Novel investigational drugs targeting IL-6 signaling for the treatment of depression

Abstract

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• antidepressant
• cytokine
• IL-6
• inflammation
• major depression
• soluble gp130Fc
• soluble IL-6 receptor
• trans-signaling

Declaration of interest

TM Fonseka is a recipient of a Canadian Institutes of Health Research (CIHR) 2012 Frederick Banting and Charles Best Masters Award. RS McIntyre has received grant/research support from Stanley Medical Research Institute, National Alliance for Research on Schizophrenia and Depression (NARSAD), and National Institutes of Mental Health. SH Kennedy has received grant/research support from Ontario Brain Institute, and CIHR. Furthermore, RS McIntyre has received research grants from Eli Lilly and Co., Janssen-Ortho, Shire, AstraZeneca, Pfizer, Inc., and Lundbeck A/S. RS McIntyre has served on advisory boards and/or speakers bureaus, and/or participated in CME activities for AstraZeneca, Bristol-Myers Squibb, France Foundation, GlaxoSmithKline, Janssen-Ortho, Eli Lilly and Co., Organon, Lundbeck A/S, Pfizer, Inc., Shire, Merck & Co., I3CME, Physicians’ Postgraduate Press, CME Outfitters and Optum Health. JK Soczynska has received fellowship funding from Eli Lilly Canada. SH Kennedy has received research support from Lundbeck A/S, St. Jude Medical, Bristol-Myers Squibb and Clera, Inc. They have also received speaking fees from and/or are members of an advisory board for Eli Lilly & Co., Lundbeck A/S, the Lundbeck Institute, Pfizer, Inc., Bristol Myers Squibb, Servier and Forest Laboratories. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

This box summarizes key points contained in the article.