Abstract
Major depressive disorder (MDD) is primarily treated with antidepressants, yet many patients fail to respond adequately, and identifying antidepressant response biomarkers is thus of clinical significance. Some hypothesis-driven investigations of epigenetic markers for treatment response have been previously made, but genome-wide approaches remain unexplored. Healthy participants (n = 112) and MDD patients (n = 211) between 18–60 years old were recruited for an 8-week trial of escitalopram treatment. Responders and non-responders were identified using differential Montgomery-Åsberg Depression Rating Scale scores before and after treatment. Genome-wide DNA methylation and gene expression analyses were assessed using the Infinium MethylationEPIC Beadchip and HumanHT-12 v4 Expression Beadchip, respectively, on pre-treatment peripheral blood DNA and RNA samples. Differentially methylated positions (DMPs) located in regions of differentially expressed genes between responders (n = 82) and non-responders (n = 95) were identified, and technically validated using a targeted sequencing approach. Three DMPs located in the genes CHN2 (cg23687322, p = 0.00043 and cg06926818, p = 0.0014) and JAK2 (cg08339825, p = 0.00021) were the most significantly associated with mRNA expression changes and subsequently validated. Replication was then conducted with non-responders (n = 76) and responders (n = 71) in an external cohort that underwent a similar antidepressant trial. One CHN2 site (cg06926818; p = 0.03) was successfully replicated. Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response. Future studies can provide further insight on robustness of our candidate biomarkers, and greater characterization of functional components.
Highlights
Antidepressants are considered an effective treatment option for major depressive disorder (MDD), a severe affective disorder that is currently deemed to be the leading cause of global disability[1]
Our findings indicate that differential methylation at CpG sites upstream of the CHN2 and JAK2 TSS regions are possible peripheral predictors of antidepressant treatment response
We identified significantly differentially methylated CpGs associated with antidepressant response through a genome-wide method in peripheral blood samples retrieved prior to receiving 10–20 mg of escitalopram treatment
Summary
Antidepressants are considered an effective treatment option for major depressive disorder (MDD), a severe affective disorder that is currently deemed to be the leading cause of global disability[1]. Treatment selection is clinically subjective, response is determined by trial and error, and objective patient improvement is difficult to distinguish from the placebo effect[2]. In addition to the long period of symptom evaluation, the uncomfortable side effects of antidepressants greatly contribute to noncompliance with treatment. A treatment paradigm that reliably matches patients with effective antidepressants as early on as possible would minimize their suffering, and avoid adversities associated with selecting appropriate medications. Predictive biomarkers for antidepressant response could greatly benefit clinical practice by decreasing the duration of evaluating drug efficacy[6]
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