title: Novel investigational drugs targeting IL-6 signaling for the treatment of depression.
abstract: BACKGROUND
  Elevated levels of IL-6 have been implicated in the pathophysiology and treatment of major depressive disorder (MDD). Convergent evidence suggests that IL-6 primarily mediates proinflammatory functions via the soluble IL-6 receptor/trans-signaling, and anti-inflammatory functions via a transmembrane receptor (IL-6R). A targeted approach to selectively inhibit IL-6 trans-signaling may offer putative antidepressant effects.
  
  
  METHODS
  This review addresses three primary domains. The first focuses on the biological role of IL-6 within inflammation and its signal transduction pathways. The second addresses the potential contributions of IL-6 to the pathophysiology of MDD, and the mechanisms that may mediate these effects. Finally, the article outlines the therapeutic benefits of incorporating anti-inflammatory properties into the pharmacological treatment of MDD, and proposes inhibition of IL-6 signaling as a viable treatment strategy.
  
  
  CONCLUSIONS
  To improve drug development for the treatment of MDD, there is a critical need to identify promising targets. Target identification will require guidance from a strategic framework such as The Research Domain Criteria, and convincing evidence relating known targets to brain function under both physiological and pathological conditions. Although current evidence provides rationale for administering anti-IL-6 treatments in MDD, further studies confirming safety, target affinity and therapeutic benefits are warranted.
authors.affiliation: University of Toronto, University Health Network, Department of Psychiatry , 200 Elizabeth Street, 8-EN-238, Toronto, M5G 2C4, ON , Canada +1 416 340 3888 ; +1 416 340 4198 ; sidney.kennedy@uhn.ca.
authors.forename: Trehani M
authors.initials: TM
authors.lastname: Fonseka
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
authors.forename: Joanna K
authors.initials: JK
authors.lastname: Soczynska
authors.forename: Sidney H
authors.initials: SH
authors.lastname: Kennedy
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D003865:Major Depressive Disorder / Q000188:drug therapy* / Q000503:physiopathology; D015195:Drug Design; D015507:Drugs, Investigational / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000093242:Interleukin-6 Inhibitors
chemical_list: D000928:Antidepressive Agents; D015507:Drugs, Investigational; D019947:Receptors, Interleukin-6; D000093242:Interleukin-6 Inhibitors
keywords: IL-6; antidepressant; cytokine; inflammation; major depression; soluble IL-6 receptor; soluble gp130Fc; trans-signaling