Association Between Inflammatory Markers and Cognitive Function in Adults With Bipolar Disorder: A Systematic Review

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INTRODUCTION: Bipolar disorder (BD) is frequently associated with cognitive dysfunction, which can significantly impact the quality of life and functional recovery of affected individuals. Growing evidence suggests that inflammation may contribute to the cognitive dysfunction observed in BD. METHODS: We conducted a systematic review following PRISMA guidelines, searching six databases on March 23, 2023 (PubMed, Embase, Cochrane Library, Web of Science, PsycINFO, and ClinicalTrials.gov), with the aim of identifying studies that examined the relationship between peripheral or central inflammatory markers and cognitive function in adults with BD. Studies involving animals, abstracts, protocols, reviews, and non-English publications were excluded. The quality of included studies was assessed using the Risk of Bias in Non-Randomized Studies-of Exposure (ROBINS-E). A narrative synthesis was completed, stratifying results based on the associations between inflammatory markers and cognitive domains in BD. The review protocol was pre-registered in PROSPERO (CRD42023415437). RESULTS: Out of 2680 identified records, 25 studies involving 3567 adults with BD (mean age: 43.6 years; 1839 females and 1728 males) met the inclusion criteria. Seventeen studies were classified as low risk of bias, seven as having some concerns, and one as high risk. Elevated levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1 receptor antagonist (IL-1Ra) were most commonly associated with cognitive dysfunction in domains such as executive function, processing speed, and memory. Findings for other inflammatory markers were less consistent. Most studies relied on cross-sectional designs, which limit causal interpretations. CONCLUSION: This review found a consistent association between inflammation and cognitive dysfunction in BD, particularly involving CRP, TNF-α, IL-6, and IL-1RA in areas such as executive function, processing speed, and memory. Targeting inflammation may offer a promising approach to mitigating these cognitive challenges. Future studies should prioritize longitudinal designs, standardized cognitive assessments, and the exploration of central inflammatory markers to better understand the neurobiological processes underlying cognitive dysfunction in BD. These findings may help inform the development of adjunctive anti-inflammatory strategies to support cognitive health in individuals with BD.

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