Rianne A. de Kleine

A randomized placebo-controlled trial of D-cycloserine to enhance exposure therapy for posttraumatic stress disorder

BACKGROUND Posttraumatic stress disorder (PTSD) is a complex and debilitating anxiety disorder, and, although prolonged exposure therapy has been proven effective, many patients remain symptomatic after treatment. In other anxiety disorders, the supplementary use of D-cycloserine (DCS), a partial agonist at the glutamatergic N-methyl-D-aspartate receptor, showed promise in enhancing treatment effects. We examined whether augmentation of prolonged exposure therapy for PTSD with DCS enhances treatment efficacy. METHODS In a randomized, double-blind, placebo-controlled trial we administered 50 mg DCS or placebo 1 hour before each exposure session to 67 mixed trauma patients, recruited from regular referrals, with a primary PTSD diagnosis satisfying DSM-IV criteria. RESULTS Although DCS did not enhance overall treatment effects, the participants having received DCS did show a stronger treatment response. Exploratory session-by-session analyses revealed that DCS yielded higher symptom reduction in those participants that had more severe pretreatment PTSD and needed longer treatment. CONCLUSIONS The present study found preliminary support for the augmentation of exposure therapy with DCS, specifically for patients with more severe PTSD needing longer treatment.

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.

Pharmacological enhancement of exposure-based treatment in PTSD: a qualitative review

There is a good amount of evidence that exposure therapy is an effective treatment for posttraumatic stress disorder (PTSD). Notwithstanding its efficacy, there is room for improvement, since a large proportion of patients does not benefit from treatment. Recently, an interesting new direction in the improvement of exposure therapy efficacy for PTSD emerged. Basic research found evidence of the pharmacological enhancement of the underlying learning and memory processes of exposure therapy. The current review aims to give an overview of clinical studies on pharmacological enhancement of exposure-based treatment for PTSD. The working mechanisms, efficacy studies in PTSD patients, and clinical utility of four different pharmacological enhancers will be discussed: d-cycloserine, MDMA, hydrocortisone, and propranolol.

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).

Prescriptive variables for d-cycloserine augmentation of exposure therapy for posttraumatic stress disorder

In recent years, several studies have demonstrated efficacy of d-cycloserine (DCS) enhanced exposure therapy across anxiety disorders. In this study we examined person-level variables that predicted response to DCS enhanced exposure therapy in a chronic, mixed trauma PTSD sample. The sample consisted of 67 treatment-seeking individuals, randomly allocated to receive exposure therapy augmented with DCS (50 mg) or identical looking placebo. We examined the following baseline predictors of treatment response: (1) demographic characteristics (age, gender, marital status, and education); (2) clinical characteristics (initial PTSD symptom severity, Axis I comorbidity, depression symptom severity, and antidepressants use); (3) personality characteristics (openness, conscientiousness, extraversion, agreeableness, and neuroticism). Outcome was measured with the PTSD Symptom Scale, Self-Report, which was assessed weekly during treatment. Two prescriptive variables were identified: conscientiousness and extraversion. For high conscientious participants, those who received DCS showed better outcome than those who received placebo. And for low extraversion, DCS showed superior outcome relative to placebo. Education was identified as a prognostic variable, it predicted response across both groups: higher education was related to worse outcome. Our results provide support for the influence of personality traits on DCS augmented exposure outcome and give more insight into possible working mechanisms of this novel treatment strategy. Ultimately, this may contribute to treatment matching strategies in order to improve treatment efficacy of exposure therapy for PTSD.

Extinction learning as a moderator of d-cycloserine efficacy for enhancing exposure therapy in posttraumatic stress disorder

Augmentation of exposure therapy with d-cycloserine (DCS) has proven efficacious across anxiety disorders, although results in PTSD have been mixed. Work in animals and anxiety-disordered patients suggest that the potentiating effects of DCS are dependent on the level of extinction learning during extinction training and exposure treatment, respectively. The aim of the current study was to replicate and extend previous work by examining the association between the degree of extinction learning and DCS efficacy in our randomized clinical trial on DCS (50 mg) versus placebo enhancement of exposure therapy in a chronic mixed-trauma PTSD sample (N=67; de Kleine, Hendriks, Kusters, Broekman, & van Minnen, 2012). The decline in subjective units of distress ratings collected during and across the exposure sessions were evaluated as indices of extinction learning. First, we examined whether extinction learning during an exposure session moderated DCS effects on self-reported PTSD symptoms at the next session. Second, we examined whether averaged extinction learning over the course of treatment interacted with group assignment to predict change over time and post treatment outcome. We did not find evidence that DCS effects were moderated by the degree of extinction learning, although, extinction learning was related to outcome regardless of group assignment. In PTSD, not one extinction-learning index has been consistently linked to DCS enhanced exposure treatment outcome. More (experimental) work needs to been done to unravel the complex interplay between extinction learning and DCS enhancement, especially in PTSD patients.

