Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine

Clozapine is the only antipsychotic drug that has been approved for treatment resistant
patients with schizophrenia. However, up to 50% of patients treated with clozapine fail to
respond and continue to exhibit clinically significant residual positive and negative
symptoms and cognitive impairments. An emerging trend in treatment is the addition of a
second antipsychotic drug. This study will determine if risperidone when given as adjunctive
treatment is more effective than placebo in treating schizophrenic patients failing clozapine
therapy.

Participants are randomly assigned to add either adjunctive risperidone or placebo to their
current clozapine treatment in a single, daily dose for 16 weeks. Positive and negative
symptoms, cognitive impairments, side effects of the treatment, anxiety, depression,
hostility symptoms, and quality of life are assessed. Neurological tests, self administered
questionnaires, and interviews are used to assess patients.

Inclusion Criteria:

- DSM-IV criteria for schizophrenia or schizoaffective disorder

- Current clozapine treatment

- Moderate illness severity and inadequate positive symptom response to clozapine
treatment

- 6 month period of clozapine treatment with documented clozapine blood level greater
than or equal to 350 ng/ml or clozapine and norclozapine blood level greater than or
equal to 450 ng/ml

Exclusion Criteria:

- Organic brain disorder

- Mental retardation

- Medical condition whose pathology or treatment could alter the presentation or
treatment of schizophrenia or significantly increase the risk associated with the
proposed treatment protocol

- Pregnancy

- DSM-IV criteria for current alcohol or substance dependence within the last 6 months
or DSM-IV criteria for alcohol or substance abuse within the last month

- Previously received adjunctive risperidone (at doses greater than or equal to 8
mg/day) with their clozapine treatment for greater than or equal to 6 weeks