Abstract
Mitochondrial dysfunction has been implicated in major depressive disorder (MDD). A measure of mitochondrial respiratory chain (RC) enzymatic activity—the Mitochondrial Health Index (MHI)—has previously been found to correlate with stress and emotional states in caregivers. We here report mitochondrial RC activities, mitochondrial DNA copy number (mtDNAcn), and the composite MHI in unmedicated and somatically healthy subjects with MDD (n = 47) and healthy controls (HC) (n = 11). We also explore, in a subset of the MDD sample (n = 33), whether these markers are associated with response to 8 weeks of SSRI treatment. Mitochondrial RC complexes I, II, IV, citrate synthase (CS), mtDNAcn, and the MHI were assayed in peripheral blood mononuclear cells. Treatment response was defined as >50% decrease on the 25-item Hamilton Depression Rating Scale (HRDS-25). There were no significant differences in MHI or any of the mitochondrial markers between MDD subjects and HCs. Compared to SSRI nonresponders, SSRI responders had significantly higher baseline mitochondrial content markers CS (p = 0.02) and mtDNAcn (p = 0.02), and higher complex I activity (p = 0.01). Complex II activity increased significantly over treatment, irrespective of clinical response (p = 0.03). Complex I activity decreased in responders (n = 9), but increased in nonresponders (n = 18) (group x time interaction, p = 0.02). Absolute treatment-associated change in HDRS-25 scores correlated significantly with change in complex I activity between baseline and week 8 (r = 0.47, p = 0.01). Although mitochondrial markers did not distinguish MDD from controls, they did distinguish SSRI responders from nonresponders. If larger studies validate these mitochondrial differences, they may become useful biomarkers and identify new drug targets.
Highlights
Major Depressive Disorder (MDD) is a prevalent debilitating condition, but its overall pathophysiology remains unknown
There were no significant differences in age, BMI, or smoking between responders and nonresponders, but responders were more likely to be females
Age was significantly correlated with mitochondrial respiratory chain (RC) complex IV (r = −0.29, p = 0.04)
Summary
Major Depressive Disorder (MDD) is a prevalent debilitating condition, but its overall pathophysiology remains unknown. Apart from its psychiatric and behavioral manifestations, MDD is associated with early mortality and increased risk for several somatic conditions [2], raising the possibility of systemic pathologies, perhaps even cellular disturbances, such as telomere length shortening, inflammation, oxidative stress, and mitochondrial dysregulation [3,4,5,6,7,8]. Individuals with primary mitochondrial cytopathies have a very high risk of developing psychiatric disorders, MDD [14, 15]. This and other evidence have suggested a link between mitochondrial function and psychiatric symptoms, including MDD and other conditions [14, 16, 17]
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