Lower pro- to anti-inflammatory ratios associated with reduced neurocognitive flexibility in symptomatic adolescents with bipolar disorder

Introduction: Peripheral inflammatory markers, such as C-reactive protein (CRP), are elevated among adolescents and adults with bipolar disorder (BD), particularly during symptomatic episodes. Neurocognition, predominantly in the domain of executive function, is also impaired among adults and youth with BD. In adults with BD, CRP is negatively associated with neurocognitive functioning. We aim to investigate this relationship in BD adolescents. Methods: Serum levels of CRP and five other inflammatory markers (interleukin (IL)-1 beta, IL-6, IL-10, IL-4 and tumor necrosis factor alpha (TNF)) were examined in 60 adolescents with BD (34 symptomatic, 26 asymptomatic) age-and sex-matched to 51 healthy controls (HC). Diagnoses were confirmed using semi-structured interviews. Pro-to anti-inflammatory marker ratios were also examined. Neurocognitive flexibility was assessed via the intra/extradimensional shift (IED) task from the CANTAB battery. Multivariate linear regression controlled for age, sex and race. Results: Within symptomatic BD adolescents, but not asymptomatic BD or HC adolescents, lower IL-6/IL-10 and lower CRP/IL-10 ratios were significantly associated with worse performance on the neurocognitive flexibility task (p = 0.03 and p = 0.04, respectively). Both models accounted for 13.3% of variance in neurocognitive flexibility. No significant CRP by diagnosis interaction effects were observed on neurocognitive flexibility. Limitations: Limited sample-size restricted ability to separate the symptomatic BD adolescents into varying mood states. Conclusion: More balanced pro-to anti-inflammatory ratios were associated with better neurocognitive flexibility in symptomatic BD adolescents. Prospective studies are warranted to assess the direction of these findings.