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Background and Objectives: Inhibitory Learning Theory (ILT) framework implies that in-session distress variability may promote extinction learning and thereby enhance exposure therapy efficacy. Thus far, research has mainly focused on in-session distress reduction. The aim of the current study was to assess whether in-session distress variability predicts next session PTSD symptom decline in PTSD patients receiving prolonged exposure (PE)., Methods: Eighty-six patients with PTSD received 14 to 16 sessions of PE. Using dynamic panel models, we assessed the temporal relation (i.e., within-persons) between in-session distress variability and PTSD symptom decline. Moreover, we assessed the averaged relation (i.e., between-persons) between in-session distress variability and PTSD symptom decline., Results: Temporal analyses showed that in-session distress variability did not precede PTSD symptom improvement. Averaged analyses showed that distress variability was related to PTSD symptom improvement., Limitation: The operationalization of distress variability appeared to deviate from its theoretical conceptualization., Conclusions: In absence of distress reduction, distress variability can vary. However, our findings suggest that in-session distress variability does not drive symptom reduction during PE. In contrast, averaged over participants, distress variability was related to symptom improvement, suggesting that those with a more variable distress pattern across sessions show better treatment response. More empirical work is needed to shed light on the effect of distress variability during exposure sessions on treatment outcome and to offer grounds for clinical recommendations., Competing Interests: Declaration of competing interest There are no conflicts of interest to disclose., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Working alliance is considered an important determinant of outcome of psychotherapy. Patients with posttraumatic stress disorder (PTSD) following childhood abuse (CA-PTSD) may have challenges in building interpersonal relationships, including working alliance. Phase-based treatment provides an opportunity to strengthen alliance prior to trauma-focused treatment. This study aimed to compare the development of working alliance among patients with CA-PTSD in three variants of prolonged exposure (PE) therapy: standard PE, intensive PE (iPE), and skill training in affective and interpersonal regulation + prolonged exposure (STAIR + PE). We also examined the effect of alliance on treatment outcome and dropout., Method: Self-reported PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, fifth edition (Blevins et al., 2015) and patient-rated Working Alliance Inventory (Tracey & Kokotovic, 1989) were assessed in a clinical trial. We analyzed data from 138 adult patients (76.1% female; 42% non-Western). Analyses were performed using mixed-effects models., Results: Patients established a satisfactory alliance early in treatment, which increased over time. For PE and STAIR + PE, a larger decrease in PTSD symptom severity was related to a higher alliance in the subsequent session, but not the other way around. In STAIR + PE, a higher alliance in Phase 1 was related to lower PTSD symptoms in Phase 2. In all conditions, a higher initial working alliance was related to a lower chance of treatment dropout., Conclusion: In the treatment of CA-PTSD, all three variants of prolonged exposure foster positive development of the working alliance. Across conditions, working alliance did not precede symptom decline. Therapists should strive for a strong alliance at the beginning of treatment as this reduces the likelihood of dropout. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Recent studies indicated that Prolonged Exposure (PE) is safe and effective for posttraumatic stress disorder (PTSD). It is unclear whether PE also leads to a reduction in comorbid diagnoses. Data from a large randomized controlled trial ( N  = 149) on the effects of three variants of PE for PTSD were used. We examined the treatment effects on co-morbid diagnoses of depressive, anxiety, obsessive compulsive, substance abuse, psychotic, eating and personality disorders in a sample of patients with PTSD related to childhood abuse. Outcomes were assessed with clinical interviews at baseline, post-treatment and at 6- and 12-month follow-up. All variants of PE led to a decrease from baseline to post-treatment in diagnoses of depressive, anxiety, substance use and personality disorders. Improvements were sustained during follow-up. We found an additional decrease in the number of patients that fulfilled the diagnostic criteria of a depressive disorder between 6- and 12-month follow-up. No significant changes were observed for the presence of OCD, psychotic and eating disorders. Findings suggest that it is effective to treat PTSD related to childhood abuse with trauma-focused treatments since our 14-to-16 weeks PE for PTSD resulted in reductions in comorbid diagnoses of depressive, anxiety, substance use and personality disorders.

