Get Alert
Please Wait... Processing your request... Please Wait.
You must sign in to sign-up for alerts.

Please confirm that your email address is correct, so you can successfully receive this alert.

Articles   |    
A Randomized, Double-Blind Evaluation of d-Cycloserine or Alprazolam Combined With Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder in Iraq and Afghanistan War Veterans
Barbara Olasov Rothbaum, Ph.D.; Matthew Price, Ph.D.; Tanja Jovanovic, Ph.D.; Seth D. Norrholm, Ph.D.; Maryrose Gerardi, Ph.D.; Boadie Dunlop, M.D.; Michael Davis, Ph.D.; Bekh Bradley, Ph.D.; Erica J. Duncan, M.D.; Albert Rizzo, Ph.D.; Kerry J. Ressler, M.D., Ph.D.
Am J Psychiatry 2014;171:640-648. doi:10.1176/appi.ajp.2014.13121625
View Author and Article Information

Dr. Rothbaum is a consultant to and owns equity in Virtually Better, Inc., which creates virtual environments; however, Virtually Better did not create the Virtual Iraq environment tested in this study; the terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Rothbaum also has funding from Department of Defense Clinical Trial Grant W81XWH-10-1-1045 (“Enhancing Exposure Therapy for PTSD: Virtual Reality and Imaginal Exposure With a Cognitive Enhancer”), from NIMH grant U19 MH-069056 (“The Emory-MSSM-GSK-NIMH Collaborative Mood and Anxiety Disorders Initiative”), from NIMH grant R01 MH-70880 (“A Cognitive Enhancer May Facilitate Behavioral Exposure Therapy”), from NIMH grant R01 MH-094757 (“Prospective Determination of Psychobiological Risk Factors for Posttraumatic Stress”), from a Brain and Behavior Research Foundation (NARSAD) Distinguished Investigator Grant (“Optimal Dose of Early Intervention to Prevent PTSD”), and from the McCormick Foundation (“BraveHeart: MLB’s Welcome Back Veterans Southeast Initiative”); she has received previous support from Transcept Pharmaceuticals (“A Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Low-Dose Ondansetron for Adjunctive Therapy in Adult Patients With Obsessive-Compulsive Disorder Who Have Not Adequately Responded to Treatment With a Serotonin Reuptake Inhibitor”); she receives royalties from Oxford University Press, Guilford, American Psychiatric Publishing, and Emory University; and she received one advisory board payment from Genentech. Dr. Dunlop has received grant support from Bristol-Myers Squibb, Forest, GlaxoSmithKline, Novartis, and Pfizer in the past 3 years and has served as a consultant to Roche and Bristol-Myers Squibb. Drs. Ressler and Davis are founding members of Extinction Pharmaceuticals/Therapade Technologies, which seek to develop d-cycloserine and other compounds for use to augment the effectiveness of psychotherapy; they have received no equity or income from this relationship within the last 3 years; the terms of these arrangements have been reviewed and approved by Emory University in accordance with its conflict of interest policies. Dr. Duncan has received research support from the Posit Science Corporation and grant support from NIMH and the National Institute on Drug Abuse; she is on salary as an Attending Psychiatrist in the Mental Health Service, Department of Veterans Affairs Medical Center, Decatur, Ga. The remaining authors report no financial relationships with commercial interests.

Supported by NIMH grant R01 MH-70880 to Dr. Rothbaum.

Clinicaltrials.gov identifier: NCT00356278

From the Trauma and Anxiety Recovery Program and the Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta; the Trauma Recovery Program and Mental Health Service, Department of Veterans Affairs Medical Center, Atlanta; the Department of Psychology, University of Vermont, Burlington; the Howard Hughes Medical Institute, Chevy Chase, Md.; and the Institute for Creative Technologies and the Department of Psychiatry and Behavioral Sciences, University of Southern California, Playa Vista, Calif.

Presented at the 29th Annual Meeting of the International Society for Traumatic Stress Studies, Nov. 7–9, 2013, Philadelphia.

Address correspondence to Dr. Rothbaum (brothba@emory.edu).

Copyright © 2014 by the American Psychiatric Association

Received December 11, 2013; Revised January 03, 2014; Revised January 22, 2014; Accepted January 29, 2014.


