title: Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline resistance.
abstract: 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.
authors.affiliation: Department of Psychiatry, Vanderbilt University, Nashville, TN 37212, USA. richard.shelton@vanderbilt.edu
authors.forename: Richard C
authors.initials: RC
authors.lastname: Shelton
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Williamson
authors.forename: Sara A
authors.initials: SA
authors.lastname: Corya
authors.forename: Todd M
authors.initials: TM
authors.lastname: Sanger
authors.forename: Luann E
authors.initials: LE
authors.lastname: Van Campen
authors.forename: Michael
authors.initials: M
authors.lastname: Case
authors.forename: Susan D
authors.initials: SD
authors.lastname: Briggs
authors.forename: Gary D
authors.initials: GD
authors.lastname: Tollefson
mesh_terms: 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
chemical_list: 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