Social avoidance has been associated with more persistent social anxiety disorder (SAD) symptoms and low testosterone levels in individuals with SAD. We tested whether pre-treatment avoidance tendencies moderate the efficacy of testosterone-augmented exposure therapy. Fifty-five females with SAD received two exposure sessions during which fear levels were assessed. Session 1 was augmented with testosterone (0.50 mg) or placebo. Avoidance tendencies and symptom severity were assessed pre- and post-exposure. Participants showed stronger avoidance for social versus non-social stimuli and this tendency remained stable over time. Stronger pretreatment avoidance tendencies were associated with larger fear reduction in the testosterone but not the placebo condition. This effect did not transfer to the second non-enhanced session or symptom severity. The findings support the hypothesis that individuals suffering from SAD with relatively stronger pretreatment avoidance tendencies benefit more from testosterone-augmentation, pointing to a potential behavioral marker for testosterone enhancement of exposure therapy., Competing Interests: Declaration of Competing Interest The other authors declared no conflicts of interest with respect to the authorship or the publication of this article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Anxiety-related disorders are characterized by high levels of avoidance, but experimental research into avoidance learning in patients is scarce. To fill this gap, we compared healthy controls (HC, n = 47) with patients with obsessive-compulsive disorder (OCD, n = 33), panic disorder with agoraphobia (PDA, n = 40), and post-traumatic stress disorder (PTSD, n = 66) in a computer-based avoidance learning task, in order to examine (1) differences in rates of avoidance responses, (2) differences in action-safety learning during avoidance, and (3) differences in subjective relief following successful avoidance. The task comprised aversive negative pictures (unconditional stimulus, US) that followed pictures of two colored lamps (conditional stimuli, CS+), but not a third colored lamp (safety stimulus, CS-), and could be avoided by pressing a button during one CS+ (CS+ avoidable) but not the other (CS+ unavoidable). Participants rated their US-expectancy and level of relief on a trial-by-trial basis. Compared to the HC group, patient groups displayed higher levels of avoidance to the safety stimulus, and higher levels of US-expectancy and relief following the safety and avoidable danger stimulus. We propose that patients with anxiety disorders have low confidence in the safety consequences of avoidance actions, which induces increased relief during US omissions that reinforce the avoidance action., Competing Interests: Conflict of interest All authors declare to have no conflict of interest related to the presented work., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Change in negative posttraumatic cognitions is a proposed mechanism through which Prolonged Exposure (PE) leads to symptom reduction of posttraumatic stress disorder (PTSD). A strong case for posttraumatic cognitions as a change mechanism in PTSD treatment can be made by establishing temporal precedence of change in cognitions. The current study examines the temporal relationship between change in posttraumatic cognitions and PTSD symptoms during PE, using the Posttraumatic Cognitions Inventory. Patients with DSM-5 defined PTSD following childhood abuse (N = 83) received a maximum of 14-16 sessions of PE. Clinician-rated PTSD symptom severity and posttraumatic cognitions were assessed at baseline, week 4, 8, and 16 (post-treatment). Using time-lagged mixed effect regression models, we found that posttraumatic cognitions predicted subsequent PTSD symptom improvement. Notably, when using the items of an abbreviated version of the PTCI (PTCI-9), we found a mutual relationship between posttraumatic cognitions and PTSD symptom improvement. Crucially, the effect of change in cognitions on PTSD symptom change was greater than the reverse effect. The current findings corroborate change in posttraumatic cognitions as a change process during PE, but cognitions and symptoms cannot be completely separated. The PTCI-9 is a short instrument that appears suitable to track cognitive change over time., Competing Interests: Declaration of competing interest None., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Prolonged exposure (PE) is an effective treatment for post-traumatic stress disorder (PTSD). Objective: This study aimed to analyse the cost-effectiveness of three exposure-based treatments in patients with childhood abuse-related PTSD. Method: A net-benefit analysis was conducted alongside a pragmatic randomized controlled trial with participants ( N  = 149) randomized to three conditions: PE ( n =  48), intensified PE (i-PE, n  = 51), and phase-based PE [Skills Training in Affective and Interpersonal Regulation (STAIR) + PE, n  = 50]. Assessments took place at baseline (T0), post-treatment (T3), 6 month follow-up (T4), and 12 month follow-up (T5). Costs stemming from healthcare utilization and productivity losses were estimated using the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness. Quality-adjusted life-years (QALYs) were based on the 5-level EuroQoL 5 Dimensions (EQ-5D-5L) using the Dutch tariff. Missing values of costs and utilities were multiply imputed. To compare i-PE to PE and STAIR + PE to PE, pair-wise unequal-variance t -tests were conducted. Net-benefit analysis was used to relate costs to QALYs and to draw acceptability curves. Results: Intervention costs did not differ across the three treatment conditions. Total medical costs, productivity losses, total societal costs, and EQ-5D-5L-based QALYs did not differ between treatment conditions either (all p  > .10). At the relevant €50,000/QALY threshold, the probability of one treatment being more cost-effective than another was 32%, 28%, and 40% for PE, i-PE, and STAIR-PE, respectively. Conclusion: Three equally effective treatments were compared and no differences in cost-effectiveness between treatments were found. Therefore, we advocate the implementation and adoption of any of the treatments and endorse shared decision making.

