A Randomized, Double-Blind Evaluation ofd-Cycloserine or Alprazolam Combined With Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder in Iraq and Afghanistan War Veterans

Abstract

Objective To determine the effectiveness of Virtual Reality Exposure (VRE) augmented with D-cycloserine (50mg) or alprazolam (0.25mg), compared to placebo, in reducing PTSD due to military trauma in Iraq and Afghanistan. Method A double-blind, placebo-controlled randomized clinical trial comparing augmentation methods for VRE for subjects (n= 156) with PTSD was conducted. Results PTSD symptoms significantly improved from pre- to post-treatment over the 6-session VRE treatment (p<.001) across all conditions and were maintained at 3, 6, and 12 months follow-up. There were no overall differences between the D-cycloserine group on symptoms at any time-point. The alprazolam and placebo conditions significantly differed on the post-treatment Clinician Administered PTSD scale (p = .006) and the 3-month post-treatment PTSD diagnosis, such that the alprazolam group showed greater rates of PTSD (79.2% alprazolam vs. 47.8% placebo). Between-session extinction learning was a treatment-specific enhancer of outcome for the D-cycloserine group only (p<.005). At post-treatment, the D-cycloserine group was the lowest on cortisol reactivity (p<.05) and startle response during VR scenes (p<.05). Conclusions A small number of VRE sessions were associated with reduced PTSD diagnosis and symptoms in Iraq/Afghanistan veterans, although there was no control condition for the VRE. Overall, there was no advantage of D-cycloserine on PTSD symptoms in primary analyses. In secondary analyses, benzodiazepine use during treatment may impair recovery, and D-cycloserine may enhance VRE in patients who demonstrate within-session learning. D-cycloserine augmentation treatment in PTSD patients may reduce cortisol and startle reactivity compared to the alprazolam and placebo treatment, consistent with the animal literature.

Clinical Virtual Reality tools to advance the prevention, assessment, and treatment of PTSD

“…Moreover, greater improvement in PTSD symptoms at the three- and six-month follow-up was found with PE. One possible explanation for these follow-up results, that are in sharp contrast to previous findings indicating strong durability of VRET treatment gains (Difede et al, 2014; Rizzo et al, 2010; Rothbaum et al, 2014), is that the study employed the more limited four scenario Virtual Iraq/Afghanistan system that may have provided less relevant content to this specific group of active duty SM clients. Previous feedback from clinicians using this system indicated that, when the client’s trauma experience was not well matched to the available content in this initial system, clinicians would shift to imaginal PE.…”

“…There are also reports from two other large scale VRET trials, which have examined the augmentation of the traditional exposure component with additional psychosocial treatment (Beidel et al, 2017) and with a pharmacological supplement (Rothbaum et al, 2014). Beidel et al (2017) combined VRET with Trauma Management Therapy (TMT) within an intensive daily outpatient programme conducted over three weeks.…”

“…Finally, Rothbaum et al (2014) compared the effects of five VRET sessions augmented by D-cycloserine (DCS), which has been found to facilitate extinction in other fear-based disorders (Ressler et al, 2004), alprazolam, and placebo in a study with 156 OIF/OIF Veterans with PTSD. Although there were no differences in treatment outcome across medication conditions, with the exception of posttreatment and three-month follow-up CAPS scores indicating that the alprazolam group showed a higher rate of PTSD than the placebo group, PTSD symptoms significantly improved across all conditions at posttreatment and at the three-, six-, and 12-month follow-ups.…”

“…This recognition of the potential impact of VR technology has led to the emergence of a significant, albeit still maturing, research literature that documents the many clinical and research targets where VR can add value relative to traditional assessment and intervention methods. A short list of the areas where Clinical VR has been usefully applied includes fear reduction in persons with specific phobias (Morina et al, 2015; Opris et al, 2012; Parsons & Rizzo, 2008; Powers & Emmelkamp, 2008), treatment for posttraumatic stress disorder (Beidel, Frueh, Neer, & Lejuez, 2017; Botella et al, 2015; Difede & Hoffman, 2002; Difede et al, 2007, 2014; Maples-Keller et al, 2017; McLay et al, 2011; Rizzo et al, 2010, 2013, 2017; Rothbaum, Hodges, Ready, Graap, & Alarcon, 2001; Rothbaum et al, 2014), cue-exposure for addiction and relapse prevention (Hone-Blanchet, Wensing, & Fecteau, 2014; Yoon et al, 2014), depression (Falconer et al, 2016), paranoid delusions (Freeman et al, 2016), discomfort reduction in cancer patients undergoing chemotherapy (Schneider, Kisby, & Flint, 2010), acute pain reduction during wound care and physical therapy with burn patients (Hoffman et al, 2011), other painful procedures (Gold et al, 2006; Mosadeghi, Reid, Martinez, Rosen, & Spiegel, 2016), body image disturbances in patients with eating disorders (Riva, 2011), navigation and spatial training in children and adults with motor impairments (John, Pop, Day, Ritsos, & Headleand, 2017), functional skill training and motor rehabilitation in patients with central nervous system dysfunction (e.g. stroke, traumatic brain injury, spinal cord injury, cerebral palsy, multiple sclerosis, etc.)…”

On the Road to Translation for PTSD Treatment: Theoretical and Practical Considerations of the Use of Human Models of Conditioned Fear for Drug Development

“…However, the translation to exposure therapy effects in PTSD patients is less compelling. Four studies have examined DCS enhancement of exposure therapy, with either positive effects (Difede et al 2014), equivocal, or marginal effects (de Kleine et al 2012;Rothbaum et al 2014), negative effects (Scheeringa and Weems 2014), or even deleterious effects (Litvin et al 2007). These mixed results have suggested a number of potential issues that need consideration when designing treatment trials for DCS (and other putative extinction enhancing treatments): (1) are the effects of DCS more on speed of response rather than magnitude of response to exposure, two differing hypotheses that will require different experimental designs/analysis to probe efficacy; (2) what is the correct dosing/timing of treatment; (3) does DCS's cognitive enhancement promote inhibitory learning to the extinction context, which might subsequently contribute to contextual renewal of fear (Vervliet 2008); and (4) does DCS need to be targeted toward only the successful therapy sessions [for a detailed review, see Hofmann et al (2015)].…”