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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.

Abstract

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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References

Kessler  RC;  Berglund  P;  Demler  O;  Jin  R;  Merikangas  KR;  Walters  EE:  Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.  Arch Gen Psychiatry 2005; 62:593–602
[CrossRef] | [PubMed]
 
Davidson  JR;  Foa  EB;  Huppert  JD;  Keefe  FJ;  Franklin  ME;  Compton  JS;  Zhao  N;  Connor  KM;  Lynch  TR;  Gadde  KM:  Fluoxetine, comprehensive cognitive behavioral therapy, and placebo in generalized social phobia.  Arch Gen Psychiatry 2004; 61:1005–1013
[CrossRef] | [PubMed]
 
Clark  DM;  Ehlers  A;  McManus  F;  Hackmann  A;  Fennell  M;  Campbell  H;  Flower  T;  Davenport  C;  Louis  B:  Cognitive therapy versus fluoxetine in generalized social phobia: a randomized placebo-controlled trial.  J Consult Clin Psychol 2003; 71:1058–1067
[CrossRef] | [PubMed]
 
Heimberg  RG;  Liebowitz  MR;  Hope  DA;  Schneier  FR;  Holt  CS;  Welkowitz  LA;  Juster  HR;  Campeas  R;  Bruch  MA;  Cloitre  M;  Fallon  B;  Klein  DF:  Cognitive behavioral group therapy vs phenelzine therapy for social phobia: 12-week outcome.  Arch Gen Psychiatry 1998; 55:1133–1141
[CrossRef] | [PubMed]
 
Stein  MB;  Liebowitz  MR;  Lydiard  RB;  Pitts  CD;  Bushnell  W;  Gergel  I:  Paroxetine treatment of generalized social phobia (social anxiety disorder): a randomized controlled trial.  JAMA 1998; 280:708–713
[CrossRef] | [PubMed]
 
Blomhoff  S;  Haug  TT;  Hellström  K;  Holme  I;  Humble  M;  Madsbu  HP;  Wold  JE:  Randomised controlled general practice trial of sertraline, exposure therapy, and combined treatment in generalised social phobia.  Br J Psychiatry 2001; 179:23–30
[CrossRef] | [PubMed]
 
Otto  MW;  Smits  JAJ;  Reese  HE:  Combined psychotherapy and pharmacotherapy for mood and anxiety disorders in adults: review and analysis.  Clin Psychol 2005; 12:72–86
 
Blanco  C;  Heimberg  RG;  Schneier  FR;  Fresco  DM;  Chen  H;  Turk  CL;  Vermes  D;  Erwin  BA;  Schmidt  AB;  Juster  HR;  Campeas  R;  Liebowitz  MR:  A placebo-controlled trial of phenelzine, cognitive behavioral group therapy, and their combination for social anxiety disorder.  Arch Gen Psychiatry 2010; 67:286–295
[CrossRef] | [PubMed]
 
Falls  WA;  Miserendino  MJD;  Davis  M:  Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala.  J Neurosci 1992; 12:854–863
[PubMed]
 
Myers  KM;  Davis  M:  Behavioral and neural analysis of extinction.  Neuron 2002; 36:567–584
[CrossRef] | [PubMed]
 
Ledgerwood  L;  Richardson  R;  Cranney  J:  Effects of d-cycloserine on extinction of conditioned freezing.  Behav Neurosci 2003; 117:341–349
[CrossRef] | [PubMed]
 
Davis  M;  Walker  DL;  Myers  KM:  Role of the amygdala in fear extinction measured with potentiated startle.  Ann N Y Acad Sci 2003; 985:218–232
[CrossRef] | [PubMed]
 
Walker  DL;  Ressler  KJ;  Lu  KT;  Davis  M:  Facilitation of conditioned fear extinction by systemic administration or intra-amygdala infusions of d-cycloserine as assessed with fear-potentiated startle in rats.  J Neurosci 2002; 22:2343–2351
[PubMed]
 