There is growing evidence that change in distress is an indicator of change during Prolonged Exposure (PE) for posttraumatic stress disorder (PTSD). However, temporal sequencing studies investigating whether change in distress precedes PTSD symptom decline are lacking. These studies are essential since the timeline between indicators of change and treatment outcome is a key assumption for mediation. The aim of the present study was to assess the temporal relationship between within- and between-session change in subjective distress and PTSD symptom decrease. We analyzed session data from 86 patients with PTSD. Data were analyzed using dynamic panel models. We distinguished temporal effects (within-persons) from averaged effects (between-persons). Results regarding the temporal effect showed that within-session change in subjective distress preceded PTSD symptom improvement while the reversed effect was absent. Averaged within-session change in subjective distress was also related to PTSD symptom improvement. Results regarding the temporal effect of between-session change in subjective distress showed that it did not precede PTSD symptom improvement. Averaged between-session change in subjective distress was related to PTSD symptom improvement. This study provides evidence for within- but not between-session change in subjective distress as indicator of change during PE. We also found that the way of modeling potential indicators of change affects results and implications. We recommend future studies to analyze mediators during treatment using temporal rather than averaged effects., Competing Interests: Conflict of Interest Statement The authors declare that there are no conflicts of interest., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Differences in effectiveness among treatments for posttraumatic stress disorder (PTSD) are typically small. Given the variation between patients in treatment response, personalization offers a new way to improve treatment outcomes. The aim of this study was to identify predictors of psychotherapy outcome in PTSD and to combine these into a personalized advantage index (PAI)., Methods: We used data from a recent randomized controlled trial comparing prolonged exposure (PE; n = 48), intensified PE (iPE; n = 51), and skills training (STAIR), followed by PE ( n = 50) in 149 patients with childhood-abuse-related PTSD (CA-PTSD). Outcome measures were clinician-assessed and self-reported PTSD symptoms. Predictors were identified in the exposure therapies (PE and iPE) and STAIR+PE separately using random forests and subsequent bootstrap procedures. Next, these predictors were used to calculate PAI and to retrospectively determine optimal and suboptimal treatment in a leave-one-out cross-validation approach., Results: More depressive symptoms, less social support, more axis-1 diagnoses, and higher severity of childhood sexual abuse were predictors of worse treatment outcomes in PE and iPE. More emotion regulation difficulties, lower general health status, and higher baseline PTSD symptoms were predictors of worse treatment outcomes in STAIR+PE. Randomization to optimal treatment based on these predictors resulted in more improvement than suboptimal treatment in clinician assessed (Cohens' d = 0.55) and self-reported PTSD symptoms (Cohens' d = 0.47)., Conclusion: Personalization based on PAI is a promising tool to improve therapy outcomes in patients with CA-PTSD. Further studies are needed to replicate findings in prospective studies.

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus-pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD., (© 2021. The Author(s).)

