Association of inflammation with depression and anxiety: evidence for symptom-specificity and potential causality from UK Biobank and NESDA cohorts

Yuri Milaneschi, Nils Kappelmann, Zheng Ye, Femke Lamers, Sylvain Moser, Peter B Jones, Stephen Burgess, Brenda W J H Penninx, Golam M Khandaker, Yuri Milaneschi, Nils Kappelmann, Zheng Ye, Femke Lamers, Sylvain Moser, Peter B Jones, Stephen Burgess, Brenda W J H Penninx, Golam M Khandaker

Abstract

We examined whether inflammation is uniformly associated with all depressive and anxiety symptoms, and whether these associations are potentially causal. Data was from 147,478 individuals from the UK Biobank (UKB) and 2,905 from the Netherlands Study of Depression and Anxiety (NESDA). Circulating C-reactive protein (CRP) was measured in both cohorts and interleukin-6 (IL-6) in NESDA. Genetic instruments for these proteins were obtained from published GWAS and UKB. Depressive and anxiety symptoms were assessed with self-report questionnaires. In NESDA, neurovegetative (appetite, sleep, psychomotor) symptoms were disaggregated as increased vs. decreased. In joint analyses, higher CRP was associated with depressive symptoms of depressed mood (OR = 1.06, 95% CI = 1.05-1.08), altered appetite (OR = 1.25, 95%CI = 1.23-1.28), sleep problems (OR = 1.05, 95%CI = 1.04-1.06), and fatigue (OR = 1.12, 95% CI = 1.11-1.14), and with anxiety symptoms of irritability (OR = 1.06, 95% CI = 1.05-1.08) and worrying control (OR = 1.03, 95% CI = 1.02-1.04). In NESDA, higher IL-6 was additionally associated with anhedonia (OR = 1.30, 95% CI = 1.12-1.52). Higher levels of both CRP (OR = 1.27, 95% CI = 1.13-1.43) and IL-6 (OR = 1.26, 95% CI = 1.07-1.49) were associated with increased sleep. Higher CRP was associated with increased appetite (OR = 1.21, 95% CI = 1.08-1.35) while higher IL-6 with decreased appetite (OR = 1.45, 95% CI = 1.18-1.79). In Mendelian Randomisation analyses, genetically predicted higher IL-6 activity was associated with increased risk of fatigue (estimate = 0.25, SE = 0.08) and sleep problems (estimate = 0.19, SE = 0.07). Inflammation was associated with core depressive symptoms of low mood and anhedonia and somatic/neurovegetative symptoms of fatigue, altered sleep and appetite changes. Less consistent associations were found for anxiety. The IL-6/IL-6R pathway could be causally linked to depression. Experimental studies are required to further evaluate causality, mechanisms, and usefulness of immunotherapies for depressive symptoms.

Conflict of interest statement

BWJHP has received research funding (unrelated to the work reported here) from Jansen Research and Boehringer Ingelheim. The remaining authors declare that they have no conflict of interest.

© 2021. The Author(s).

Figures

Fig. 1. Association estimates of CRP with…
Fig. 1. Association estimates of CRP with depressive and anxiety symptoms from UKB and NESDA cohorts.
Association estimates are shown with individual depressive and anxiety symptoms (A) and depressive summary scores (B). Models have been adjusted for age, sex and SES (Model 1), additionally adjusted for smoking, alcohol consumption, physical activity and T2D/CVD (Model 2), and additionally adjusted for BMI (Model 3).
Fig. 2. NESDA association estimates of CRP…
Fig. 2. NESDA association estimates of CRP and IL-6 with depressive and anxiety symptoms.
Association estimates are shown with individual depressive and anxiety symptoms (A) and depressive summary scores (B). Models have been adjusted for age, sex and SES (Model 1), additionally adjusted for smoking, alcohol consumption, physical activity and T2D/CVD (Model 2), and additionally adjusted for BMI (Model 3).
Fig. 3. Mendelian randomisation results of CRP…
Fig. 3. Mendelian randomisation results of CRP and IL-6 with depressive and anxiety symptoms.
MR association estimates are shown with individual depressive and anxiety estimates (A) and depression summary scores (B). Results reflect MR IVW estimates based on Georgakis et al. [28] instruments; exact numeric values are presented in Supplementary Tables 11 and 12.

