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Articles   |    
d-Cycloserine as an Augmentation Strategy With Cognitive-Behavioral Therapy for Social Anxiety Disorder
Stefan G. Hofmann, Ph.D.; Jasper A.J. Smits, Ph.D.; David Rosenfield, Ph.D.; Naomi Simon, M.D.; Michael W. Otto, Ph.D.; Alicia E. Meuret, Ph.D.; Luana Marques, Ph.D.; Angela Fang, M.A.; Candyce Tart, Ph.D.; Mark H. Pollack, M.D.
Am J Psychiatry 2013;170:751-758. doi:10.1176/appi.ajp.2013.12070974
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Dr. Hofmann has received royalties from multiple publishers, including Routledge, the publisher of the CBT manual used in this study. Dr. Smits has received royalties from multiple publishers. Dr. Simon has received research support from the American Foundation for Suicide Prevention, Forest Laboratories, NIMH, and the Department of Defense and has participated in CME activity in the Massachusetts General Hospital Psychiatry Academy; her spouse has equity in Elan, Dandreon, G Zero, and Gatekeeper. Dr. Otto has served as a consultant for MicroTransponder and has received royalties from multiple publishers, including Routledge, the publisher of the CBT manual used in this study. Dr. Meuret has served as a consultant for Palo Alto Health Sciences. Dr. Pollack has served as an adviser or consultant for or received research support from Bristol-Myers Squibb, Euthymics, Eli Lilly, Forest Laboratories, GlaxoSmithKline, Medavante, National Center for Complementary and Alternative Medicine, National Institute on Drug Abuse, NIMH, Otsuka, and Targia Pharmaceuticals; he has equity in Medavante, Mensante Corporation, Mindsite, and Targia Pharmaceuticals, and he receives royalties for the SIGH-A and SAFER interviews.

Supported by NIMH grant R01MH078308 to Dr. Hofmann and grant R01MH075889 to Dr. Pollack.

Clinicaltrials.gov identifier: NCT00633984.

From the Department of Psychology, Boston University, Boston; the Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston; and the Department of Psychology, Southern Methodist University, Dallas.

Presented in part at the 32nd annual meeting of the Anxiety Disorders Association of America, Arlington, Va., April 12–15, 2012; and the 67th annual scientific meeting of the Society of Biological Psychiatry, Philadelphia, May 3–5, 2012.

Address correspondence to Dr. Hofmann (shofmann@bu.edu).

Copyright © 2013 by the American Psychiatric Association

Received July 26, 2012; Revised November 02, 2012; Revised November 09, 2012; Revised January 04, 2013; Accepted January 17, 2013.


Objective  The authors examined whether d-cycloserine, a partial agonist at the glutamatergic N-methyl-d-aspartate receptor, augments and accelerates a full course of comprehensive cognitive-behavioral therapy (CBT) in adults with generalized social anxiety disorder.

Method  This was a multisite randomized placebo-controlled efficacy study with 169 medication-free adults with generalized social anxiety disorder, of whom 144 completed the 12-week treatment and 131 completed the three follow-up assessments. Patients were randomly assigned to receive 50 mg of d-cycloserine or placebo 1 hour before each of five exposure sessions that were part of a 12-session cognitive-behavioral group treatment. Response and remission status was determined at baseline, throughout treatment, at end of treatment, and at 1-, 3-, and 6-month follow-up assessments by assessors who were blind to treatment condition.

Results  d-Cycloserine-augmented and placebo-augmented CBT were associated with similar completion rates (87% and 82%), response rates (79.3% and 73.3%), and remission rates (34.5% and 24.4%) at the posttreatment assessment; response and remission rates were largely maintained at the follow-up assessments. Although d-cycloserine was associated with a 24%–33% faster rate of improvement in symptom severity and remission rates relative to placebo during the treatment phase, the groups did not differ in response and remission rates.

Conclusions  d-Cycloserine did not augment a full course of comprehensive CBT for social anxiety disorder.

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FIGURE 1. Mean Growth Curves of Social Phobic Disorders Severity Scale Scores in Patients With Social Anxiety Disorder Treated With d-Cycloserine-Augmented or Placebo-Augmented Cognitive-Behavioral Therapya

a Randomization to the two study groups occurred at week 3. The study pills were administered weekly 1 hour prior to each of five sessions from week 3 through week 7. The posttreatment assessment point was at week 13. Error bars indicate standard deviations.

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TABLE 1.Baseline Demographic Characteristics of Patients With Social Anxiety Disorder Treated With d-Cycloserine-Augmented or Placebo-Augmented Cognitive-Behavioral Therapy (CBT)
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TABLE 2.Unadjusted Outcomes at Posttreatment and Follow-up Assessments Among Patients With Social Anxiety Disorder Treated With d-Cycloserine-Augmented or Placebo-Augmented Cognitive-Behavioral Therapy (CBT)
Table Footer Note

a Response was defined as an improvement score of 1 (“very much improved”) or 2 (“much improved”) on the Social Phobic Disorders Change scale; remission was defined as an improvement score of 1 or 2 on the Social Phobic Disorders Change scale and a score <30 on the Liebowitz Social Anxiety Scale.



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Clinical trials have shown that traditional pharmacotherapy and cognitive behavioral therapy (CBT) are only moderately efficacious for treating social anxiety disorders. What can be said about the efficacy of combining pharmacotherapy and CBT?
D-cycloserine might offer a novel strategy to augment cognitive behavioral therapy (CBT) for treating anxiety disorders. What is the mechanism through which D-cycloserine augments CBT?
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