Background: One reason for the inclusion of Complex Posttraumatic Stress Disorder (CPTSD) in the 11th revision of the International Classification of Diseases (ICD-11) was its suspected relevance for treatment indications. We investigated whether CPTSD predicted and moderated treatment outcomes of Prolonged Exposure (PE), intensified PE (iPE) and Skills Training in Affective and Interpersonal Regulation followed by PE (STAIR + PE). We expected that CPTSD would predict worse treatment outcomes across treatments. Secondly, we expected that CPTSD would lead to better treatment effect in STAIR + PE compared to PE and iPE., Methods: We analyzed 149 patients with childhood-abuse related PTSD from a randomized clinical trial. CPTSD diagnosis and symptom severity were measured with the International Trauma Questionnaire. The main outcome was change in clinician-assessed PTSD symptoms. Assessments took place at baseline, week 4, week 8, week 16 (post-treatment) and at a 6-and 12-month follow-up. Analyses were based on an intention-to-treat sample using mixed effect models., Results: More than half (54 %) of the patients met criteria for CPTSD at baseline. CPTSD was related to more severe PTSD symptoms and higher comorbidity at baseline. CPTSD neither predicted nor moderated treatment outcome., Limitations: Inclusion was limited to patients with PTSD related to childhood abuse. Replication is needed in different samples., Conclusions: CPTSD is associated with more severe PTSD and with higher comorbidity. CPTSD did not predict treatment outcome and did not indicate differential treatment outcome of STAIR + PE compared to PE and iPE., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background : It is unclear whether the evidence-based treatments for PTSD are as effective in patients with CA-PTSD. Objective : We aimed to investigate the effectiveness of three variants of prolonged exposure therapy. Method : We recruited adults with CA-PTSD. Participants were randomly assigned to Prolonged Exposure (PE; 16 sessions in 16 weeks), intensified Prolonged Exposure (iPE; 12 sessions in 4 weeks followed by 2 booster sessions) or a phase-based treatment, in which 8 sessions of PE were preceded by 8 sessions of Skills Training in Affective and Interpersonal Regulation (STAIR+PE; 16 sessions in 16 weeks). Assessments took place in week 0 (baseline), week 4, week 8, week 16 (post-treatment) and at a 6-and 12-month follow-up. The primary outcome was clinician-rated PTSD symptom severity. Results : We randomly assigned 149 patients to PE (48), iPE (51) or STAIR+PE (50). All treatments resulted in large improvements in clinician assessed and self-reported PTSD symptoms from baseline to 1-year follow-up (Cohen's d > 1.6), with no significant differences among treatments. iPE led to faster initial symptom reduction than PE for self-report PTSD symptoms ( t 135  = -2.85, p = .005, d = .49) but not clinician-assessed symptoms (t 135  = -1.65, p = .10) and faster initial symptom reduction than STAIR+PE for self-reported ( t 135  = -4.11, p < .001, d = .71) and clinician-assessed symptoms ( t 135  = -2.77, p = .006, Cohen's d = .48) STAIR+PE did not result in significantly more improvement from baseline to 1-year follow-up on the secondary outcome emotion regulation, interpersonal problems and self-esteem compared to PE and iPE. Dropout rates did not differ significantly between conditions. Conclusions : Variants of exposure therapy are tolerated well and lead to large improvements in patients with CA-PTSD. Intensifying treatment may lead to faster improvement but not to overall better outcomes. The trial is registered at the clinical trial registry, number NCT03194113, https://clinicaltrials.gov/ct2/show/NCT03194113., Competing Interests: Dr. van Minnen reports personal fees from Royalties and fees, outside the submitted work; Dr. Cloitre reports personal fees from Royalites and fees British Psychological Society San Francisco University Department of Psychiatry during the conduct of the study; Drs. Oprel, Drs. Hoeboer, Dr. Schoorl, Dr. van der Does, Drs. Wigard and Dr. de Kleine report no financial relationships with commercial interests., (© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Many patients with post-traumatic stress disorder (PTSD) experience dissociative symptoms. The question of whether these dissociative symptoms negatively influence the effectiveness of psychotherapy for PTSD is unresolved., Aims: To determine the influence of dissociative symptoms on psychotherapy outcome in PTSD., Method: We conducted a systematic search in Cochrane, Embase, PILOTS, PsycINFO, PubMed and Web of Science for relevant clinical trials. A random-effects meta-analysis examined the impact of dissociation on psychotherapy outcome in PTSD (pre-registered at Prospero CRD42018086575)., Results: Twenty-one trials (of which nine were randomised controlled trials) with 1714 patients were included. Pre-treatment dissociation was not related to treatment effectiveness in patients with PTSD (Pearson's correlation coefficient 0.04, 95% CI -0.04 to 0.13). Between-study heterogeneity was high but was not explained by moderators such as trauma focus of the psychotherapy or risk of bias score. There was no indication for publication bias., Conclusions: We found no evidence that dissociation moderates the effectiveness of psychotherapy for PTSD. The quality of some of the included studies was relatively low, emphasising the need for high-quality clinical trials in patients with PTSD. The results suggest that pre-treatment dissociation does not determine psychotherapy outcome in PTSD.

