A novel biomarker of interleukin 6 activity and clinical and cognitive outcomes in depression.

BACKGROUND: Inflammatory cytokines like interleukin-6 (IL-6) are implicated in depression, but most studies have hitherto focused on circulating levels of IL-6 rather than its activity. IL-6 trans-signalling is thought to be responsible for most of the pathogenic effects of IL-6 and is implicated in autoimmune diseases like rheumatoid arthritis. We tested the association between a multi-protein-derived measure of IL-6 trans-signalling and clinical and cognitive outcomes in patients with depression. We hypothesised that this novel measure of IL-6 activity/bioavailability would be associated with clinical and cognitive measures previously reported to be associated with inflammation in depression. METHODS: Using data from 86 patients with International Classification of Diseases-10 diagnosis of depression, we calculated a ratio score representing IL-6 activity/bioavailability using serum IL-6, soluble IL-6 receptor (sIL-6R), and soluble glycoprotein 130 levels. We tested the relationship of this novel biomarker with 12 cytokines using correlation analyses and with cognitive and clinical measures using multivariable linear regression, following z-transformation of all immune exposures. RESULTS: The novel measure of IL-6 activity/bioavailability was correlated with IL-6 (r=0.42, P=0.03), C-reactive protein (CRP) (r=0.42, P=0.03), sIL-6R (r=0.91, P<0.01), and tumour necrosis factor alpha (r=0.43, P=0.03). The IL-6 activity/bioavailability measure was associated with higher somatic symptoms of depression (ß=1.09; 95% CI 0.30, 1.88; PFDR=0.01), fatigue (ß=4.34; 95% CI 1.26, 7.42; PFDR=0.03), depression severity (ß=3.06; 95% CI 0.71, 5.40; P=0.02), poorer quality of life (ß=-0.07; 95% CI -0.13, -0.01; PFDR=0.045), and decreased psychomotor speed (ß=-5.46; 95% CI -9.09, -1.84; PFDR=0.01),. There was little evidence of associations with reaction time, anhedonia, anxiety, emotional perception and recall, executive function, and sustained attention (Ps>0.05). The effect estimates for the associations of the novel measure with depression outcomes were comparable to those for individual immune proteins (i.e., IL-6, CRP, sIL-6R). CONCLUSION: A novel multi-protein-derived measure of IL-6 activity/bioavailability shows robust associations with various inflammation-related clinical and cognitive outcomes in depression and performs well in comparison to single inflammatory proteins. We need replication of these findings in other samples, experiments for mechanistic validity of this novel biomarker, and clinical studies to assess its usefulness as a marker of illness risk and prognosis.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Inflammation is associated with a range of neuropsychiatric symptoms; however, the nature of the causal relationship is unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognition. We tested in ≈ 55,098 (59% female) individuals from the Dutch Lifelines cohort the concurrent/prospective associations of C-reactive protein (CRP) with: depressive and anxiety disorders; positive/negative affect; and attention, psychomotor speed, episodic memory, and executive functioning. Additionally, we examined the association between inflammatory GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (N max =57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (N max =23,268). In non-genetic analyses, higher CRP was associated with a depressive disorder, lower positive/higher negative affect, and worse executive function, attention, and psychomotor speed after adjusting for potential confounders. In genetic analyses, CRP GRS was associated with any anxiety disorder (ß = 0.002, p = 0.037) whereas GlycA GRS was associated with major depressive disorder (ß = 0.001, p = 0.036). Both CRP GRS (ß = 0.006, p = 0.035) and GlycA GRS (ß = 0.006, p = 0.049) were associated with greater negative affect. Inflammatory GRSs were not associated with cognition, except sIL-6R GRS which was associated with poorer memory (ß=-0.009, p = 0.018). There was weak evidence for a CRP-anxiety association using MR (ß = 0.12; p = 0.054). Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms.

Role of Inflammation in Depressive and Anxiety Disorders, Affect, and Cognition: Genetic and Non-Genetic Findings in the Lifelines Cohort Study.

Background: Low-grade systemic inflammation is implicated in the pathogenesis of various neuropsychiatric conditions affecting mood and cognition. While much of the evidence concerns depression, large-scale population studies of anxiety, affect, and cognitive function are scarce. Importantly, causality remains unclear. We used complementary non-genetic, genetic risk score (GRS), and Mendelian randomization (MR) analyses to examine whether inflammatory markers are associated with affect, depressive and anxiety disorders, and cognitive performance in the Lifelines Cohort; and whether associations are likely to be causal. Methods: Using data from up to 55,098 (59% female) individuals from the Dutch Lifelines cohort, we tested the cross-sectional and longitudinal associations of C-reactive protein (CRP) with (i) depressive and anxiety disorders; (ii) positive and negative affect scores, and (iii) five cognitive measures assessing attention, psychomotor speed, episodic memory, and executive functioning (figural fluency and working memory). Additionally, we examined the association between inflammatory marker GRSs (CRP, interleukin-6 [IL-6], IL-6 receptor [IL-6R and soluble IL-6R (sIL-6R)], glycoprotein acetyls [GlycA]) on these same outcomes (Nmax=57,946), followed by MR analysis examining evidence of causality of CRP on outcomes (Nmax=23,268). In genetic analyses, all GRSs and outcomes were z-transformed. Results: In non-genetic analyses, higher CRP was associated with diagnosis of any depressive disorder, lower positive and higher negative affect scores, and worse performance on tests of figural fluency, attention, and psychomotor speed after adjusting for potential confounders, although the magnitude of these associations was small. In genetic analyses, CRPGRS was associated with any anxiety disorder (ß=0.002, p=0.037, N=57,047) whereas GlycAGRS was associated with major depressive disorder (ß=0.001, p=0.036; N=57,047). Both CRPGRS (ß=0.006, p=0.035, N=57,946) and GlycAGRS (ß=0.006, p=0.049; N=57,946) were associated with higher negative affect score. Inflammatory marker GRSs were not associated with cognitive performance, except sIL-6RGRS which was associated with poorer memory performance (ß=-0.009, p=0.018, N=36,783). Further examination of the CRP-anxiety association using MR provided some weak evidence of causality (ß=0.12; p=0.054). Conclusions: Genetic and non-genetic analyses provide consistent evidence for an association between CRP and negative affect. Genetic analyses suggest that IL-6 signaling could be relevant for memory, and that the association between CRP and anxiety disorders could be causal. These results suggest that dysregulated immune physiology may impact a broad range of trans-diagnostic affective symptoms. However, given the small effect sizes and multiple tests conducted, future studies are required to investigate whether effects are moderated by sub-groups and whether these findings replicate in other cohorts.