Effectiveness of the massed delivery of unified protocol for emotional disorders within an intensive outpatient program for military service members and veterans.

Recent evidence supports the implementation of massed delivery of disorder-specific treatments in the military service member and veteran population. However, many treatment settings serve patients with a wide range of diagnoses, and often patients present with comorbid conditions. Growing evidence suggests transdiagnostic cognitive behavioral treatments are effective for a wide range of emotional disorders and may reduce barriers to access. Little is known about the feasibility and outcomes of the massed delivery of transdiagnostic treatments. The present study examined real-world outcomes of a 2-week intensive outpatient program using the Unified Protocol for emotional disorders (UP-IOP). The sample included military service members and veterans diagnosed with a range of emotional disorders, namely trauma- and stressor-related disorders, unipolar depressive disorders, and anxiety disorders. The present study examined outcomes of UP-IOP (depression, trauma-related symptom severity, and emotion dysregulation). Participants included all patients who sought UP-IOP in its first 15 months of operation (N = 117). A diagnosis of posttraumatic stress disorder (PTSD) was an exclusion criterion because the site had an established PTSD-specific IOP treatment option. Findings indicate UP-IOP was feasible, had 94% patient retention, and was effective in reducing symptom severity (Cohen's d = 0.76 for depression symptom severity, Cohen's d = 0.80 for trauma-related symptom severity). There was no observed reduction in emotion dysregulation over the 2-week course of treatment. The intensive transdiagnostic approach resulted in effective symptom reduction in an accelerated timeframe while minimizing patient attrition. These findings indicate massed delivery of transdiagnostic cognitive behavioral therapy (CBT) treatments should continue to be explored, especially for this population. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Comorbid treatment of traumatic brain injury and mental health disorders.

BACKGROUND: The Emory Healthcare Veterans Program (EHVP) is a multidisciplinary intensive outpatient treatment program for post-9/11 veterans and service members with invisible wounds, including posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), substance use disorders (SUD), and other anxiety- and depression-related disorders. OBJECTIVE: This article reviews the EHVP. METHODS: The different treatment tracks that provide integrated and comprehensive treatment are highlighted along with a review of the standard, adjunctive, and auxiliary services that complement individualized treatment plans. RESULTS: This review particularly emphasizes the adjunctive neurorehabilitation service offered to veterans and service members with a TBI history and the EVHP data that indicate large reductions in PTSD and depression symptoms across treatment tracks that are maintained across 12 months follow up. Finally, there is a discussion of possible suboptimal treatment response and the pilot programs related to different treatment augmentation strategies being deploying to ensure optimal treatment response for all. CONCLUSION: Published data indicate that the two-week intensive outpatient program is an effective treatment program for a variety of complex presentations of PTSD, TBI, SUD, and other anxiety- and depression-related disorders in veterans and active duty service members.

Substance Use after Completion of an Intensive Treatment Program with Concurrent Treatment for Posttraumatic Stress Disorder and Substance Use among Veterans: Examining the Role of PTSD Symptoms.

OBJECTIVE: Substance use disorders (SUDs) and posttraumatic stress disorder (PTSD) are costly and highly co-occurring diagnoses, particularly among veterans, suggesting a need to understand this comorbidity and effectively treat both disorders among this population. METHODS: The current study aimed to examine substance use outcomes among post-9/11 veterans and service members (N = 48) who completed a two-week intensive outpatient program with concurrent treatment for and PTSD using Prolonged Exposure and substance use. Substance use was assessed at two weeks and three months posttreatment. RESULTS: The intensive program had high completion rates and demonstrated decreases in substance use at two weeks and three months posttreatment. Additionally, lower PTSD symptoms at treatment completion were related to less substance use posttreatment. CONCLUSIONS: Concurrent intensive treatment of PTSD and SUDs can lead to symptom improvement in a short period of time. Findings support the self-medication model, such that PTSD symptoms at treatment completion were related to substance use at follow-up.

Impact of dissociation on exposure therapy for PTSD outcomes and Adherence among U.S. Military service members.

