Exploratory Analysis for a Targeted Patient Population Responsive to the Metabotropic Glutamate 2/3 Receptor Agonist Pomaglumetad Methionil in Schizophrenia

Biol Psychiatry. 2015 Dec 1;78(11):754-62. doi: 10.1016/j.biopsych.2015.03.016. Epub 2015 Mar 19.

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.

Trial registration: ClinicalTrials.gov NCT00149292 NCT00520923 NCT01086748 NCT01125358 NCT01307800.

Keywords: Epigenetic; Glutamate; Pomaglumetad; Risperidone; Schizophrenia; Treatment history.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antipsychotic Agents / therapeutic use*
  • Bridged Bicyclo Compounds, Heterocyclic / therapeutic use*
  • Cyclic S-Oxides / therapeutic use*
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Psychiatric Status Rating Scales
  • Randomized Controlled Trials as Topic
  • Receptors, Metabotropic Glutamate / agonists*
  • Schizophrenia / drug therapy*
  • Treatment Outcome
  • Young Adult

Substances

  • 4-aminho-2-thiabicyclo(3.1.0)hexane-4,6-dicarboxylic acid
  • Antipsychotic Agents
  • Bridged Bicyclo Compounds, Heterocyclic
  • Cyclic S-Oxides
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor 3

Associated data

  • ClinicalTrials.gov/NCT00149292
  • ClinicalTrials.gov/NCT00520923
  • ClinicalTrials.gov/NCT01086748
  • ClinicalTrials.gov/NCT01125358
  • ClinicalTrials.gov/NCT01307800