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NIHR Health Technology Assessment programme: Executive Summaries. Southampton (UK): NIHR Journals Library; 2003-.

NIHR Health Technology Assessment programme: Executive Summaries.

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

N Fleeman, C McLeod, A Bagust, S Beale, A Boland, Y Dundar, A Jorgensen, K Payne, M Pirmohamed, S Pushpakom, T Walley, P de Warren-Penny, and R Dickson.

Author Information

Published: 2010.

Objectives

The overarching questions that this review aimed to answer were:

  • Could testing for cytochrome P450 (CYP) polymorphisms in adults entering antipsychotic treatment for schizophrenia lead to improvement in outcomes?
  • Are testing results for CYP polymorphisms useful in medical, personal or public health decision-making?
  • Is testing for CYP polymorphisms in schizophrenia patients treated with antipsychotics a cost-effective use of health-care resources?

Background

Mental health is recognised as a major challenge in UK clinical practice and as such it is one of the nine National Service Frameworks. Schizophrenia is a condition requiring immediate attention but it is complex both to diagnose and to treat. Treatment of schizophrenia is especially difficult because of the large amount of interindividual variability in patient response to therapy. This high degree of heterogeneity is associated with adverse drug reactions (ADRs) or therapeutic failure, which has important implications for both the patient and the UK NHS.

The interindividual variability to therapy may in part be explained by differences in the enzymes responsible for metabolising drugs to their excretable forms, in particular the CYP enzyme system. A number of antipsychotics (both typical and atypical) are metabolised by CYP2D6 and CYP3A4, and to a lesser extent CYP1A2, including haloperidol, risperidone and clozapine.

Diagnostic genotyping tests for certain CYP enzymes are now available. The first licensed test is the AmpliChip® CYP450 test, which tests for both CYP2D6 and CYP2C19. CYP testing for prescribing antipsychotics to schizophrenia patients would be attractive if it could improve response rates or reduce side effects from treatment.

Methods

A systematic review of the analytical validity, clinical validity and clinical utility of CYP testing was undertaken. A review of economic evaluations of CYP testing in the field of psychiatry was also undertaken, as was a review of schizophrenia models.

Several search strategies were used in various databases including EMBASE, MEDLINE and the Cochrane Library. Searches related to analytical and clinical validity were carried out up to January 2008, whereas searches for clinical utility were carried out up to March 2008.

Data were extracted into structured tables and are narratively discussed in the relevant sections of the report. Meta-analysis was also undertaken where possible. For the purpose of meta-analysis, patients with multiple copies (more than two) of wt alleles were considered to be wt/wt, which it should be noted may dilute effects, given that such patients are ultrarapid metabolisers (UMs) and so will metabolise drugs quicker than patients with just two wt alleles. Given data limitations, economic modelling was not feasible, therefore key issues relating to the existing evidence base and future research needs were narratively discussed.

Inclusion criteria

For the reviews of analytical validity, clinical validity and clinical utility any study design except single case studies was included. In the case of analytical validity any patient population was accepted, whereas in the case of clinical validity and clinical utility only adults with schizophrenia receiving treatment were included. Outcome measures included accuracy of the test, measures of pharmacokinetic bioavailability, efficacy, ADRs and clinical outcomes.

For the economic literature review, economic evaluations that considered both the costs and the benefits of CYP testing were included in the review. For the review of schizophrenia models, models were included if they modelled antipsychotic therapy in any schizophrenia population and if they were published in English.

