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A Double-Blind, Randomized Clozapine-Olanzapine Comparison

Philip Shaw, MD; Alex Sporn, MD; Nitin Gogtay, MD; Gerald P. Overman, PharmD; Deanna Greenstein, PhD; Peter Gochman, MA; Julia W. Tossell, MD; Marge Lenane, MSW; Judith L. Rapoport, MD

Arch Gen Psychiatry. 2006;63:721-730.

Background  Childhood-onset schizophrenia is a rare but severe form of the disorder that is frequently treatment resistant. The psychiatrist has a limited evidence base to guide treatment, particularly as there are no trials in children comparing atypical antipsychotics, the mainstay of current treatment.

Objective  To compare the efficacy and safety of olanzapine and clozapine, hypothesizing that clozapine would be more efficacious.

Design  Double-blind randomized 8-week controlled trial, with a 2-year open-label follow-up.

Setting  National Institute of Mental Health study, January 1998 to June 2005. Patients underwent reassessment 2 years after discharge.

Patients  Children and adolescents recruited nationally, aged 7 to 16 years, meeting unmodified DSM-IV criteria for schizophrenia, and resistant to treatment with at least 2 antipsychotics.

Interventions  After drug washout and a 1- to 3-week antipsychotic-free period, patients were randomized to treatment with clozapine (n = 12) or olanzapine (n = 13).

Main Outcome Measures  The Clinical Global Impression Severity of Symptoms Scale and Schedule for the Assessment of Negative/Positive Symptoms.

Results  Clozapine was associated with a significant reduction in all outcome measures, whereas olanzapine showed a less consistent profile of clinical improvement. While there were moderate to large differential treatment effects in favor of clozapine, these reached significance only in the alleviation of negative symptoms from an antipsychotic-free baseline (P = .04; effect size, 0.89). Clozapine was associated with more overall adverse events. At 2-year follow-up, 15 patients were receiving clozapine with evidence of sustained clinical improvement, but additional adverse events emerged, including lipid anomalies (n = 6) and seizures (n = 1).

Conclusions  While not demonstrating definitively the superiority of clozapine compared with olanzapine in treatment-refractory childhood-onset schizophrenia, the study suggests that clozapine has a more favorable profile of clinical response, which is balanced against more associated adverse events.

Author Affiliations: Child Psychiatry Branch, National Institute of Mental Health (Drs Shaw, Sporn, Gogtay, Greenstein, Tossell, and Rapoport; Mr Gochman; and Ms Lenane), and Clinical Center Pharmacy Department, National Institutes of Health (Dr Overman), Bethesda, Md.

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