Identification of antidepressant response-related changes to DNA methylation and gene expression

BACKGROUND: Major depressive disorder (MDD) is a debilitating condition that is commonly treated with antidepressants. However, many people do not respond to treatment, and the molecular mechanisms underlying antidepressant response remain poorly understood. Baseline DNA methylation differences have been observed between individuals who respond to treatment compared to those who do not respond; however, little is known regarding DNA methylation changes that occur during treatment or how they may relate to clinical response. METHODS: We assessed peripheral levels of DNA methylation and gene expression at baseline and after 8 weeks of treatment in 154 individuals with MDD who were treated with escitalopram or desvenlafaxine, using the Infinium MethylationEPIC Beadchip and RNA sequencing. We identified methylation sites whose levels changed over time in relation to changes in depressive symptoms, as well as corresponding changes to gene expression levels after 8 weeks of treatment. RESULTS: We identified 2 sites, in sodium voltage-gated channel alpha subunit 7 and IQ Motif and ankyrin repeat containing 1, whose methylation changes over time were correlated with changes in depressive symptoms at the epigenome-wide level. Gene ontology analyses of genes displaying response-related methylation changes highlighted several processes previously implicated in depression, including small GTPase-related signaling and the Wnt signaling pathway. Additionally, we identified methylation sites in 10 genes that displayed significant changes in methylation over time in relation to improvement of depressive symptoms, whose expression levels at week 8 were correlated with the level of depressive symptoms, and for which methylation levels were functionally related to gene expression. CONCLUSIONS: Antidepressant treatment response is associated with changes in peripheral DNA methylation over time, as well as corresponding alterations in gene expression. Significance Statement Major depressive disorder (MDD) is commonly treated with antidepressants; however, many people do not respond to treatment. In order to better understand the molecular changes that occur during antidepressant treatment, we analyzed DNA methylation and gene expression in the blood of 154 individuals with MDD who were treated with escitalopram or desvenlafaxine. We found 10 methylation sites within 10 genes whose methylation levels changed over time in relation to clinical improvement, and whose levels of expression were related to both methylation and antidepressant response.