¹National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Department of Psychiatry, Tainan, Taiwan, ²Chung Shan Medical University, School of Medicine, Taichung, Taiwan, ³Chung Shan Medical University Hospital, Department of Psychiatry, Taichung, Taiwan, ⁴Institute of ATP, Changhua Christian Hospital, Vascular and Genomic Center, Changhua, Taiwan, ⁵Changhua Christian Hospital, Department of Neurology, Changhua, Taiwan, ⁶College of Medicine, National Cheng Kung University, Institute of Behavioral Medicine, Tainan, Taiwan

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.