BACKGROUND: The relationship between depression and increased oxidative stress is well known. DNA damage by oxidation factors is an important cause of the aging process in psychiatric disorders.AIMS: Owing to the scarcity of human studies and high inconsistencies in studies of the effects of antidepressants on DNA damage, the current study was undertaken to investigate the effects of depression and its treatment on DNA damage.METHODS: In a 15-week open-label study of citalopram (n = 25) and sertraline (n = 20), levels of DNA damage were measured by comet assay, proinflammatory (Interlukin-6 (IL-6)) and oxidative DNA damage (8-hydroxy-2'-deoxyguanosine (8-OHdG)) markers by ELISA, and gene expression of base excision repair enzymes (8-oxoguanine glycosylase (OGG1) and poly (ADP)-ribose polymerase-1 (PARP1)) by quantitative real-time polymerase chain reaction in healthy control patients (n = 14), with depression at the baseline and the same patients after week 15.RESULTS: DNA damage, 8-OHdG, IL-6 and expression of PARP1 were elevated in patients with depression compared with the healthy controls (p < 0.001). Selective serotonin reuptake inhibitor (SSRI) therapy could significantly reduce the depression score (p < 0.01), DNA damage (p < 0.001), as well as 8-OHdG and IL-6 (p < 0.0001). Nevertheless, the expression of PARP1 and OGG1 showed no significant changes after treatment.CONCLUSIONS: This is the first study on the effect of SSRIs on the DNA damage and some of the repair enzymes in depression. Based on the results, depression can cause increased DNA damage. This damage is followed by activation of compensatory mechanisms whereby the expression of DNA damage repair enzymes is elevated. Finally, the treatment of psychiatric disorder by antidepressants can lower the level of oxidative DNA damage.