A placebo-controlled add-on trial of the Ampakine, CX516, for cognitive deficits in schizophrenia

Neuropsychopharmacology. 2008 Feb;33(3):465-72. doi: 10.1038/sj.npp.1301444. Epub 2007 May 9.


AMPA-receptor-positive modulators (Ampakines) facilitate learning and memory in animal models and in preliminary trials in human subjects. CX516 is the first Ampakine to be studied for cognitive enhancement in schizophrenia. Stable schizophrenia patients treated with clozapine (n=52), olanzapine (n=40), or risperidone (n=13) were randomly assigned to add-on treatment with CX516 900 mg three times daily or placebo for 4 weeks. Subjects were assessed with a cognitive battery at baseline, week 4, and at 4-week follow-up. Clinical scales and safety monitoring were also performed. The primary endpoint was the change from baseline in a composite cognitive score at week 4 for the intent-to-treat sample. Additional analyses examined change in symptom rating scores and examined drug effects on patients treated with clozapine separately from patients treated with either olanzapine or risperidone. A total of 105 patients were randomized and 95 (90%) completed the 4-week trial. Patients treated with CX516 did not differ from placebo in change from baseline on the composite cognitive score, or on any cognitive test at weeks 4 or 8. The between groups effect size at week 4 for the cognitive composite score was -0.19 for clozapine-treated patients and 0.24 for patients treated with olanzapine or risperidone. The placebo group improved more on the PANSS total score than the CX516 group; no other clinical rating differed between treatment groups. CX516 was associated with fatigue, insomnia and epigastric discomfort compared to placebo, but was generally well tolerated. CX516 was not effective for cognition or for symptoms of schizophrenia when added to clozapine, olanzapine, or risperidone.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / therapeutic use
  • Benzodiazepines / therapeutic use
  • Clozapine / therapeutic use
  • Cognition Disorders / drug therapy*
  • Cognition Disorders / etiology*
  • Dioxoles / adverse effects
  • Dioxoles / therapeutic use*
  • Double-Blind Method
  • Female
  • Humans
  • Male
  • Middle Aged
  • Neuropsychological Tests
  • Olanzapine
  • Pilot Projects
  • Piperidines / adverse effects
  • Piperidines / therapeutic use*
  • Psychiatric Status Rating Scales
  • Psychomotor Performance / drug effects
  • Risperidone / therapeutic use
  • Sample Size
  • Schizophrenia / drug therapy*
  • Schizophrenic Psychology*


  • 1-(quinoxalin-6-ylcarbonyl)piperidine
  • Antipsychotic Agents
  • Dioxoles
  • Piperidines
  • Benzodiazepines
  • Clozapine
  • Risperidone
  • Olanzapine