The clinical effectiveness and cost-effectiveness of testing for cytochrome P450 polymorphisms in patients with schizophrenia treated with antipsychotics: a systematic review and economic evaluation.

Liverpool Reviews and Implementation Group, University of Liverpool, UK.
Health technology assessment (Winchester, England) 01/2010; 14(3):1-157, iii. DOI: 10.3310/hta14030
Source: PubMed

ABSTRACT To determine whether testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia leads to improvement in outcomes, is useful in medical, personal or public health decision-making, and is a cost-effective use of health-care resources.
The following electronic databases were searched for relevant published literature: Cochrane Controlled Trials Register, Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effectiveness, EMBASE, Health Technology Assessment database, ISI Web of Knowledge, MEDLINE, PsycINFO, NHS Economic Evaluation Database, Health Economic Evaluation Database, Cost-effectiveness Analysis (CEA) Registry and the Centre for Health Economics website. In addition, publicly available information on various genotyping tests was sought from the internet and advisory panel members.
A systematic review of analytical validity, clinical validity and clinical utility of CYP testing was undertaken. Data were extracted into structured tables and narratively discussed, and meta-analysis was undertaken when possible. A review of economic evaluations of CYP testing in psychiatry and a review of economic models related to schizophrenia were also carried out.
For analytical validity, 46 studies of a range of different genotyping tests for 11 different CYP polymorphisms (most commonly CYP2D6) were included. Sensitivity and specificity were high (99-100%). For clinical validity, 51 studies were found. In patients tested for CYP2D6, an association between genotype and tardive dyskinesia (including Abnormal Involuntary Movement Scale scores) was found. The only other significant finding linked the CYP2D6 genotype to parkinsonism. One small unpublished study met the inclusion criteria for clinical utility. One economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants and 28 economic models of schizophrenia were identified; none was suitable for developing a model to examine the cost-effectiveness of CYP testing.
Tests for determining genotypes appear to be accurate although not all aspects of analytical validity were reported. Given the absence of convincing evidence from clinical validity studies, the lack of clinical utility and economic studies, and the unsuitability of published schizophrenia models, no model was developed; instead key features and data requirements for economic modelling are presented. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To demonstrate how value of information (VOI) analysis can be used to establish research priorities regarding the use of pharmacogenetic tests using CYP2D6 testing to select adjuvant hormonal therapy in early stage breast cancer as a case study. The following four treatment pathways are compared in a Markov model: tamoxifen treatment; CYP2D6 test and treat homozygous and heterozygous wild type patients (wt/wt; wt/*4) with tamoxifen and *4/*4 patients with anastrozole (HetTam); CYP2D6 test and treat homozygous wild type patients with tamoxifen and others with anastrozole (HomTam); and anastrozole treatment. Pharmacogenetic testing efficacy is estimated by synthesizing randomized controlled trial data comparing tamoxifen to anastrozole with observational data linking CYP2D6 genotype to tamoxifen outcomes. In order of increasing effectiveness the comparators are tamoxifen, HetTam, HomTam, anastrozole. Health outcomes for test and treatment strategies are highly uncertain. Differences in comparator costs depend on assumptions made regarding anastrozole patent expiry. The expected value of a decision taken with perfect information is £69 to £106 million (pound sterling) for the United Kingdom depending on patent expiry assumptions and the acceptable cost-effectiveness threshold. The most valuable research (VOI £53-£82 million) elucidates the relationship between CYP2D6 genotype and tamoxifen effectiveness. It is uncertain whether values of other research designs would exceed their costs. Retrospective analysis of one of the large adjuvant aromatase inhibitor trials is warranted to better understand any association between CYP2D6 genotype and tamoxifen outcomes. VOI approaches may be helpful for prioritising evidence needs and structuring coverage with evidence development agreements for pharmacogenetics.
