efficacy in the GENDEP project.
        J Affect Disord. 2009; 118: 147-154
        • Del Giudice M.
        • Gangestad S.W.
        Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters.
        Brain Behav Immun. 2018; 70: 61-75

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