There are numerous resources clinicians may
There are numerous resources clinicians may use to gather information on the strength of evidence related to pharmacogenetic-based dosing and treatment decisions, as well as specific dosing guidelines, some of which are summarized in this review. These include resources from CPIC, which provides peer-reviewed recommendations and drug/gene guidelines (Swen et al., 2011). The Pharmacogenomic Knowledge Base (PharmGKB), curates knowledge and evidence for the impact of specific genetic variations on drug metabolism (Altman, 2007). The Pharmacogenetic Research Network is funded by the National Institutes of Health and brings together numerous research initiatives.
The Royal Dutch Association for the Advancement of Pharmacy has developed pharmacogenetics-based therapeutic dose recommendations based on the available evidence (Swen et al., 2011). The guidelines currently provide recommendations for over 50 drugs and 100 genotype/phenotype–drug combinations. Identified studies are graded for the quality of evidence and clinical relevance for the gene–drug interaction. Risk analysis is then used to develop recommendations for dose adjustments and therapeutic strategies, such as therapeutic drug monitoring, alternative drug selections, or warning for adverse events.
The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) initiative, established by the Centers for Disease Control and Prevention (CDC), has created guidelines for evaluation and evidence-based application of genetic tests (Teutsch et al., 2009). The EGAPP provides an analytic framework for examining evidence related to pharmacogenetic testing. Fig. 4 illustrates a hypothetical application of this framework to the problem of Cytidine 5-triphosphate synthesis testing for antipsychotic use. This approach emphasizes the analytic validity (sensitivity and specificity of the genotype test), clinical validity (ability of the test to predict the association of genotype with the circulating levels or clinical response predicted by the genotype), and clinical utility (likelihood that use of the test to guide drug choice will improve outcomes). A recent meta analysis of CYP450 testing for prescribing antipsychotics in adults with schizophrenia found 41 of 2841 studies reported analytic validity, 47 of 2151 reported data on clinical validity, and only 1 of 1234 reported clinical utility (Fleeman et al., 2011).
Conclusion The US FDA has increasingly required inclusion of pharmacogenetic information in product labeling, and provides guidance on incorporation of pharmacogenetic studies in drug development. Plasma levels—and potentially the efficacy and safety—of many antipsychotic drugs are influenced by known CYP450 genetic variants. CLIA-approved assays are available to test for these polymorphisms in patients and are relatively inexpensive. No randomized clinical trials have yet evaluated whether use of CYP450 genotyping in antipsychotic treatment decision making is associated with better treatment response or reduced likelihood of adverse events in adult psychiatric patients. Randomized trials are not only cost prohibitive, they may not be practical because some polymorphisms are too infrequent (Mrazek and Lerman, 2011). Additionally, given the current high predictive value of pharmacogenetic tests, it would not be ethical to randomize patients to treatments that are potentially toxic for known phenotypes. Most studies to date have been unable to provide sufficient evidence to support the use of CYP450 genotype testing to improve therapeutic efficacy in the use of antipsychotic medications and the clinical utility of this strategy has not been determined. The inability to conclusively demonstrate a therapeutic benefit of genotype testing may be limited by several factors, including: 1) retrospective or cross-sectional design, 2) inadequate statistical power from small study groups and/or infrequent alleles, 3) heterogeneous patient groups with regard to ethnicity, diagnoses, illness severity, medication, treatment duration, and dose, and 4) a wide variety of outcomes measures. Collectively, the literature provides a consistent body of evidence supporting the use of genotypic testing to prevent adverse events in adults receiving some antipsychotics. The role of additional genetic variants beyond CYP450 in the therapeutic and adverse responses to antipsychotics is currently being evaluated, including those polymorphisms related to pharmacodynamic targets such as dopamine and serotonin receptors, and cellular transporters (Arranz et al., 2011, Zhang and Malhotra, 2011). These studies offer additional avenues to predict efficacy and may be useful to prevent adverse effects, including weight gain and EPS (Fraguas and Kirchoff, 2006, Lett et al., 2012).