Rapport: Rutinebrug af CYP-test ved antipsykotisk behandling

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SummaryIntroductionA large part of the psychotropic drugs that are currently used in psychiatry, are metabolizedby the enzymes Cytochrome P450 2D6 (CYP2D6) and Cytochrome P4502C19 (CYP2C19). Both enzymes exhibit genetic polymorphism. This means thatthere are variations in the genes encoding the enzymes that cause changes in theenzyme’s metabolic activity. Thus, 5-10 % of the Caucasian population have aCYP2D6-genotype resulting in a significantly reduced enzyme activity (poor metabolizers(PM)) while 30-40 % have a slightly reduced enzyme activity (inter-mediametabolizers (IM)) compared with the normal population (extensive metabolizers(EM). Approximately 1 % has a significant increase in the metabolic rate (ultrarapidmetabolizers (UM)). For CYP 2C19, 2-3 % of the population are PM’s, while the frequencyof occurrence of UM’s is unknown.The genotype of both CYP2C19, CYP2D6 is analyzed by means of a simple bloodtest, also called CYP-test. It is used to predict an individual’s ability to excrete drugsmetabolized by the enzymes CYP2D6 and CYP2C19.It is well documented that PM’s achieves significantly higher drug concentrations at agiven drug dose, while the concentrations in UM’s is correspondingly low. PMs aregenerally considered to have an increased risk of adverse drug reactions, while UM’srisk treatment failure due to relative under dosing. In theory, individualization accordingto the CYP-test results could improve these conditions. This, however, has neverproven scientifically. In addition, ethical, organizational and social aspects of genotypingare largely unknown, despite the fact that these aspects are likely to be significantfor the use of gene tests in clinical practice.Despite this, the CYP-test is widely used in psychiatry. In 2006, a regional board ofmental health care specialists (H:S Sundhedsfagligt Råd for Psykiatri) released recommendationsto implement genotyping in treatment routines, and several centers haveestablished the necessary laboratory facilities.In the present MTV, we have chosen to focus on antipsychotic drug treatment,although the principles of the genetically determined drug metabolism also apply toother therapeutic areas – somatic and psychiatric. The reasons are mainly practical, aspatients with diagnoses in the schizophrenic spectrum – who are the primary target forantipsychotic drugs – are a large part of the psychiatric patient population. Numerousantipsychotic drugs are metabolized by CYP2D6, which metabolic activity far moreoften is affected by genetically changes than CYP2C19. In other words, there are morePM’s for CYP2D6 than CYP2C19. Finally, antipsychotic drug treatment is complicatedby the frequent occurrence of side effects and treatment failure, which can lead topoor treatment adherence and increased risk of recurrence of illness and readmissions.PurposeIn this HTA we want to answer the question whether CYP-test should be used as aroutine measurement in psychiatry with focus on antipsychotic drug treatment consideringits effect (technology), organizational aspects, the patient’s perspective and costeffectiveness(economy).14 Rutinebrug af CYP-test ved antipsykotisk behandling
Target groupThe primary audience for this report is the leading consultants in psychiatric wards,who will take the decision to introduce CYP-test as a routine measure, but other decisionmakers at departmental, hospital and regional level may also find the report useful.DelimitationThe present HTA evaluates only the routine use of genotyping for CYP2D6 andCYP2C19 (CYP-test) in connection with antipsychotic drug treatment in psychiatry.The use of the CYP-test for a particular indication or testing of the genes coding forthe other CYP-enzymes, which may also be involved in the metabolism of psychiatricdrugs (including antipsychotics), is not mentioned. Although many patients with psychiatricdisorders also receive drugs for somatic disorders such as diabetes, asthma orhypertension, the use of CYP-test for medical treatment of somatic disorders is notwithin the scope of this report.MethodThe main study in this project is a randomized, controlled trial of the clinical efficacyof routine use of the CYP-test. In order to use existing data available at the largestPsychiatric Centre in Denmark, Psychiatric Center Sct. Hans, two retrospective cohortstudies based on medical records were conducted. The aim was to analyze whether theindividual patient’s CYP2D6 and CYP2C19 drug metabolizing capacity, is reflected inthe psychiatrists prescription pattern of antipsychotics as well as adverse medication(anticholinergic drugs).A third retrospective cohort study combines a quantitative and qualitative approachusing descriptive data from medical records and ethnographic observations to elucidatewhether CYP-test result affects the choice of treatment. In addition, an ethnographicfield study of CYP-test’s ethical, patient-related and organizational consequences andan economic study of cost implications and cost-effectiveness of the use of CYP-testwere conducted.Furthermore, a systematic literature review of the HTS’s different subject areas (clinical,economic, and social science) was performed.TechnologyThe CYP-test is a genetic test. By means of a single blood sample genes encoding thedrug metabolizing enzymes CYP2D6 and CYP2C19 are analyzed. The genotype usedto predict individual patient’s ability to excrete drugs metabolized by these enzymes.The intention is to individualize drug treatment according to the patient’s genetic profileand thereby reduce the risk of side effects or treatment failure.In order to utilize the CYP-tests information effectively, a number of preconditionsmust be fulfilled. Firstly, the CYP-genotype must be associated with a relevant clinicaloutcome, such as increased risk of adverse reactions or therapeutic failure. Next, theCYP-test result must be translated into a medical decision, which ultimately shouldlead to an improved treatment. The technology section attempts to elucidate theseaspects by answering the following HTA-questions:15 Rutinebrug af CYP-test ved antipsykotisk behandling
Page 1 and 2: Rutinebrug af CYP-test vedantipsyko
Page 3 and 4: IndholdHvad er Medicinsk Teknologiv
Page 5: Hvad er Medicinsk Teknologivurderin
Page 8 and 9: TeknologiCYP-testen er en gentest.
