Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response

Domschke, Katharina; Tidow, Nicola; Schwarte, Kathrin; Deckert, J.; Lesch, Klaus‐Peter; Arolt, Volker; Zwanzger, Peter; Baune, Bernhard T.

doi:10.1017/s146114571400039x

Cited by 152 publications

(95 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For instance, polymorphisms in the SLC6A4 gene were associated with antidepressant response or remission [28,68,76,81,88,91]. Similar SLC6A4 variants have shown an association with lithium treatment outcomes in patients with BPD [75,102].…”

Section: Lithium Treatment For Bipolar Disordermentioning

confidence: 97%

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

2017

Self Cite

View full text Add to dashboard Cite

Personalized medicine (personalized psychiatry in a specific setting) is a new model towards individualized care, in which knowledge from genomics and other omic pillars (microbiome, epigenomes, proteome, and metabolome) will be combined with clinical data to guide efforts to new drug development and targeted prescription of the existing treatment options. In this review, we summarize pharmacogenomic studies in mood disorders that may lay the foundation towards personalized psychiatry. In addition, we have discussed the possible strategies to integrate data from omic pillars as a future path to personalized psychiatry. So far, the progress of uncovering single nucleotide polymorphisms (SNPs) underpinning treatment efficacy in mood disorders (e.g., SNPs associated with selective serotonin re-uptake inhibitors or lithium treatment response in patients with bipolar disorder and major depressive disorder) are encouraging, but not adequate. Genetic studies have pointed to a number of SNPs located at candidate genes that possibly influence response to; (a) antidepressants COMT, HTR2A, HTR1A, CNR1, SLC6A4, NPY, MAOA, IL1B, GRIK4, BDNF, GNB3, FKBP5, CYP2D6, CYP2C19, and ABCB1 and (b) mood stabilizers (lithium) 5-HTT, TPH, DRD1, FYN, INPP1, CREB1, BDNF, GSK3β, ARNTL, TIM, DPB, NR3C1, BCR, XBP1, and CACNG2. We suggest three alternative and complementary strategies to implement knowledge gained from pharmacogenomic studies. The first strategy can be to implement diagnostic, therapeutic, or prognostic genetic testing based on candidate genes or gene products. The second alternative is an integrative analysis (systems genomics approach) to combine omics data obtained from the different pillars of omics investigation, including genomics, epigenomes, proteomics, metabolomics and microbiomes. The main goal of system genomics is an identification and understanding of biological pathways, networks, and modules underlying drug-response. The third strategy aims to the development of multivariable diagnostic or prognostic algorithms (tools) combining individual's genomic information (polygenic score) with other predictors (e.g., omics pillars, neuroimaging, and clinical characteristics) to finally predict therapeutic outcomes. An integration of molecular science with that of traditional clinical practice is the way forward to drug discoveries and novel therapeutic approaches and to characterize psychiatric disorders leading to a better predictive, preventive, and personalized medicine (PPPM) in psychiatry. With future advances in the omics technology and methodological developments for data integration, the goal of PPPM in psychiatry is promising.

show abstract

Section: Lithium Treatment For Bipolar Disordermentioning

confidence: 97%

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

2017

Self Cite

View full text Add to dashboard Cite

show abstract

“…ESME performs quality control, normalizes signals, corrects for incomplete bisulfite conversion, and aligns generated bisulfite sequence and reference sequence to compare C with T peak heights at CpG sites (Lewin et al, 2004) as successfully used to analyze methylation profiles in other psychiatric phenotypes (see, eg, Alasaari et al, 2012;Domschke et al, 2013;Domschke et al, 2012;Domschke et al, 2014b;Domschke et al, 2014a;Tadic et al, 2013). To account for run variability, all samples were tested in duplicate, yielding a mean individual methylation score for each CpG.…”

Section: Bisulfite Sequencingmentioning

confidence: 99%

Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

Ziegler

Dannlowski

Bräuer

et al. 2015

Neuropsychopharmacol

Self Cite

164

100

View full text Add to dashboard Cite

Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approachinvestigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (po0.001, Cohen's d ¼ 0.535), (2) increased SPS and SIAS scores (po0.001), (3) increased cortisol response to the TSST (p ¼ 0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p corr o0.001; left: p corr ¼ 0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.

show abstract

“…These findings support the hypothesis that SLC6A4 methylation status may be a proxy of childhood adversities (other than a hereditary factor) and thus it may be a useful marker of MDD susceptibility in combination with the 5-HTTLPR S allele. SLC6A4 methylation status was also investigated in relation to antidepressant treatment response, but with mixed results (Kang et al 2013b;Domschke et al 2014;Okada et al 2014).…”

Section: Gene Methylationmentioning

confidence: 99%

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Fabbri

Hosák

Mößner

et al. 2016

The World Journal of Biological Psychiatry

View full text Add to dashboard Cite

Major depressive disorder (MDD) is a heritable disease with a heavy personal and socio-economic burden. Antidepressants of different classes are prescribed to treat MDD, but reliable and reproducible markers of efficacy are not available for clinical use. Further complicating treatment, the diagnosis of MDD is not guided by objective criteria, resulting in the risk of under-or overtreatment. A number of markers of MDD and antidepressant response have been investigated at the genetic, epigenetic, gene expression and protein levels. Polymorphisms in genes involved in anti-depressant metabolism (cytochrome P450 isoenzymes), antidepressant transport (ABCB1), glucocorticoid signalling (FKBP5) and serotonin neurotransmission (SLC6A4 and HTR2A) were among those included in the first pharmacogenetic assays that have been tested for clinical applicability. The results of these investigations were encouraging when examining patient-outcome improvement. Furthermore, a nine-serum biomarker panel (including BDNF, cortisol and soluble TNF-a receptor type II) showed good sensitivity and specificity in differentiating between MDD and healthy controls. These first diagnostic and response-predictive tests for MDD provided a source of optimism for future clinical applications. However, such findings should be considered very carefully because their benefit/cost ratio and clinical indications were not clearly demonstrated. Future tests may include combinations of different types of biomarkers and be specific for MDD subtypes or pathological dimensions.

show abstract

Serotonin transporter gene hypomethylation predicts impaired antidepressant treatment response

Cited by 152 publications

References 55 publications

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

Consensus paper of the WFSBP Task Force on Genetics: Genetics, epigenetics and gene expression markers of major depressive disorder and antidepressant response

Contact Info

Product

Resources

About