Clinical trial NCT00001656: Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
Official title: Childhood Onset Psychotic Disorders: Characterization and Treatment With Atypical Neuroleptics
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Childhood Schizophrenia
Psychotic Disorder
Schizophrenia
Keywords: Clozapine
Olanzapine
Drug Response
Safety
Childhood Onset Schizophrenia
Schizoaffective Disorder
Multidimensionally Impaired Syndrome
Phenomenology
Biochemical Correlates
Brain Imaging
Schizophrenia
Childhood Schizophrenia
Psychosis
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 1999-11-04
Enrollment: 25
Sex: ALL
Minimum age (years): 7
Maximum age (years): 18
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the effectiveness and side effects of the drugs clozapine and olanzapine in children and adolescents with schizophrenia and psychoses.

Childhood psychosis is a serious disorder that may have devastating consequences. Effective treatments for the condition are under continual investigation. This study will examine the causes of and offer treatment for childhood psychosis.

Participants in this study will undergo psychological tests, blood and urine tests, electroencephalogram (EEG), electrocardiogram (EKG), and magnetic resonance imaging (MRI) scans of the brain for the first 1 to 2 weeks of the study while taking their regular medications. Participants will then be tapered off their medications over 1 to 3 weeks and will continue to stay off medications for an additional 2 days to 3 weeks. During this time, participants will undergo psychiatric, neurological, and cardiac examinations as well as blood tests. After this period without medications, participants will be randomly assigned to receive either clozapine or olanzapine for 8 weeks. An EEG will be performed prior to treatment and after 6 weeks of study medication. Participants who respond well to the study drugs may continue to receive them through their own physician. Participants who do not respond to either clozapine or olanzapine or cannot tolerate their side effects will be treated individually with other drugs until optimum treatment is identified. Regular telephone updates and in person visits to NIH for repeat testing and MRIs will be conducted.

Detailed description: The purpose of this protocol is to compare efficacy of clozapine and olanzapine in children and adolescents with schizophrenia and psychoses, as well as to learn about side effects of these medication in pediatric population. The underlying hypothesis is that clozapine has superior efficacy over olanzapine.

Children and adolescents, ages 7 to 18 years, meeting DSM-IV criteria for schizophrenia, schizoaffective disorder and psychotic disorder not otherwise specified, with onset of psychosis before their 13th birthday, who have not responded to at least two prior trials with typical or a typical neuroleptics, will be eligible to participate in a double-blind, parallel group, trial of olanzapine-clozapine.

This study will be done in conjunction with the Screening protocol, which will include characterization by clinical phenomenology, eye tracking, MRI brain imaging, plasma biochemistry, and chromosomal analysis.

This study will consist of the following phases 1) Tapering of psychotropic medications (1-4 weeks, depending upon type and dosage). 2) Observation for up to 2 weeks drug free, in order to establish a baseline prior to starting medication trial. 3) An 8 week double-blind trial of either clozapine or olanzapine. Efficacy and tolerability of clozapine and olanzapine will be compared using specified criteria. 4) If desired improvement not achieved or trial is interrupted, an 8 week open trial of the second medication and 5) Discharge following medication optimization for up to 4 weeks, or as clinically appropriate. This protocol also includes a follow-up every 2 to 3 years for a period of 10 years.

Eligibility criteria: * INCLUSION CRITERIA:

Males and females, age 7 to 18 years

Onset of psychotic symptoms before 13th birthday and a DSM-IV diagnosis of either schizophrenia, schizoaffective disorder, MDI syndrome, or psychosis NOS (not otherwise specified).

Current significant impairment due to the illness (current psychotic symptoms, decline of functioning academically and socially, significant discomfort due to psychotic symptoms).

Failure of two prior trials with antipsychotic medications (either typical or atypical) used at adequate doses (greater than or equal to 100 mg/day in chlorpromazine equivalents) and for adequate duration (at least 4 weeks, unless terminated due to intolerable side effects). Failure is defined as either insufficient response with persistence of symptoms significantly impairing child's functioning, according to child's and parental reports and medical and school records, or intolerable side effects to drugs other than clozapine and olanzapine.

Subjects may be included if their previous trial(s) of olanzapine failed to reach the dose of 20. mg/day or a duration of fewer than four weeks.

Subjects may be included if their previous trial(s) of clozapine failed to reach the dose of 200. mg/day or a duration of fewer than six weeks.

Comorbid psychiatric disorders in the past 12 months are permitted as long as not clinically significant.

EXCLUSION CRITERIA:

Prepsychotic full-scale IQ less than 70.

Unstable major neurological or medical conditions.

Current pregnancy or plan to become pregnant during the first three months (the duration of the study) in woman of childbearing age; breast-feeding in woman with infants.

DSM-IV substance abuse or dependence in the past 6 months.

True non-responders to either olanzapine or clozapine. True non-response is defined as: a) intolerance to either of the medications preventing an adequate trial, or b) only minimal (less than 20%) benefit with the adequate trial of either of the medications. Adequate trial constitutes at least 8 weeks of the medication with the dose of 20 mg on olanzapine or 200 mg of clozapine.

Primary outcomes:
measure: Change in the Scale for the Assessment of Negative Symptoms
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in the Clinical Global Impression Severity of Symptoms Scale
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in the Brief Psychiatric Rating Scale-24
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in the Scale for the Assessment of Positive Symptoms
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in the Bunney-Hamburg Rating Scale for Psychosis
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in Bunney-Hamburg Rating Scale for Depression
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in Bunney-Hamburg Rating Scale for Mania
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in the Bunney-Hamburg Rating Scale for Anxiety
timeFrame: 8 week double-blind study period; baseline and 8 weeks
Secondary outcomes:
Other outcomes:
measure: Change in Weight
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in Body Mass Index (BMI)
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in Extrapyramidal Movements as Measured by the Abnormal Involuntary Movements Scale (AIMS)
timeFrame: 8 week double-blind study period; baseline and 8 weeks
measure: Change in Extrapyramidal Movements as Measured by the Simpson Angus Scale Score
timeFrame: 8 week double-blind study period; baseline and 8 weeks
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: Child Psychiatry Branch, NIMH, NIH
name: Judith L Rapoport, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gordon CT, Frazier JA, McKenna K, Giedd J, Zametkin A, Zahn T, Hommer D, Hong W, Kaysen D, Albus KE, et al. Childhood-onset schizophrenia: an NIMH study in progress. Schizophr Bull. 1994;20(4):697-712. doi: 10.1093/schbul/20.4.697.
citation: Nicolson R, Rapoport JL. Childhood-onset schizophrenia: rare but worth studying. Biol Psychiatry. 1999 Nov 15;46(10):1418-28. doi: 10.1016/s0006-3223(99)00231-0.
citation: Shaw P, Sporn A, Gogtay N, Overman GP, Greenstein D, Gochman P, Tossell JW, Lenane M, Rapoport JL. Childhood-onset schizophrenia: A double-blind, randomized clozapine-olanzapine comparison. Arch Gen Psychiatry. 2006 Jul;63(7):721-30. doi: 10.1001/archpsyc.63.7.721.