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Articles   |    
A Double-Blind Randomized Controlled Trial of Augmentation and Switch Strategies for Refractory Social Anxiety Disorder
Mark H. Pollack, M.D.; Michael Van Ameringen, M.D.; Naomi M. Simon, M.D., M.Sc.; John W. Worthington, M.D.; Elizabeth A. Hoge, M.D.; Aparna Keshaviah, Sc.M.; Murray B. Stein, M.D., M.P.H.
Am J Psychiatry 2014;171:44-53. doi:10.1176/appi.ajp.2013.12101353
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Clinicaltrials.gov identifier NCT00282828.

Supported by NIMH (grant 1R01MH070919). Support for study drug and packaging received from Pfizer and Wyeth Pharmaceuticals.

Dr. Pollack has received advisory board or consulting fees from Brain Cells, Concept Pharma, Corcept, Edgemont, Eli Lilly, Ironwood Pharmaceuticals, Johnson and Johnson, Labopharm, Medavante, Merck, Mindsite, Otsuka, Pfizer, Sepracor, Targia, and Transcept; grant support from Bristol-Myers Squibb, Eli Lilly, Euthymics, Forest Laboratories, GlaxoSmithKline, the National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, NIMH, and Sepracor; CME activity support from AstraZeneca, Pfizer, and Sepracor; royalty or patent funds from the Structured Interview Guide for the Hamilton Anxiety Scale, SAFER interviews; and equity from Doyen Medical, Medavante, Mensante Corporation, Mindsite, and Targia. Dr. Van Ameringen has received grant or research support from the Canadian Foundation for Innovation, Forest Laboratories, Janssen-Ortho, NIH, Pfizer, Servier, and Wyeth-Ayerst and has received speakers bureau, consultant, or advisory board fees from AstraZeneca, Biovail, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Janssen-Ortho, Labo Pharm, Lundbeck, Pfizer, Shire, and Valiant. Dr. Simon has received grant support or consulting fees from the American Cancer Society, American Foundation for Suicide Prevention, Department of Defense, Eli Lilly, Forest Research, GlaxoSmithKline, Highland Street Foundation, Massachusetts General Hospital Psychiatry Academy, NARSAD, NIH, NIMH, Pfizer, and Sepracor and her spouse has equity in Elan, Dandreon, G Zero, and Gatekeeper. Dr. Worthington has received grant or research support from Eli Lilly, Forest Pharmaceuticals, Pfizer, and Sepracor. Dr. Stein has a patent on the use of genetic testing to predict treatment outcomes in social anxiety disorder and receives payment for his work as Co-Editor-in-Chief of UpToDate in Psychiatry and as Deputy Editor of Depression and Anxiety and Biological Psychiatry. Dr. Hoge and Ms. Keshaviah report no financial relationships with commercial interests.

From Rush University Medical Center, Chicago; McMaster University, Hamilton, Ontario; Massachusetts General Hospital, Boston; and the University of California, San Diego.

Address correspondence to Dr. Pollack (mark_pollack@rush.edu).

Copyright © 2014 by the American Psychiatric Association

Received October 25, 2012; Revised May 23, 2013; Revised July 29, 2013; Accepted August 15, 2013.

An erratum to this article has been published | view the erratum

Objective  Most patients remain symptomatic after an initial intervention with approved treatments for generalized social anxiety disorder. This randomized controlled trial provides systematic, prospectively derived data on the relative benefits of “next-step” pharmacotherapies to improve outcomes for individuals with generalized social anxiety disorder who remain symptomatic after initial treatment.

Method  This three site, 12-week, double-blind randomized controlled trial compared the relative benefits of three strategies for patients remaining symptomatic (Liebowitz Social Anxiety Scale [LSAS] score >50) after a 10-week trial of sertraline alone: the addition of up to 3.0 mg/day of clonazepam (sertraline plus clonazepam), a switch to up to 225 mg/day of venlafaxine, or prolonged sertraline treatment with placebo (sertraline plus placebo).

Results  A total of 397 participants received at least one dose of sertraline; 181 nonresponders (LSAS score >50) at week 10 were randomly assigned to sertraline plus clonazepam, switch to venlafaxine, or sertraline plus placebo. Overall, 21% of patients achieved remission (LSAS score ≤30) at the endpoint, and 27% of patients assigned to sertraline plus clonazepam achieved remission compared with patients assigned to sertraline plus placebo (17%) or venlafaxine (19%), but the differences did not reach significance. Sertraline plus clonazepam was associated with a significantly greater drop in LSAS severity (p=0.020) and disability (p=0.0028) compared with sertraline plus placebo; no significant differences were observed on these parameters between venlafaxine and either sertraline plus placebo or sertraline plus clonazepam. In supplemental analysis, the overall response rate (LSAS score ≤50) was 46%, including a significantly greater proportion of patients in the sertraline plus clonazepam group (56%) compared with the sertraline plus placebo group responding (36%; p=0.027); differences did not reach significance between venlafaxine and sertraline plus placebo or sertraline plus clonazepam.

Conclusions  The findings suggest that the clonazepam augmentation strategy provides relative benefits for sertraline nonresponders in social anxiety disorder.

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FIGURE 1. CONSORT Diagram of Individuals in a Study of Augmentation and Switch Strategies for Refractory Social Anxiety Disorder

a Lost to follow-up, adverse event, noncompliance, life circumstances, or not willing to continue.

FIGURE 2. Mean Liebowitz Social Anxiety Scale Total Score by Week and Treatment Group in a Study of Refractory Social Anxiety Disorder

a Significant difference in mean Liebowitz Social Anxiety Scale total score between the sertraline plus clonazepam group and the sertraline plus placebo group at the unadjusted alpha=0.05 level.

b Significant difference in mean Liebowitz Social Anxiety Scale total score between the sertraline plus clonazepam group and the sertraline plus placebo group at the Bonferroni-adjusted alpha=0.006 level (p<0.001).

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TABLE 1.Characteristics of the Intention-to-Treat Population by Randomized Treatment Group in a Study of Refractory Social Anxiety Disorder
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a Anorexia or bulimia in the past 6 months, alcohol or drug dependence in the past 6 months, and alcohol or drug abuse in the past 3 months were exclusion criteria.

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TABLE 2.Comparison of Primary, Secondary, and Exploratory Outcomes by Treatment Group in a Study of Refractory Social Anxiety Disorder
Table Footer Note

a LSAS=Liebowitz Social Anxiety Scale.

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b Significant at alpha=0.05.

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TABLE 3.Association Between Treatment and Change (Last Visit − Week 10) in Secondary Measures
Table Footer Note

a CGI-I=Clinical Global Impressions improvement scale; MADRS=Montgomery-Åsberg Depression Rating Scale; SDS=Sheehan Disability Scale; HAM-A=Hamilton Anxiety Rating Scale; Q-LES-Q=Quality of Life Enjoyment and Satisfaction Questionnaire.

Table Footer Note

b Significant at alpha=0.05.



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