title: Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications.
abstract: BACKGROUND
  Bipolar disorder (BD) has been associated with cognitive impairment during depressed, manic and euthymic periods. Inflammation has been shown to be involved in the pathophysiology of BD and cognitive impairment.
  
  
  METHODS
  For this systematic review, the MEDLINE/PubMed, Embase, Google Scholar and ClinicalTrials.gov databases were searched for relevant articles assessing the association between cognitive function and inflammatory markers in BD subjects. A discussion of potential mechanisms and therapeutic implications is also included to provide further context to the subject matter.
  
  
  RESULTS
  Eight studies, including a total of 555 BD subjects, assessing the association between cognitive function and inflammatory markers were identified. Cognitive dysfunction was associated with elevated levels of pro-inflammatory markers YKL40, IL-6, sCD40L, IL-1Ra, hsCRP and TNF-α. Mechanistically, elevation in inflammatory cytokines alters monoamine levels leading to cognitive and affective dysfunction. Neuro-inflammation, manifesting as microglial activation, leads to increased oxidative stress, pathologic synaptic pruning and impaired neuroplasticity in key brain regions sub-serving mood and cognition. Immune dysfunction also activates the hypothalamic-pituitary-adrenal (HPA) axis leading to hypercortisolemia and metabolic dysfunction, further promoting neuronal dysfunction. Anti-inflammatory agents are therefore currently being investigated in the treatment of BD and appear to exert an antidepressant effect; however, cognitive outcomes have yet to be reported.
  
  
  CONCLUSIONS
  Several studies suggest that immune dysfunction is associated with cognitive impairment in BD. Several neurobiological pathways have been identified whereby immune dysfunction may promote cognitive impairment in BD. Future investigations of anti-inflammatory agents targeting cognitive function as a treatment outcome are merited.
authors.affiliation: Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Rosenblat
authors.affiliation: Interdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Paulo, Sao Paulo, Brazil; Program of Recognition and Intervention in Individuals in AT-Risk Mental States (PRISMA), Department of Psychiatry, Universidade FeInterdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Pauloderal de São Paulo, São Paulo, Brazil.
authors.forename: Elisa
authors.initials: E
authors.lastname: Brietzke
authors.affiliation: Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Interdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Paulo, Sao Paulo, Brazil; Program of Recognition and Intervention in Individuals in AT-Risk Mental States (PRISMA), Department of Psychiatry, Universidade FeInterdisciplinary Laboratory of Clinical Neurosciences (LINC), Federal University of Sao Pauloderal de São Paulo, São Paulo, Brazil.
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Mansur
authors.affiliation: Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Maruschak
authors.affiliation: Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
authors.forename: Yena
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: roger.mcintyre@uhn.ca.
authors.forename: Roger S
authors.initials: RS
authors.lastname: McIntyre
mesh_terms: D000893:Anti-Inflammatory Agents / Q000627:therapeutic use; D001714:Bipolar Disorder / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D003071:Cognition / Q000502:physiology; D003072:Cognition Disorders / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000503:physiopathology; D007249:Inflammation / Q000150:complications / Q000276:immunology*; D008297:Male; D010913:Pituitary-Adrenal System / Q000503:physiopathology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines
keywords: Anti-inflammatory agents; Cytokines; Inflammation; Infliximab; Mood disorders; TNF-alpha