Serotonin Transporter Gene Promoter Hypomethylation as a Predictor of Antidepressant Treatment Response in Major Depression: A Replication Study

Abstract

Background The serotonin transporter gene (SLC6A4; 5-HTT; SERT) is considered a prime candidate in pharmacogenetic research in major depressive disorder (MDD). Besides genetic variation, recent advances have spotlighted the involvement of epigenetic mechanisms such as DNA methylation in predicting antidepressant treatment response in “pharmaco-epigenetic” approaches. In MDD, lower SLC6A4 promoter methylation has been suggested to predict impaired response to serotonergic antidepressants. The present study sought to replicate and extend this finding in a large, independent sample of MDD patients. Methods The sample comprised N=236 Caucasian patients with MDD receiving antidepressant medication in a naturalistic treatment setting. Functional DNA methylation of 9 CpG sites located in the SLC6A4 promoter region was analyzed via direct sequencing of sodium bisulfite treated DNA extracted from blood cells. Patients were assessed over the course of 6-week in-patient treatment using the Hamilton Depression Scale (HAM-D). Results Results confirm relative SLC6A4 hypomethylation to predict impaired antidepressant response both dimensionally and categorically (HAM-D reductions ≥50%), and to furthermore be indicative of non-remission (HAM-D≤7). This also held true in a homogenous subgroup of patients continuously treated with SSRIs or SNRIs (N=110). Conclusions Impaired response to serotonergic antidepressants via SLC6A4 hypomethylation may be conveyed by increased gene expression and consequently decreased serotonin availability, which may counteract the effects of serotonergic antidepressants. The present results could in the future inform clinical decision making towards a more personalized treatment of MDD.

The Impact Of The Serotonin Transporter Gene Promoter DNA Methylation And Parenting Styles On Anorexia Nervosa

“…Our study showed a signi cant correlation between SLC6A4 methylation and AN, which was in concordance with the observation in patients with depression [39,40]. Probably because SLC6A4 hypermethylation causes the decrease of mRNA expression, which leads to the decrease of 5-HT transporter protein and 5-HT reuptake, then resulting in the increase of 5-HT concentration in synaptic space and the decrease of 5-HT synthesis by negative feedback, nally it may increase the e cacy of serotonergic antidepressants [41]. While previous studies did not nd positive results in ANs [42,43], which may be due to the differences in the samples and fragments selected.…”

The Impact of the Serotonin Transporter Gene Promoter DNA Methylation on Anorexia Nervosa：A Preliminary Longitudinal Study

“…Our study showed a signi cant association between SLC6A4 methylation and AN, which was in concordance with the observation in patients with depression [26,27]. Probably because SLC6A4 hypermethylation causes the decrease of mRNA expression, which leads to the decrease of 5-HT transporter protein and 5-HT reuptake, then resulting in the increase of 5-HT concentration in synaptic space and the decrease of 5-HT synthesis by negative feedback, nally it may increase the e cacy of serotonergic antidepressants [28]. While previous study did not nd positive results in AN patients [29], which may be due to the differences in the samples and fragments selected.…”

“…Considering the possible effect of 5-HTTLPR methylation on long-term AN outcome, some studies have reported the predictive effect of 5-HTTLPR methylation on the therapeutic response in depression patients, the higher the 5-HTTLPR methylation level, the better the antidepressant response [28,33], but there were also contrary results [34], as for how gene methylation affects the therapeutic effect has not been reported. It was the methylation level of CpG11 unit in 5-HTTLPR that was signi cantly associated with therapeutic responses [35].…”

“…One of which indicated that the Sallele of the 5-HTTLPR genotype particularly increased the risk susceptibility for AN and was related to its instability and depressive comorbidity [32]. Thus, a study has reported that the effects of 5-HTTLPR genetic variants may contribute to the regulation in modifying its methylation [36], which has been validated in patients with depression [26,28] and anxiety [37].However, Our epigenetic study of 5-HTTLPR did not consider its genotypes, which may make it hard to determine the real consistency of data. Further investigation is needed to examine the underlying mechanisms.…”

Neuroinflammatory Basis of Depression: Learning From Experimental Models

“…As these factors are highly variable, epistatic, and complex, they are thought to regulate vulnerability to depression development and responsiveness to antidepressant therapy. Various polymorphisms have been reported in genes regulating the hypothalamic-pituitary-adrenal (HPA) axis, serotonin recycling, and immune responses, including corticotropin-releasing hormone receptor 1, the sodium-dependent serotonin transporter gene (SLC6A4), and interleukin-1β (IL-1β) (Baune et al, 2010;Schiele et al, 2021). Moreover, environmental stressors are associated with epigenetic modification of BDNF, its receptor tropomyosin-related kinase B gene, glucocorticoid receptor gene (NR3C1), and glutamate ionotropic receptor NMDA type subunit 2B (GRIN2B) (Ernst et al, 2009;Jiang et al, 2010;Sun et al, 2013;Efstathopoulos et al, 2018).…”