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/)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background : Negative appraisals of the trauma and its sequelae play a crucial role in the development and maintenance of Posttraumatic Stress Disorder (PTSD). Experimental studies have shown promise in reducing negative appraisal through Cognitive Bias Modification (CBM) training. Objective : To determine whether an online CBM training designed to modify dysfunctional appraisals is successful in reducing appraisal bias in PTSD patients. Method : In this double-blinded 2-arm randomised clinical trial, 107 patients with PTSD were randomly allocated to active ( n = 49) or control online CBM training ( n = 57). Training comprised the completion of four sessions of online CBM training within one week. Change in bias, as measured by a scenario task and questionnaire (i.e. PostTraumatic Cognition Inventory), was the primary outcome. Secondary outcome included change in PTSD symptoms. Assessments took place prior to training, during training sessions, post-training and at 1- and 6-month follow-up. Results : Intent-to-treat analysis indicated that there was no interaction effect of condition by time. Regardless of training condition, participants showed a small to moderate decline in appraisal bias and PTSD symptoms from pre- to post-training. In both conditions, bias change during training sessions was related to decline in PTSD symptomatology following training. No moderators of outcome were found. Conclusions : There was no evidence that active training was more effective than control training in reducing dysfunctional appraisals. In both conditions, participants showed a decline in dysfunctional appraisals and PTSD symptoms following training. Importantly, bias reduction during training was related to PTSD symptom decline following training. Explanations and future research directions are discussed.

Background: Childhood abuse related posttraumatic stress disorder (CA-PTSD) is associated with a high burden of disease and with treatment response rates that leave room for improvement. One of the treatments for PTSD, prolonged exposure (PE), is effective but has high drop-out rates and remission rates are relatively low. An intensified form of PE (iPE) was associated with good response and low drop-out rates in PTSD and has not yet been tested in a controlled trial in CA-PTSD. Phase-based treatment (PBT), in which PE is preceded by skills training may improve overall outcomes in this population. We will assess the effectiveness and cost-effectiveness of standard PE, iPE and PBT in patients with CA-PTSD., Methods/design: Multi-center randomized controlled trial. Treatment conditions are: prolonged exposure (PE; maximum of 16 sessions in 16 weeks); intensified PE (iPE; maximum of 12 sessions in four weeks and two booster sessions); phase-based treatment (PBT; maximum of eight sessions skills training followed by eight sessions PE in 16 weeks)., Primary Outcome: Clinician-rated PTSD symptom severity., Secondary Outcomes: loss of PTSD diagnosis, self-reported PTSD symptom severity, comorbid symptom severity and quality of life. Moreover, we will examine cost-effectiveness and moderators and mediators of treatment outcome., Target Population: adults with CA-PTSD (N = 150). Assessments in weeks 0, 4, 8, 16, 26 and 52., Discussion: Given that no consensus yet exists about the treatment guidelines for patients with CA-PTSD, the present study may have important implications for the treatment of CA-PTSD., Trail Registration: Registered at C.C.M.O. on Sept 7, 2016 (NL57984.058.16); retrospectively registered at June 21, 2017 at clinicaltrials.gov identifier: NCT03194113 .

Tonic Immobility (TI) is an evolved defence response, characterized by physical immobility. Peritraumatic TI has been linked to posttraumatic stress disorder (PTSD). However, samples sizes in clinical studies have been small, and little is known about TI reactions post trauma, for instance during trauma reminders. The prevalence of peritraumatic TI and TI during re-experiencing the traumatic event was examined by self-report in 184 patients with chronic PTSD. Moderate peritraumatic TI was reported by 26.6% of the participants (n = 49) and extreme peritraumatic TI by 52.2% (n = 96). During re-experiencing the traumatic event, 35.3% (n = 65) reported moderate TI, and 37.0% (n = 68) extreme TI. Peritraumatic TI was related to PTSD symptom severity and TI during re-experiencing mediated this relationship. In line with previous findings, reports of peritraumatic TI were high among PTSD patients. In addition, we showed that it often re-occurred during re-experiencing the traumatic event. The prevalence of TI at different stages post trauma warrants future study., (Copyright © 2018. Published by Elsevier B.V.)

Background : Suboptimal response and high dropout rates leave room for improvement of trauma-focused treatment (TFT) effectiveness in ameliorating posttraumatic stress disorder (PTSD) symptoms. Objective : To explore the effectiveness and safety of intensive prolonged exposure (iPE) targeting chronic PTSD patients with a likely diagnosis of ICD-11 Complex PTSD following multiple interpersonal trauma and a history of multiple treatment attempts. Method : Participants ( N  = 73) received iPE in 12 × 90-minute sessions over four days (intensive phase) followed by four weekly 90-minute booster prolonged exposure (PE) sessions (booster phase). The primary outcomes, clinician-rated severity of PTSD symptoms, and diagnostic status (Clinician-Administered PTSD Scale; CAPS-IV) were assessed at baseline, post-treatment, and at three and six months. Treatment response trajectories were identified and predictors of these trajectories explored. Results : Mixed model repeated measures analysis of CAPS-IV scores showed a baseline-to-posttreatment decrease in PTSD symptom severity ( p  < .001) that persisted during the three- and six-month follow-ups with large effect sizes (Cohen's d  > 1.2); 71% of the participants responded. None of the participants dropped out during the intensive phase and only 5% during the booster phase. Adverse events were extremely low and only a minority showed symptom exacerbation. Cluster analysis demonstrated four treatment response trajectories: Fast responders (13%), Slow responders (26%), Partial responders (32%), and Non-responders (29%). Living condition and between-session fear habituation were found to predict outcome. Participants living alone were more likely to belong to the Partial responders than to the Non-responders cluster, and participants showing more between-session fear habituation were more likely to belong to the Fast responders than to the Non-responders cluster. Conclusions : The results of this open study suggest that iPE can be effective in PTSD patients with multiple interpersonal trauma and after multiple previous treatment attempts. In addition, in this chronic PTSD population iPE was safe., Competing Interests: The authors declare that there are no conflicts of interest.

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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: The current study evaluated the effectiveness and safety of intensive prolonged exposure (PE) targeting adolescent patients with complex posttraumatic stress disorder (PTSD) and comorbid disorders following multiple interpersonal trauma., Methods: Ten adolescents meeting full diagnostic criteria for PTSD were recruited from a specialized outpatient mental health clinic and offered a standardized intensive PE. The intensive PE consisted of three daily 90-min exposure sessions delivered on five consecutive weekdays, followed by 3 weekly 90-min booster sessions. In a single-trial design, the participants were randomly allocated to one of five baseline lengths (4-8 weeks) before starting the intensive PE. Before, during, and after intensive PE completion, self-reported PTSD symptom severity was assessed weekly as a primary outcome (a total of 21 measurements). Furthermore, clinician-administered PTSD diagnostic status and symptom severity (primary outcome), as well as self-reported comorbid symptoms (secondary outcomes), were assessed at four single time points (baseline-to-6-month follow-up)., Results: Time-series analyses showed that self-reported PTSD symptom severity significantly declined following treatment (p = .002). Pre-postgroup analyses demonstrated significant reductions of clinician-administered PTSD symptom severity and self-reported comorbidity that persisted during the 3- and 6-month follow-ups (all ps < .05), where 80% of adolescents had reached diagnostic remission of PTSD. There was neither treatment dropout nor any adverse events., Conclusions: The results of this first proof of concept trial suggest that intensive PE can be effective and safe in an adolescent population with complex PTSD, although the gains achieved need to be confirmed in a randomized controlled trial., (© 2017 Association for Child and Adolescent Mental Health.)

Exposure therapy has proven efficacy in the treatment of posttraumatic stress disorder (PTSD). Emotional processing theory proposes that fear habituation is a central mechanism in symptom reduction, but the empirical evidence supporting this is mixed. Recently it has been proposed that violation of harm expectancies is a crucial mechanism of action in exposure therapy. But to date, changes in harm expectancies have not been examined during exposure therapy in PTSD. The goal of the current study was to examine harm expectancy violation as mechanism of change in exposure therapy for posttraumatic stress disorder (PTSD). Patients (N=50, 44 female) with a primary diagnosis of chronic PTSD received intensive exposure therapy. Harm expectancies, harm experiences and subjective units of distress (SUDs) were assessed at each imaginal exposure session, and PTSD symptoms were assessed pre- and posttreatment with the Clinician Administered PTSD Scale (CAPS). Results showed that harm expectancies were violated within and strongly declined in-between exposure therapy sessions. However, expectancy violation was not related to PTSD symptom change. Fear habituation measures were moderately related to PTSD symptom reductions. In line with theory, exposure therapy promotes expectancy violation in PTSD patients, but this is not related to exposure therapy outcome. More work is warranted to investigate mechanisms of change during exposure therapy in PTSD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

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.

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)., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

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.

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., (Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)