Enhanced exposure therapy for combat-related Posttraumatic Stress Disorder (PTSD): Study protocol for a randomized controlled trial

Jo Ann Difede*, Barbara O. Rothbaum, Albert A. Rizzo, Katarzyna Wyka, Lisa Spielman, Tanja Jovanovic, Christopher Reist, Michael J. Roy, Seth D. Norrholm, Charles Glatt, Francis Lee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Background: PTSD, which has been identified in up to 23% of post-9-11 veterans, often results in a chronic, pernicious course. Thus, effective treatments are imperative. The Institute of Medicine (IOM) concluded that the only intervention for PTSD with sufficient evidence to conclude efficacy is exposure therapy. This Phase III trial compares the efficacy of exposure therapy for combat-related PTSD delivered in two different formats- via virtual reality exposure therapy (VRE) or prolonged exposure therapy (PE)- combined with D-Cycloserine (DCS), a cognitive enhancer shown to facilitate the extinction of fear. Methods/design: Military personnel of any duty status and civilians deployed to Iraq and Afghanistan were eligible. Participants were randomly assigned to 9 sessions of exposure therapy (VRE or PE) and medication (50 mg DCS or placebo). Participants were treated at three geographically diverse sites. Participants were re-assessed at 3-months post-treatment. The co-primary hypotheses are that (1) DCS will augment response to exposure therapy (both VRE and PE) on PTSD symptoms; (2) VRE will be associated with greater improvement than PE. Genetic and psychophysiological markers will be evaluated as potential moderators and mediators of treatment outcomes as well as secondary outcomes. Discussion: This study is the first to compare the relative efficacy of DCS-augmented VRE versus PE on PTSD symptoms. The design has several advantages: participants received an active, effective treatment and predictors of response to treatment included genetic and psychobiological measures. The results may directly influence the future delivery of services, and contribute to the development of a standardized treatment protocol. Trial registration: NCT01352637.

Original languageEnglish
Article number105857
JournalContemporary Clinical Trials
StatePublished - Dec 2019
Externally publishedYes


  • Augmentation strategies
  • D-cycloserine
  • Genetics
  • PTSD
  • Prolonged exposure therapy
  • Virtual reality


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