Inflammation and Immunity in Depression: from novel mechanisms towards therapeutics (360G-Wellcome-201486_B_16_Z)

Animal experimental, epidemiological and treatment studies support an association between the immune system and depression, where inflammatory cytokines such as interleukin 6 (IL-6) are thought to play a key role. I will apply adequately powered randomised designs, at population and experimental medicine levels, to test conclusively whether the association between IL-6 and depression is causal. Particular attention will be paid to neurovegetative symptoms of depression which are likely to be closely related to inflammation. Study 1 will apply Mendelian randomization design to test causality between IL-6 and depression by addressing residual confounding using existing data on serum IL-6 concentrations, genetic polymorphisms regulating serum IL-6 concentration, and depressive symptoms from 14 cohorts that will be brought together by establishing a consortium. Study 2 will test whether neurovegetative symptoms mediate the relationship between IL-6 and depression. Study 3 will translate animal experimental findings regarding inflammation- induced depression to humans and elucidate whether the IL-6 pathway is causally linked to depression by using a proof-of-concept, double-blind, randomized, placebo-controlled experiment; I will test whether complete inhibition of IL-6 classic and trans-signalling with single intravenous infusion of the IL-6 receptor monoclonal antibody tocilizumab reduces serum proinflammatory cytokine concentrations and improves neurovegetative symptoms in treatment resistant depression.