title: Intuitive pharmacogenetic dosing of risperidone according to CYP2D6 phenotype extrapolated from genotype in a cohort of first episode psychosis patients.
abstract: Risperidone (R) is the most prescribed antipsychotic drug for patients with a first episode of psychosis (FEP). In a naturalistic cohort of chronic psychiatric inpatients, we demonstrated that clinicians adjust R dosage by CYP2D6 activity, despite being blinded to the genotype, which we described as an "intuitive pharmacogenetic" process. The aim of the present study is to replicate our previous findings of intuitive pharmacogenetic in a cohort of FEP patients using CYP2D6 phenotype extrapolated from genotypes. 70 FEP patients, under baseline treatment with R monotherapy were genotyped using the iPLEX® ADME PGx multiplex panel and TaqMan® Genotyping and Copy Number Assays. Plasma concentrations of R and its metabolite, 9-hydroxyrisperidone (9-OH), were determined. The predictive properties of those variables associated with R dosage were tested using a multiple linear regression model as well as regression trees. Significant differences in the mean daily dosage of R among CYP2D6 phenotypes were observed (Kruskal-Wallis test p=0.02): PM (4.00±2.3mg/mL), IM (4.56±2.44), EM (6.22±4.0mg/day) and UM (10.20±4.91mg/day). However, non-significant differences were observed in the R/9-OH ratio or in the Concentration/Dose ratio. Regression tree provided better estimations of R dosage than the multiple linear regression model (MAE=0.958 and R2=0.871). We confirm the "intuitive pharmacogenetic" dosing of R according to the CYP2D6 phenotype in a FEP cohort. The results presented provides a rationale for the clinical use of CYP2D6 genotyping in personalized medicine.
authors.affiliation: Dept. Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain. Electronic address: sergimash@ub.edu.
authors.forename: Sergi
authors.initials: S
authors.lastname: Mas
authors.affiliation: Dept. Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gassó
authors.affiliation: Pharmacology and Toxicology Department, CDB, Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Mercé
authors.initials: M
authors.lastname: Torra
authors.affiliation: Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Miquel
authors.initials: M
authors.lastname: Bioque
authors.affiliation: Instituto de Investigación Sanitaria Aragón (IIS Aragón), Dept. of Medicine and Psychiatry, University Zaragoza, CIBERSAM, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lobo
authors.affiliation: BIOARABA Health Research Institute, OSI Araba. University Hospital, University of the Basque Country, CIBERSAM, Vitoria, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: González-Pinto
authors.affiliation: Psychiatry Department, Hospital General Universitario Gregorio Marañón, Spain.
authors.forename: Maria Soledad
authors.initials: MS
authors.lastname: Olmeda
authors.affiliation: Department of Psychiatry, Hospital de Sant Pau, Barcelona, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Iluminada
authors.initials: I
authors.lastname: Corripio
authors.affiliation: Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Vieta
authors.affiliation: Department of Child and Adolescent Psychiatry and Psychology, SGR489, Institute of Neuroscience, Hospital Clínic of Barcelona, IDIBAPS, CIBERSAM, Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain.
authors.forename: Josefina
authors.initials: J
authors.lastname: Castro-Fornieles
authors.affiliation: Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Rodriguez-Jimenez
authors.affiliation: Psychiatry Department, University of Oviedo, Oviedo, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Julio
authors.initials: J
authors.lastname: Bobes
authors.affiliation: Research Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Usall
authors.affiliation: CICAB Clinical Research Center, Extremadura University Hospital and Medical School, Servicio Extremeño de Salud, Badajoz, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Adrián
authors.initials: A
authors.lastname: Llerena
authors.affiliation: Hospital Ramon y Cajal, Universidad de Alcala, IRYCIS, CIBERSAM, Madrid, Spain.
authors.forename: Jerónimo
authors.initials: J
authors.lastname: Saiz-Ruiz
authors.affiliation: Barcelona Clínic Schizophrenia Unit, Hospital Clínic de Barcelona, IDIBAPS, Barcelona, Spain; Dept. Psychiatry and Clinical Psychobiology, University of Barcelona, Spain; CIBERSAM, Barcelona, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Bernardo
authors.affiliation: Dept. Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain.
authors.forename: Amalia
authors.initials: A
authors.lastname: Lafuente
authors.affiliation: Dept. Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain; Psychiatry Department, Hospital General Universitario Gregorio Marañón, Spain; Child and Adolescent Psychiatry Department, Hospital General Universitario Gregorio Marañón, School of Medicine, Universidad Complutense, IiSGM, CIBERSAM, Madrid, Spain; Department of Psychiatry, Hospital de Sant Pau, Barcelona, Spain; BIOARABA Health Research Institute, OSI Araba. University Hospital, University of the Basque Country, CIBERSAM, Vitoria, Spain; Instituto de Investigación Sanitaria Aragón (IIS Aragón), Dept. of Medicine and Psychiatry, University Zaragoza, CIBERSAM, Spain; Clinic Hospital Valencia, INCLIVA, Valencia University, CIBERSAM, Spain; Hospital del Mar Medical Research Institute (IMIM), Barcelona, Universitat Autonoma de Barcelona, Barcelona. CIBERSAM, Spain; Institute of Neuroscience, Hospital Clínic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Spain; Department of Child and Adolescent Psychiatry and Psychology, SGR489, Institute of Neuroscience, Hospital Clínic of Barcelona, IDIBAPS, CIBERSAM, Spain; Psychiatry Department, Bellvitge University Hospital-IDIBELL, Barcelona, Spain; Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, Spain; Psychiatry Department, University of Oviedo, Oviedo, Spain; Araba University Hospital, Bioaraba Research Institute, Vitoria, Spain; University of the Basque Country (UPV/EHU), Department of Neurosciences. CIBERSAM, Spain; Cruces University Hospital, Department of Psychiatry, BioCruces Health Research Institute, Vizcaya, Spain; Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain; CIBERSAM, Barcelona, Spain; Research Unit, Parc Sanitari Sant Joan de Déu, Sant Boi de Llobregat, Barcelona, Spain; FIDMAG Hermanas Hospitalarias Research Foundation, Barcelona, Spain; Neuroscience Research Australia, Sydney, NSW, Australia; School of Medical Sciences, University of New South Wales, Sydney, NSW, Australia; ARC Centre of Excellence in Cognition and its Disorders, Sydney, NSW, Australia; Hospital Ramon y Cajal, Universidad de Alcala, IRYCIS, CIBERSAM, Madrid, Spain; Department of Psychiatry, Complejo Hospitalario de Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Spain; Mental Health Centre of Catarroja, University of Valencia, CIBERSAM, Spain.
authors.lastname: PEPs Group
mesh_terms: D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage; D015331:Cohort Studies; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D010597:Pharmacogenetics / Q000379:methods*; D010641:Phenotype; D011446:Prospective Studies; D011618:Psychotic Disorders / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics*; D018967:Risperidone / Q000008:administration & dosage*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D019389:Cytochrome P-450 CYP2D6; D018967:Risperidone
keywords: Antipsychotic; CYP2D6; Pharmacogenetics; Pharmacokinetics