title: Pharmacogenetic predictor of extrapyramidal symptoms induced by antipsychotics: multilocus interaction in the mTOR pathway.
abstract: Antipsychotic (AP) treatment-emergent extrapyramidal symptoms (EPS) are acute adverse reactions of APs. The aim of the present study is to analyze gene-gene interactions in nine genes related to the mTOR pathway, in order to develop genetic predictors of the appearance of EPS. 243 subjects (78 presenting EPS: 165 not) from three cohorts participated in the present study: Cohort 1, patients treated with risperidone, (n=114); Cohort 2, patients treated with APs other than risperidone (n=102); Cohort 3, AP-naïve patients with first-episode psychosis treated with risperidone, paliperidone or amisulpride, n=27. We analyzed gene-gene interactions by multifactor dimensionality reduction assay (MDR). In Cohort 1, we identified a four-way interaction, including the rs1130214 (AKT1), rs456998 (FCHSD1), rs7211818 (Raptor) and rs1053639 (DDIT4), that correctly predicted 97 of the 114 patients (85% accuracy). We validated the predictive power of the four-way interaction in Cohort 2 and in Cohort 3 with 86% and 88% accuracy respectively. We develop and validate a powerful pharmacogenetic predictor of AP-induced EPS. For the first time, the mTOR pathway has been related to EPS susceptibility and AP response. However, validation in larger and independent populations will be necessary for optimal generalization.
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: S
authors.initials: S
authors.lastname: Mas
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: P
authors.initials: P
authors.lastname: Gassó
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: M A
authors.initials: MA
authors.lastname: Ritter
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Malagelada
authors.affiliation: Clinical Schizophrenia Program, Psychiatry Service, Hospital Clínic de Barcelona, Barcelona, Spain; Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Bernardo
authors.affiliation: Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona, Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Barcelona, Spain. Electronic address: amalialafuente@ub.edu.
authors.forename: A
authors.initials: A
authors.lastname: Lafuente
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000328:Adult; D014150:Antipsychotic Agents / Q000009:adverse effects*; D001480:Basal Ganglia Diseases / Q000139:chemically induced* / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D011569:Psychiatric Status Rating Scales; D000076223:Regulatory-Associated Protein of mTOR; D015203:Reproducibility of Results; D018967:Risperidone / Q000009:adverse effects*; D015398:Signal Transduction / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014150:Antipsychotic Agents; D002352:Carrier Proteins; C469991:DDIT4 protein, human; C495298:FCHSD1 protein, human; D008565:Membrane Proteins; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D014157:Transcription Factors; C546842:MTOR protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D018967:Risperidone
keywords: Antipsychotic; Extrapyramidal symptoms; Multifactor dimensionality reduction; Pharmacogenetics; Predictors; mTOR