Feasibility of brief intensive exposure therapy for PTSD patients with childhood sexual abuse: a brief clinical report

Despite the strong empirical support for the effectiveness of exposure-based treatments in ameliorating post-traumatic stress disorder (PTSD), improvement of treatment is wanted given relatively high dropout rates and challenges of treating patients with high comorbidity and treatment-interfering stressors. The purpose of the current paper is to introduce an intensive exposure treatment program, illustrated by four case descriptions of PTSD patients, who suffered multiple (sexual) traumas in childhood, had high levels of comorbidity and psychosocial stressors, and failed to improve during “regular” trauma-focused treatment programs. The program consisted of psychoeducation, prolonged imaginal exposure, exposure in vivo, exposure by drawings combined with narrative reconstructing, and writing assignments about central trauma-related cognitions. The treatment included 5 working days with individual sessions (in total 30 h of treatment) provided by a team of four therapists. The PTSD symptoms of all patients decreased substantially and the effect sizes were large (Cohens d resp. 1.5 [pre–post], 2.4 [pre-FU1 month], and 2.3 [pre-FU3 months]). Also, none of the patients showed symptom worsening or dropped out. The evaluation of these four pilot cases suggests that it is possible to intensify exposure treatment, even for multiple traumatized PTSD patients with high comorbidity. We concluded that the first results of this new, intensive exposure program for PTSD patients with childhood sexual abuse are promising. For abstract or full text in other languages, please see Supplementary files under Reading Tools online

Optimizing the efficacy of exposure in PTSD treatment

No abstract available. (Published: 8 April 2015) Citation: European Journal of Psychotraumatology 2015, 6 : 27628 - http://dx.doi.org/10.3402/ejpt.v6.27628

Exposing therapists to trauma-focused treatment in psychosis: effects on credibility, expected burden, and harm expectancies

Background Despite robust empirical support for the efficacy of trauma-focused treatments, the dissemination proves difficult, especially in relation to patients with comorbid psychosis. Many therapists endorse negative beliefs about the credibility, burden, and harm of such treatment. Objective This feasibility study explores the impact of specialized training on therapists’ beliefs about trauma-focused treatment within a randomized controlled trial. Method Therapist-rated (n=16) credibility, expected burden, and harm expectancies of trauma-focused treatment were assessed at baseline, post-theoretical training, post-technical training, post-supervised practical training, and at 2-year follow-up. Credibility and burden beliefs of therapists concerning the treatment of every specific patient in the trial were also assessed. Results Over time, therapist-rated credibility of trauma-focused treatment showed a significant increase, whereas therapists’ expected burden and harm expectancies decreased significantly. In treating posttraumatic stress disorder (PTSD) in patients with psychotic disorders (n=79), pre-treatment symptom severity was not associated with therapist-rated credibility or expected burden of that specific treatment. Treatment outcome had no influence on patient-specific credibility or burden expectancies of therapists. Conclusions These findings support the notion that specialized training, including practical training with supervision, has long-term positive effects on therapists’ credibility, burden, and harm beliefs concerning trauma-focused treatment. Highlights of the article Specialized training improved therapists’ credibility, burden, and harm beliefs. Patients’ symptom severity and treatment outcome did not affect these beliefs. Replication of our findings in larger cohorts with a control group is warranted.

Core mechanisms of cognitive behavioral therapy for anxiety and depression: A review

This article reviews the extant literature on mediators of change in cognitive behavioral therapy (CBT) for anxiety and depression. The authors briefly discuss the efficacy of CBT for anxiety and depression and methods of mediation analysis and detection. Then the authors discuss fear extinction in anxiety treatment and cognitive change in depression treatment.