Siegmund  A;  Golfels  F;  Finck  C;  Halisch  A;  Räth  D;  Plag  J;  Ströhle  A:  d-Cycloserine does not improve but might slightly speed up the outcome of in-vivo exposure therapy in patients with severe agoraphobia and panic disorder in a randomized double blind clinical trial.  J Psychiatr Res 2011; 45:1042–1047
[CrossRef] | [PubMed]
 
Guastella  AJ;  Dadds  MR;  Lovibond  PF;  Mitchell  P;  Richardson  R:  A randomized controlled trial of the effect of d-cycloserine on exposure therapy for spider fear.  J Psychiatr Res 2007; 41:466–471
[CrossRef] | [PubMed]
 
Storch  EA;  Merlo  LJ;  Bengtson  M;  Murphy  TK;  Lewis  MH;  Yang  MC;  Jacob  ML;  Larson  M;  Hirsh  A;  Fernandez  M;  Geffken  GR;  Goodman  WK:  d-Cycloserine does not enhance exposure-response prevention therapy in obsessive-compulsive disorder.  Int Clin Psychopharmacol 2007; 22:230–237
[CrossRef] | [PubMed]
 
Berry  AC;  Rosenfield  D;  Smits  JAJ:  Extinction retention predicts improvement in social anxiety symptoms following exposure therapy.  Depress Anxiety 2009; 26:22–27
[CrossRef] | [PubMed]
 
Hofmann  SG:  Cognitive processes during fear acquisition and extinction in animals and humans: implications for exposure therapy of anxiety disorders.  Clin Psychol Rev 2008; 28:199–210
[CrossRef] | [PubMed]
 
Hofmann  SG;  Sawyer  AT;  Asnaani  A:  d-Cycloserine as an augmentation strategy for cognitive behavioral therapy for anxiety disorders: an update.  Curr Pharm Des 2012; 18:5659–5662
[CrossRef] | [PubMed]
 
Hofmann  SG;  Meuret  AE;  Smits  JAJ;  Simon  NM;  Pollack  MH;  Eisenmenger  K;  Shiekh  M;  Otto  MW:  Augmentation of exposure therapy with d-cycloserine for social anxiety disorder.  Arch Gen Psychiatry 2006; 63:298–304
[CrossRef] | [PubMed]
 
Guastella  AJ;  Richardson  R;  Lovibond  PF;  Rapee  RM;  Gaston  JE;  Mitchell  P;  Dadds  MR:  A randomized controlled trial of d-cycloserine enhancement of exposure therapy for social anxiety disorder.  Biol Psychiatry 2008; 63:544–549
[CrossRef] | [PubMed]
 
de Kleine  RA;  Hendriks  GJ;  Kusters  WJ;  Broekman  TG;  van Minnen  A:  A randomized placebo-controlled trial of d-cycloserine to enhance exposure therapy for posttraumatic stress disorder.  Biol Psychiatry 2012; 71:962–968
[CrossRef] | [PubMed]
 
Litz  BT;  Salters-Pedneault  K;  Steenkamp  MM;  Hermos  JA;  Bryant  RA;  Otto  MW;  Hofmann  SG:  A randomized placebo-controlled trial of d-cycloserine and exposure therapy for posttraumatic stress disorder.  J Psychiatr Res 2012; 46:1184–1190
[CrossRef] | [PubMed]
 
Wilhelm  S;  Buhlmann  U;  Tolin  DF;  Meunier  SA;  Pearlson  GD;  Reese  HE;  Cannistraro  P;  Jenike  MA;  Rauch  SL:  Augmentation of behavior therapy with d-cycloserine for obsessive-compulsive disorder.  Am J Psychiatry 2008; 165:335–341
[CrossRef] | [PubMed]
 
Storch  EA;  Murphy  TK;  Goodman  WK;  Geffken  GR;  Lewin  AB;  Henin  A;  Micco  JA;  Sprich  S;  Wilhelm  S;  Bengtson  M;  Geller  DA:  A preliminary study of d-cycloserine augmentation of cognitive-behavioral therapy in pediatric obsessive-compulsive disorder.  Biol Psychiatry 2010; 68:1073–1076
[CrossRef] | [PubMed]
 
