With regard to sex, in a recent review, it was explored whether methylation of DNA might play a role in contributing to the observed sex differences in the prevalence of stress-related mental disorders like posttraumatic stress disorder and depression. It was suggested that sex differences in methylation should be investigated in future studies in order to find an explanation for sex differences in mental disorders. Yet, research since that study has been inconclusive; a previous study showed that females had lower SLC6A4 methylation than men. About one third of the participants of that study had a history of MDD, and the large majority of the participants had no current MDD symptomatology. In another study in healthy young adults, no sex differences were found. In the present study, males had significantly higher methylation in SLC6A4 compared to females, independent of childhood abuse or MDD diagnosis. These differing results highlight that there is no convincing evidence that methylation in the SLC6A4 gene contributes to sex differences in prevalence of depression. L-690,488 Interestingly, MDD patients currently receiving SSRIs showed increased methylation of SLC6A4 compared to patients who were currently medication-free, while controlling for the other predictors. In an experimental study, mice treated with fluoxetine after an experimental brain injury showed increased neurogenesis, increased methylation, and increased histone H3 acetylation in the dentate gyrus. This finding might point toward an acute effect of SSRIs on DNA methylation, but needs to be extended to human studies using longitudinal designs. We did not find SLC6A4 genotype to be associated with DNA methylation, which is consistent with our previous study in healthy volunteers, with a study that used participants with various levels clinical depressive symptoms, and with one that used a large sample of healthy adults. A previous study found that higher SLC6A4 methylation was associated with increased responses to loss or other trauma in carriers of the ll genotype. The observation in the present study of higher methylation levels in carriers of the ll genotype who were also exposed to childhood trauma, relative to s carriers with or without childhood trauma, is consistent with this previous finding. As in our previous study, mRNA L-694,247 expression was not related to DNA methylation, nor was it associated with any of our outcome measures.