title: Exploratory analysis for a targeted patient population responsive to the metabotropic glutamate 2/3 receptor agonist pomaglumetad methionil in schizophrenia.
abstract: BACKGROUND
  Accumulating evidence indicates that glutamatergic tone in schizophrenia may vary as a function of illness duration or medication history. We conducted an exploratory analysis of the existing clinical trial database of pomaglumetad methionil (pomaglumetad) to demonstrate treatment response in targeted patient populations.
  
  
  METHODS
  Results of the H8Y-MC-HBBM (HBBM) study and an integrated analysis based on five placebo-controlled trials were summarized. Patients with schizophrenia were randomly assigned to receive either pomaglumetad, 40 or 80 mg twice daily (BID), placebo, or risperidone, 2 mg BID, for up to 6 weeks. Patient subgroups were analyzed to determine the efficacy of pomaglumetad treatment in patients early-in-disease (≤3 years) and late-in-disease (≥10 years) (HBBM, 40 mg, n = 206, 80 mg, n = 198; integrated analysis, 40 mg, n = 382, 80 mg, n = 381) and in patients previously treated with central nervous system drugs with prominent serotonin 2A receptor antagonist activity (S2 group) or with predominant dopamine D2 receptor antagonist activity (D2 group; HBBM, 40 mg, n = 275, 80 mg, n = 269; integrated analysis, 40 mg, n = 590, 80 mg, n = 506).
  
  
  RESULTS
  In the HBBM study and integrated analysis, only patients early-in-disease or previously treated with D2 drugs exhibited significantly greater improvement relative to those receiving placebo, when treated with pomaglumetad, 40 mg (but not 80 mg) BID. Treatment response to risperidone did not appear to depend upon these patient subgroups.
  
  
  CONCLUSIONS
  Demonstration of antipsychotic efficacy of a potential glutamate-based pharmacotherapy for schizophrenia may require the identification of appropriate patient subgroups whose treatment responsiveness may be fundamentally related to dysregulation of central nervous system glutamatergic tone.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; Lundbeck LLC, Deerfield, Illinois. Electronic address: bkin@lundbeck.com.
authors.forename: Bruce J
authors.initials: BJ
authors.lastname: Kinon
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Millen
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana.
authors.forename: David L
authors.initials: DL
authors.lastname: McKinzie
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000627:therapeutic use*; D003499:Cyclic S-Oxides / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011569:Psychiatric Status Rating Scales; D016032:Randomized Controlled Trials as Topic; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C517803:4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid; D014150:Antipsychotic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003499:Cyclic S-Oxides; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; C102718:metabotropic glutamate receptor 3
keywords: Epigenetic; Glutamate; Pomaglumetad; Risperidone; Schizophrenia; Treatment history