Objective  The authors examined the effectiveness of virtual reality exposure augmented with d-cycloserine or alprazolam, compared with placebo, in reducing posttraumatic stress disorder (PTSD) due to military trauma.

Method  After an introductory session, five sessions of virtual reality exposure were augmented with d-cycloserine (50 mg) or alprazolam (0.25 mg) in a double-blind, placebo-controlled randomized clinical trial for 156 Iraq and Afghanistan war veterans with PTSD.

Results  PTSD symptoms significantly improved from pre- to posttreatment across all conditions and were maintained at 3, 6, and 12 months. There were no overall differences in symptoms between d-cycloserine and placebo at any time. Alprazolam and placebo differed significantly on the Clinician-Administered PTSD Scale score at posttreatment and PTSD diagnosis at 3 months posttreatment; the alprazolam group showed a higher rate of PTSD (82.8%) than the placebo group (47.8%). Between-session extinction learning was a treatment-specific enhancer of outcome for the d-cycloserine group only. At posttreatment, the d-cycloserine group had the lowest cortisol reactivity and smallest startle response during virtual reality scenes.

Conclusions  A six-session virtual reality treatment was associated with reduction in PTSD diagnoses and symptoms in Iraq and Afghanistan veterans, although there was no control condition for the virtual reality exposure. There was no advantage of d-cycloserine for PTSD symptoms in primary analyses. In secondary analyses, alprazolam impaired recovery and d-cycloserine enhanced virtual reality outcome in patients who demonstrated within-session learning. d-Cycloserine augmentation reduced cortisol and startle reactivity more than did alprazolam or placebo, findings that are consistent with those in the animal literature.

Abstract Teaser
Figures in this Article

Your Session has timed out. Please sign back in to continue.
Sign In Your Session has timed out. Please sign back in to continue.
Sign In to Access Full Content
Sign in via Athens (What is this?)
Athens is a service for single sign-on which enables access to all of an institution's subscriptions on- or off-site.
Not a subscriber?

Subscribe Now/Learn More

PsychiatryOnline subscription options offer access to the DSM-5 library, books, journals, CME, and patient resources. This all-in-one virtual library provides psychiatrists and mental health professionals with key resources for diagnosis, treatment, research, and professional development.

Need more help? PsychiatryOnline Customer Service may be reached by emailing PsychiatryOnline@psych.org or by calling 800-368-5777 (in the U.S.) or 703-907-7322 (outside the U.S.).

FIGURE 1. Effect of Treatment on Clinician-Rated Symptoms and Extinction Learning in Iraq and Afghanistan Veterans With PTSD Treated With Virtual Reality Exposure Plus d-Cycloserine, Alprazolam, or Placebo

a Model implied from a mixed-effect model that used all participants (N=156).

b Differences are significant outside of the area defined by the blue lines. The confidence bands indicate that there was a significant difference between d-cycloserine and alprazolam when relative learning was less than –6.29 and greater than 18.99. There was a significant difference between d-cycloserine and placebo when relative learning was less than 4.78 and greater than 23.94.

c Extinction learning was defined as the difference between peak subjective distress ratings in successive sessions. Subjective discomfort was rated from 0 (no anxiety) to 100 (maximum anxiety). The mean of the differences across time was used as an index of average extinction learning.

FIGURE 2. Posttreatment Cortisol and Startle Responses in Iraq and Afghanistan Veterans With PTSD Treated With Virtual Reality Exposure Plus d-Cycloserine, Alprazolam, or Placeboa

a Cortisol data were available for 104 participants at baseline, and 39 had data at all three time points (baseline, posttreatment, 6-month follow-up). Startle data were available for 117 patients at baseline, and 32 had data at all three times.

b Change from baseline to 15 minutes after virtual reality exposure.

c Cortisol response for d-cycloserine group differed significantly from responses for alprazolam (F=3.40, df=1, 23, p<0.05) and placebo (F=11.42, df=1, 23, p<0.05).

d Startle was measured by electromyography of the orbicularis oculi muscle contraction in response to white noise bursts. Values are represented as percentages of baseline values in order to correct for pretreatment group differences.

e The d-cycloserine group showed a significant difference over time (F=51.65, df=2, 12, p=0.001).

