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Association of Inflammation with Depression and Anxiety: Evidence for Symptom-Specificity and Potential Causality from UK Biobank and NESDA Cohorts

By Yuri Milaneschi, Nils Kappelmann, Zheng Ye, Femke Lamers, Sylvain Moser, Peter B. Jones, Stephen Burgess, Brenda WJH Penninx, Golam M Khandaker

Posted 09 Jan 2021
medRxiv DOI: 10.1101/2021.01.08.20248710

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, circulating 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). Further analyses in NESDA using IL-6 as exposure confirmed associations with depressive symptoms, including anhedonia (OR=1.30, 95%CI=1.12-1.52). 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. CRP was associated with increased appetite (OR=1.21, 95%CI=1.08-1.35) while IL-6 with decreased appetite (OR=1.45, 95%CI=1.18-1.79). In Mendelian Randomization analyses, increased risk of fatigue (estimate=0.25, SE=0.08) and sleep problems (estimate=0.19, SE=0.07) were associated with genetically-predicted higher IL-6 activity. 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.

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