    Value in Health 12/2011; 14(8):989-1001. DOI:10.1016/j.jval.2011.05.048 · 2.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genetic variation of the CYP2D6 gene has been associated with altered drug metabolism; however, limited studies have investigated CYP2D6 sequence diversity in African populations. We devised a CYP2D6 genotyping strategy to analyse the South African Xhosa population and genotype a Xhosa schizophrenia cohort, as CYP2D6 metabolises many antipsychotics and antidepressants. The entire CYP2D6 gene locus was sequenced in 15 Xhosa control individuals and the data generated were used to design a comprehensive genotyping strategy. Over 25 CYP2D6 alleles were genotyped in Xhosa controls and Xhosa schizophrenia patients using long-range PCR, DNA sequencing and single nucleotide primer extension analysis. Bioinformatic algorithms were used to predict the functional consequences of relevant mutations and samples were assigned CYP2D6 activity scores. A unique allele distribution was revealed and two rare novel alleles, CYP2D6*73 and CYP2D6*74, were identified. No significant differences in allele frequencies were detected between Xhosa controls and schizophrenia patients. This study provides i) comprehensive data on a poorly characterised population, ii) a valuable CYP2D6 genotyping strategy and iii) due to their unique genetic profile, provides the basis for pharmacogenetic intervention for Xhosa individuals.
    Annals of Human Genetics 07/2010; 74(4):340-50. DOI:10.1111/j.1469-1809.2010.00585.x · 1.93 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and purpose: Antipsychotics (APs) are the primary method of treatment for schizophrenia and other psychotic disorders. Unfortunately, lengthy trial-and-error approaches are typically required to find the optimal medication and dosage due to a large interindividual variability with outcome to AP treatment. The literature has shown abundant evidence for a genetic component in individuals' responses to APs. Pharmacogenetic studies analyze specific genetic markers and their association with symptom improvement and occurrence of side effects with APs. This research aims to optimize AP drug treatment by usage of predictive testing and to personalize medicine. Recent findings: This review will highlight the most consistent findings in pharmacogenetics of APs and will update the reader on the clinical implications. This will include how genetic variants modulate AP drug levels, side effects, and therapeutic symptom improvement (i.e. response) to AP treatment. Summary: Several promising findings were obtained implicating gene variants of the dopamine receptor genes in addition to gene variants of serotonin receptors for response and common side effects. Notably, effect sizes appear to be particularly high in the genetics of side effects compared to response. One example is antipsychotic-induced weight gain where the leptin, HTR2C and in particular the melanocortin-4-receptor (MC4R) genes have been implicated in weight gain in children and adolescents. Consistent findings were also obtained for genes implicated in tardive dyskinesia and agranulocytosis. However, the most clinically relevant findings pertain to genes involved in drug metabolism such as the CYP2D6 and CYP2C19 genes which have been included in the first genetic test kits such as the Amplichip CYP450 Test and more recently the DMET TM Plus Panel, the Genecept TM Assay, the Genomas HILOmet PhyzioType TM System, and the GeneSight Test. D ue to a large interindividual variability with response to psychotropic drugs, a lengthy trial-and-error approach is typically required to find the right medication and dosage. This variability results from various factors such as age, gender, ethnicity, disease symptoms, drugÁdrug interactions, and most importantly genetics. Friedrich Vogel coined the term pharmacogenetics in 1959, referring to interactions between the response to drugs and genetics in an individual (1Á4). In particular, pharmacogenetic research aims to identify specific genetic markers and their association with treatment outcome to drugs (5, 6). Pharmacogenetics bears the promise to become a tool in psychiatry, used to tailor treatment to an individual's genetic make-up. Several areas of research have now embraced pharma-cogenetics as a way to improve treatment with medi-cation. There are many tests emerging in all fields of medicine such as cardiology, pain management, cancer treatment, and psychiatry (7, 8). Many efforts are cur-rently being made to integrate pharmacogenetic testing into the clinical setting to improve patient care as well as work toward personalized medicine. Pharmacology usually differentiates between pharma-cokinetics and pharmacodynamics. Pharmacokinetics is the study of how drugs are metabolized (including
    08/2014; 2. DOI:10.3402/tdp.v2.24663