title: AZD8529, a positive allosteric modulator at the mGluR2 receptor, does not improve symptoms in schizophrenia: A proof of principle study.
abstract: BACKGROUND
  Activation of metabotropic glutamate (mGluR2/3) receptors has been proposed as an alternative mechanism to dopaminergic-based antipsychotics to correct glutamatergic deficits hypothesized to underlie schizophrenia symptoms. This study investigates the efficacy and safety of AZD8529, a selective positive allosteric modulator (PAM) at the mGlu2 receptor, in symptomatic patients with schizophrenia.
  
  
  METHODS
  Patients were randomized to receive AZD8529 40 mg, risperidone 4 mg, or placebo as monotherapy. Treatment lasted for 28 days, and clinical efficacy was assessed using Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impression (CGI) scores.
  
  
  RESULTS
  There were no significant differences between patients treated with AZD8529 versus placebo in change from baseline to endpoint in PANSS total, negative and positive symptom subscale, or CGI-S scores. In contrast, risperidone demonstrated significant efficacy relative to placebo.
  
  
  CONCLUSIONS
  These results do not support a role for the mGluR-2 PAM AZD8529 as an antipsychotic and indicate that positive modulation of mGluR type 2 receptors alone is not sufficient for antipsychotic effects in acutely ill schizophrenia patients.
authors.affiliation: CBH Health, LLC, 9210 Corporate Blvd., Suite 110, Rockville, MD, United States; Georgetown University, 3700 O St. NW, Washington, DC 20057, United States.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Litman
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19542, United States; Teva Pharmaceuticals, 41 Moores Rd., Frazer, PA 19355, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19542, United States; Sage Therapeutics, 215 First St., Cambridge, MA 02142, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Doherty
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19542, United States.
authors.forename: Alan
authors.initials: A
authors.lastname: Cross
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19542, United States; 2b Analytics, LLC, 128 Westminster Dr., Wallingford, PA 19086, United States.
authors.forename: Shane
authors.initials: S
authors.lastname: Raines
authors.affiliation: California Clinical Trials Medical Group, 1560 East Chevy Chase Dr., Suite 140, Glendale, CA 91206, United States.
authors.forename: Lev
authors.initials: L
authors.lastname: Gertsik
authors.affiliation: AstraZeneca Pharmaceuticals, 1800 Concord Pike, Wilmington, DE 19542, United States; Forest Research Institute, Jersey City, NJ, United States; Haborside Financial Center, Plaza V, Jersey City, NJ 07311, United States.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Zukin
mesh_terms: D000293:Adolescent; D000328:Adult; D000494:Allosteric Regulation; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D010069:Oxadiazoles / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use*; D011569:Psychiatric Status Rating Scales; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D018967:Risperidone / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C000608263:AZD8529; D014150:Antipsychotic Agents; D007211:Indoles; D010069:Oxadiazoles; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018967:Risperidone