Psychiatric disorders have long been associated with accelerated biological aging. People with depression and related conditions show, on average, higher rates of age-related somatic disease and shortened life expectancy, and one of the molecular processes thought to underlie this link is oxidative stress. Reactive oxygen species, the chemically unstable byproducts of aerobic metabolism, constantly attack the cell’s macromolecules. When they strike DNA or RNA, they generate oxidized nucleosides that can be measured in urine and blood. The most widely used of these biomarkers is 8-oxo-2′-deoxyguanosine, a fingerprint of DNA oxidation, and its RNA counterpart, 8-oxo-guanosine. Because oxidative damage to genetic material accumulates over a lifetime and contributes to cellular senescence, these markers are considered validated gauges of systemic molecular wear.

The researchers, led by Anders Jorgensen of Psychiatric Center Copenhagen and the University of Copenhagen, took advantage of a large community cohort with comprehensive, register-based information on psychotropic prescriptions. This design allowed them to classify participants according to whether they were in active antidepressant treatment, had never been treated, or had discontinued treatment. By measuring urinary excretion of the DNA and RNA oxidation markers across these groups, they could ask a deceptively simple question: is the oxidative damage that accompanies psychiatric illness modified by the drugs used to treat it?

The answer, at least for DNA, appears to be yes. Compared with individuals who had never received antidepressants or who were off treatment at the time of sampling, those in active treatment showed approximately 12.5 percent lower levels of the DNA oxidation marker. That is a substantial difference for a biomarker of this kind, and it points to a genuinely reduced burden of systemic oxidative stress on the genome. Intriguingly, the parallel RNA oxidation marker did not differ between the groups. This selectivity is scientifically important. DNA damage is a canonical driver of cellular aging and mutagenesis, whereas oxidized RNA is more closely associated with transient cellular stress and protein synthesis errors. A treatment that lowers DNA oxidation specifically touches what many biogerontologists regard as the more consequential of the two lesions.

The observation is consistent with earlier work by overlapping research groups, which had reported reduced systemic DNA and RNA oxidation after serotonergic treatment of unipolar depression. What distinguishes the new study is its scale and its translational ambition. Rather than stopping at the human association, the team set out to identify the mechanism. Their leading hypothesis concerned the mitochondria, the intracellular power plants that generate most of the cell’s ATP and, as an unavoidable byproduct of electron transport, most of its endogenous free radicals. If antidepressants somehow improved mitochondrial efficiency or dampened mitochondrial radical production, that could plausibly explain the lower DNA damage seen in treated patients.

To test this, the researchers turned to controlled laboratory models. They exposed cells to antidepressants in vitro and treated animals subchronically in vivo with compounds acting through two distinct monoaminergic mechanisms, one serotonergic and one noradrenergic, mirroring the pharmacological profiles of commonly prescribed antidepressant classes. They then measured two specific aspects of mitochondrial physiology: the production of reactive oxygen species by mitochondria and the respiratory capacity of the organelles, which reflects how efficiently the respiratory chain converts substrate into energy. These are the parameters that, if altered, would be expected to change the flux of radicals reaching nuclear DNA.

The result was a clear null. Across the in vitro and animal experiments, antidepressant exposure produced no detectable effect on mitochondrial reactive oxygen species production and no detectable effect on respiratory capacity. Whatever is driving the lower DNA oxidation in treated patients, the authors conclude, it is probably not a direct action on the mitochondrial machinery that generates free radicals. This is an instructive outcome. Translational research often advances as much by eliminating plausible mechanisms as by confirming them, and this study cleanly rules out one of the most obvious candidates.

Several alternative explanations remain open. Antidepressants could act downstream of radical formation, for instance by enhancing DNA repair pathways or by modulating the enzymatic systems that excise and clear oxidized bases from the genome. They could influence antioxidant defenses, shifting the balance of glutathione, superoxide dismutase, or catalase activity in ways that were not captured by the mitochondrial assays. There is also the possibility of confounding by indication or by lifestyle: people who remain engaged in psychiatric care and adhere to treatment may differ systematically in diet, physical activity, smoking, or illness severity from those who are untreated, and some of those differences could influence oxidative stress markers independently of pharmacology. The register-based design mitigates some of these concerns but cannot eliminate them entirely, which is why the authors are careful to describe their finding as an association in humans rather than a demonstrated causal drug effect.

Even with those caveats, the implications are provocative. If antidepressant treatment genuinely reduces the systemic burden of oxidative DNA damage, then these medications, already prescribed to hundreds of millions of people worldwide, may be modulating a fundamental process of biological aging. That would reframethe risk-benefit calculus for long-term treatment and could point toward biomarker-guided psychiatry, in which molecular markers of aging help clinicians weigh when to initiate, continue, or taper therapy. It would also sharpen the puzzle of how the drugs work at the systems level: a molecule that changes genome-level damage trajectories must be doing something physiologically significant beyond the synapse.

The Danish team is careful about what their data do and do not show. The human finding is robust within its design and concordant with prior smaller studies; the mechanistic experiments are equally clear in their negative result. Together they sketch a research agenda: identify the actual pathway linking antidepressant exposure to reduced DNA oxidation, determine whether the effect is causal or reflects the treated state itself, and test whether lowering oxidative nucleic acid damage translates into reduced somatic disease in patients with psychiatric illness. For now, the study stands as a striking example of translational psychiatry in action, a field that follows a clinical observation from population registers down to isolated mitochondria and back again, willing to report the answer even when the answer is no.

Subject of Research: The association between antidepressant exposure, oxidative nucleic acid damage, and mitochondrial function

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

Article References: Jorgensen, A., Wörtwein, G., Thy, A. L., Jensen, I. K., Ellervik, C., Brandslund, I., Blom, I., Helms, E. F. H., Christensen, I. B., Henriksen, T., Weimann, A., Torp-Pedersen, C., Jørgensen, M. B., Larsen, S., & Poulsen, H. E. (2026). Translational characterization of oxidative stress-induced nucleic acid damage and mitochondrial function during antidepressant exposure. Translational Psychiatry. https://doi.org/10.1038/s41398-026-04496-3

Image Credits: AI Generated

DOI: 10.1038/s41398-026-04496-3

Keywords: antidepressants, oxidative stress, DNA damage, mitochondria, translational psychiatry, biological aging, biomarkers, reactive oxygen species, depression, nucleic acid oxidation, register-based cohort, pharmacology