Genotoxicity and DNA Damage in Long‐Term SSRI Therapy: A Review Across SSRIs With Citalopram as a Case Study

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are first-line therapies for depressive and anxiety disorders and are often used for years, including in reproductive-age patients and during pregnancy. This has intensified concern about possible genotoxicity and DNA damage. Citalopram is emphasized because it has the most extensive and consistently positive in vivo genotoxicity evidence among SSRIs, particularly in rodent comet and micronucleus endpoints. This review summarizes genotoxicity data for SSRIs, focusing on citalopram, across in vitro assays, animal studies, human biomonitoring, and environmental research. We briefly define mutagenicity and clastogenic and aneugenic effects, describe major DNA lesions, and review commonly applied methods: comet, micronucleus, and chromosomal aberration tests, plus biomarker approaches such as γH2AX and measures of oxidative DNA damage. Potential off-target mechanisms are considered in light of SSRI pharmacology and pharmacokinetics, including direct DNA interactions, mitochondrial dysfunction, reactive oxygen species generation, and disruption of chromosome segregation. Comparative findings indicate that citalopram and fluoxetine show the most consistent experimental genotoxic signals, whereas paroxetine and escitalopram are less frequently implicated. For citalopram, rodent studies report DNA strand breaks, combined clastogenic/aneugenic effects in bone marrow, germ cell DNA damage, and reproductive toxicity, with additional positive findings in non-mammalian models. Human studies are few and provide mixed, largely indirect evidence. Work suggests antioxidants can reduce SSRI-related oxidative stress and DNA damage in some models. Environmental studies raise concern for aquatic organisms. Overall, citalopram shows genuine experimental genotoxic potential, but clinical relevance in humans remains uncertain and warrants robust longitudinal investigation and careful risk-benefit assessment in practice.