A Randomized, Double-blind Comparison of Clozapine and High-dose Olanzapine in Treatment-resistant Patients with Schizophrenia

Background: Clozapine, despite its side-effect burden, has been considered to be the drug of choice for patients with schizophrenia whose psychotic symptoms fail to respond adequately to other anti-psychotic drugs. There are conflicting data concerning the potential utility of olanzapine in treatment-resistant schizophrenia at doses beyond the 10- to 20-mg/day range that has proven to be effective for most nonrefractory patients with schizophrenia.

Objective: The main objective of this study was to compare the efficacy and tolerability of high-dose olanzapine (target dose, 25-45 mg/day) and clozapine (300-900 mg/day) in patients with schizophrenia or schizoaffective disorder who had failed to respond adequately to prior treatment with other antipsychotic drugs.

Study Design/method: This 6-month, randomized, double-blind, parallel-group study compared the efficacy and tolerability of olanzapine (mean dose, 34 mg/day; N = 19) or clozapine (mean dose, 564 mg/day; N = 21) in patients with treatment-resistant schizophrenia or schizoaffective disorder, diagnosed according to DSM-IV criteria. Outcome measures included psychopathology, cognitive performance (as assessed with a comprehensive neuropsychological test battery), and tolerability. The study was conducted between May 2000 and December 2003.

Results: Robust and significant (mostly p < .001) improvement in multiple measures of psychopathology, mainly between 6 weeks and 6 months of treatment, was found in both treatment groups, with no significant difference between the 2 treatments except for the Global Assessment of Functioning score, which favored clozapine (p = .01). Improvement in some domains of cognition was significant-and equivalent for both drugs, as well. Nonsignificantly different improvement in Verbal List Learning-Immediate Recall (p < .05), Controlled Word Association Test (p < .05), and Digit Symbol Substitution Test (p < .001) was found. There were no significant differences in extrapyramidal symptoms. Weight gain was significantly (p = .01) greater with olanzapine.

Conclusions: Olanzapine, at higher than customary doses, demonstrated similar efficacy to clozapine in treatment-resistant schizophrenia and schizoaffective disorder in this study. However, the small sample size precludes definitively concluding that the 2 treatments are equivalent, at these doses, in treatment-resistant schizophrenia. The metabolic side effects of olanzapine are a limitation in its use.

Clinical Trials Registration: ClinicalTrials.gov identifier NCT00179231.