Olanzapine/Fluoxetine Combination for Treatment-Resistant Depression: A Controlled Study of SSRI and Nortriptyline Resistance
J Clin Psychiatry 2005;66(10):1289-1297
© Copyright 2015 Physicians Postgraduate Press, Inc.
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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.
Method: 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 <= .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
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.