title: Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response.
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.
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy,University of Wuerzburg,Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Domschke
authors.affiliation: Department of Psychiatry and Psychotherapy,University of Muenster,Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Tidow
authors.affiliation: Department of Psychiatry and Psychotherapy,University of Muenster,Germany.
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schwarte
authors.affiliation: Department of Psychiatry, Psychosomatics and Psychotherapy,University of Wuerzburg,Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Deckert
authors.affiliation: Division of Molecular Psychiatry, Laboratory of Translational Neuroscience, Department of Psychiatry, Psychosomatics and Psychotherapy,University of Wuerzburg,Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Lesch
authors.affiliation: Department of Psychiatry and Psychotherapy,University of Muenster,Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Arolt
authors.affiliation: Department of Psychiatry and Psychotherapy,University of Muenster,Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Zwanzger
authors.affiliation: Department of Psychiatry,University of Adelaide,Australia.
authors.forename: Bernhard T
authors.initials: BT
authors.lastname: Baune
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D015283:Citalopram / Q000627:therapeutic use; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000188:drug therapy / Q000235:genetics; D004351:Drug Resistance / Q000187:drug effects / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012189:Retrospective Studies; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics*; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
chemical_list: D000928:Antidepressive Agents; D050486:Serotonin Plasma Membrane Transport Proteins; D015283:Citalopram