Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.
BACKGROUND
This 8-week, double-blind, multicenter study was undertaken to replicate, in a larger sample of patients with treatment-resistant major depressive disorder (MDD; DSM-IV criteria), the results of a pilot study of the olanzapine/fluoxetine combination.


METHODS
The study was begun in August 1999. The primary entry criterion was a history of failure to respond to a selective serotonin reuptake inhibitor (SSRI). Patients (N = 500) who subsequently failed to respond to nortriptyline during an open-label lead-in phase were randomly assigned to 1 of 4 treatment groups: olanzapine (6-12 mg/day) plus fluoxetine (25-50 mg/day) combination, olanzapine (6-12 mg/day), fluoxetine (25-50 mg/day), or nortriptyline (25-175 mg/day). The primary outcome measure was baseline-to-endpoint mean change in score on the Montgomery-Asberg Depression Rating Scale (MADRS).


RESULTS
At the 8-week study endpoint, MADRS total scores decreased by a mean 8.7 points from baseline (28.5) with the olanzapine/fluoxetine combination, 7.0 points from baseline (28.4) with olanzapine (p = .08), 8.5 points from baseline (28.4) with fluoxetine (p = .84), and 7.5 points from baseline (28.8) with nortriptyline (p = .30), with no significant differences among the therapies. The olanzapine/fluoxetine combination was associated with significantly (p < or = .05) greater improvement (decrease) in MADRS scores than olanzapine at weeks 2, 4, 6, and 7; than fluoxetine at weeks 2 through 5; and than nortriptyline at weeks 1 through 4. A post hoc analysis of a subgroup of patients who had an SSRI treatment failure during their current MDD episode (N = 314) revealed that the olanzapine/fluoxetine combination group had a significantly (p = .005) greater decrease in MADRS scores than the olanzapine group at endpoint. Safety data for the olanzapine/fluoxetine combination were similar to those for its component monotherapies.


CONCLUSIONS
The olanzapine/fluoxetine combination did not differ significantly from the other therapies at endpoint, although it demonstrated a more rapid response that was sustained until the end of treatment. The results raised several methodological questions, and recommendations are made regarding the criteria for study entry and randomization.
Shelton
Richard C
RC
Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, USA. richard.shelton@vanderbilt.edu
Williamson
Douglas J
DJ
Corya
Sara A
SA
Sanger
Todd M
TM
Van Campen
Luann E
LE
Case
Michael
M
Briggs
Susan D
SD
Tollefson
Gary D
GD
D000328:Adult; D014150:Antipsychotic Agents / Q000627:therapeutic use*; D001569:Benzodiazepines / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D039721:Diagnostic and Statistical Manual of Mental Disorders; D004311:Double-Blind Method; D004338:Drug Combinations; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D009661:Nortriptyline / Q000494:pharmacology / Q000627:therapeutic use*; D000077152:Olanzapine; D010865:Pilot Projects; D010919:Placebos; D011569:Psychiatric Status Rating Scales / Q000706:statistics & numerical data; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
D014150:Antipsychotic Agents; D001569:Benzodiazepines; D004338:Drug Combinations; D005473:Fluoxetine; D009661:Nortriptyline; D000077152:Olanzapine; D010919:Placebos; D017367:Selective Serotonin Reuptake Inhibitors; C492572:olanzapine-fluoxetine combination