Schizophrenia
Conditions
Keywords
Psychotic Disorders, Schizophreniform Disorder
Brief summary
This study will evaluate the safety and efficacy of risperidone (Risperdal®), olanzapine (Zyprexa®), and molindone (Moban®) for the treatment of children and adolescents with schizophrenia or schizoaffective disorder.
Detailed description
Little research has been conducted on the use of psychotropic agents in children and adolescents with early onset schizophrenia spectrum disorders. This study will compare antipsychotic agents with different mechanisms of action in children and adolescents who have schizophrenia or schizoaffective disorder with active psychotic symptoms. Participants are randomly assigned to receive risperidone (Risperdal), olanzapine (Zyprexa), or molindone (Moban) for 8 weeks. After 11/2005, no additional patients will be assigned to olanzapine treatment. Patients with significant improvement and without side effects continue maintenance therapy for another 44 weeks. Participants who show significant negative symptoms after 8 weeks may be started on a mood stabilizer or antidepressant. Weight gain, metabolic changes, neurocognition, functional outcome, psychotic symptoms, extrapyramidal side effects, and the ability to sustain effective therapy over time are assessed.
Interventions
DRUGRisperidone
oral risperidone 0.5mg to 6mg daily for up to 52 weeks
DRUGOlanzapine (enrollment closed in this treatment)
oral olanzapine 5-20mg per day for up to 52 weeks
DRUGMolindone
oral molindone from 10-140mg/daily for up to 52 weeks
Sponsors
National Institute of Mental Health (NIMH)
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
8 Years to 19 Years
Healthy volunteers
No
Inclusion criteria
* Schizophrenia, schizophreniform disorder, or schizoaffective disorder with psychotic symptoms * Free of depot antipsychotic medication for at least 6 months. Oral antipsychotic medication at entry into the study is allowed, provided the participant has not had an adequate trial during the present episode of psychosis. * If taking antidepressant or mood stabilizing medication, stable dosing for at least 30 days prior to entry. * Good physical health
Exclusion criteria
* Risperidone (RIS), olanzapine (OLA)\*, or molindone (MOL) for 8 weeks or more during THIS episode, with 2 weeks at the maximal dose (6 mg/day of RIS, 20 mg/day of OLA, or 140 mg/day of MOL) * If using antidepressant and/or mood stabilizing medications, treatment for fewer than 30 days immediately before entry * Intolerance or nonresponse to RIS, OLA\*, or MOL during any previous treatment * Bipolar affective disorder,post traumatic stress disorder, personality disorder, or psychosis not otherwise specified * Currently meeting Diagnostic and Statistical Manual version IV (DSM IV) criteria for major depression episode * DSM IV criteria for substance abuse or dependence with intention to continue illicit substance abuse * Endocrinological or neurological conditions which confound the diagnosis or are a contraindication to treatment with antipsychotics * Mental retardation * Risk of suicide or homicide that is not adequately controlled in the current setting * Pregnancy or refusal to practice contraception during the study \* OLA exclusion not applicable after 11/2005
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at 8 Weeks | 8 weeks | Assessed with the Positive and Negative Syndrome Scale in which a clinician rates various psychotic symptoms on the basis of observation of the participant, interview with the participant, and review of all other available information including informant reports. The scale consists of 30 items which are rated categorically between 1 - no symptoms to 7 - extreme symptoms. The minimal score is 0 and the maximal score is 210, with higher scores reflecting more symptoms. Typically scores \> that 60 are considered clinically significant. |
| Change From Baseline in PANSS Positive Symptom Subscale Score at 8 Weeks. | 8 weeks | The PANSS (described above) includes 7 items that reflect positive psychotic symptoms such as hallucinations and delusions. As are all items within the PANSS, items are categorically rated by the clinician between 0 - no symptoms to 7 extreme symptoms. The minimal score is 0 reflecting no positive symptoms to 49 reflecting that all items were extreme. Higher scores reflect more severe symptoms. Scores above 18 are usually clinically significant. |
