Schizophrenia
Conditions
Brief summary
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
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.
Interventions
DRUGPlacebo
Placebo capsule daily for 16 weeks
DRUGRisperdal
Risperdal 4 mg per day for 16 weeks
Sponsors
National Institute of Mental Health (NIMH)
Ortho-McNeil Janssen Scientific Affairs, LLC
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Positive Symptom Item Scores by Week and Treatment Group | Baseline and every two weeks for 16 weeks. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropsychological Testing - Overall Composite Z-score | Baseline and Week 16 | 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. |
| Negative Symptom Total Score by Week and Treatment Group | Baseline and every two weeks for 16 weeks. | 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. |
Countries
United States
Participant flow
Recruitment details
Though funding was in place beginning in 2001, recruitment took place from 2003 to 2008. Subjects were recruited from the Maryland Psychiatric Research Center Outpatient Reseach clinic, the Treatment Research Program, and community mental health centers.
Pre-assignment details
86 Participants signed informed consent. 15 were ineligible or excluded. 71 Participants entered the evaluation phase. Two were withdrawn prior to randomization. Four people withdrew after randomization but prior to starting study medications.
Participants by arm
| Arm | Count |
|---|---|
| Risperidone Participants assigned to risperidone | 30 |
| Placebo Participants assigned to placebo | 35 |
| Total | 65 |
Baseline characteristics
| Characteristic | Placebo | Risperidone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 35 Participants | 30 Participants | 65 Participants |
| Age, Continuous | 44.1 years STANDARD_DEVIATION 9.3 | 48.3 years STANDARD_DEVIATION 7.2 | 46.1 years STANDARD_DEVIATION 8.6 |
| Region of Enrollment United States | 35 participants | 30 participants | 65.0 participants |
| Sex: Female, Male Female | 10 Participants | 11 Participants | 21 Participants |
| Sex: Female, Male Male | 25 Participants | 19 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 30 | 0 / 35 |
| serious Total, serious adverse events | 1 / 30 | 2 / 35 |
Outcome results
Primary
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.
Time frame: Baseline and every two weeks for 16 weeks.
Population: The intent to treat analysis included all participants who received at least one dose of study medication and completed the BPRS rating at the specified week.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 0 | 15.5 units on a scale | Standard Deviation 3.8 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 6 | 13.9 units on a scale | Standard Deviation 3.9 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 8 | 13.5 units on a scale | Standard Deviation 4.2 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 10 | 13.9 units on a scale | Standard Deviation 4.2 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 12 | 13.8 units on a scale | Standard Deviation 3.7 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 14 | 13.4 units on a scale | Standard Deviation 3.5 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 16 | 13.2 units on a scale | Standard Deviation 3.5 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Change Score | -2.6 units on a scale | Standard Deviation 3.1 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 2 | 14.6 units on a scale | Standard Deviation 3.7 |
| Risperidone | Positive Symptom Item Scores by Week and Treatment Group | Week 4 | 13.3 units on a scale | Standard Deviation 4 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 0 | 15.5 units on a scale | Standard Deviation 4.2 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 4 | 14.4 units on a scale | Standard Deviation 3.5 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 14 | 14.2 units on a scale | Standard Deviation 3.8 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 6 | 14.7 units on a scale | Standard Deviation 3.8 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Change Score | -1.5 units on a scale | Standard Deviation 3.4 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 8 | 14.9 units on a scale | Standard Deviation 3.9 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 16 | 14.1 units on a scale | Standard Deviation 3.6 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 10 | 14.9 units on a scale | Standard Deviation 4.2 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 2 | 15.1 units on a scale | Standard Deviation 4 |
| Placebo | Positive Symptom Item Scores by Week and Treatment Group | Week 12 | 15.3 units on a scale | Standard Deviation 4.6 |
Secondary
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.
Time frame: Baseline and every two weeks for 16 weeks.
Population: The intent to treat analysis included all participants who received at least one dose of study medication and completed the SANS rating at the specified treatment week.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 10 | 30.6 units on a scale | Standard Deviation 10.9 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 16 | 31.3 units on a scale | Standard Deviation 11.9 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 6 | 31.2 units on a scale | Standard Deviation 10.3 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 12 | 31.6 units on a scale | Standard Deviation 10.7 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 2 | 30.8 units on a scale | Standard Deviation 11.5 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 4 | 29.8 units on a scale | Standard Deviation 11.6 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 8 | 30.4 units on a scale | Standard Deviation 11.3 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 14 | 31.7 units on a scale | Standard Deviation 11 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Change Score | -2.6 units on a scale | Standard Deviation 5.6 |
| Risperidone | Negative Symptom Total Score by Week and Treatment Group | Week 0 | 32.3 units on a scale | Standard Deviation 11.6 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Change Score | 1.1 units on a scale | Standard Deviation 10.8 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 2 | 34.0 units on a scale | Standard Deviation 12.1 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 6 | 33.0 units on a scale | Standard Deviation 12.7 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 10 | 33.1 units on a scale | Standard Deviation 13.3 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 12 | 32.4 units on a scale | Standard Deviation 12.5 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 14 | 34.4 units on a scale | Standard Deviation 14.1 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 16 | 34.4 units on a scale | Standard Deviation 14.8 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 0 | 33.0 units on a scale | Standard Deviation 13.3 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 4 | 32.9 units on a scale | Standard Deviation 13.3 |
| Placebo | Negative Symptom Total Score by Week and Treatment Group | Week 8 | 34.0 units on a scale | Standard Deviation 14.1 |
Secondary
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.
Time frame: Baseline and Week 16
Population: Two participants completed 9 or fewer of the 13 individual tests in the neurocognitive battery, and were omitted from calculation of the overall composite score
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Risperidone | Neuropsychological Testing - Overall Composite Z-score | Baseline | 0.02 z-score | Standard Deviation 0.66 |
| Risperidone | Neuropsychological Testing - Overall Composite Z-score | Week 16 | 0.12 z-score | Standard Deviation 0.66 |
| Placebo | Neuropsychological Testing - Overall Composite Z-score | Baseline | -0.03 z-score | Standard Deviation 0.46 |
| Placebo | Neuropsychological Testing - Overall Composite Z-score | Week 16 | 0.07 z-score | Standard Deviation 0.47 |