title: Pharmacogenetic analysis of the mGlu2/3 agonist LY2140023 monohydrate in the treatment of schizophrenia.
abstract: The goal of this study was to identify genetic markers associated with LY2140023 monohydrate response in patients with schizophrenia. Variants in eight candidate genes related to the mechanism of action of LY2140023 or olanzapine were investigated in a genetic cohort collected from two clinical trials. Results from this genetic analysis indicate that 23 single nucleotide polymorphisms (SNPs) were associated with a change in Positive and Negative Syndrome Scale total score in response to LY2140023 at 28 days (P<0.01; false discovery rate <0.2). Sixteen of these SNPs were located in the serotonin 2A receptor (HTR2A). Bioinformatic analyses identified a putative antisense nested gene in intron 2 of HTR2A in the region of the genetic markers associated with LY2140023 response. These data suggest a genetic association exists between SNPs in several genes, such as HTR2A, and response to LY2140023 treatment. Additional clinical trials are needed to establish replication of these results.
authors.affiliation: Eli Lilly and Company, Indianapolis, IN, USA.
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: A C M
authors.initials: AC
authors.lastname: Downing
authors.forename: L M
authors.initials: LM
authors.lastname: Munsie
authors.forename: P
authors.initials: P
authors.lastname: Chen
authors.forename: M R
authors.initials: MR
authors.lastname: Reed
authors.forename: C L
authors.initials: CL
authors.lastname: Ruble
authors.forename: K T
authors.initials: KT
authors.lastname: Landschulz
authors.forename: B J
authors.initials: BJ
authors.lastname: Kinon
authors.forename: L K
authors.initials: LK
authors.lastname: Nisenbaum
mesh_terms: D000328:Adult; D000596:Amino Acids / Q000627:therapeutic use*; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D005260:Female; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D020890:Neuregulin-1 / Q000235:genetics; D000077152:Olanzapine; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D044402:Receptor, Serotonin, 5-HT2A / Q000235:genetics; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D012426:Russia; D012559:Schizophrenia / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D012565:Schizophrenic Psychology; D016896:Treatment Outcome; D014481:United States
chemical_list: D000596:Amino Acids; D014150:Antipsychotic Agents; D018690:Excitatory Amino Acid Agonists; C534551:LY 2140023; C094131:NRG1 protein, human; D020890:Neuregulin-1; D044402:Receptor, Serotonin, 5-HT2A; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3; D001569:Benzodiazepines; D000077152:Olanzapine