Iris Grossman

Pharmacogenetics of antipsychotic response in the CATIE trial: a candidate gene analysis

The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Phase 1 Schizophrenia trial compared the effectiveness of one typical and four atypical antipsychotic medications. Although trials such as CATIE present important opportunities for pharmacogenetics research, the very richness of the clinical data presents challenges for statistical interpretation, and in particular the risk that data mining will lead to false-positive discoveries. For this reason, it is both misleading and unhelpful to perpetuate the current practice of reporting association results for these trials one gene at a time, ignoring the fact that multiple gene-by-phenotype tests are being carried out on the same data set. On the other hand, suggestive associations in such trials may lead to new hypotheses that can be tested through both replication efforts and biological experimentation. The appropriate handling of these forms of data therefore requires dissemination of association statistics without undue emphasis on select findings. Here we attempt to illustrate this approach by presenting association statistics for 2769 polymorphisms in 118 candidate genes evaluated for 21 pharmacogenetic phenotypes. On current evidence it is impossible to know which of these associations may be real, although in total they form a valuable resource that is immediately available to the scientific community.

Review of evidence for genetic testing for CYP450 polymorphisms in management of patients with nonpsychotic depression with selective serotonin reuptake inhibitors

Purpose: Cytochrome P450 (CYP450) enzymes metabolize selective serotonin reuptake inhibitor (SSRI) drugs used in treatment of depression. Variants in these genes may impact treatment efficacy and tolerability. The purpose of this study was 2-fold: to systematically review the literature for evidence supporting CYP450 genotyping to guide SSRI treatment for major depression, and, where evidence is inadequate, to suggest future research.Methods: We searched MEDLINE® and other databases for studies addressing five key questions suggested by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Eligibility criteria were defined, and studies were reviewed independently by paired researchers. A conceptual model was developed to guide future research.Results: Review of 1200 abstracts led to the final inclusion of 37 articles. The evidence indicates relatively high analytic sensitivity and specificity of tests detecting a subset of polymorphisms of CYP2D6, 2C19, 2C8, 2C9, and 1A1. We found marginal evidence regarding a clinical association between CYP450 variants and SSRI metabolism, efficacy, and tolerability in the treatment of depression.Conclusions: Current evidence does not support the use of CYP450 genotyping to guide SSRI treatment of patients with depression. Studies are proposed that will effectively guide decision-making in the area of CYP450 testing in depression, and genetic testing more generally.

Routine pharmacogenetic testing in clinical practice: dream or reality?

Pharmacogenetics (PGx) has become progressively popular in recent years, thanks to growing anticipation among scientists, healthcare providers and the general public for the incorporation of genetic tests into the diagnostic arsenal at the physicians disposal. Indeed, much research has been dedicated to elucidation of genetic determinants underlying interindividual variability in pharmacokinetic parameters, as well as drug safety and efficacy. However, few PGx applications have thus far been realized in healthcare management. This review uses examples from PGx research of psychiatric drugs to illustrate why the current published findings are inadequate and insufficient for utilization as routine clinical predictors of treatment safety, efficacy or dosing. I therefore suggest the necessary steps to demonstrate the validity, utility and cost-effectiveness of PGx. These recommendations include a whole range of aspects, starting from standardization of criteria and assessment of the technical quality of genotyping assays, up to design of prospective PGx studies, providing the basis for reimbursement programs to be recognized in routine clinical practice.

Genetic Determinants of Variable Metabolism Have Little Impact on the Clinical Use of Leading Antipsychotics in the CATIE study

Purpose: To evaluate systematically in real clinical settings whether functional genetic variations in drug metabolizing enzymes influence optimized doses, efficacy, and safety of antipsychotic medications.Methods: DNA was collected from 750 patients with chronic schizophrenia treated with five antipsychotic drugs (olanzapine, quetiapine, risperidone, ziprasidone, and perphenazine) as part of the Clinical Antipsychotic Trials of Intervention Effectiveness study. Doses for each of the medicines were optimized to 1, 2, 3, or 4× units in identically appearing capsules in a double-blind design. We analyzed 25 known functional genetic variants in the major and minor metabolizing enzymes for each medication. These variants were tested for association with optimized dose and other relevant clinical outcomes.Results: None of the tested variants showed a nominally significant main effect in association with any of the tested phenotypes in European-Americans, African-Americans, or all patients. Even after accounting for potential covariates, no genetic variant was found to be associated with dosing, efficacy, overall tolerability, or tardive dyskinesia.Conclusion: There are no strong associations between common functional genetic variants in drug metabolizing enzymes and dosing, safety, or efficacy of leading antipsychotics, strongly suggesting merely modest effects on the use of these medicines in most patients in typical clinical settings.