Anchor for Jump
TABLE 1.Baseline Characteristics of Iraq and Afghanistan Veterans With PTSD Treated With Virtual Reality Exposure Plus d-Cycloserine, Alprazolam, or Placebo
Anchor for Jump
TABLE 2.Means Estimated From Piecewise Model Predicting Symptom Scores for Iraq and Afghanistan Veterans With PTSD Treated With Virtual Reality Exposure Plus d-Cycloserine, Alprazolam, or Placebo
Table Footer Note

a The CI is needed to provide a range for the population parameter estimate. The CI around the baseline measure indicates that all of the groups started at the same point.

Anchor for Jump
TABLE 3.Proportion of Iraq and Afghanistan Veterans With PTSD Who Met PTSD Criteria After Virtual Reality Exposure Plus d-Cycloserine, Alprazolam, or Placeboa
Table Footer Note

a Significantly higher rate than for placebo (χ2=7.11, df=1, p=0.008).



Committee on the Assessment of Ongoing Effects in the Treatment of Posttraumatic Stress Disorder, Institute of Medicine:  Summary, in  Treatment for Posttraumatic Stress Disorder in Military and Veteran Populations: Initial Assessment .  Washington, DC,  National Academies Press, 2012, pp 1–16
Hoge  CW;  Castro  CA;  Messer  SC;  McGurk  D;  Cotting  DI;  Koffman  RL:  Combat duty in Iraq and Afghanistan, mental health problems, and barriers to care.  N Engl J Med 2004; 351:13–22
Institute of Medicine:  Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence .  Washington, DC,  National Academies Press, 2008
Foa  EB;  Hembree  E;  Rothbaum  BO:  Prolonged Exposure Therapy for PTSD: Emotional Processing of Traumatic Experiences, Therapist Guide .  New York,  Oxford University Press, 2007
Gerardi  M;  Cukor  J;  Difede  J;  Rizzo  A;  Rothbaum  BO:  Virtual reality exposure therapy for post-traumatic stress disorder and other anxiety disorders.  Curr Psychiatry Rep 2010; 12:298–305
Gerardi  M;  Rothbaum  BO;  Ressler  K;  Heekin  M;  Rizzo  A:  Virtual reality exposure therapy using a virtual Iraq: case report.  J Trauma Stress 2008; 21:209–213
Foa  EB;  Rothbaum  BO:  Treating the Trauma of Rape: Cognitive-Behavior Therapy for PTSD .  New York,  Guilford Press, 1998
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
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
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
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
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
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
Hofmann  SG;  Smits  JA;  Rosenfield  D;  Simon  N;  Otto  MW;  Meuret  AE;  Marques  L;  Fang  A;  Tart  C;  Pollack  MH:  D-Cycloserine as an augmentation strategy with cognitive-behavioral therapy for social anxiety disorder.  Am J Psychiatry 2013; 170:751–758
Bouton  ME;  Kenney  FA;  Rosengard  C:  State-dependent fear extinction with two benzodiazepine tranquilizers.  Behav Neurosci 1990; 104:44–55
Lund  BC;  Bernardy  NC;  Vaughan-Sarrazin  M;  Alexander  B;  Friedman  MJ:  Patient and facility characteristics associated with benzodiazepine prescribing for veterans with PTSD.  Psychiatr Serv 2013; 64:149–155
Management of Post-Traumatic Stress Working Group:  VA/DoD Clinical Practice Guideline for Management of Post-Traumatic Stress .  Washington, DC,  Department of Veterans Affairs, Department of Defense, 2010
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
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
Difede  J;  Cukor  J;  Wyka  K;  Olden  M;  Hunter  H;  Lee  FS;  Altemus  M:  D-cycloserine augmentation of exposure therapy for posttraumatic stress disorder: a pilot randomized clinical trial.  Neuropsychopharmacol  (Epub ahead of print, Nov 12, 2013)
