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.

Optogenetics enables manipulation of biological processes with light at high spatio-temporal resolution to control the behavior of cells, networks, or even whole animals. In contrast to the performance of excitatory rhodopsins, the effectiveness of inhibitory optogenetic tools is still insufficient. Here we report a two-component optical silencer system comprising photoactivated adenylyl cyclases (PACs) and the small cyclic nucleotide-gated potassium channel SthK. Activation of this ‘PAC-K’ silencer by brief pulses of low-intensity blue light causes robust and reversible silencing of cardiomyocyte excitation and neuronal firing. In vivo expression of PAC-K in mouse and zebrafish neurons is well tolerated, where blue light inhibits neuronal activity and blocks motor responses. In combination with red-light absorbing channelrhodopsins, the distinct action spectra of PACs allow independent bimodal control of neuronal activity. PAC-K represents a reliable optogenetic silencer with intrinsic amplification for sustained potassium-mediated hyperpolarization, conferring high operational light sensitivity to the cells of interest.

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.

Background: Concentrations of C-reactive protein (CRP), interleukin 6 (IL-6) and other inflammatory markers are elevated in people with depression and anxiety compared to controls, but evidence for disorder-specificity, linearity and potential causality is sparse. Methods: Using population-based data from up to 144,890 UK Biobank cohort participants, we tested associations of circulating CRP concentrations with depression and anxiety symptom scores and probable diagnosis, including tests for linearity, disorder-specificity and sex difference. We examined potential causality using 1sample and 2-sample Mendelian randomisation (MR) analyses testing associations of genetically-predicted CRP concentration and IL-6 activity with depression and anxiety. The study was conducted from June 2019 to February 2021. Findings: CRP concentration was associated with depressive and anxiety symptom scores and with probable diagnoses of depression and generalised anxiety disorder (GAD) in a dose-response fashion. These associations were stronger for depression than for anxiety, and for women than for men although less consistently. MR analyses provided consistent results suggesting that genetically predicted higher IL-6 activity was associated with increased risk for depressive symptoms, while genetically-predicted higher CRP concentration was associated with decreased risks of depressive and anxiety symptoms. Interpretation: Altered activity of the IL-6/IL-6R pathway could be a risk factor for depression. The field now requires experimental studies of IL-6 modulation in humans and animal models to further examine causality, mechanisms and treatment potential. Such studies are also needed to elucidate mechanisms for divergent associations of genetically-predicted higher IL-6 activity (risk increasing) and higher CRP concentrations (protective) with depression/anxiety.

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