Global pharmacogenetics: genetic substructure of Eurasian populations and its effect on variants of drug-metabolizing enzymes

AIMS To study the frequency distribution of cytochrome P450 (CYP) functional genetic variants in five Eurasian populations from the territory of Siberia in Russia. MATERIALS & METHODS Unrelated healthy Tuvinians, Buryats, Altaians, Yakuts and Russians (n = 87-88) were genotyped for CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, CYP3A5*3 and CYP3A5*6. Standard pairwise genetic distances, locus-specific and global Fst statistics were calculated. RESULTS CYP allele and genotype frequencies demonstrated significant variability. Overall, the degree of between-population variance displayed by CYP SNPs was lower than that recorded from neutral short tandem repeats and Alu-insertion polymorphism, indicating evolutionary conservation of CYP polymorphisms. CYP-based genetic distances were well correlated with the geographic distances across populations (r = 0.822, p = 0.008). CONCLUSIONS Although the tested variants were present in the neighboring, yet secluded, populations at the expected range of frequencies, the observed frequencies were significantly variable across Eurasian populations, indicating potential relevance to clinical decision making.

Pharmacogenetics and Pharmacogenomics

Publisher Summary Pharmacogenetics and pharmacogenomics exist in the scientific literature, each with its own connotation and a range of alternative distinctions. Pharmacogenetics (PGx) has historical priority, according to its broadest meaning—relating heritable variation to inter-individual variation in drug response. Pharmacogenomics describes the study of differential gene-expression profiles in tissues of interest and their relation to drug-response phenotypes. This chapter focuses on inherited sequence variation, insertions deletions, copy number variations, micro-satellites, and Alu repeats and its association with treatment response end-points. A comprehensive review of gene-expression signatures, their association with response to chemotherapy, and search for underlying genetic determinants is presented. The discipline of PGx is closely tied to human genetics and genomics, focusing on specific phenotypes of interest. While disease predisposition research in the realm of non-Mendelian traits is faced with extremely complex etiology dictated by interplay between various pathways in the human body, pharmacogenetic phenotypes are largely governed by a limited number of molecules. Most of these interact with the drug as pharmacokinetic or pharmacodynamic entities. Pharmacogenomics focuses on treatment efficacy, dosing, and safety.

Clinical Trials of AD Delay of Onset: Enrichment by a Prognostic Genetic Biomarker

Modern medicine is shifting its focus to predictive and preventive healthcare utilization. To support this change, early intervention clinical trials that delay the onset of symptomatic disease must be conducted in a safe and cost-effective manner, and within a reasonable timeframe. Biomarkers in general, and pharmacogenetic determinants in particular, hold great promise for enabling the conduct of early intervention studies by allowing enrichment of the study population with high risk individuals while also minimizing participation of low risk subjects. In this chapter, we review one possible approach for the co-development of a therapeutic and companion prognostic. In the example cited, at the conclusion of the clinical trial, the biomarker will be evaluated for its utility in identifying individuals at risk of developing mild cognitive impairment (MCI) due to Alzheimer’s disease (AD) in the next 5 years (i.e. prospective data will be generated to determine the biomarker’s qualification as a prognostic). Simultaneously, the therapeutic will be evaluated for its efficacy in delaying the onset of MCI due to AD in high risk subjects with normal cognition at study entry. This clinical trial in planning is projected to launch internationally in 2013. The strategic and operational aspects of this development program are expected to pave the way to the application of similar approaches for other early intervention indications, particularly within the context of neurodegenerative diseases.