191. MITOCHONDRIAL DNA COPY NUMBER AS A MEDIATOR OF THE RELATIONSHIP BETWEEN INSULIN RESISTANCE AND COGNITIVE FUNCTION IN PATIENTS WITH EUTHYMIC BIPOLAR DISORDER

Abstract Background Patients with bipolar disorder (BD) often experience cognitive deficits that persist even during periods of mood stability. Our previous studies suggested insulin resistance may interact with BD to impact executive function. Mitochondrial DNA (mtDNA) copy number, a biomarker for mitochondrial dysfunction, is inversely associated with the severity of insulin resistance and cognitive impairment. Given the posited bidirectional relationship between insulin resistance and mitochondrial dysfunction, it is possible that mtDNA copy number might bridge the gap between metabolic dysfunction and cognitive capacity. Aims & Objectives To investigate whether mtDNA copy number can serve as an intermediary factor linking insulin resistance to executive dysfunction in patients with euthymic BD. Method In 68 study participants (27 female, 39 with bipolar I disorder) with euthymic BD, insulin resistance was assessed according to fasting glucose and insulin levels. mtDNA copy number was quantified from leukocytes, and executive function was measured with the Wisconsin Card-Sorting Test. Mediation models were applied to explore the statistical relationship between insulin resistance, mtDNA copy number, and executive function. Both linear regression and Poisson distribution approaches with robust bootstrap simulations were used for significance testing. Results The results indicated that insulin resistance indirectly affects executive function via mtDNA copy number. This mediation relationship was statistically significant for both preservation errors and completion of categories in the Wisconsin card-sorting test, although there were no significant direct effects of insulin resistance on the executive functions. Discussion & Conclusions We therefore concluded that insulin resistance is associated with reduced mtDNA copy number in blood, which may negatively impact executive functions in patients with euthymic BD. Further work is warranted to determine if improving metabolic and mitochondrial health may lead to better cognitive outcomes in BD.