A randomized, double-blind comparison of olanzapine/fluoxetine combination, olanzapine, fluoxetine, and venlafaxine in treatment-resistant depression.
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-Asberg 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.
Corya
Sara A
SA
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285, USA. corya_sara@lilly.com
Williamson
Doug
D
Sanger
Todd M
TM
Briggs
Susan D
SD
Case
Michael
M
Tollefson
Gary
G
D001569:Benzodiazepines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D010054:Brief Psychiatric Rating Scale; D003511:Cyclohexanols / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000175:diagnosis / Q000188:drug therapy* / Q000453:epidemiology; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D005473:Fluoxetine / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008403:Mass Screening / Q000379:methods; D008875:Middle Aged; D000077152:Olanzapine; D011446:Prospective Studies; D012074:Remission Induction; D017367:Selective Serotonin Reuptake Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012720:Severity of Illness Index; D016312:Treatment Refusal / Q000706:statistics & numerical data; D000069470:Venlafaxine Hydrochloride
D001569:Benzodiazepines; D003511:Cyclohexanols; D005473:Fluoxetine; D000077152:Olanzapine; D017367:Selective Serotonin Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride