Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications

Joshua D Rosenblat; Elisa Brietzke; Rodrigo B Mansur; Nadia A Maruschak; Yena Lee; Roger S McIntyre

doi:10.1016/j.jad.2015.08.058

Inflammation as a neurobiological substrate of cognitive impairment in bipolar disorder: Evidence, pathophysiology and treatment implications

J Affect Disord. 2015 Dec 1:188:149-59. doi: 10.1016/j.jad.2015.08.058. Epub 2015 Sep 2.

Authors

Joshua D Rosenblat¹, Elisa Brietzke², Rodrigo B Mansur³, Nadia A Maruschak⁴, Yena Lee⁴, Roger S McIntyre⁵

Affiliations

¹ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
² 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.
³ 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.
⁴ Mood Disorder Psychopharmacology Unit, University Health Network, Toronto, ON, Canada.
⁵ 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.

PMID: 26363613
DOI: 10.1016/j.jad.2015.08.058

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.

Conclusion: 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.

Keywords: Anti-inflammatory agents; Cytokines; Inflammation; Infliximab; Mood disorders; TNF-alpha.

Publication types

Research Support, Non-U.S. Gov't
Review
Systematic Review

MeSH terms

Anti-Inflammatory Agents / therapeutic use
Bipolar Disorder / complications
Bipolar Disorder / drug therapy
Bipolar Disorder / immunology*
Cognition / physiology
Cognition Disorders / complications
Cognition Disorders / drug therapy
Cognition Disorders / immunology*
Cytokines / immunology
Humans
Hypothalamo-Hypophyseal System / physiopathology
Inflammation / complications
Inflammation / immunology*
Male
Pituitary-Adrenal System / physiopathology

Substances

Anti-Inflammatory Agents
Cytokines