title: Anti-inflammatory agents in the treatment of bipolar depression: a systematic review and meta-analysis.
abstract: OBJECTIVE
  Inflammation has been implicated in the risk, pathophysiology, and progression of mood disorders and, as such, has become a target of interest in the treatment of bipolar disorder (BD). Therefore, the objective of the current qualitative and quantitative review was to determine the overall antidepressant effect of adjunctive anti-inflammatory agents in the treatment of bipolar depression.
  
  
  METHODS
  Completed and ongoing clinical trials of anti-inflammatory agents for BD published prior to 15 May 15 2015 were identified through searching the PubMed, Embase, PsychINFO, and Clinicaltrials.gov databases. Data from randomized controlled trials (RCTs) assessing the antidepressant effect of adjunctive mechanistically diverse anti-inflammatory agents were pooled to determine standard mean differences (SMDs) compared with standard therapy alone.
  
  
  RESULTS
  Ten RCTs were identified for qualitative review. Eight RCTs (n = 312) assessing adjunctive nonsteroidal anti-inflammatory drugs (n = 53), omega-3 polyunsaturated fatty acids (n = 140), N-acetylcysteine (n = 76), and pioglitazone (n = 44) in the treatment of BD met the inclusion criteria for quantitative analysis. The overall effect size of adjunctive anti-inflammatory agents on depressive symptoms was -0.40 (95% confidence interval -0.14 to -0.65, p = 0.002), indicative of a moderate and statistically significant antidepressant effect. The heterogeneity of the pooled sample was low (I² = 14%, p = 0.32). No manic/hypomanic induction or significant treatment-emergent adverse events were reported.
  
  
  CONCLUSIONS
  Overall, a moderate antidepressant effect was observed for adjunctive anti-inflammatory agents compared with conventional therapy alone in the treatment of bipolar depression. The small number of studies, diversity of agents, and small sample sizes limited interpretation of the current analysis.
authors.affiliation: Mood Disorders Psychopharmacology Unit, University Health Network, Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rosenblat
authors.affiliation: Mood Disorders Psychopharmacology Unit, University Health Network, Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.|Department of Psychiatry, Western University, London and Windsor, ON, Canada.
authors.forename: Ron
authors.initials: R
authors.lastname: Kakar
authors.affiliation: IMPACT Strategic Research Centre, School of Medicine, Deakin University, Geelong, Vic., Australia.|Department of Psychiatry, The Florey Institute of Neuroscience and Mental Health, and Orygen, The National Centre of Excellence in Youth Mental Health, Centre for Youth Mental Health, University of Melbourne, Parkville, Vic., Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.affiliation: Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences and Department O, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars V
authors.initials: LV
authors.lastname: Kessing
authors.affiliation: Psychiatric Center Copenhagen, Faculty of Health and Medical Sciences and Department O, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Maj
authors.initials: M
authors.lastname: Vinberg
authors.affiliation: Discipline of Psychiatry, University of Adelaide, Adelaide, SA, Australia.
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
authors.affiliation: Mood Disorders Psychopharmacology Unit, University Health Network, Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.|Interdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Paulo, São Paulo, Brazil.|Program of Recognition and Intervention in Individuals in AT-Risk Mental States (PRISMA), Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Mansur
authors.affiliation: Interdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Paulo, São Paulo, Brazil.|Program of Recognition and Intervention in Individuals in AT-Risk Mental States (PRISMA), Department of Psychiatry, Universidade Federal de São Paulo, São Paulo, Brazil.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.affiliation: Departments of Psychiatry, Pharmacology, and Psychological Clinical Science, Centre for Youth Bipolar Disorder, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada.
authors.forename: Benjamin I
authors.initials: BI
authors.lastname: Goldstein
authors.affiliation: Mood Disorders Psychopharmacology Unit, University Health Network, Department of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada.
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000175:diagnosis / Q000188:drug therapy / Q000503:physiopathology; D003863:Depression / Q000188:drug therapy*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000523:psychology; D016032:Randomized Controlled Trials as Topic
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal
keywords: N-acetylcysteine (NAC); aspirin; bipolar disorder; depression; inflammation; infliximab; minocycline; nonsteroidal anti-inflammatory drugs (NSAIDs); omega 3 polyunsaturated fatty acids; pioglitazone