References

    1. Udina M, Castellvi P, Moreno-Espana J, Navines R, Valdes M, Forns X, et al. Interferon-induced depression in chronic hepatitis C: a systematic review and meta-analysis. J Clin Psychiatry. 2012;73:1128–1138.
    1. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK, et al. A meta-analysis of cytokines in major depression. Biol Psychiatry. 2010;67:446–457.
    1. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med. 2009;71:171–186.
    1. Goldsmith DR, Rapaport MH, Miller BJ. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry. 2016;21:1–14.
    1. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206–215.
    1. Köhler CA, Freitas TH, Maes M, de Andrade NQ, Liu CS, Fernandes BS, et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr Scand. 2017;135:373–387.
    1. Mac Giollabhui, N., Ng, T.H., Ellman, L.M. et al. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis, and meta-regression. Mol Psychiatry. 2021;26:3302–3314
    1. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019;49:1958–1970.
    1. Costello H, Gould RL, Abrol E, Howard R. Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder. BMJ Open. 2019;9:e027925.
    1. Jokela M, Virtanen M, Batty G, Kivimäki M. Inflammation and specific symptoms of depression. JAMA Psychiatry. 2016;73:87–88.
    1. Lamers F, Milaneschi Y, de Jonge P, Giltay EJ, Penninx BWJH. Metabolic and inflammatory markers: associations with individual depressive symptoms. Psychol Med. 2018;48:1102–1110.
    1. Fried EI, von Stockert S, Haslbeck JMB, Lamers F, Schoevers RA, Penninx BWJH. Using network analysis to examine links between individual depressive symptoms, inflammatory markers, and covariates. Psychol Med. 2020;50:2682–2690.
    1. Simmons WK, Burrows K, Avery JA, Kerr KL, Taylor A, Bodurka J, et al. Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry. 2020;25:1457–1468.
    1. Moriarity DP, Horn SR, Kautz MM, Haslbeck JMB, Alloy LB. How handling extreme C-reactive protein (CRP) values and regularization influences CRP and depression criteria associations in network analyses. Brain Behav Immun. 2021;91:393–403.
    1. Badini I, Coleman JR, Hagenaars SP, Hotopf M, Breen G, Lewis CM, et al. Depression with atypical neurovegetative symptoms shares genetic predisposition with immuno-metabolic traits and alcohol consumption. Psychol Med. 2020:1–11. 10.1017/S0033291720002342. [Epub ahead of print].
    1. Köhler-Forsberg O, Buttenschøn HN, Tansey KE, Maier W, Hauser J, Dernovsek MZ, et al. Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression. Brain Behav Immun. 2017;62:344–350.
    1. Milaneschi Y, Lamers F, Peyrot WJ, Abdellaoui A, Willemsen G, Hottenga J-J, et al. Polygenic dissection of major depression clinical heterogeneity. Mol Psychiatry. 2016;21:516–522.
    1. Milaneschi Y, Lamers F, Peyrot WJ, Baune BT, Breen G, Dehghan A, et al. Genetic association of major depression with atypical features and obesity-related immunometabolic dysregulations. JAMA Psychiatry. 2017;74:1214–1225.
    1. Lamers F, Milaneschi Y, Vinkers CH, Schoevers RA, Giltay EJ, Penninx BWJH. Depression profilers and immuno-metabolic dysregulation: Longitudinal results from the NESDA study. Brain Behav Immun. 2020;88:174–183.
    1. Lawlor DA, Harbord RM, Sterne JAC, Timpson N, Davey, Smith G. Mendelian randomization: using genes as instruments for making causal inferences in epidemiology. Stat Med. 2008;27:1133–1163.
    1. Kappelmann N, Arloth J, Georgakis MK, Czamara D, Rost N, Ligthart S, et al. Dissecting the association between inflammation, metabolic dysregulation, and specific depressive symptoms. JAMA Psychiatry. 2021;78:161–170.
    1. Sudlow C, Gallacher J, Allen N, Beral V, Burton P, Danesh J, et al. UK Biobank: an open access resource for identifying the causes of a wide range of complex diseases of middle and old age. PLOS Med. 2015;12:e1001779.
    1. Penninx BWJH, Beekman ATF, Smit JH, Zitman FG, Nolen WA, 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.
    1. Davis KAS, Coleman JRI, Adams M, Allen N, Breen G, Cullen B, et al. Mental health in UK Biobank – development, implementation and results from an online questionnaire completed by 157 366 participants: a reanalysis. BJPsych Open. 2020;6:e18.
    1. Thorp JG, Marees AT, Ong J-S, An J, MacGregor S, Derks EM. Genetic heterogeneity in self-reported depressive symptoms identified through genetic analyses of the PHQ-9. Psychol Med. 2019;9:1–12.
    1. Townsend P, Phillimore P, Beattie A. Health and deprivation: inequality and the North. London: Routledge; 1988.
    1. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–188.
    1. Georgakis MK, Malik R, Gill D, Franceschini N, Sudlow CLM, Dichgans M. Interleukin-6 Signaling Effects on Ischemic Stroke and Other Cardiovascular Outcomes: A Mendelian Randomization Study. Circ Genom Precis Med. 2020;13:e002872.
    1. C Reactive Protein Coronary Heart Disease Genetics Collaboration (CCGC Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data. BMJ. 2011;342:d548.
    1. Collaboration IGC and ERF Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012;379:1205–1213.
    1. The Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012;379:1214–1224.
    1. Burgess S, Davey Smith G, Davies NM, Dudbridge F, Gill D, Glymour MM, et al. Guidelines for performing Mendelian randomization investigations. Wellcome Open Res. 2020;4:186.
    1. Del Greco MF, Minelli C, Sheehan NA, Thompson JR. Detecting pleiotropy in Mendelian randomisation studies with summary data and a continuous outcome. Stat Med. 2015;34:2926–2940.
    1. Lamers F, Milaneschi Y, Smit JH, Schoevers RA, Wittenberg G, Penninx BWJH. Longitudinal association between depression and inflammatory markers: results from the Netherlands Study of Depression and Anxiety. Biol Psychiatry. 2019;85:829–837.
    1. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker M. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2019;76:74–81.
    1. Khandaker GM, Pearson RM, Zammit S, Lewis G, Jones PB. 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.
    1. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56.
    1. Milaneschi Y, Lamers F, Berk M, Penninx BWJH. Depression heterogeneity and its biological underpinnings: toward immunometabolic depression. Biol Psychiatry. 2020;88:369–380.
    1. Chen K, Li F, Li J, Cai H, Strom S, Bisello A, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. 2006;12:425–432.
    1. Timper K, Denson JL, Steculorum SM, Heilinger C, Engström-Ruud L, Wunderlich CM, et al. IL-6 improves energy and glucose homeostasis in obesity via enhanced central IL-6 trans-signaling. Cell Rep. 2017;19:267–280.
    1. Timpson NJ, Nordestgaard BG, Harbord RM, Zacho J, Frayling TM, Tybjærg-Hansen A, et al. C-reactive protein levels and body mass index: elucidating direction of causation through reciprocal Mendelian randomization. Int J Obes. 2011;35:300–308.
    1. Milaneschi Y, Lamers F, Penninx BWJH. Dissecting depression biological and clinical heterogeneity-the importance of symptom assessment resolution. JAMA Psychiatry. 2021;78:341.
    1. Ligthart S, Vaez A, Võsa U, Stathopoulou MG, de Vries PS, Prins BP, et al. Genome analyses of >200,000 individuals identify 58 loci for chronic inflammation and highlight pathways that link inflammation and complex disorders. Am J Hum Genet. 2018;103:691–706.
    1. Howard DM, Adams MJ, Clarke T-K, Hafferty JD, Gibson J, Shirali M, et al. Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions. Nat Neurosci. 2019;22:343–352.
    1. Khandaker GM. Commentary: causal associations between inflammation, cardiometabolic markers and schizophrenia: the known unknowns. Int J Epidemiol. 2019;48:1516–1518.
    1. Kelly K, Smith JA, Mezuk B. Depression and interleukin-6 signaling: A Mendelian Randomization Study. Brain Behav Immun. 2021. 10.1016/j.bbi.2021.02.019.
    1. Khandaker GM, Zuber V, Rees JM, Carvalho L, Mason AM, Foley CN, et al. Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort. Mol Psychiatry. 2020;25:1477–1486.
    1. Del Giudice M, Gangestad SW. Rethinking IL-6 and CRP: why they are more than inflammatory biomarkers, and why it matters. Brain Behav Immun. 2018;70:61–75.
    1. Hunter CA, Jones SA. IL-6 as a keystone cytokine in health and disease. Nat Immunol. 2015;16:448–457.
    1. Lynall M-E, Turner L, Bhatti J, Cavanagh J, de Boer P, Mondelli V, et al. Peripheral blood cell–stratified subgroups of inflamed depression. Biol Psychiatry. 2020;88:185–196.
    1. Branchi I, Poggini S, Capuron L, Benedetti F, Poletti S, Tamouza R, et al. Brain-immune crosstalk in the treatment of major depressive disorder. Eur Neuropsychopharmacol. 2021;45:89–107.
    1. Köhler-Forsberg O, Nicolaisen Lydholm C, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139:404–419.
    1. Kappelmann N, Lewis G, Dantzer R, Jones PB, Khandaker GM. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol Psychiatry. 2018;23:335–343.
    1. Wittenberg GM, Stylianou A, Zhang Y, Sun Y, Gupta A, Jagannatha PS, et al. Effects of immunomodulatory drugs on depressive symptoms: a mega-analysis of randomized, placebo-controlled clinical trials in inflammatory disorders. Mol Psychiatry. 2020;25:1275–1285.
    1. . Identifier NCT02473289, an efficacy and safety study of sirukumab in participants with major depressive disorder. , 2019.
    1. Khandaker GM, Oltean BP, Kaser M, Dibben CRM, Ramana R, Jadon DR, et al. Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open. 2018;8:e025333.
    1. Fourrier C, Sampson E, Mills NT, Baune BT. Anti-inflammatory treatment of depression: Study protocol for a randomised controlled trial of vortioxetine augmented with celecoxib or placebo. Trials. 2018;19:1–14.

Source: PubMed

スポンサーと協力者

医学的状態

薬物療法

3
購読する