| Change From Baseline in PANSS Negative Symptom Subscale at Week 8 | 8 weeks | The PANSS (described above) includes 7 items that reflect negative psychotic symptoms such as amotivation and social withdrawal. As are all items within the PANSS, items are categorically rated by the clinician between 0 - no symptoms to 7 extreme symptoms. The minimal score is 0 reflecting no positive symptoms to 49 reflecting that all items were extreme. Higher scores reflect more severe symptoms. Scores above 18 are usually clinically significant. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Weight at Week 8 | 8 weeks | change in weight from baseline to week 8 in kg |
| Change From Baseline in Barnes Akathisia Scale at Week 8 | 8 weeks | Barnes Akathisia Scale is a clinician rated scale which considers information based on observation of the participant as well as participant report. The scale includes 3 items rated between 0- none to 3 severe and 1 summary item rated between 0 none to 5 severe. All items are summed to obtain the total score. The minimal total score is 0 and the maximal score is 14 with higher scores reflecting more severe akathisia. A score of 4 or more is clinically significant. |
| Change From Baseline in Body Mass Index Change, kg/m2, at Week 8 | 8 weeks | Change from baseline in Body Mass Index Change, kg/m2, at week 8, last observation was carried forward for individuals who withdrew from treatment early. |
Countries
United States
Participant flow
Recruitment details
From February 2002 to May 2006, youth were screened at four academic sites: University of North Carolina at Chapel Hill, McLean Hospital and Cambridge Health Alliance at Harvard Medical School, University of Washington, and Case Western Reserve University.
Participants by arm
| Arm | Count |
|---|---|
| Olanzapine oral olanzapine 5-20mg per day for up to 52 weeks | 35 |
| Risperidone oral risperidone 0.5mg to 6mg daily for up to 52 weeks | 41 |
| Molindone oral molindone from 10-140mg/daily for up to 52 weeks | 40 |
| Total | 116 |
Baseline characteristics
| Characteristic | Risperidone | Molindone | Olanzapine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 40 Participants | 39 Participants | 35 Participants | 114 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 1 Participants | 0 Participants | 2 Participants |
| Age, Continuous | 14.54 years STANDARD_DEVIATION 2.38 | 14.3 years STANDARD_DEVIATION 2.4 | 13.84 years STANDARD_DEVIATION 2.41 | 14.25 years STANDARD_DEVIATION 2.39 |
| Region of Enrollment United States | 41 participants | 40 participants | 35 participants | 116 participants |
| Sex: Female, Male Female | 14 Participants | 17 Participants | 10 Participants | 41 Participants |
| Sex: Female, Male Male | 27 Participants | 23 Participants | 25 Participants | 75 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 26 / 35 | 35 / 41 | 36 / 40 |
| serious Total, serious adverse events | 2 / 35 | 4 / 41 | 2 / 40 |
Outcome results
Primary
Change From Baseline in PANSS Negative Symptom Subscale at Week 8
The PANSS (described above) includes 7 items that reflect negative psychotic symptoms such as amotivation and social withdrawal. As are all items within the PANSS, items are categorically rated by the clinician between 0 - no symptoms to 7 extreme symptoms. The minimal score is 0 reflecting no positive symptoms to 49 reflecting that all items were extreme. Higher scores reflect more severe symptoms. Scores above 18 are usually clinically significant.
Time frame: 8 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in PANSS Negative Symptom Subscale at Week 8 | -5.3 units on a scale | Standard Deviation 7.6 |
| Risperidone | Change From Baseline in PANSS Negative Symptom Subscale at Week 8 | -5.1 units on a scale | Standard Deviation 7.8 |
| Molindone | Change From Baseline in PANSS Negative Symptom Subscale at Week 8 | -5.8 units on a scale | Standard Deviation 6.8 |
Primary
Change From Baseline in PANSS Positive Symptom Subscale Score at 8 Weeks.
