Changes in Dosing and Dose Timing of D-Cycloserine Explain Its Apparent Declining Efficacy for Augmenting Exposure Therapy for Anxiety-related Disorders: An Individual Participant-data Meta-analysis.

The apparent efficacy of d-cycloserine (DCS) for enhancing exposure treatment for anxiety disorders appears to have declined over the past 14 years. We examined whether variations in how DCS has been administered can account for this "declining effect". We also investigated the association between DCS administration characteristics and treatment outcome to find optimal dosing parameters. We conducted a secondary analysis of individual participant data obtained from 1047 participants in 21 studies testing the efficacy of DCS-augmented exposure treatments. Different outcome measures in different studies were harmonized to a 0-100 scale. Intent-to-treat analyses showed that, in participants randomized to DCS augmentation (n = 523), fewer DCS doses, later timing of DCS dose, and lower baseline severity appear to account for this decline effect. More DCS doses were related to better outcomes, but this advantage leveled-off at nine doses. Administering DCS more than 60 minutes before exposures was also related to better outcomes. These predictors were not significant in the placebo arm (n = 521). Results suggested that optimal DCS administration could increase pre-to-follow-up DCS effect size by 50%. In conclusion, the apparent declining effectiveness of DCS over time may be accounted for by how it has been administered. Optimal DCS administration may substantially improve outcomes. Registration: The analysis plan for this manuscript was registered on Open Science Framework (https://osf.io/c39p8/).

Investigating Relationships Between PTSD Symptom Clusters Within Virtual Reality Exposure Therapy for OEF/OIF Veterans.

Several cognitive behavioral therapeutic approaches have been demonstrated to be effective in reducing post-traumatic stress disorder (PTSD) symptoms (Foa, Keane, Friedman, & Cohen, 2008). The bulk of PTSD treatment research has relied on pre-post designs, which are limited in their ability to investigate the therapeutic process over time. The present study investigated the relations between PTSD symptom clusters using symptom assessment at pretreatment, midtreatment, and posttreatment using cross-lagged panel design over the course of Virtual Reality Exposure (VRE) treatment. Participants were 156 Iraq and/or Afghanistan veterans who met DSM-IV criteria for PTSD due to military trauma. Using structural equation modeling, the final reexperiencing model demonstrated good fit, χ2(34)=39.95, p=.22; RMSEA=.034, 90% CI: [0.00, 0.07], CFI=.993, and results suggested that reexperiencing at pretreatment demonstrated a significant effect on numbing, avoidance, hyperarousal at midtreatment, and reexperiencing symptoms at midtreatment demonstrate a significant effect on each of the three symptom clusters at posttreatment. These findings suggest that reexperiencing symptoms are indeed a key aspect of the therapeutic process within exposure therapy for PTSD. Additional research examining the impact of reexperiencing-focused intervention strategies on treatment outcomes is warranted.

D-Cycloserine Augmentation of Exposure-Based Cognitive Behavior Therapy for Anxiety, Obsessive-Compulsive, and Posttraumatic Stress Disorders: A Systematic Review and Meta-analysis of Individual Participant Data.

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.

Baseline psychophysiological and cortisol reactivity as a predictor of PTSD treatment outcome in virtual reality exposure therapy.

Baseline cue-dependent physiological reactivity may serve as an objective measure of posttraumatic stress disorder (PTSD) symptoms. Additionally, prior animal model and psychological studies would suggest that subjects with greatest symptoms at baseline may have the greatest violation of expectancy to danger when undergoing exposure based psychotherapy; thus treatment approaches which enhanced the learning under these conditions would be optimal for those with maximal baseline cue-dependent reactivity. However methods to study this hypothesis objectively are lacking. Virtual reality (VR) methodologies have been successfully employed as an enhanced form of imaginal prolonged exposure therapy for the treatment of PTSD. Our goal was to examine the predictive nature of initial psychophysiological (e.g., startle, skin conductance, heart rate) and stress hormone responses (e.g., cortisol) during presentation of VR-based combat-related stimuli on PTSD treatment outcome. Combat veterans with PTSD underwent 6 weeks of VR exposure therapy combined with either d-cycloserine (DCS), alprazolam (ALP), or placebo (PBO). In the DCS group, startle response to VR scenes prior to initiation of treatment accounted for 76% of the variance in CAPS change scores, p < 0.001, in that higher responses predicted greater changes in symptom severity over time. Additionally, baseline cortisol reactivity was inversely associated with treatment response in the ALP group, p = 0.04. We propose that baseline cue-activated physiological measures will be sensitive to predicting patients' level of response to exposure therapy, in particular in the presence of enhancement (e.g., DCS).

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.

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.

Pharmacological innovations for posttraumatic stress disorder and medication- enhanced psychotherapy.

Posttraumatic stress disorder (PTSD) is a common condition for which existing treatments are ineffective for many patients. Recent discoveries in the neurobiology of learning and memory, along with expanding knowledge of how those systems are impacted by the biology of the stress response, have opened new arenas for potential medication treatments for PTSD. We conducted a review of registered clinical trials investigating the efficacy of new agents for PTSD. The glucocoritcoid and adrenergic signaling systems are the most frequent targets of these investigational approaches to the prevention and treatment of PTSD. Additional trials are evaluating modulation of other CNS targets, including neurosteroids, glutamate, gamma-amino butyric acid, endocannabinoids, oxytocin, neurokinin/Substance P, and dopamine. A particularly exciting area of research is studies examining Medication-Enhanced Psychotherapy (MEP). Medications provided before or after exposure therapy for PTSD can enhance outcomes by: 1) strengthening learning and memory of fear extinction; 2) disrupting reconsolidation, thereby weakening fear memories; or 3) facilitating engagement in psychotherapy by reducing fear and enhancing openness to experience. The next few years promise to produce insight into the neurobiology and clinical efficacy of several novel approaches in the pharmacologic treatment and prevention of PTSD.

Cortisol Response Following Exposure Treatment for PTSD in Rape Victims.

This study examined changes in salivary cortisol levels pre-to-post-treatment in adult female rape victims diagnosed with post traumatic stress disorder (PTSD) randomly assigned to be treated with either Prolonged Exposure Therapy or Eye Movement Desensitization and Reprocessing. Salivary cortisol was collected at baseline, session 3, and session 9. A significant decrease in salivary cortisol levels was observed in individuals classified as treatment responders in both treatment conditions. Findings suggest that successful exposure-based treatments for PTSD which result in trauma-related and depressive symptom reduction may impact the action of the hypothalamic-pituitary-adrenal axis as measured by changes in level of salivary cortisol from pre-to-post-treatment.

Virtual reality exposure therapy for post-traumatic stress disorder and other anxiety disorders.

Anxiety disorders, including phobias and post-traumatic stress disorder, are common and disabling disorders that often involve avoidance behavior. Cognitive-behavioral treatments, specifically imaginal and in vivo forms of exposure therapy, have been accepted and successful forms of treatment for these disorders. Virtual reality exposure therapy, an alternative to more traditional exposure-based therapies, involves immersion in a computer-generated virtual environment that minimizes avoidance and facilitates emotional processing. In this article, we review evidence on the application of virtual reality exposure therapy to the treatment of specific phobias and post-traumatic stress disorder and discuss its advantages and cautions.

Pharmacological enhancement of behavioral therapy: focus on posttraumatic stress disorder.

Improved efficacy in the treatment of posttraumatic stress disorder (PTSD) and other anxiety disorders is urgently needed. Traditional anxiety treatments of hypnosis and psychodynamic therapy may be of some help, but uncontrolled studies lead to inconclusive results on the efficacy of these treatment techniques. There is a larger literature supporting the efficacy of cognitive-behavioral procedures with PTSD, including prolonged exposure therapy, eye movement desensitization and reprocessing, and anxiety management techniques. The cutting-edge technology of virtual reality-based exposure therapy for PTSD is particularly exciting. To further build on effective psychosocial treatments, current pharmacological augmentation approaches to emotional learning are being combined with psychotherapy. In particular, D-cycloserine, a partial NMDA agonist, has shown to be effective in facilitating the exposure/extinction therapy to improve the efficacy of treating anxiety disorders, and may guide the way for new pharmacological enhancements of behavioral therapy.

Virtual reality exposure therapy using a virtual Iraq: case report.

Posttraumatic stress disorder (PTSD) has been estimated to affect up to 18% of returning Operation Iraqi Freedom (OIF) veterans. Soldiers need to maintain constant vigilance to deal with unpredictable threats, and an unprecedented number of soldiers are surviving serious wounds. These risk factors are significant for development of PTSD; therefore, early and efficient intervention options must be identified and presented in a form acceptable to military personnel. This case report presents the results of treatment utilizing virtual reality exposure (VRE) therapy (virtual Iraq) to treat an OIF veteran with PTSD. Following brief VRE treatment, the veteran demonstrated improvement in PTSD symptoms as indicated by clinically and statistically significant changes in scores on the Clinician Administered PTSD Scale (CAPS; Blake et al., 1990) and the PTSD Symptom Scale Self-Report (PSS-SR; Foa, Riggs, Dancu, & Rothbaum, 1993). These results indicate preliminary promise for this treatment.

A pilot study of an exposure-based intervention in the ED designed to prevent posttraumatic stress disorder.

Early interventions to prevent PTSD have been limited in scope and effectiveness. This pilot study examines the feasibility and preliminary effectiveness of a model for brief preventive intervention: 1-session individualized exposure-based therapy delivered in the emergency department (ED). Eligible patients who experienced exposure to a traumatic event in the previous 24 hours were screened and assigned to assessment-only (n = 5) or intervention (imaginal exposure, n = 5) conditions. Both groups returned for 1-week follow-up. Results indicate that patients receiving this intervention reported slightly decreased levels of depression at 1-week follow-up and were rated lower on clinician-rated global severity of symptoms than patients in the assessment-only condition. The level of subject participation and ED staff support in this pilot study argues for feasibility of data collection, intervention, and follow-up with this population. Results also offer evidence that the intervention did not appear to harm participants and in fact may be helpful.