Results

Clinical evaluation

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 was typically found to be 99–100%. For clinical validity, 51 studies were found in which very few patients had either the mut/mut genotype or multiple copies (more than two) of the wt allele. These studies mainly focused on ADRs; there was some evidence from prospective studies of patients tested for CYP2D6 that, compared with those with the wt/wt genotype, patients with the wt/mut and mut/mut + wt/mut genotypes were at increased risk of tardive dyskinesia (TD) [odds ratio (OR) 2.08, 95% confidence interval (CI) 1.21 to 3.57, and OR 1.83, 95% CI 1.09 to 3.08 respectively]. In cross-sectional studies, those with the mut/mut genotype also had higher Abnormal Involuntary Movement Scale (AIMS) scores (measuring TD severity) than those with the wt/wt genotype [weighted mean difference (WMD) 1.80, 95% CI 0.40 to 3.19]. The only other significant finding was that patients with the CYP2D6 mut/mut + wt/mut genotype were significantly more likely to develop parkinsonism than those with the wt/wt genotype (OR 1.64, 95% CI 1.04 to 2.58). No published studies were found that met the inclusion criteria for clinical utility.

Economic evaluation

Only one economic evaluation assessing the costs and benefits of CYP testing for prescribing antidepressants was identified from our search and subsequently included in our review. Although not directly relevant to our decision problem the study did highlight the difficulties in undertaking an economic analysis in this area. Results from our search for a suitable schizophrenia model for adaptation and use in our review identified a total of 28 models, none of which was suitable for our purposes.

The absence of published economic studies of CYP testing for schizophrenia, the lack of evidence from the clinical component of this review and the unsuitability of published schizophrenia models meant that no model was developed; instead, the key features and data requirements of an economic model were discussed. This identified that there are still a number of factors that are unknown both for schizophrenia as a condition and in relation to the CYP pharmacogenetic test.

Conclusions

From this review of the literature, tests for determining genotypes appear to be highly accurate. However, not all aspects of analytical validity have been reported in the studies (quality control and assay robustness being commonly neglected). In terms of clinical validity, research is being conducted to assess the links between genotype and metabolism and ADRs. However, to date the research is limited and no firm conclusions can be drawn. No studies assessing clinical utility have been reported.

In terms of assessing the cost-effectiveness of using such pharmacogenetic testing, in the opinion of the authors it is too soon to tell. An economic model was not developed as a part of this report but, from previous work carried out in the area of pharmacogenetic testing in depression and through the assessment of published economic models of schizophrenia, a suggested model framework has been developed.

Our proposed model framework consists of four main modules: pharmacogenetic test module (assigning patient to phenotype), clinical effects module (linking phenotype to outcomes), transitional module (effect of test results on clinical decision) and the schizophrenia module (projecting treatment effects over a patient's lifetime). Without all four components and the information to populate them it is not possible to determine the cost-effectiveness of CYP testing in schizophrenia.

However, on the basis of a single test per patient costing around £300, the expected lifetime benefit per patient need be only about 0.01 quality-adjusted life-years (QALYs) to achieve cost-effectiveness of ≤ £30,000 per QALY gained. If any survival improvement can be shown to be supported by evidence then this level of gain appears to be modest, particularly if opportunities arise to target testing to those patients most likely to show improvements in their care and expected outcomes. Therefore, CYP pharmacogenetic testing still shows promise, but further research is needed.

Recommendations for future research

Although the current evidence base does not support the use of pharmacogenetic testing in this area, it does indicate that further study in each of the key areas is needed to either demonstrate or refute the ability of pharmacogenetic testing to assist in the development of individualised patient care in the area of schizophrenia. Recommendations for future research cover both aspects of research quality and data that will be required to inform the development of future economic models.

Analytical validity

  • Studies of analytical validity need to be explicit about patient selection, quality control, assay robustness and the sensitivity and specificity of tests. Study findings should not only report on allele frequencies but also report appropriate genotype data.

Clinical validity

  • Further evidence is required to link phenotype to genotype. Such studies need to include larger numbers of patients with the UM (multiple copies of the wt allele) and poor metaboliser (mut/mut) phenotypes and be prospective in design.
  • Studies need to consider the impact of environmental factors such as smoking, concomitant medicines, medication adherence and ethnicity. In relation to medication adherence, genotypes need to be related not only to clinical parameters but also to pharmacokinetic parameters.
  • Studies need to ensure that all currently used antipsychotics are investigated. However, given the uncertainty about the full extent of the role played by CYP2D6, further studies focusing on patients taking risperidone and olanzapine would also be useful.
  • Future research will need to consider a comprehensive approach that considers not only CYP isoforms involved in the metabolism of antipsychotics but also other targets such as dopamine and 5-hydroxytryptamine receptors.

