1. ¹Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
2. ²Department of Psychiatry, University of Rochester Medical Center, Rochester, NY, USA
3. ³Department of Psychiatry, Weill Medical College of Cornell University, New York, NY, USA
4. ⁴Department of Psychiatry and Biobehavioral Sciences, Semel Neuropsychiatric Institute, UCLA, Los Angeles, CA, USA
5. ⁵Department of Psychiatry, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA
6. ⁶Department of Psychiatry, Center for Psychopharmalogic Research and Treatment, University of Massachusetts Medical School, Worcester, MA, USA
7. ⁷Department of Psychiatry, Dr John C Corrigan Mental Health Center, Harvard Medical School, Fall River, MA, USA
8. ⁸Cortex Pharmaceuticals Inc., Irvine, CA, USA

Correspondence: Dr DC Goff, Department of Psychiatry, Massachusetts General Hospital, Freedom Trail Clinic, 25 Staniford Street, 2nd floor, Boston, MA 02114, USA. Tel: +1 617 912 7899; Fax: +1 617 723 3919; E-mail: goff@psych.mgh.harvard.edu

Received 23 October 2006; Revised 8 March 2007; Accepted 26 March 2007; Published online 9 May 2007.

Abstract

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.