Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response.

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Domschke K, Tidow N, Schwarte K, Deckert J, Lesch KP, Arolt V, Zwanzger P, Baune BT

Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response.

Int J Neuropsychopharmacol. 2014 Aug;17(8):1167-76. doi: 10.1017/S146114571400039X. Epub 2014 Mar 28.

PubMed ID

24679990 [ View in PubMed

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Abstract

Variation in the serotonin transporter gene (5-HTT; SERT; SLC6A4) has been suggested to pharmacogenetically drive interindividual differences in antidepressant treatment response. In the present analysis, a 'pharmaco-epigenetic' approach was applied by investigating the influence of DNA methylation patterns in the 5-HTT transcriptional control region on antidepressant treatment response. Ninety-four patients of Caucasian descent with major depressive disorder (MDD) (f = 61) were analysed for DNA methylation status at nine CpG sites in the 5-HTT transcriptional control region upstream of exon 1A via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were also genotyped for the functional 5-HTTLPR/rs25531 polymorphisms. Clinical response to treatment with escitalopram was assessed by intra-individual changes of HAM-D-21 scores after 6 wk of treatment. Lower average 5-HTT methylation across all nine CpGs was found to be associated with impaired antidepressant treatment response after 6 wk (p = 0.005). This effect was particularly conferred by one individual 5-HTT CpG site (CpG2 (GRCh37 build, NC_000017.10 28.563.102; p = 0.002). 5-HTTLPR/rs25531 haplotype was neither associated with 5-HTT DNA methylation nor treatment response. This analysis suggests that DNA hypomethylation of the 5-HTT transcriptional control region - possibly via increased serotonin transporter expression and consecutively decreased serotonin availability - might impair antidepressant treatment response in Caucasian patients with MDD. This pharmaco-epigenetic approach could eventually aid in establishing epigenetic biomarkers of treatment response and thereby a more personalized treatment of MDD.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Mirtazapine	Sodium-dependent serotonin transporter	Protein	Humans	Unknown	Substrate Inhibitor	Details