title: Genetic variation in CYP3A43 explains racial difference in olanzapine clearance.
abstract: The antipsychotic drug, olanzapine, one of the most widely used drugs in clinical medicine, has a high rate of discontinuation due to inefficacy and/or adverse effects. We identified a single nucleotide polymorphism in the drug metabolizing enzyme, cytochrome P450 3A43 (CYP3A43; rs472660), that highly significantly predicted olanzapine clearance in the Clinical Antipsychotic Trials of Intervention Effectiveness trial (P=5.9e(-7)). Moreover, at standard antipsychotic doses, 50% of individuals with the high clearance genotype (AA) have trough blood levels below the therapeutic range. Interestingly, a much higher proportion of African Americans carry the A allele compared with Caucasians (allele frequency 67 vs 14%). After accounting for CYP3A43 genotype, race is no longer a significant predictor of olanzapine clearance. Olanzapine clearance was associated with measures of clinical response. Patients with greater clearance had higher symptom ratings and were more likely to discontinue treatment due to an inadequate response. Our data identify a genetic mechanism for variation in olanzapine response and demonstrate that blood level monitoring of olanzapine treatment is advisable.
authors.affiliation: Genes, Cognition, and Psychosis Program, National Institute of Mental Health, NIH, Bethesda, MD, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Bigos
authors.forename: R R
authors.initials: RR
authors.lastname: Bies
authors.forename: B G
authors.initials: BG
authors.lastname: Pollock
authors.forename: J J
authors.initials: JJ
authors.lastname: Lowy
authors.forename: F
authors.initials: F
authors.lastname: Zhang
authors.forename: D R
authors.initials: DR
authors.lastname: Weinberger
mesh_terms: D001741:Black or African American / Q000235:genetics*; D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001569:Benzodiazepines / Q000493:pharmacokinetics* / Q000627:therapeutic use; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D005947:Glucose / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D008956:Models, Chemical; D000077152:Olanzapine; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011569:Psychiatric Status Rating Scales; D012559:Schizophrenia / Q000188:drug therapy / Q000378:metabolism; D012737:Sex Factors; D012907:Smoking / Q000235:genetics; D015430:Weight Gain / Q000187:drug effects; D044465:White People / Q000235:genetics*
chemical_list: D014150:Antipsychotic Agents; D001569:Benzodiazepines; D051544:Cytochrome P-450 CYP3A; D005947:Glucose; D000077152:Olanzapine