M85 - DNA METHYLATION AND 5-HTTLPR GENOTYPE OF THE SEROTONIN TRANSPORTER GENE (SLC6A4) IN ANTIDEPRESSANT TREATMENT RESPONSE OF MAJOR DEPRESSIVE DISORDER

Abstract

Background The current process used to prescribe antidepressant medication is markedly inefficient, as more than 50% of treated patients fail to reach remission. Antidepressant treatment success has been associated with genetic variation, but studies are not well replicated and epigenetic mechanisms remain under investigated. DNA methylation may provide more information regarding antidepressant response and guide physicians in choosing the most effective medication for each patient. We investigated the influence of SLC6A4 methylation and 5-HTTLPR genotypes on antidepressant response in our sample. Methods A subset of depression patients with complete clinical data (European Caucasian, n=166), were selected from our discovery sample (IMPACT; N=8,000). Saliva samples were collected at enrollment and genetic testing was done of cytochrome P450 liver enzyme, 5HTTLPR and 5HT2A variants to guide clinical choice and dosage of psychotropic medications. As such, a significant component of our sample includes treatment refractory, as well as medication intolerant patients. DNA was bisulfite converted and methylation profiles were interrogated using the Infinium HumanMethylation450 Beadchip array. Nine CpG probes located across the SLC6A4 promoter region were selected, based on previous studies, to quantify methylation levels. Change in Beck Depression Inventory II (BDI-II) score was used to measure antidepressant response over eight weeks. The relationship among genotype, methylation levels, and antidepressant response was analysed using linear regression modeling. Results Increased methylation in the promoter region of the SLC6A4 gene was nominally associated with impaired response to antidepressants in our sample. The effect was driven by methylation site cg05016953, located in exon 1 A. Increased methylation level as measured by CpG cg05016953 was associated with less improvement in BDI-II score over eight weeks of antidepressant treatment (F(3,163)=6.14, puncorr=0.012). 5-HTTLPR genotype was not associated with SLC6A4 DNA methylation or antidepressant treatment response. Discussion An increase in SLC6A4 DNA methylation at cg05016953 may be associated impaired response to antidepressant medications in our sample. The SLC6A4 transcriptional control region contains a CpG island, previously shown to functionally influence mRNA levels depending on 5-HTTLPR genotypes. Typically, hypermethylation in promoter regions is associated with decreased gene expression. Theoretically, hypermethylation of the 5-HTT promoter would reduce the number of serotonin transporters, and reduce serotonin re-uptake, which in simple terms should improve response to SSRI treatment. Further pharmaco-epigenetic studies are required to elucidate the effect of DNA methylation changes on antidepressant response.