Page 10 and 11: Samlet påviser dette studie, at en
Page 12 and 13: sættelse. Dette skyldes den store
Page 16: • Are CYP2D6 and/or CYP2C19 geno
Page 20 and 21: The costs of pharmacy-dispensed dru
Page 23 and 24: Sundhedsstyrelsen vil gerne takke p
Page 25 and 26: 1 Introduktion1.1 BaggrundDen medik
Page 27 and 28: faktor for testens anvendelighed. S
Page 29 and 30: lægens ordination af såvel antips
Page 31 and 32: NomenklaturCYP-enzymerne inddeles i
Page 33 and 34: I det følgende præsenteres egne s
Page 35 and 36: Figur 2 Studiepopulationerne i stud
Page 37 and 38: ner. Således er de hyppigste mutat
Page 39 and 40: lerens kendskab til CYP2D6-genotype
Page 41 and 42: 3.3 Diskussion af resultaterFra CYP
Page 43 and 44: I RCT'et er valgt at vurdere effekt
Page 45 and 46: CYP2C19. Ud fra et teoretisk ration
Page 47 and 48: Den begrænsede eksisterende viden
Page 49 and 50: 4.2 ResultaterDet centrale spørgsm
Page 51 and 52: med en læge fra det afsnit, han er
Page 53 and 54: • Til tværfaglige behandlingsko
Page 55 and 56: liver det tydeligt, at CYP-testen k
Page 57 and 58: Lægerne i DPC udtrykker i spørges
Page 59 and 60: På linje med hvad der er fundet i
Page 61 and 62: Patienter er en central aktør i or
Page 63 and 64: live udsat for den ’trial and err
Page 65 and 66:
Samtidig rapporterer blot halvdelen
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Anna ved, at hun er blevet CYP-test
Page 70 and 71:
dering, er den et godt redskab til
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CYP-testens potentiale ligger i at
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De enkelte omkostningskomponenter,
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medført at anvende CYP-testen. Kon
Page 79 and 80:
Gennemsnittene er dog påvirket af
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Tabel 9 Resultaterne fra to-trins-m
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dette forbrug. Resultaterne viser s
Page 86 and 87:
7 Samlet vurderingDet overordnede f
Page 88 and 89:
8 Referencer1. Lieberman JA, Stroup
Page 90 and 91:
27. Ellingrod VL, Schultz SK, Arndt
Page 92 and 93:
51. Fleeman N, Dundar Y, Dickson R,
Page 94 and 95:
79. Cohen AP. Participant observati
Page 96 and 97:
109. Psykiatrisk Center Sankt Hans.
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Bilag 1 Søgestrategi for Teknologi
Page 100 and 101:
Bilag 3 Metodebeskrivelse af det ra
Page 102 and 103:
Statistiske analyserBehandlingspers
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Bilag 4 Skemaer over fundne studier
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Reference Design CYP2D6 alleles Pop
Page 108 and 109:
Page 110 and 111:
Page 112 and 113:
Bilag 6 IM’ere versus EM’ere me
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Til intensiveret fokus på en regel
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Påvirkning Spørgsmål Rating afin
Page 118 and 119:
Symptom Spørgsmål Rating af svær
Page 120 and 121:
Vrangforestillinger Spørgsmål Rat
Page 122 and 123:
Bilag 8 Søgebeskrivelse: socioetis
Page 124 and 125:
Embase((Mental disease.mp. or menta
Page 126 and 127:
York CRD-databasernePharmacogenetic
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19841983198219811980197919781977197
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I hvilket omfang føler du dig klæ
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Indtryk af CYP-testenI hvilket omfa
Page 134 and 135:
Hvor hyppigt bruger du følgende re
Page 136 and 137:
Holdninger til CYP-testenAfslutning
Page 138 and 139:
Bilag 10 Søgestrategi for den Sund
Page 140 and 141:
Bilag 12 Resultaterne fra den blind
Page 142 and 143:
Bilag 13 Variable i den økonomiske
Page 144 and 145:
Bilag 15 Studiepopulation i den øk
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IndholdsfortegnelseSide 2:Side 3:Si
Page 148 and 149:
Hvem anvender undersøgelsen:Rekvir
Page 150 and 151:
Samtlige genotyper:CYP2D6Genotype A
Page 152 and 153:
CYP 2D6 vejledninger:Tabel 1. Hurti
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Bilag 17 APPENDIKS til instruks ved
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(19-hydroxy-risperidon).Det må for
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CYP 2C19 analyseTabel 4. CYP 2C19-a
Page 161 and 162:
Tabel 5. CYP 2C19-tilpasset doserin
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Rapport: Rutinebrug af CYP-test ved antipsykotisk behandling

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