Mitochondrial DNA Copy Number Raises the Potential of Left Frontopolar Hemodynamic Response as a Diagnostic Marker for Distinguishing Bipolar Disorder From Major Depressive Disorder

Abstract

Background: Given a lack of markers, diagnoses of bipolar disorder (BD) and major depressive disorder (MDD) rely on clinical assessment of symptoms. However, the depressive mood states of BD and depressive symptoms of MDD are often difficult to distinguish, which leads to misdiagnoses, which in turn leads to inadequate treatment. Previous studies have shown that the hemodynamic responses of the left frontopolar cortex measured by near-infrared spectroscopy (NIRS) differ between BD and MDD; these hemodynamic responses are associated with altered mitochondrial metabolism; and mitochondrial DNA copy number (mtDNAcn), an index of mitochondrial dysfunction, tends to decrease in BD and increase in MDD patients. In this study, we confirmed that mtDNAcn trends in opposite directions in BD and MDD. We then determined whether mtDNAcn could enhance the utility of NIRS as a diagnostic marker to distinguish between BD and MDD. Methods: We determined mtDNAcn in peripheral blood samples from 58 healthy controls, 79 patients with BD, and 44 patients with MDD. Regional hemodynamic responses during a verbal fluency task (VFT) in 24 BD patients and 44 MDD patients, matched by age and depression severity, were monitored using NIRS. Results: Measurements of mtDNAcn were lower in BD patients and higher in MDD patients than in controls. The left frontopolar region exhibited the most significant differences in mean VFT-related oxy-Hb changes between the BD and MDD groups. Multivariate logistic regression analysis with variables including age, sex, hemodynamic response of the left frontopolar region, and mtDNAcn showed high accuracy for distinguishing BD from MDD (area under the curve = 0.917; 95% confidence interval = 0.849–0.985). For the BD group, we observed a positive correlation between hemodynamic responses in the left frontopolar region and mtDNAcn, while for the MDD group, we observed a negative correlation. Conclusions: Our findings suggest that the association between hemodynamic response and mitochondrial dysfunction in BD or MDD plays an important role in differentiating the pathophysiological mechanisms of BD from those of MDD.

Circulating Brain-Derived Neurotrophic Factor, Antioxidant Enzymes Activities, and Mitochondrial DNA in Bipolar Disorder: An Exploratory Report

“…A significant decreased mtDNAcn levels in manic patients was found in this study. The change of mtDNAcn was discussed in our previous report ( 28 ) and confirmed in later studies ( 56 , 57 ). To the best of our knowledge, this is the first study to explore the relationship between BDNF and mtDNAcn in BD.…”

Neurobiology of bipolar disorders: a review of genetic components, signaling pathways, biochemical changes, and neuroimaging findings

“…Regarding BD, there is an inconsistency in mtDNA copy number (mtDNAcn) studies that could be attributed to the diversity in clinical features, tissue types, and ethnicity. 71,[152][153][154][155] A recent meta-analysis identified no significant differences in mtDNAcn exhibited by BD patients or controls, while an Asian-specific meta-analysis for BD-mtDNAcn studies revealed significantly lower mtDNAcn in patients with BD, with a low level of heterogeneity. 155 Moreover, mtDNAcn was inversely correlated with the number of relapses of manic episodes.…”

Leukocyte mitochondrial DNA copy number and built environment in Mexican Americans: a cross-sectional study

“…Second, the demographic data used in our study were self-reported. Third, mtDNA copy number in leukocytes may modify the risk of several types of chronic diseases and conditions 1 – 23 as well as biobehavioral factors, but the direction and strength of each association differs significantly. Thus, it is difficult to determine the exact underlying cause of each observed association and its potential health outcomes.…”

“…Molecular epidemiologic studies have shown that mitochondrial DNA (mtDNA) copy number in leukocytes may modify the risk of several types of cancers 1 – 13 , diabetes 14 , 15 , cardiovascular disease 16 , 17 , and aging-related diseases 18 , 19 , as well as psychological disorders such as stress 20 , 21 and depression 22 , 23 . Thus, mtDNA copy number may serve as an important indicator of health.…”