The Promise and Reality of Pharmacogenetics in Psychiatry

Zandi, Peter P.; Judy, Jennifer

doi:10.1016/j.psc.2009.12.001

Cited by 33 publications

(12 citation statements)

References 492 publications

(310 reference statements)

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“…The task of unraveling psychiatric genetics is further complicated by the interaction of genetic and environmental variables, with the latter playing an important role in the development of most disorders [7]. In addition, although pharmacogenomic tests are being actively marketed to psychiatrists today, the database supporting their use is weak, another limitation on the use of genetic testing in the field [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Anticipating the Ethical Challenges of Psychiatric Genetic Testing

Appelbaum

Benston

2017

Curr Psychiatry Rep

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Purpose of Review Genetic testing for mental illness is likely to become increasingly prevalent as the science behind it is refined. This article identifies anticipated ethical challenges for patients, psychiatrists, and genetic counselors and makes recommendations for addressing them. Recent Findings Many of the ethical challenges of psychiatric genetic testing are likely to stem from failures to comprehend the nature and implications of test results. Recent studies have identified gaps in the knowledge base of psychiatrists and genetic counselors, which limit their abilities to provide patients with appropriate education. A small number of studies have demonstrated the value of counseling in empowering patients to deal with relevant genetic information. Summary Psychiatrists and other health professionals must be able to assist patients and families in making informed decisions about genetic testing and interpreting test results. Filling their knowledge gaps on these issues will be a critical step towards meeting these responsibilities.

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Section: Introductionmentioning

confidence: 99%

Anticipating the Ethical Challenges of Psychiatric Genetic Testing

Appelbaum

Benston

2017

Curr Psychiatry Rep

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“…Associations have been found with, for example, the MHC region (Shi et al , 2009) and novel loci such as ZNF804A (O’Donovan et al , 2008). To date, though, the number of GWAS on antipsychotic response is considerably more modest (Zandi and Judy, 2010). …”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Pharmacogenomic Study of Neurocognition As an Indicator of Antipsychotic Treatment Response in Schizophrenia

McClay

Adkins

Åberg

et al. 2010

Neuropsychopharmacol

109

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Neurocognitive deficits are a core feature of schizophrenia and therefore represent potentially critical outcome variables for assessing antipsychotic treatment response. We performed genome-wide association studies (GWAS) with 492K single nucleotide polymorphisms (SNPs) in a sample of 738 patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study. Outcome variables consisted of a neurocognitive battery administered at multiple time points over an 18 month period, measuring Processing Speed, Verbal Memory, Vigilance, Reasoning and Working Memory domains. Genetic mediation of improvements in each of these five domains plus a composite neurocognitive measure was assessed for each of five antipsychotics (olanzapine, perphenazine, quetiapine, risperidone and ziprasidone). Six SNPs achieved genome-wide significance using a pre-specified threshold that ensures, on average, only one in ten findings is a false discovery. These six SNPs were located within, or in close proximity to, genes EHF, SLC26A9, DRD2, GPR137B, CHST8 and IL1A. The more robust findings, i.e. those significant across multiple neurocognitive domains and having adjacent SNPs showing evidence for association, were rs286913 at the EHF gene (p-value 6.99×10−8, q-value 0.034, mediating the effects of ziprasidone on Vigilance), rs11240594 at SLC26A9 (p-value 1.4×10−7, q-value 0.068, mediating the effects of olanzapine on Processing Speed) and rs11677416 at IL1A (p-value 6.67×10−7, q-value 0.081, mediating the effects of olanzapine on Working Memory). This study has generated several novel candidate genes for antipsychotic response. However, our findings will require replication and functional validation. To facilitate replication efforts, we provide all GWAS p-values for download.

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“…There is substantial evidence to support the importance of CYP2C9, CYP2C19 and CYP2D6 genotypes in psychotropic management [5,8–12,16,22–33,102]. Moreover, many diagnostic CYP450 tests for drug metabolism are packaged as combinations of multiple CYP450 genes (e.g., the AmpliChip CYP450 test, which combines CYP2D6 and CYP2C19 ) [7,16].…”

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confidence: 99%

Novel Drug Metabolism Indices for Pharmacogenetic Functional Status Based on Combinatory Genotyping of CYP2C9 , CYP2C19 and CYP2D6 Genes

et al. 2011

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Aims We aim to demonstrate clinical relevance and utility of four novel drug-metabolism indices derived from a combinatory (multigene) approach to CYP2C9, CYP2C19 and CYP2D6 allele scoring. Each index considers all three genes as complementary components of a liver enzyme drug metabolism system and uniquely benchmarks innate hepatic drug metabolism reserve or alteration through CYP450 combinatory genotype scores. Methods A total of 1199 psychiatric referrals were genotyped for polymorphisms in the CYP2C9, CYP2C19 and CYP2D6 gene loci and were scored on each of the four indices. The data were used to create distributions and rankings of innate drug metabolism capacity to which individuals can be compared. Drug-specific indices are a combination of the drug metabolism indices with substrate-specific coefficients. Results The combinatory drug metabolism indices proved useful in positioning individuals relative to a population with regard to innate drug metabolism capacity prior to pharmacotherapy. Drug-specific indices generate pharmacogenetic guidance of immediate clinical relevance, and can be further modified to incorporate covariates in particular clinical cases. Conclusions We believe that this combinatory approach represents an improvement over the current gene-by-gene reporting by providing greater scope while still allowing for the resolution of a single-gene index when needed. This method will result in novel clinical and research applications, facilitating the translation from pharmacogenomics to personalized medicine, particularly in psychiatry where many drugs are metabolized or activated by multiple CYP450 isoenzymes.

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The Promise and Reality of Pharmacogenetics in Psychiatry

Cited by 33 publications

References 492 publications

Anticipating the Ethical Challenges of Psychiatric Genetic Testing

Anticipating the Ethical Challenges of Psychiatric Genetic Testing

Genome-Wide Pharmacogenomic Study of Neurocognition As an Indicator of Antipsychotic Treatment Response in Schizophrenia

Novel Drug Metabolism Indices for Pharmacogenetic Functional Status Based on Combinatory Genotyping of CYP2C9 , CYP2C19 and CYP2D6 Genes

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