Risperidone Augmentation in Patients With Schizophrenia Partially Responsive to Clozapine

Specific Aims - We propose a double-blind, placebo-controlled trial to study the effectiveness and tolerability of adding risperidone to stable yet only partially remitted patients with schizophrenia maintained on clozapine. We anticipate enrolling a total of 40 subjects over a period of two years at the Freedom Trail Clinic and affiliated sites in Boston, Massachusetts. Our primary outcome measure will be change in total score on the Positive and Negative Syndrome Scale (PANSS). Secondary hypotheses are (1) that the clozapine-risperidone combination is well tolerated, (2) that clozapine levels will not be influenced by risperidone, and (3) that prolactin elevation is suitable as a surrogate marker of sufficient D2 blockade to predict response.

Background - Despite a new generation of antipsychotics, many patients with schizophrenia achieve only partial syndromal remission. In an effort to improve symptomatic and functional outcomes, it has become common practice to combine antipsychotic medications. Since this strategy is largely unproven and expensive, empirical trials are urgently needed. Our group has found in an open trial that adding risperidone to clozapine was well tolerated and led to improvement in psychopathology. Additional support for increasing D2 blockade in clozapine partial responders comes form two small studies using sulpiride and pimozide. We hypothesize that there is a subgroup of patients who might benefit from additional D2 blockade beyond what clozapine alone accomplishes.

Methods - The proposed trial will be placebo-controlled, randomized, and double-blind, and it will last 8 weeks. We expect to enroll 40 subjects overall. Subjects will be eligible if they are diagnosed with schizophrenia and treated with clozapine. In addition, they must have residual symptoms of schizophrenia as we are interested in improvement of residual psychopathology. Subjects with dementia or mental retardation as well as pregnant women will be excluded. After a 2-week placebo lead-in period to assure stable psychopathology and minimize placebo-response, subjects will be randomly allocated to receive 6 weeks of either risperidone (20 subjects), or matching placebo (20 subjects) added onto their customary antipsychotic medication, clozapine. Overall, there are 5 study visits every 2 weeks plus the initial screening visit. On each visit, subjects will be evaluated with standard psychiatric rating scales of psychopathology and side effects. In addition, we will measure serum levels of the medications used, clozapine and risperidone.

Fasting glucose will be measured at screening, week 4, and week 8 visits. This is done to monitor subjects for worsening glucose control. This is a possible concern due to the association between atypical antipsychotics, including risperidone, and hyperglycemia. Subjects who are discovered to either have diabetes or develop diabetes during the study, or who have worsening glucose control if diabetic, will be discontinued and referred to their PCP for further work-up and treatment. This additional blood test will not lead to additional blood draws but will simply be added to the subject's routine and mandated biweekly WBC monitoring.

The study endpoint will be a 20% improvement on our primary rating scale of psychopathology, the Positive and Negative Syndrome Scale (PANSS). No worsening of psychopathology is expected in this trial as subjects are maintained on primary antipsychotic, clozapine.