OBJECTIVE: Atypical (second-generation) antipsychotics are considered standard 
treatment for children and adolescents with early-onset schizophrenia and 
schizoaffective disorder. However, the superiority of second-generation 
antipsychotics over first-generation antipsychotics has not been demonstrated. 
This study compared the efficacy and safety of two second-generation 
antipsychotics (olanzapine and risperidone) with a first-generation 
antipsychotic (molindone) in the treatment of early-onset schizophrenia and 
schizoaffective disorder.
METHOD: This double-blind multisite trial randomly assigned pediatric patients 
with early-onset schizophrenia and schizoaffective disorder to treatment with 
either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone 
(10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome 
was response to treatment, defined as a Clinical Global Impression (CGI) 
improvement score of 1 or 2 and >or=20% reduction in Positive and Negative 
Syndrome Scale (PANSS) total score after 8 weeks of treatment.
RESULTS: In total, 119 youth were randomly assigned to treatment. Of these 
subjects, 116 received at least one dose of treatment and thus were available 
for analysis. No significant differences were found among treatment groups in 
response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude 
of symptom reduction. Olanzapine and risperidone were associated with 
significantly greater weight gain. Olanzapine showed the greatest risk of weight 
gain and significant increases in fasting cholesterol, low density lipoprotein, 
insulin, and liver transaminase levels. Molindone led to more self-reports of 
akathisia.
CONCLUSIONS: Risperidone and olanzapine did not demonstrate superior efficacy 
over molindone for treating early-onset schizophrenia and schizoaffective 
disorder. Adverse effects were frequent but differed among medications. The 
results question the nearly exclusive use of second-generation antipsychotics to 
treat early-onset schizophrenia and schizoaffective disorder. The safety 
findings related to weight gain and metabolic problems raise important public 
health concerns, given the widespread use of second-generation antipsychotics in 
youth for nonpsychotic disorders.