Clinical utility

  • Prospective clinical utility studies are needed. As with clinical validity they should ensure that all currently used antipsychotics are investigated although, given their importance to the NHS (and the uncertainty about the full extent of the role played by CYP2D6), further studies focusing on patients taking risperidone and olanzapine would be particularly useful.

Economic evaluation

  • Improved evidence should be sought on the link between improved schizophrenia care and life expectancy.
  • Collection of longitudinal data that identify patterns of adherence, length of time in relapse and cost of care (including care provided in the community) is required.
  • A common approach to the measurement and reporting of adherence, relapse and quality of life in schizophrenia is needed.

Publication

  • Fleeman N, McLeod C, Bagust A, Beale S, Boland A, Dundar Y, et al. 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. Health Technol Assess 2010;14(3). [PubMed: 20031087]

NIHR Health Technology Assessment programme

The Health Technology Assessment (HTA) programme, part of the National Institute for Health Research (NIHR), was set up in 1993. It produces high-quality research information on the effectiveness, costs and broader impact of health technologies for those who use, manage and provide care in the NHS. 'Health technologies' are broadly defined as all interventions used to promote health, prevent and treat disease, and improve rehabilitation and long-term care.

The research findings from the HTA programme directly influence decision-making bodies such as the National Institute for Health and Clinical Excellence (NICE) and the National Screening Committee (NSC). HTA findings also help to improve the quality of clinical practice in the NHS indirectly in that they form a key component of the 'National Knowledge Service'.

The HTA programme is needs led in that it fills gaps in the evidence needed by the NHS. There are three routes to the start of projects.

First is the commissioned route. Suggestions for research are actively sought from people working in the NHS, from the public and consumer groups and from professional bodies such as royal colleges and NHS trusts. These suggestions are carefully prioritised by panels of independent experts (including NHS service users). The HTA programme then commissions the research by competitive tender.

Second, the HTA programme provides grants for clinical trials for researchers who identify research questions. These are assessed for importance to patients and the NHS, and scientific rigour.

Third, through its Technology Assessment Report (TAR) call-off contract, the HTA programme commissions bespoke reports, principally for NICE, but also for other policy-makers. TARs bring together evidence on the value of specific technologies.

Some HTA research projects, including TARs, may take only months, others need several years. They can cost from as little as £40,000 to over £1 million, and may involve synthesising existing evidence, undertaking a trial, or other research collecting new data to answer a research problem.

The final reports from HTA projects are peer reviewed by a number of independent expert referees before publication in the widely read journal series Health Technology Assessment.

Criteria for inclusion in the HTA journal series

Reports are published in the HTA journal series if (1) they have resulted from work for the HTA programme, and (2) they are of a sufficiently high scientific quality as assessed by the referees and editors.

Reviews in Health Technology Assessment are termed 'systematic' when the account of the search, appraisal and synthesis methods (to minimise biases and random errors) would, in theory, permit the replication of the review by others.

The research reported in this issue of the journal was commissioned and funded by the HTA programme on behalf of NICE as project number 06/28/01. The protocol was agreed in October 2007. The assessment report began editorial review in December 2008 and was accepted for publication in April 2009. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The HTA editors and publisher have tried to ensure the accuracy of the authors' report and would like to thank the referees for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this report.

The views expressed in this publication are those of the authors and not necessarily those of the HTA programme or the Department of Health.

Editor-in-Chief: Professor Tom Walley CBE

Series Editors: Dr Martin Ashton-Key, Dr Aileen Clarke, Professor Chris Hyde, Dr Tom Marshall, Dr John Powell, Dr Rob Riemsma and Professor Ken Stein

© 2010 Crown Copyright.

Included under terms of UK Non-commercial Government License.

PMID: 20031087

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