Impact of three variants of prolonged exposure therapy on comorbid diagnoses in patients with childhood abuse-related PTSD.

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 and testosterone enhanced exposure efficacy in women with social anxiety disorder: A pilot investigation.

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.

Exposure-based treatments for childhood abuse-related post-traumatic stress disorder in adults: a health-economic evaluation.

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.

This is the first study to compare cost-effectiveness of three exposure-based treatments in patients with CA-PTSD alongside a randomized controlled clinical trial (N = 149).The three exposure-based treatments did not differ in terms of outcomes and costs.Findings underline that any of these treatments can be implemented, and we endorse shared decision making to meet patient treatment preference.

Changes in trauma-related cognitions predict subsequent symptom improvement during prolonged exposure in patients with childhood abuse-related PTSD.

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.

Temporal Relationship Between Change in Subjective Distress and PTSD Symptom Decrease During Prolonged Exposure Therapy for Posttraumatic Stress Disorder.

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.

Effect of Prolonged Exposure, intensified Prolonged Exposure and STAIR+Prolonged Exposure in patients with PTSD related to childhood abuse: a randomized controlled trial.

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 (t135 = -2.85, p = .005, d = .49) but not clinician-assessed symptoms (t135 = -1.65, p = .10) and faster initial symptom reduction than STAIR+PE for self-reported (t135 = -4.11, p < .001, d = .71) and clinician-assessed symptoms (t135 = -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.

Antecedentes: No está claro si los tratamientos basados en la evidencia para el TEPT son tan efectivos en pacientes con TEPT relacionado con abuso infantil (TEPT-AI).Objetivo: Nuestro objetivo fue investigar la efectividad de tres variantes de la terapia de exposición prolongada.Método: Reclutamos adultos con TEPT-AI. Los participantes fueron asignados aleatoriamente a Exposición Prolongada (EP; 16 sesiones en 16 semanas), Exposición Prolongada intensificada (EPi; 12 sesiones en 4 semanas seguidas de dos sesiones de refuerzo) o un tratamiento basado en fases, en el que 8 sesiones de EP fueron precedidas por 8 sesiones de Entrenamiento de Habilidades en Regulación Afectiva e Interpersonal (STAIR+EP; 16 sesiones en 16 semanas). Las evaluaciones se llevaron a cabo en la semana 0 (línea de base), semana 4, semana 8, semana 16 (postratamiento) y en un seguimiento de 6 y 12 meses. El resultado primario fue la gravedad de los síntomas de TEPT calificada por el médico.Resultados: Asignamos aleatoriamente 149 pacientes a EP (48), EPi (51) o STAIR+EP (50). Todos los tratamientos dieron como resultado grandes mejoras en los síntomas de TEPT evaluados por el médico y autoinformados, desde el inicio hasta el seguimiento de 1 año (d de Cohen > 1.6), sin diferencias significativas entre los tratamientos. La EPi condujo a una reducción más rápida de los síntomas iniciales que la EP para los síntomas de TEPT autoinformados (t135 = −2.85, p =.005, d =.49) pero no los síntomas evaluados por el médico (t135 = −1.65, p =.10) y una reducción más rápida de síntomas iniciales que STAIR+EP para los síntomas autoinformados (t135 = −4.11, p <.001, d =.71) y evaluados por el médico (t135 = −2.77, p =.006, d de Cohen =.48) STAIR+EP no dio como resultado una mejora significativamente mayor desde el inicio hasta el seguimiento de 1 año en los resultados secundarios de regulación emocional, problemas interpersonales y autoestima en comparación con la EP y la EPi. Las tasas de abandono no difirieron significativamente entre las condiciones.Conclusiones: Las variantes de la terapia de exposición se toleran bien y conducen a grandes mejoras en pacientes con TEPT-AI. La intensificación del tratamiento puede conducir a una mejora más rápida, pero no a mejores resultados en general.

Personalization of Treatment for Patients with Childhood-Abuse-Related Posttraumatic Stress Disorder.

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.

The enhancing effects of testosterone in exposure treatment for social anxiety disorder: a randomized proof-of-concept trial.

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.

Does complex PTSD predict or moderate treatment outcomes of three variants of exposure therapy?

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.

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/).

Appraisal-based cognitive bias modification in patients with posttraumatic stress disorder: a randomised clinical trial.

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.

