Enhancement of psychosocial treatment with D-cycloserine: models, moderators, and future directions

Advances in the understanding of the neurobiology of fear extinction have resulted in the development of d-cycloserine (DCS), a partial glutamatergic N-methyl-D-aspartate agonist, as an augmentation strategy for exposure treatment. We review a decade of research that has focused on the efficacy of DCS for augmenting the mechanisms (e.g., fear extinction) and outcome of exposure treatment across the anxiety disorders. Following a series of small-scale studies offering strong support for this clinical application, more recent larger-scale studies have yielded mixed results, with some showing weak or no effects. We discuss possible explanations for the mixed findings, pointing to both patient and session (i.e., learning experiences) characteristics as possible moderators of efficacy, and offer directions for future research in this area. We also review recent studies that have aimed to extend the work on DCS augmentation of exposure therapy for the anxiety disorders to DCS enhancement of learning-based interventions for addiction, anorexia nervosa, schizophrenia, and depression. Here, we attend to both DCS effects on facilitating therapeutic outcomes and additional therapeutic mechanisms beyond fear extinction (e.g., appetitive extinction, hippocampal-dependent learning).F31 MH103969 - NIMH NIH HHS; K24 DA030443 - NIDA NIH HHS; R34 MH099309 - NIMH NIH HHS; R34 MH086668 - NIMH NIH HHS; R21 MH102646 - NIMH NIH HHS; R34 MH099318 - NIMH NIH HH

The role of dissociation-related beliefs about memory in trauma-focused treatment

OBJECTIVE: Dysfunctional cognitions play a central role in the development of post-traumatic stress disorder (PTSD). However the role of specific dissociation-related beliefs about memory has not been previously investigated. This study aimed to investigate the role of dissociation-related beliefs about memory in trauma-focused treatment. It was hypothesized that patients with the dissociative subtype of PTSD would show higher levels of dissociation-related beliefs, dissociation-related beliefs about memory would decrease after trauma-focused treatment, and higher pre-treatment dissociation-related beliefs would be associated with fewer changes in PTSD symptoms.METHOD: Post-traumatic symptoms, dissociative symptoms, and dissociation-related beliefs about memory were assessed in a sample of patients diagnosed with PTSD ( n = 111) or the dissociative subtype of PTSD ( n  = 61). They underwent intensive trauma-focused treatment consisting of four or eight consecutive treatment days. On each treatment day, patients received 90 min of individual prolonged exposure (PE) in the morning and 90 min of individual eye movement desensitization and reprocessing (EMDR) therapy in the afternoon. The relationship between dissociation-related beliefs about memory and the effects of trauma-focused treatment was investigated. RESULTS: Dissociation-related beliefs about memory were significantly associated with PTSD and its dissociative symptoms. In addition, consistent with our hypothesis, patients with the dissociative subtype of PTSD scored significantly higher on dissociation-related beliefs about memory pre-treatment than those without the dissociative subtype. Additionally, the severity of these beliefs decreased significantly after trauma-related treatment. Contrary to our hypothesis, elevated dissociation-related beliefs did not negatively influence treatment outcome.CONCLUSION: The results of the current study suggest that dissociation-related beliefs do not influence the outcome of trauma-focused treatment, and that trauma-focused treatment does not need to be altered specifically for patients experiencing more dissociation-related beliefs about memory because these beliefs decrease in association with treatment.</p

Adding physical activity to intensive trauma-focused treatment for post-traumatic stress disorder: results of a randomized controlled trial

IntroductionThis randomized controlled trial examined the effectiveness of physical activity added to an intensive trauma-focused treatment (TFT) for post-traumatic stress disorder (PTSD) in comparison to adding non-physical control activities.MethodsA total of 119 patients with PTSD were randomly assigned to a physical activity condition (PA; n = 59) or a non-physical activity control condition (nPA; n = 60). The 8-day intensive TFT programme consisted of daily prolonged exposure, EMDR therapy, and psychoeducation, which was complemented with physical activities versus controlled mixtures of guided (creative) tasks. As a primary outcome, the change in clinician and self-reported PTSD symptoms from pre-to post-treatment and at 6 months follow-up were measured.ResultsIntent-to-treat linear mixed-effects models showed no significant differences between the PA and nPA conditions on change in PTSD severity. Clinician and self-reported PTSD symptoms significantly decreased for both conditions, with large effect sizes (e.g., CAPS-5 dpre-post = 2.28). At post-treatment, 80.0% in the PA, and 82.7% in the nPA condition no longer met the diagnostic criteria for PTSD. Regarding the loss of Complex PTSD diagnoses this was 92.5% and 95.0%, respectively.ConclusionEither with additional physical or non-physical activities, intensive TFT is very effective for the treatment of (Complex) PTSD, as reflected by large effect sizes and loss of diagnostic status in both groups.Clinical trial registrationTrialregister.nl Identifier: Trial NL9120

Sequence matters: Combining Prolonged Exposure and EMDR therapy for PTSD

Objective Investigating the influence of the sequence in which two evidence-based trauma-focused treatments are offered to PTSD-patients. Methods PTSD-patients were treated using an intensive eight-day treatment program, combining Prolonged Exposure (PE) and EMDR therapy. Forty-four patients received a PE session in the morning and an EMDR session in the afternoon, while 62 patients received the reversed sequence (EMDR followed by PE). Outcome measures were PTSD symptom severity and subjective experiences. Results Patients who received PE first and EMDR second showed a significantly greater reduction in PTSD symptoms, patients preferred this sequence and valued the treatment sessions as significantly more helpful compared to patients in the EMDR-first condition. Conclusion Albeit explorative, PE and EMDR therapy can be successfully combined, but sequence matters. First applying PE sessions before EMDR sessions resulted in better treatment outcome, and better subjective patient's evaluations in terms of treatment helpfulness and preference

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.2018-05-0