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

Introduction

Psychiatric disorders are linked to accelerated aging, but whether this phenomenon is targetable for treatment remains an open question. Existing psychotropic drugs may have beneficial effects on the cellular and molecular biology of aging. Nucleic acid (DNA and RNA) damage from oxidative stress is a key event in cellular aging that has been shown to be reduced by antidepressants in previous studies.

Aims

To characterize the association between antidepressant exposure and DNA/RNA damage from oxidative stress in humans and to uncover the potential mechanistic connection between antidepressant exposure and mitochondrial production of reactive oxygen species which could underlie such an association.

Methods

We studied validated markers of nucleic acid damage from oxidative stress in a large community cohort with comprehensive, register-based information on psychotropic treatment. We further characterized the influence of various antidepressants on mitochondrial function in animal models. The human cohort consisted of 7,732 individuals from population studies, who each had one study visit where blood sampling, urine sampling and physical examination were performed. Psychotropic treatment data was obtained from the Danish national prescription registry. The urinary nucleic acid oxidation markers 8-oxo-7,8-dihydroguanosine (RNA) and 8-oxo-7,8-dihydro-2’-deoxyguanosine (DNA) was measured with ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). We further used in vitro and subchronic in vivo exposure to antidepressants and measurement of mitochondrial production of reactive oxygen species and respiratory capacity in animal models. To disentangle how different pharmacological actions of antidepressants influence mitochondrial activity, we studied mitochondrial H₂O₂ production and respiratory capacity after exposure to either an almost purely serotonergic antidepressant (escitalopram) or an almost purely noradrenergic antidepressant (reboxetine). The human data were analyzed with with univariate analysis of variance. Correction for relevant potential confounders for oxidative stress (age, sex, study site, smoking status, body mass index, glycated hemoglobin, systolic blood pressure, c-reactive protein and calculated glomerular filtration rate) were performed by linear regression. For the mitochondrial analyses, a mixed-effects models were applied.

Results

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 (p < 0.001, p (adjusted) < 0.001), whereas the analogue RNA oxidation marker did not differ between the groups. We did not find evidence for an effect of antidepressant exposure on reactive oxygen species production or respiratory capacity.

Conclusions

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 lies outside of a direct effect on mitochondrial function. Further studies on the role of antidepressants in relation to molecular aging are relevant.

References

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