A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia

Herbert Y. Meltzer, William V Bobo, Ajanta Roy, Karu Jayathilake, Yuejin Chen, Aygun Ertugrul, A. Elif Anil Yaǧcioǧlu, Joyce G. Small

Research output: Contribution to journalArticle

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Abstract

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 antipsychotic 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.

Original languageEnglish (US)
Pages (from-to)274-285
Number of pages12
JournalJournal of Clinical Psychiatry
Volume69
Issue number2
StatePublished - Feb 2008
Externally publishedYes

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olanzapine
Clozapine
Schizophrenia
Psychotic Disorders
Therapeutics
Psychopathology
Antipsychotic Agents
Word Association Tests
Verbal Learning
Neuropsychological Tests
Short-Term Memory
Diagnostic and Statistical Manual of Mental Disorders
Pharmaceutical Preparations
Sample Size

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Clinical Psychology

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A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. / Meltzer, Herbert Y.; Bobo, William V; Roy, Ajanta; Jayathilake, Karu; Chen, Yuejin; Ertugrul, Aygun; Yaǧcioǧlu, A. Elif Anil; Small, Joyce G.

In: Journal of Clinical Psychiatry, Vol. 69, No. 2, 02.2008, p. 274-285.

Research output: Contribution to journalArticle

Meltzer, HY, Bobo, WV, Roy, A, Jayathilake, K, Chen, Y, Ertugrul, A, Yaǧcioǧlu, AEA & Small, JG 2008, 'A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia', Journal of Clinical Psychiatry, vol. 69, no. 2, pp. 274-285.
Meltzer, Herbert Y. ; Bobo, William V ; Roy, Ajanta ; Jayathilake, Karu ; Chen, Yuejin ; Ertugrul, Aygun ; Yaǧcioǧlu, A. Elif Anil ; Small, Joyce G. / A randomized, double-blind comparison of clozapine and high-dose olanzapine in treatment-resistant patients with schizophrenia. In: Journal of Clinical Psychiatry. 2008 ; Vol. 69, No. 2. pp. 274-285.
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abstract = "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 antipsychotic 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.",
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AU - Jayathilake, Karu

AU - Chen, Yuejin

AU - Ertugrul, Aygun

AU - Yaǧcioǧlu, A. Elif Anil

AU - Small, Joyce G.

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N2 - 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 antipsychotic 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.

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