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.


METHODS
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.


BACKGROUND
ClinicalTrials.gov identifier NCT00179231.
Meltzer
Herbert Y
HY
Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tenn., USA. herbert.meltzer@Vanderbilt.Edu
Bobo
William V
WV
Roy
Ajanta
A
Jayathilake
Karu
K
Chen
Yuejin
Y
Ertugrul
Aygun
A
Anil Yağcioğlu
A Elif
AE
Small
Joyce G
JG
D000328:Adult; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003024:Clozapine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D011446:Prospective Studies; D011569:Psychiatric Status Rating Scales; D011618:Psychotic Disorders / Q000188:drug therapy; D012559:Schizophrenia / Q000188:drug therapy*; D012565:Schizophrenic Psychology; D012702:Serotonin Antagonists / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D015430:Weight Gain
D014150:Antipsychotic Agents; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D003024:Clozapine; D000077152:Olanzapine