Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

Fabbri, Chiara; Serretti, Alessandro

doi:10.1007/s11920-015-0594-9

Cited by 71 publications

(37 citation statements)

References 168 publications

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“…Despite controversial pharmacogenetic findings being reported for the FKBP5 gene, results obtained in a large sample of Caucasian subjects suggested that rs1360780, rs3800373, rs4713916 and rs352428 poly-morphisms may modulate antidepressant response (Fabbri and Serretti, 2015). The effect of rs3800373 and rs1360780 on antidepressant response was confirmed in subjects of Caucasian ethnicity by a recent meta-analysis (Niitsu et al 2013).…”

Section: Genetic Polymorphismsmentioning

confidence: 96%

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: Genetic Polymorphismsmentioning

confidence: 96%

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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“…SSRIs) treatment response accounts for genetic factors, progress in uncovering the particular genetic polymorphisms has been slow [112]. As described in Table 1, candidate gene studies have pointed to a number of genes and SNPs that may influence antidepressant treatment outcomes [6, 7, 8-10, 26, 27, 54], including polymorphisms within the COMT [8,30], HTR2A [54,86,121], HTR1A [26], CNR1 [26], SLC6A4 [9], NPY [6], MAOA [27,30], IL1B [7,30], GRIK4 [64], BDNF [30,86], GNB3 [30], FKBP5 [86], CYP2D6 [31,121], CYP2C19 [31,121], and ABCB1 [12,86] genes (Table 1). For example, a negative influence of a higher activity COMT 158 val/val genotype on antidepressant treatment response was shown [].…”

Section: Ssris Treatment For Major Depressive Disordermentioning

confidence: 99%

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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“…However, the * 17 allele associated with increased function is found in only 2.7% of East Asians and 20% of Caucasians. Poor metabolizers are likely to experience higher side effects while ultra-rapid metabolizers are likely to have worse outcomes with antidepressant treatment [23]. Genotyping for these polymorphisms is justified in clinical practice in order to optimize drug dosing for efficacy and prevention of side effects.…”

Section: Cyp450 Genes and Drug Metabolismmentioning

confidence: 99%

“…Successful antidepressant treatment response has been directly associated with a decrease in FKBP5 leukocyte mRNA expression [35]. Four SNPs within this gene have been identified as potential candidates for pharmacogenetics: rs1360780, rs3800373, rs4713916, and rs352428 [23]. Polymorphism rs352428 worsens the response to antidepressant treatment in Caucasians [36].…”

Section: Fkbp5 and The Hypothalamic-pituitary-adrenal Axismentioning

confidence: 99%

Pharmacogenetics of Antidepressants, A Review of Significant Genetic Variants in Different Populations

Reyes-Barron¹,

Tonarelli²,

Delozier³

et al. 2017

Clin Depress

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Major depressive disorder is a highly prevalent disease that is challenging to treat, often requiring medication and dose adjustments. Genetic factors play an important role in psychotropic medication responses. However, the translation of pharmacogenetics findings to clinical recommendations with regards to antidepressant responses is still in its early stages. We reviewed recent primary research articles, meta-analyses, and reviews on the pharmacogenetics of antidepressant treatment for major depressive disorder in different populations. We identified eight genes with likely associations with treatment responses and summarized genetic variants most likely to influence treatment responses. We determined the frequency of these variants in Caucasian, Asian, Hispanic, and African American populations. The genes are related to functions in drug metabolism, transport, signalling, stress response, and neuroplasticity. Clinical recommendations already exist for CYP2D6 and CYP2C19 cytochrome P450 drug metabolism genes. The other genes are: ABCB1 with single nucleotide polymorphisms (SNPs) rs2032583 and rs2235015; FKBP5 with SNPs rs1360780, rs3800373, and rs4713916; GNB3 with SNP rs5443; BDNF with SNP rs6265; HTR2A with SNPs rs7997012 and rs6313; and SLC6A4 with polymorphisms 5-HTTLPR and STin2. There is significant variability of the frequencies of these polymorphisms in the different populations we reviewed. There is also variability in the antidepressant responses between populations carrying the same polymorphism in some cases, indicating a likely polygenic influence. Future studies in the pharmacogenetics of antidepressants would benefit from including more subjects from underrepresented ethnic groups and stratifying results.

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Pharmacogenetics of Major Depressive Disorder: Top Genes and Pathways Toward Clinical Applications

Cited by 71 publications

References 168 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

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

Pharmacogenetics of Antidepressants, A Review of Significant Genetic Variants in Different Populations

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