A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression

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Abstract
Based on preliminary evidence of its usefulness in treatment‐resistant depression (TRD), an olanzapine/fluoxetine combination (OFC) was examined in comparison with olanzapine, fluoxetine, and venlafaxine in a TRD population. In this 12‐week double‐blind study, 483 subjects with unipolar, nonpsychotic TRD, with historic failure on a selective serotonin reuptake inhibitor (SSRI) and prospective failure on open–label venlafaxine, were randomized to an OFC or to an olanzapine, fluoxetine, or venlafaxine monotherapy group. Venlafaxine was continued randomly in the double–blind acute phase to explore the benefits of continuation versus switching therapy. The Montgomery–Åsberg Depression Rating Scale (MADRS) total change score at end point was the primary outcome measure. The OFC group had significantly greater improvement in depressive symptoms by week 1 of treatment (MADRS mean change =−7.2, baseline =29.6), in comparison to olanzapine (−4.8, P=.03), fluoxetine (−4.7, P=.03), or venlafaxine (−3.7, P=.002) groups and maintained its statistical separation from all three monotherapy groups through week 6. At end point, the OFC group was significantly different only from the olanzapine group (−14.1 vs. −7.7, P<.001). Analysis of a subgroup of subjects who had an SSRI failure in their current depressive episode (n=334) revealed statistical separation from both olanzapine and fluoxetine (but not venlafaxine) at end point: OFC (−14.6) versus olanzapine (−9.4, P<.001) versus fluoxetine (−10.7, P=.006) versus venlafaxine (−14.7, P=.98). The OFC had a safety profile comparable to its component monotherapies (i.e., olanzapine and fluoxetine), showed a rapid onset of antidepressant effect, and was effective in this TRD sample. At the study end point, OFC, fluoxetine, venlafaxine, and low–dose OFC all appeared to be similarly effective. Depression and Anxiety 23:364–372, 2006.