Vermetten  E;  Vythilingam  M;  Schmahl  C;  De Kloet  C;  Southwick  SM;  Charney  DS;  Bremner  JD:  Alterations in stress reactivity after long-term treatment with paroxetine in women with posttraumatic stress disorder.  Ann N Y Acad Sci 2006; 1071:184–202
Orr  SP;  Roth  WT:  Psychophysiological assessment: clinical applications for PTSD.  J Affect Disord 2000; 61:225–240
Norrholm  SD;  Jovanovic  T;  Olin  IW;  Sands  LA;  Karapanou  I;  Bradley  B;  Ressler  KJ:  Fear extinction in traumatized civilians with posttraumatic stress disorder: relation to symptom severity.  Biol Psychiatry 2011; 69:556–563
Smits  JA;  Rosenfield  D;  Otto  MW;  Powers  MB;  Hofmann  SG;  Telch  MJ;  Pollack  MH;  Tart  CD:  D-Cycloserine enhancement of fear extinction is specific to successful exposure sessions: evidence from the treatment of height phobia.  Biol Psychiatry 2013; 73:1054–1058
Smits  JA;  Rosenfield  D;  Otto  MW;  Marques  L;  Davis  ML;  Meuret  AE;  Simon  NM;  Pollack  MH;  Hofmann  SG:  D-Cycloserine enhancement of exposure therapy for social anxiety disorder depends on the success of exposure sessions.  J Psychiatr Res 2013; 47:1455–1461
Blake  DD;  Weathers  FW;  Nagy  LM;  Kaloupek  DG;  Gusman  FD;  Charney  DS;  Keane  TM:  The development of a Clinician-Administered PTSD Scale.  J Trauma Stress 1995; 8:75–90
Sheehan  DV;  Lecrubier  Y;  Sheehan  KH:  The Mini-International Neuropsychiatric Interview (MINI): the development and validation of a structured diagnostic psychiatric interview for DSM-IV and ICD-10.  J Clin Psychiatry 1998; 1959:22–33
Foa  EB;  Riggs  DS;  Dancu  CV;  Rothbaum  BO:  Reliability and validity of a brief instrument for assessing post-traumatic stress disorder.  J Trauma Stress 1993; 6:459–473
Preacher  KJ;  Curran  PJ;  Bauer  DJ:  Computational tools for probing interactions in multiple linear regression: multilevel modeling, and latent curve analysis.  J Educ Behav Stat 2006; 31:437–448
Reger  GM;  Gahm  GA:  Virtual reality exposure therapy for active duty soldiers.  J Clin Psychol 2008; 64:940–946
Eftekhari  A;  Ruzek  JI;  Crowley  JJ;  Rosen  CS;  Greenbaum  MA;  Karlin  BE:  Effectiveness of national implementation of prolonged exposure therapy in Veterans Affairs care.  JAMA Psychiatry 2013; 70:949–955
Ledgerwood  L;  Richardson  R;  Cranney  J:  D-Cycloserine and the facilitation of extinction of conditioned fear: consequences for reinstatement.  Behav Neurosci 2004; 118:505–513
Guastella  AJ;  Lovibond  PF;  Dadds  MR;  Mitchell  P;  Richardson  R:  A randomized controlled trial of the effect of D-cycloserine on extinction and fear conditioning in humans.  Behav Res Ther 2007; 45:663–672
Kuriyama  K;  Honma  M;  Yoshiike  T;  Kim  Y:  Valproic acid but not D-cycloserine facilitates sleep-dependent offline learning of extinction and habituation of conditioned fear in humans.  Neuropharmacology 2013; 64:424–431
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
References Container

CME Activity

There is currently no quiz available for this resource. Please click here to go to the CME page to find another.
Submit a Comments
Please read the other comments before you post yours. Contributors must reveal any conflict of interest.
Comments are moderated and will appear on the site at the discertion of APA editorial staff.

* = Required Field
(if multiple authors, separate names by comma)
Example: John Doe

Web of Science® Times Cited: 2

Related Content
See Also...
Gabbard's Treatments of Psychiatric Disorders, 4th Edition > Chapter 32.  >
Gabbard's Treatments of Psychiatric Disorders, 4th Edition > Chapter 30.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 12.  >
The American Psychiatric Publishing Textbook of Psychiatry, 5th Edition > Chapter 12.  >
Manual of Clinical Psychopharmacology, 7th Edition > Chapter 6.  >
Topic Collections
Psychiatric News
PubMed Articles