Epigenetic signatures in antidepressant treatment response: a methylome-wide association study in the EMC trial

Abstract

Although the currently available antidepressants are well established in the treatment of the major depressive disorder (MDD), there is strong variability in the response of individual patients. Reliable predictors to guide treatment decisions before or in an early stage of treatment are needed. DNA-methylation has been proven a useful biomarker in different clinical conditions, but its importance for mechanisms of antidepressant response has not yet been determined. 80 MDD patients were selected out of >500 participants from the Early Medication Change (EMC) cohort with available genetic material based on their antidepressant response after four weeks and stratified into clear responders and age- and sex-matched non-responders (N = 40, each). Early improvement after two weeks was analyzed as a secondary outcome. DNA-methylation was determined using the Illumina EPIC BeadChip. Epigenome-wide association studies were performed and differentially methylated regions (DMRs) identified using the comb-p algorithm. Enrichment was tested for hallmark gene-sets and in genome-wide association studies of depression and antidepressant response. No epigenome-wide significant differentially methylated positions were found for treatment response or early improvement. Twenty DMRs were associated with response; the strongest in an enhancer region in SORBS2, which has been related to cardiovascular diseases and type II diabetes. Another DMR was located in CYP2C18, a gene previously linked to antidepressant response. Results pointed towards differential methylation in genes associated with cardiac function, neuroticism, and depression. Linking differential methylation to antidepressant treatment response is an emerging topic and represents a step towards personalized medicine, potentially facilitating the prediction of patients’ response before treatment.

Leveraging DNA Methylation to Predict Treatment Response in Major Depressive Disorder: A Critical Review

“…However, studies focusing on genome-scale analyses of methylation are also emerging and have become more frequent in the last few years ( N=6 ). The majority of such genome-scale efforts have investigated pharmacological treatments of MDD as the treatment modality ( N=4 )(Engelmann et al, 2022; Ju et al, 2019; Martinez-Pinteno et al, 2021; Takeuchi et al, 2017) with only a few focused on ECT ( N=2)(Moschny, Zindler, et al, 2020; Sirignano et al, 2021) .…”

“…Genome-scale studies have the potential to reveal novel loci and pathways associated with MDD that have not been considered before in candidate gene approaches. To date, only six studies have used a genome-scale approach to elucidate the relationship between baseline DNAm and treatment outcomes in MDD of which four efforts have been pharmaco-epigenetic studies (Engelmann et al, 2022; Ju et al, 2019; Martinez-Pinteno et al, 2021; Takeuchi et al, 2017).…”

“…A recent study profiled genome-scale baseline DNAm in responders and non-responders to escitalopram, venlafaxine, and lithium treatment in 80 European MDD patients (Engelmann et al, 2022). Despite the inability to identify any differentially methylated positions on an epigenome-scale associated with treatment response, the authors observed 18 hypermethylated and 2 hypomethylated regions associated with positive treatment outcomes including one site in SORBS2 and CYP2C18 .…”

“…Another important consideration for genome-scale approaches is the heterogeneity in technologies used. While one study (Takeuchi et al, 2017) used older array technology assessing 450,000 CpGs, four studies employed the Epic Methylation array capable of interrogating 850,000 probes(Engelmann et al, 2022; Ju et al, 2019; Martinez-Pinteno et al, 2021; Sirignano et al, 2021). Moshny and Colleagues used the Nextseq 550 with EPIC kit capable of interrogating over 3.3 million CpGs (Moschny, Zindler, et al, 2020).…”

“…The majority of findings from previous studies have yet to be replicated in independent cohorts suggesting that well-designed studies investigating the DNAm associated with a treatment response have much to contribute. Those studies will be most informative when multiple genomic measures are integrated into epigenetic studies of depression (Engelmann et al, 2022;Fuh, Fiori, Turecki, Nagy, & Li, 2023;Ju et al, 2019;Wang, Lv, et al, 2018;Wang, Zhang, et al, 2018), in order to gain more wholistic insights into the functional relevance of observed epigenetic variation in MDD treatment response. Assessing DNAm at multiple timepoints throughout the treatment could be particularly informative and perhaps bring clinically significant opportunities.…”