Pharmacologic implications of inflammatory comorbidity in bipolar disorder Joshua D Rosenblat 1 , Jonathan M Gregory 2 and Roger S McIntyre 3,4 Bipolar disorder (BD) is a chronic illness associated with significant morbidity and mortality. Epidemiological studies have established a strong association between BD and inflammatory comorbidities. Furthermore, illness course is more severe and treatment resistant in BD with comorbid inflammatory disease and vice versa. Immune dysfunction has therefore been proposed as a key pathophysiological nexus sub-serving the bidirectional interaction between BD and inflammatory comorbidities. The foregoing observations have provided the rational and impetus for repurposing anti-inflammatory agents for the treatment of BD. Clinical trials have shown promising results for a variety of mechanistically diverse anti-inflammatory agents. N-Acetylcysteine, infliximab, pioglitazone, celecoxib, aspirin, and omega-3 polyunsaturated fatty acids have shown an antidepressant effect in BD when administered adjunctively to conventional treatments. Currently, insufficient evidence exists to support the routine use of anti-inflammatory agents in the treatment of BD with inflammatory comorbidities; however, several more clinical trials are current underway which may guide clinical application in the near future. Anti-inflammatory agents will likely be most useful for the subpopulation of BD where immune dysfunction is a driving pathogenic factor, such as in patients with inflammatory comorbidities. Future studies are striving to stratify subjects based on immune function or dysfunction in order to better understand which subset of BD subjects will benefit most from anti-inflammatory therapies. Addresses 1 Resident of Psychiatry, Clinician Scientist Stream, University of Toronto, Toronto, ON, Canada 2 Resident of Psychiatry, Western University, London, ON, Canada 3 Mood Disorder Psychopharmacology Unit, University Health Network, Canada 4 Psychiatry and Pharmacology, University of Toronto, Toronto, ON, Canada Corresponding author: McIntyre, Roger S (roger.mcintyre@uhn.ca, roger.mcintyre@uhn.ca) Current Opinion in Pharmacology 2016, 29:63–69 This review comes from a themed issue on Immunomodulation Edited by Fulvio D’Acquisto For a complete overview see the Issue and the Editorial Available online 9th July 2016 http://dx.doi.org/10.1016/j.coph.2016.06.007 1471-4892/# 2016 Elsevier Ltd. All rights reserved. Introduction Bipolar disorder (BD) is a chronic, relapsing and remitting illness that is associated with significant morbidity and mortality [1,2]. Patients with BD have a significantly decreased life expectancy, with an average life span of 8–16 years shorter than the general populations, primarily attributable to the high co-prevalence of medical comor- bidities [3,4  ]. More specifically, increased all-cause mor- tality in BD is primarily attributed to cardiovascular disease, a disease in which prognosis is highly dependent on inflammatory processes [3,4  ]. Replicated findings from large epidemiological studies have shown a strong association between BD and inflam- matory comorbidities [5  ]. Several inflammatory comor- bidities have been associated with BD including inflammatory bowel disease (IBD), systemic lupus erythematosis (SLE), autoimmune thyroiditis, psoriasis, Guillain-Barre ´ syndrome (GBS), autoimmune hepatitis, multiple sclerosis (MS), migraines, rheumatoid arthritis (RA), obesity, atherosclerosis and type II diabetes melli- tus [6–17]. Further, the presence of the foregoing inflam- matory comorbidities has been associated with a more severe BD illness and lower probability of recovering. [18,19  ]. In addition, BD has been associated with a less favorable outcome of inflammatory conditions [18]. Given the high co-occurrence of BD and inflammatory comorbidities, there is a need to develop novel pharmaco- logical approaches to improve outcomes in the treatment of this frequently encountered and often treatment-resis- tant populations [20  ]. Therefore, the aim of the current review is to discuss potential novel drug targets in the treatment of BD when comorbid immune dysfunction is present. A review of completed and ongoing clinical trials assessing the effects of anti-inflammatory agents in BD will subsequently ensue. Immune dysfunction: a common pathway with novel targets of interest Epidemiological findings of the association between BD and inflammatory disorders have led to the investi- gation of the role of immune dysfunction in BD in hopes of identifying a common pathophysiological pathway [5  ]. Preclinical and clinical studies have sug- gested that immune dysfunction may play a significant role in the pathophysiology of BD [19  ]. For a subpop- ulation of BD, some investigators have proposed that Available online at www.sciencedirect.com ScienceDirect www.sciencedirect.com Current Opinion in Pharmacology 2016, 29:63–69 Downloaded for Christopher Sendi (csendi@sendi.org) at Inova Fairfax Hospital - JCon from ClinicalKey.com by Elsevier on August 17, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved.