Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine

Study Overview
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Brief Summary
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This study will determine whether adding the drug risperidone (Risperdal®) is more effective than placebo in treating schizophrenic patients who are taking the drug clozapine.

Detailed Description
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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.

Official Title
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Clozapine Treatment of Schizophrenic Patients

Conditions
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Schizophrenia

Intervention / Treatment
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* Drug: Placebo
* Drug: Risperdal


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active<br>Participants assigned to risperidone | Drug: Risperdal<br>* Risperdal 4 mg per day for 16 weeks<br>* Other names: Risperidone;|
| Placebo Comparator: Placebo<br>Participants assigned to placebo | Drug: Placebo<br>* Placebo capsule daily for 16 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Positive Symptom Item Scores by Week and Treatment Group | The Brief Psychiatric Rating Scale (BPRS) positive symptom items are: conceptual disorganization, hallucinatory behavior, unusual thought content, and suspiciousness. The total score is calculated by adding the scores for each item. Each scale ranges from 1=Not Present to 7=Very Severe. The minimum score is 4 and the maximum score is 28. A higher score indicates a more severe positive symptom rating. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change. | Baseline and every two weeks for 16 weeks. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neuropsychological Testing - Overall Composite Z-score | The neuropsychological testing measured attention, executive function/problem solving, motor speed, processing speed/response generation, and verbal, visual, and working memory. The individual test raw scores were converted to z-scores and an overall composite z-score was computed from the average of the individual test z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance. | Baseline and Week 16 | 
| Negative Symptom Total Score by Week and Treatment Group | The Scale for the Assessment of Negative Symptoms (SANS) total score, minus the global items, inappropriate affect, poverty of content of speech, and attention items, used to measure negative symptoms. SANS total score range = 0-85. Higher scores indicate more severe negative symptoms. A mixed model for unbalanced repeated measures analysis of covariance (ANCOVA), in which follow-up symptom score = baseline symptom score + treatment + week + treatment x week, and week is treated as a categorical, rather than a continuous measure. The treatment term estimates the average across weeks of the week-specific group differences, and is used as the main test for treatment effects on symptom change. | Baseline and every two weeks for 16 weeks. |