Translational characterization of oxidative stress-induced nucleic acid damage and mitochondrial function during antidepressant exposure

Psychiatric disorders are linked to accelerated aging, but whether this phenomenon is targetable for treatment remains an open question. Here, we studied validated markers of nucleic acid damage from oxidative stress in a large community cohort with comprehensive, register-based information on psychotropic treatment. In concordance with previous findings, we provide evidence that in humans, active exposure to antidepressants is associated with reduced levels of systemic oxidative stress on DNA, an important event in cellular aging. Hence, compared to individuals never treated or off treatment with antidepressants, individuals in active treatment had an approximately 12.5% lower level of the DNA oxidation marker, whereas the analogue RNA oxidation marker did not differ between the groups. To study a potential causal pathway underlying this observation, we further characterized how in vitro and subchronic in vivo exposure to antidepressants with serotonergic and noradrenergic mechanisms of action, respectively, influenced mitochondrial production of reactive oxygen species and respiratory capacity in animal models. We did not find evidence for an effect of antidepressant exposure on these specific aspects of mitochondrial physiology. Collectively, these findings show that antidepressant exposure is associated with reduced levels of oxidative stress on DNA in humans and indicate that the molecular underpinning of this observation may lie outside of a direct effect on mitochondrial formation of free radicals.