Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project

Uher, Rudolf; Perroud, Nader; Ng, Mandy; Hauser, Joanna; Henigsberg, Neven; Maier, Wolfgang; Mors, Ole; Placentino, Anna; Rietschel, Marcella; Souery, Daniel; Žagar, Tina; Czerski, Piotr M.; Jerman, Borut; Larsen, Erik Roj; Schulze, Thomas G.; Zobel, Astrid; Cohen‐Woods, Sarah; Pirlo, Katrina; Butler, Amy W.; Muglia, Pierandrea; Barnes, Michael R.; Lathrop, Mark; Farmer, Anne; Breen, Gerome; Aitchison, Katherine J.; Craig, Ian W.; Lewis, Cathryn M.; McGuffin, Peter

doi:10.1176/appi.ajp.2009.09070932

Cited by 322 publications

(259 citation statements)

References 42 publications

(27 reference statements)

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“…However, only a small study investigated the potential role of the SNP in MDD and it reported negative findings (Clerici et al 2009), while an additional study reported no association between MDD and the SNP at -634 in a Chinese population (Hong et al 2005). Our findings suggest further investigation of IL-6 polymorphisms in MDD is warranted, particularly as a suggestive signal (rs7801617 SNP) for association with escitalopram response was detected in the IL-6 gene in the Genome-Based Therapeutic Drugs for Depression (GENDEP) genome-wide association study (Uher et al 2010).…”

Section: Interleukin-6mentioning

confidence: 71%

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

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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.

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Section: Interleukin-6mentioning

confidence: 71%

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

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“…We selected 25 depressed patients (10 females, 15 males) from the Genome-based Therapeutic Drugs for Depression (GENDEP) study who were drug-naïve or had been drug-free for at least 2 wk before assessment (17,36). Controls (7 females, 7 males) were recruited in London through local advertisement and volunteer databases, as part of the GENDEP study.…”

Section: Methodsmentioning

confidence: 99%

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

Anacker

Cattaneo

Musaelyan

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum-and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.antidepressants | hypothalamus-pituitary-adrenal axis | stem cells | neuroplasticity

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“…Similarly, two SNPs rs17135437 (p = 3.27 × 10 ) in the IL11 gene associated with citalopram response [116].…”

Section: -Hydroxytryptamine Receptor 2amentioning

confidence: 96%

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

2017

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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.

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Genome-Wide Pharmacogenetics of Antidepressant Response in the GENDEP Project

Cited by 322 publications

References 42 publications

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

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

Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

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

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