Org 24448 (Ampakine) for Cognitive Deficits in Schizophrenia

• Status: Withdrawn
• Trial end date: 2009-04-01
• Target enrollment: 0
• Participant gender: All

Summary

The TURNS is a National Institute of Mental Health (NIMH) funded contract for the evaluation of new compounds for the treatment of cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.). Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications for the treatment of schizophrenia, many patients continue to be plagued by impairments in social and work functioning. Persons with schizophrenia commonly show deficits in a number of areas of cognition that include impairments in attention, memory, and executive functioning (the ability and organize one's behavior). Importantly, a large body of literature now shows a link between cognition and community functioning in schizophrenia. It is believed that treatments that improve cognitive deficits may lead to improvements in work and social functioning.

A promising approach to improve the community functioning of patients with schizophrenia is to develop new agents that treat the cognitive deficits of the illness. One type of pharmacological compound that has shown promise at improving cognition is a group of drugs called ampakines. These drugs are believed to improve the activity of a neurotransmitter system in the brain called the glutamate system. Increased activity of this system has been linked to improvements in cognitive functioning. The current study is an eight-week trial comparing two doses of the ampakine drug, Org 24448, that will be added to patients' current atypical antipsychotic medication. One hundred thirty-five patients with schizophrenia, drawn from seven sites, will participate in the study. Cognition will be measured using a variety of paper-and-pencil and computerized measures from the consensus-derived NIMH Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) cognitive battery. Psychiatric symptoms and the ability to perform community-based tasks of daily living will also be measured. Because previous trials with this drug and other similar drugs have detected lasting cognitive benefits, this trial will also repeat clinical assessments four weeks after completion of the study medication.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of California, Los Angeles
• Collaborators: Beth Israel Deaconess Medical Center; Columbia University; Duke University; Massachusetts General Hospital; Nathan Kline Institute for Psychiatric Research; University of Maryland; University of Maryland, College Park; Washington University School of Medicine

Criteria

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