The PANSS (described above) includes 7 items that reflect positive psychotic symptoms such as hallucinations and delusions. As are all items within the PANSS, items are categorically rated by the clinician between 0 - no symptoms to 7 extreme symptoms. The minimal score is 0 reflecting no positive symptoms to 49 reflecting that all items were extreme. Higher scores reflect more severe symptoms. Scores above 18 are usually clinically significant.
Time frame: 8 weeks
Population: All randomized patients who took at least one dose of drug and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in PANSS Positive Symptom Subscale Score at 8 Weeks. | -8.9 units on a scale | Standard Deviation 6 |
| Risperidone | Change From Baseline in PANSS Positive Symptom Subscale Score at 8 Weeks. | -8.4 units on a scale | Standard Deviation 8.1 |
| Molindone | Change From Baseline in PANSS Positive Symptom Subscale Score at 8 Weeks. | -8.8 units on a scale | Standard Deviation 5.4 |
Primary
Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at 8 Weeks
Assessed with the Positive and Negative Syndrome Scale in which a clinician rates various psychotic symptoms on the basis of observation of the participant, interview with the participant, and review of all other available information including informant reports. The scale consists of 30 items which are rated categorically between 1 - no symptoms to 7 - extreme symptoms. The minimal score is 0 and the maximal score is 210, with higher scores reflecting more symptoms. Typically scores \> that 60 are considered clinically significant.
Time frame: 8 weeks
Population: All randomized patients who took at least one dose of drug and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at 8 Weeks | -26.6 units on a scale | Standard Deviation 17.8 |
| Risperidone | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at 8 Weeks | -23.7 units on a scale | Standard Deviation 25.5 |
| Molindone | Change From Baseline in Positive and Negative Syndrome Scale (PANSS) Total Score at 8 Weeks | -27.0 units on a scale | Standard Deviation 17.7 |
p-value: 0.05Mixed Models Analysis
Secondary
Change From Baseline in Barnes Akathisia Scale at Week 8
Barnes Akathisia Scale is a clinician rated scale which considers information based on observation of the participant as well as participant report. The scale includes 3 items rated between 0- none to 3 severe and 1 summary item rated between 0 none to 5 severe. All items are summed to obtain the total score. The minimal total score is 0 and the maximal score is 14 with higher scores reflecting more severe akathisia. A score of 4 or more is clinically significant.
Time frame: 8 weeks
Population: All randomized patients who took at least one dose of drug and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in Barnes Akathisia Scale at Week 8 | 0.19 units on a scale | Standard Deviation 2.12 |
| Risperidone | Change From Baseline in Barnes Akathisia Scale at Week 8 | 0.41 units on a scale | Standard Deviation 2.37 |
| Molindone | Change From Baseline in Barnes Akathisia Scale at Week 8 | 1.23 units on a scale | Standard Deviation 3.34 |
Secondary
Change From Baseline in Body Mass Index Change, kg/m2, at Week 8
Change from baseline in Body Mass Index Change, kg/m2, at week 8, last observation was carried forward for individuals who withdrew from treatment early.
Time frame: 8 weeks
Population: All randomized patients who took at least one dose of drug and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in Body Mass Index Change, kg/m2, at Week 8 | 1.27 kg/m2 | Standard Deviation 1.51 |
| Risperidone | Change From Baseline in Body Mass Index Change, kg/m2, at Week 8 | 2.20 kg/m2 | Standard Deviation 1.24 |
| Molindone | Change From Baseline in Body Mass Index Change, kg/m2, at Week 8 | 0.15 kg/m2 | Standard Deviation 1.26 |
Secondary
Change From Baseline in Weight at Week 8
change in weight from baseline to week 8 in kg
Time frame: 8 weeks
Population: All randomized patients who took at least one dose of drug and had at least one post-baseline assessment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Olanzapine | Change From Baseline in Weight at Week 8 | 6.12 Kg | Standard Deviation 3.6 |
| Risperidone | Change From Baseline in Weight at Week 8 | 3.64 Kg | Standard Deviation 3.95 |
| Molindone | Change From Baseline in Weight at Week 8 | 0.34 Kg | Standard Deviation 2.86 |