Org 24448 (Ampakine) for Cognitive Deficits in Schizophrenia

Inclusion Criteria:

1. Diagnosis: schizophrenia, any subtype (DSM-IV/DSM-IV-TR)
2. Age: 18-55 years
3. Gender: male or female
4. Capable of providing informed consent
5. Antipsychotic: aripiprazole, olanzapine, quetiapine, risperidone or ziprasidone.
6. Subjects must have been maintained on current psychotropic medications for 8 weeks and on current doses for 4 weeks.
7. Subjects must be clinically stable and in the residual (non-acute) phase of their illness for at least 12 weeks.

8. Symptom Ratings:

   • No more than a "moderate" severity rating on hallucinations and delusions (i.e., Brief Psychiatric Rating Scale (BPRS) Hallucinatory Behavior or Unusual Thought Content item score 4)
   • No more than a "moderate" severity rating on positive formal thought disorder (i.e., BPRS Conceptual Disorganization item score 4)
   • No more than "moderate" severity rating on negative symptoms (i.e., all Scale for the Assessment of Negative Symptoms global items 3)
   • A minimal level of extrapyramidal symptoms (i.e., Simpson-Angus Scale total score 6)
   • A minimal level of depressive symptoms (i.e., Calgary Depression Scale total score 10).

9. Cognitive Status:

   • Performance less than the maximum cutoff (in parentheses) for ONE of the following MCCB tests:
   • Letter-number span (.20)
   • Hopkins Verbal Learning Test (HVLT) total (.31) and
   • Continuous Performance Test- Identical Pairs (CPT) d-prime (.3.47)
   • Able to complete the baseline MCCB validly as assessed by Chief Neuropsychologist or neuropsychology tester
   • Raw score of 6 or greater on the WTAR

Exclusion Criteria:

1. Concomitant medications are allowed except for:

   • Conventional antipsychotics and clozapine
   • Antipsychotic polypharmacy
   • Anticholinergic agents (including anticholinergic antidepressants)
   • Carbamazepine, phenytoin and lamotrigine
2. DSM-IV/DSM-IV-TR diagnosis of alcohol or substance abuse (other than nicotine) within the last 3 months or a DSM-IV/DSM-IV-TR diagnosis of alcohol or substance dependence (other than nicotine) within the last 6 months

3. A history of significant head injury/trauma, as defined by:

   • Loss of consciousness (LOC) for more than 1 hour
   • Recurring seizures resulting from the head injury
   • Clear cognitive sequelae of the injury
   • Cognitive rehabilitation following the injury
4. History of seizures or abnormal EEG
5. Epileptogenic abnormalities on screening EEG
6. A baseline white blood count (WBC) less than 3500/mm3 or absolute neutrophil count (ANC) less than 2000/mm3
7. Serious medical or neurological illness (unstable cardiac disease, AIDS, malignancy, liver or renal impairment) or treatment for a medical disorder that could interfere with study participation.
8. History of transient ischemic attack (TIA) or cerebral vascular accident (CVA)
9. History of neutropenia or medication-induced blood dyscrasia
10. Clinically-significant abnormalities on screening laboratory or EKG.
11. Untreated hyper- or hypothyroidism
12. Pregnancy, nursing, or if female and fertile, unwilling to use appropriate birth control measures during study participation
13. Unable to complete neuropsychological tests
14. Serious suicidal or homicidal risk within the past six months
15. Participation in a trial of another investigational agent within 2 months
16. Treatment with Electroconvulsive therapy (ECT) within 2 months