Elsevier

Biological Psychiatry

Volume 59, Issue 3, 1 February 2006, Pages 211-215
Biological Psychiatry

Original article
Olanzapine Augmentation of Fluoxetine for Refractory Generalized Anxiety Disorder: A Placebo Controlled Study

https://doi.org/10.1016/j.biopsych.2005.07.005Get rights and content

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 ≤ 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.

Section snippets

Methods and Materials

This study was approved by the Institutional Review Board at the Massachusetts General Hospital, and all subjects received and signed informed consent prior to study entry. Eligible subjects were male and female outpatients, aged 18 to 72 years, with a primary diagnosis of DSM-IV generalized anxiety disorder (comorbid depression or dysthymia and other anxiety disorders except for PTSD and OCD were permitted if GAD was considered primary by the clinician and patient based on disorder severity

Results

During the initial 6 weeks of the trial (weeks 0 to 6) on open fluoxetine treatment, overall HAM-A scores dropped from 24.6 to 17.9 (paired t = 5.85; p < .001) and CGI-S scores dropped from 4.7 (moderately to severely ill) to 3.8 (mild to moderately ill) (paired t = 4.95; p < .001) in the ITT sample. It should be noted that at week 6 randomization, there was, by chance, a trend for lower severity on the HAM-A in the olanzapine group (mean 17.4 ± 6.5) compared with the placebo group (mean 22.6 ±

Discussion

This is, to our knowledge, one of the few prospective, randomized controlled studies of any adjunctive pharmacotherapy for patients with GAD remaining symptomatic despite initial pharmacotherapy and the first to be reported for olanzapine augmentation of an SSRI. Although conclusions from this study are limited by its small randomized sample size and pilot nature of our findings, there was evidence for our hypothesis of significantly greater response rates (defined as a 50% reduction in HAM-A

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