Olanzapine augmentation of fluoxetine for refractory generalized anxiety disorder: a placebo controlled study

Biol Psychiatry. 2006 Feb 1;59(3):211-5. doi: 10.1016/j.biopsych.2005.07.005. Epub 2005 Sep 1.


Background: There has been little systematic study of "next-step" interventions for patients with generalized anxiety disorder (GAD) who remain symptomatic despite initial pharmacotherapy. We present one of the first randomized controlled trials for refractory GAD, comprising double blind augmentation with olanzapine or placebo for patients remaining symptomatic on fluoxetine.

Methods: Patients remaining symptomatic after 6 weeks of fluoxetine (20 mg/day) were randomized to 6 weeks of olanzapine (mean dose 8.7 +/- 7.1 mg/day) or placebo augmentation.

Results: Twenty-four of 46 fluoxetine-treated patients were randomized. Olanzapine resulted in a greater proportion of treatment responders based on a Clinical Global Impression-Severity Scale (CGI-S) end point score of 1 or 2 (Fisher's exact test [FET] p < .05) or a 50% reduction in Hamilton Anxiety Scale (HAMA-A) score (FET p < .05). There were no other statistically significant differences for olanzapine compared with placebo augmentation in outcome measures, though rates of remission (HAM-A <or= 7) on olanzapine were higher at the level of a trend (FET, p = .1). Average weight gain for completers was greater with olanzapine than placebo augmentation (11.0 +/- 5.1 vs. -0.7 +/- 2.4 pounds: t = 6.32, p < .001).

Conclusions: Olanzapine may have a salutary effect on anxiety for some GAD patients remaining symptomatic despite initial serotonin selective reuptake inhibitor (SSRI) therapy, but the emergence of significant weight gain represents an important clinical consideration.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Anti-Anxiety Agents / adverse effects
  • Anti-Anxiety Agents / therapeutic use*
  • Antipsychotic Agents / adverse effects
  • Antipsychotic Agents / therapeutic use*
  • Anxiety Disorders / diagnosis
  • Anxiety Disorders / drug therapy*
  • Anxiety Disorders / psychology
  • Benzodiazepines / adverse effects
  • Benzodiazepines / therapeutic use
  • Double-Blind Method
  • Drug Resistance
  • Drug Synergism
  • Female
  • Fluoxetine / adverse effects
  • Fluoxetine / therapeutic use*
  • Follow-Up Studies
  • Humans
  • Male
  • Middle Aged
  • Olanzapine
  • Outcome Assessment, Health Care
  • Selective Serotonin Reuptake Inhibitors / adverse effects
  • Selective Serotonin Reuptake Inhibitors / therapeutic use*


  • Anti-Anxiety Agents
  • Antipsychotic Agents
  • Serotonin Uptake Inhibitors
  • Fluoxetine
  • Benzodiazepines
  • Olanzapine