Antecedentes: Las valoraciones negativas del trauma y sus secuelas juegan un rol crucial en el desarrollo y mantención del Trastorno de Estrés Postraumático (TEPT). Estudios experimentales han mostrado promesa en reducir las valoraciones negativas a través de un entrenamiento de modificación de sesgo cognitivo (MSC).Objetivo: Determinar si un entrenamiento MSC en línea diseñado para modificar valoraciones disfuncionales es exitoso en reducir sesgos de valoración en pacientes con TEPT.Método: En este ensayo clínico randomizado doble ciego de 2 ramas, 107 pacientes con TEPT fueron asignados a entrenamiento MSC en línea activo (n=49) o control (n=57). El entrenamiento incluyó la realización de cuatro sesiones de entrenamiento MSC en línea dentro de una semana. El cambio en el sesgo, medido por un escenario de tareas y cuestionario (por ej. Inventario de Cogniciones Postraumáticas), fue el resultado primario. El resultado secundario incluyó cambios en los síntomas de TEPT. Las evaluaciones fueron realizadas antes del entrenamiento, durante las sesiones de entrenamiento, y posterior al tratamiento al mes y a los 6 meses de seguimiento.Resultados: El análisis del tipo intención de tratar indicó que no hubo efecto en la interacción de la condición según el tiempo. Pese a la condición de entrenamiento, los participantes mostraron una disminución leve a moderada en el sesgo de valoración y síntomas de TEPT desde el periodo anterior y posterior al entrenamiento. En ambas condiciones el cambio en el sesgo durante las sesiones de entrenamiento se relacionó con la disminución de la sintomatología de TEPT tras el entrenamiento. No se encontraron moderadores de resultados.Conclusiones: No hubo evidencia de que el entrenamiento activo fuera más efectivo que el entrenamiento control en reducir las valoraciones disfuncionales. En ambas condiciones, los participantes mostraron una disminución en las valoraciones disfuncionales y síntomas de TEPT tras el entrenamiento. De forma importante, la reducción del sesgo se relacionó con la disminución de sintomatología de TEPT tras el entrenamiento. Explicaciones y orientaciones sobre futura investigación fueron discutidas.

Tonic immobility during re-experiencing the traumatic event in posttraumatic stress disorder.

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.

Intensive prolonged exposure therapy for chronic PTSD patients following multiple trauma and multiple treatment attempts.

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.

Planteamiento: La respuesta subóptima y las altas tasas de abandono dejan margen para la mejora de la eficacia del tratamiento centrado en el trauma (TCT) en la mejora de los síntomas del trastorno por estrés postraumático (TEPT). Objetivo: explorar la efectividad y la seguridad de la exposición prolongada intensiva (EPI) dirigida a pacientes con TEPT crónico con un probable diagnóstico de TEPT complejo de la CIE-11 después de múltiples traumas interpersonales y un historial de múltiples intentos de tratamiento. Método: Los participantes (N = 73) recibieron EPI en 12 sesiones de 90 minutos durante cuatro días (fase intensiva) seguidas de cuatro sesiones semanales de exposición prolongada (EP) de refuerzo de 90 minutos (fase de refuerzo). Los resultados principales, la gravedad de los síntomas del TEPT evaluados por el clínico y el estado diagnóstico evaluados por el clínico (Escala de TEPT administrada por el clínico, CAPS-IV, por sus siglas en inglés) se evaluaron al inicio, después del tratamiento, y a los tres y seis meses. Se identificaron las trayectorias de respuesta al tratamiento y se exploraron los predictores de estas trayectorias. Resultados: Los análisis de medidas repetidas de las puntuaciones de CAPS-IV desde un modelo mixto mostraron una disminución de la línea de base hasta el postratamiento en cuanto a la gravedad de los síntomas de TEPT (p <.001) que persistió durante los seguimientos a los 3 y 6 meses con tamaños de efecto grandes (d de Cohen> 1,2); el 71% de los participantes respondieron. Ninguno de los participantes abandonó durante la fase intensiva y solo el 5% lo hizo durante la fase de refuerzo. Los eventos adversos fueron extremadamente bajos y solo una minoría mostró exacerbación de los síntomas. El análisis de clusters demostró cuatro trayectorias de respuesta al tratamiento: los que responden rápidamente (13%), los que responden lentamente (26%), los que responden parcialmente (32%) y los que no responden (29%). Se descubrió que las condiciones de vida y la habituación al miedo entre sesiones predecían el resultado. Los participantes que vivían solos eran más propensos a pertenecer a los que responden parcialmente que al grupo de los que no responden, y los participantes que demostraron más habituación al miedo entre sesiones tenían más probabilidades de pertenecer a los que responden rápidamente que al grupo de los que no responden. Conclusiones: los resultados de este estudio abierto sugieren que la EPI puede ser efectiva en pacientes con TEPT con traumas interpersonales múltiples y después de múltiples intentos previos de tratamiento. Además, en esta población de TEPT crónico, la EPI era segura.

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.

Intensive prolonged exposure treatment for adolescent complex posttraumatic stress disorder: a single-trial design.

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.

Harm expectancy violation during exposure therapy for posttraumatic stress disorder.

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.

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.

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).

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.