A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, and fluoxetine in treatment-resistant major depressive disorder.
OBJECTIVE
Two parallel, 8-week double-blind studies compared olanzapine/fluoxetine combination, olanzapine, and fluoxetine in outpatients with treatment-resistant depression (TRD).


METHODS
Treatment-resistant depression was defined as a documented history of current-episode antidepressant failure plus a prospective failure on fluoxetine. Following an 8-week fluoxetine lead-in, 605 nonresponders with DSM-IV major depressive disorder were randomly assigned to olanzapine/fluoxetine combination, olanzapine, or fluoxetine. The primary outcome measure was baseline-to-endpoint mean change on the Montgomery-Asberg Depression Rating Scale (MADRS). The study was conducted from April 2002 to May 2005.


RESULTS
After 8 weeks of double-blind treatment, Study 1 revealed no statistically significant therapy differences in MADRS mean change (olanzapine/fluoxetine combination: -11.0, fluoxetine: -9.4, olanzapine: -10.5). In Study 2, olanzapine/fluoxetine combination demonstrated significantly greater MADRS improvement (-14.5) than fluoxetine (-8.6, p < .001) and olanzapine (-7.0, p < .001). Pooled study results revealed significant differences for olanzapine/ fluoxetine combination (-12.7) versus fluoxetine (-9.0, p < .001) and olanzapine (-8.8, p < .001). Pooled remission rates were 27% for olanzapine/ fluoxetine combination, 17% for fluoxetine, and 15% for olanzapine. Adverse events were consistent with previous studies. Cholesterol mean change (mg/dL) was +15.1 for olanzapine/ fluoxetine combination, +0.8 for fluoxetine, and +2.7 for olanzapine. Mean weight change (kg) was +4.9 for olanzapine/fluoxetine combination, +0.4 for fluoxetine, and +5.5 for olanzapine. Nonfasting glucose mean change (mg/dL) was +11.4 for olanzapine/fluoxetine combination, +4.9 for fluoxetine, and +9.9 for olanzapine.


CONCLUSIONS
Patients with TRD (defined as treatment failure on 2 antidepressants) taking olanzapine/fluoxetine combination demonstrated significantly greater improvement in depressive symptoms than patients taking olanzapine or fluoxetine in 1 of 2 studies and in the pooled analysis. When considered within the context of all available evidence, olanzapine/fluoxetine combination is an efficacious therapy for patients with TRD.


BACKGROUND
ClinicalTrials.gov identifier: NCT00035321.
Thase
Michael E
ME
Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. thaseme@upmc.edu
Corya
Sara A
SA
Osuntokun
Olawale
O
Case
Michael
M
Henley
David B
DB
Sanger
Todd M
TM
Watson
Susan B
SB
Dubé
Sanjay
S
D000293:Adolescent; D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004311:Double-Blind Method; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077152:Olanzapine; D017367:Selective Serotonin Reuptake Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017211:Treatment Failure
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D005473:Fluoxetine; D000077152:Olanzapine; D017367:Selective Serotonin Reuptake Inhibitors