Psychophysiological and cortisol reactivity predicts PTSD treatment outcome in virtual reality exposure therapy with D-cycloserine

BACKGROUND: Virtual reality (VR) methodologies have been successfully employed as an enhanced form of imaginal prolonged exposure therapy for the treatment of stressor-, trauma-, and anxiety-related disorders such as PTSD. To date, the efficacy of prolonged exposure therapies, including those that are VR-based, has been largely indexed through the use of clinician-administered or self-report measures of patient symptom severity or within-session distress. More recently, psychophysiological measures have been employed as complementary assessment tools for use in traumatized populations presenting with PTSD symptoms (Rabe et al., 2006; Griffin et al., 2012; Rhudy et al., 2010; Robison-Andrew et al.; 2014, Rothbaum et al., 2014.) The addition of psychophysiological indices, such as heart rate (HR), skin conductance (SC) and electromyography (EMG) responses to trauma-related cues, provides the potential to use objective assessments of treatment outcome and better understand the underlying biological changes that accompany successful PTSD treatment strategies. The goal of this study was to examine the predictive nature of psychophysiological and stress hormone responses during presentation of combat-related stimuli in a virtual reality environment on PTSD treatment outcome. METHODS: Patients with PTSD (N=50) resulting from OIF or OEF combat exposure underwent 6 weeks of VR exposure therapy combined with either 50 mg D-cycloserine (DCS), 0.25 mg alprazolam (ALP), or placebo (PBO), and were assessed pre- and post-treatment and at 6 months follow-up. Assessments included the Clinician Administered PTSD Scale (CAPS) and psychophysiological assessments. Psychophysiological responses including startle EMG, SC and HR were assessed while viewing combat-related VR scenes. Saliva cortisol was samples before and after VR scenes. Fifty patients completed all three visits, and were divided into three groups according to treatment condition. The study was randomized and double-blind and all assessments were conducted free of treatment medication. RESULTS: The study showed that startle EMG and SC responses to VR scenes decreased across timepoints, F(2,62)=6.76, p=0.006 and F(2,70)=5.13, p=0.01, respectively. HR during VR scenes did not change with treatment. In the DCS group, startle response to VR scenes prior to treatment accounted for 76% of the variance in CAPS change scores, F(1,12)=34.92, p<0.001, in that higher responses predicted greater changes in symptom severity (i.e. better outcome). The regression was not significant for either the ALP or PBO groups (both p’s>0.1). Cortisol reactivity (the difference between cortisol 15 min after VR scenes and baseline cortisol) had an opposite prediction to treatment response, in that higher reactivity was significantly associated with worse outcome. In the ALP group, cortisol reactivity prior to treatment accounted for 36% of the variance in change in CAPS scores, after controlling for baseline cortisol levels, p=0.04. In the DCS group, there was a trend for the same prediction, p=0.08. CONCLUSIONS: The results of the present study suggest that a higher level of engagement coupled with the cognitive enhancing properties of DCS may lead to more substantial improvements in patient symptom severity. There is currently a significant void in the literature with respect to objective biomarkers that are predictive of PTSD treatment efficacy. The results of the current study suggest that the inclusion of psychophysiological assessments prior to and over the course of treatment and follow-up may prove to be an invaluable tool for monitoring therapeutic progress. This study suggests that psychophysiological responses may serve as biomarkers that predict treatment outcome, by assessing patients’ level of engagement with the exposure therapy leading to better treatment response.