Kushner  MG;  Kim  SW;  Donahue  C;  Thuras  P;  Adson  D;  Kotlyar  M;  McCabe  J;  Peterson  J;  Foa  EB:  d-Cycloserine augmented exposure therapy for obsessive-compulsive disorder.  Biol Psychiatry 2007; 62:835–838
[CrossRef] | [PubMed]
 
Chasson  GS;  Buhlmann  U;  Tolin  DF;  Rao  SR;  Reese  HE;  Rowley  T;  Welsh  KS;  Wilhelm  S:  Need for speed: evaluating slopes of OCD recovery in behavior therapy enhanced with d-cycloserine.  Behav Res Ther 2010; 48:675–679
[CrossRef] | [PubMed]
 
Hofmann  SG;  Smits  JAJ;  Asnaani  A;  Gutner  CA;  Otto  MW:  Cognitive enhancers for anxiety disorders.  Pharmacol Biochem Behav 2011; 99:275–284
[CrossRef] | [PubMed]
 
Liebowitz  MR:  Social phobia.  Mod Probl Pharmacopsychiatry 1987; 22:141–173
[PubMed]
 
Montgomery  SA;  Åsberg  M:  A new depression scale designed to be sensitive to change.  Br J Psychiatry 1979; 134:382–389
[CrossRef] | [PubMed]
 
First  MB;  Spitzer  RL;  Gibbon  M;  Williams  JBW:  Structured Clinical Interview for DSM-IV Axis I Disorders, Patient Edition .  New York,  New York State Psychiatric Institute, Biometrics Research, 1995
 
DiNardo  PA;  Brown  TA;  Barlow  DH:  Anxiety Disorders Interview Schedule for DSM-IV: Lifetime Version (ADIS-IV-L) .  Albany, NY,  Graywind Publications Incorporated, 1994
 
Liebowitz  MR;  Schneier  FR;  Campeas  R;  Hollander  E;  Hatterer  J;  Fyer  A;  Gorman  J;  Papp  L;  Davies  S;  Gully  R;  Klein  DF:  Phenelzine vs atenolol in social phobia: a placebo-controlled comparison.  Arch Gen Psychiatry 1992; 49:290–300
[PubMed]
 
Hofmann  SG;  Otto  MW:  Cognitive-Behavior Therapy for Social Anxiety Disorder: Evidence-Based and Disorder-Specific Treatment Techniques .  New York,  Routledge, 2008
 
Hope  DA;  Heimberg  RG;  Turk  CL:  Managing Social Anxiety: A Cognitive-Behavioral Therapy Approach: Therapist Guide .  New York,  Oxford University Press, 2006
 
Hofmann  SG:  Cognitive factors that maintain social anxiety disorder: a comprehensive model and its treatment implications.  Cogn Behav Ther 2007; 36:193–209
 
Hamer  RM;  Simpson  PM:  Last observation carried forward versus mixed models in the analysis of psychiatric clinical trials.  Am J Psychiatry 2009; 166:639–641
[CrossRef] | [PubMed]
 
Singer  JD;  Willett  JB:  Applied Longitudinal Data Analysis .  Oxford, UK,  Oxford University Press, 2003
 
Otto  MW;  Tolin  DF;  Simon  NM;  Pearlson  GD;  Basden  S;  Meunier  SA;  Hofmann  SG;  Eisenmenger  K;  Krystal  JH;  Pollack  MH:  Efficacy of d-cycloserine for enhancing response to cognitive-behavior therapy for panic disorder.  Biol Psychiatry 2010; 67:365–370
[CrossRef] | [PubMed]
 
Ressler  KJ;  Rothbaum  BO;  Tannenbaum  L;  Anderson  P;  Graap  K;  Zimand  E;  Hodges  L;  Davis  M:  Cognitive enhancers as adjuncts to psychotherapy: use of d-cycloserine in phobic individuals to facilitate extinction of fear.  Arch Gen Psychiatry 2004; 61:1136–1144
[CrossRef] | [PubMed]
 
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Self-Assessment Quiz

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1.
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?
2.
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?
3.
What effect did D-cycloserine have on individuals who received cognitive behavioral therapy for their social anxiety disorder?
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