Emotional engagement is necessary for successful exposure therapy for posttraumatic stress disorder (PTSD), but dissociation is considered a barrier to emotional engagement. Virtual reality exposure therapy (VRE) uses multi-sensory virtual environments to increase emotional engagement during exposure therapy, and average treatment outcomes are comparable to traditional exposure therapy. However, individual factors (e.g., depression) can predict differential responses to VRE. Studies have yet to investigate whether VRE would be more effective in treating patients with dissociation compared to traditional PE. This secondary analysis of a randomized clinical trial explores whether dissociation predicts treatment outcomes to exposure therapy among active-duty soldiers (N = 108) diagnosed with PTSD. We also examine whether individuals reporting dissociative symptoms demonstrated differential treatment responses to VRE and PE. Results indicated a significant two-way interaction between dissociation and time in treatment, such that dissociation blunted the negative relationship between time and PTSD symptoms. Dissociation was not associated with treatment session attendance or drop out. Results also revealed no significant effect of treatment group (PE or VRE) on the relationship between dissociation and PTSD symptoms. Findings contribute to a body of literature supporting the potential clinical and research utility of a dissociative subtype of PTSD.

Extinction-Based Exposure Therapies Using Virtual Reality.

The focus of this chapter is an overview of integrating virtual reality (VR) technology within the context of exposure therapy for anxiety disorders, a gold standard treatment, with a focus on how VR can help facilitate extinction learning processes integral to these interventions. The chapter will include an overview of advantages of incorporating VR within exposure therapy, and benefits specifically within an inhibitory learning approach for extinction training. A review of the empirical literature on the effectiveness of VR exposure therapy for specific phobia and PTSD will be provided, as well as practical overview of how to effectively incorporate VR within exposure therapy.

Modified prolonged exposure therapy as Early Intervention after Rape (The EIR-study): study protocol for a multicenter randomized add-on superiority trial.

BACKGROUND: Sexual assault and rape are the traumatic life events with the highest probability for posttraumatic stress disorder (PTSD), which can have devastating consequences for those afflicted by the condition. Studies indicate that modified prolonged exposure (mPE) therapy may be effective in preventing the development of PTSD in recently traumatized individuals, and especially for people who have experienced sexual assault. If a brief, manualized early intervention can prevent or reduce post-traumatic symptoms in women who have recently experienced rape, healthcare services targeted for these populations (i.e., sexual assault centers, SACs) should consider implementing such interventions as part of routine care. METHODS/DESIGN: This is a multicenter randomized controlled add-on superiority trial that enrolls patients attending sexual assault centers within 72 h after rape or attempted rape. The objective is to assess whether mPE shortly after rape can prevent the development of post-traumatic stress symptoms. Patients will be randomized to either mPE plus treatment as usual (TAU) or TAU alone. The primary outcome is the development of post-traumatic stress symptoms 3 months after trauma. Secondary outcomes will be symptoms of depression, sleep difficulties, pelvic floor hyperactivity, and sexual dysfunction. The first 22 subjects will constitute an internal pilot trial to test acceptance of the intervention and feasibility of the assessment battery. DISCUSSION: This study will guide further research and clinical initiatives for implementing strategies for preventing post-traumatic stress symptoms after rape and provide new knowledge about which women may benefit the most from such initiatives and for revising existing treatment guidelines within this area. TRIAL REGISTRATION: ClinicalTrials.gov NCT05489133. Registered on 3 August 2022.

Early intervention using written exposure therapy for PTSD and AUD symptoms following sexual assault: Description of design and methodology.

The co-occurrence of posttraumatic stress disorder (PTSD) and alcohol use disorder (AUD) is common following sexual assault and associated with more severe symptomology and increased likelihood of sexual revictimization. Integrated interventions aimed at reducing PTSD and AUD symptoms following recent sexual assault are needed and should address barriers to care and early treatment termination. The proposed study will test a novel, brief (5 to 7 sessions) intervention that integrates Written Exposure Therapy for PTSD and Cognitive Behavioral Therapy for AUD, and is initiated within the first six weeks post-assault. In Phase 1, qualitative analysis of content gathered during focus groups with treatment providers will be conducted to inform intervention development. In Phase 2, a proof-of-concept pilot study (n = 10) of the intervention, Substance Use Skills Training and Exposure Post-Sexual Assault (STEPS), will be conducted. In Phase 3, a pilot randomized controlled trial (RCT) among 54 recent sexual assault survivors will be implemented using the updated manualized STEPS intervention to evaluate feasibility and preliminary efficacy in reducing PTSD and AUD symptoms. Ecological momentary assessments will be used to assess daily alcohol use, craving, affect, intrusions and avoidance. The effects of STEPS on commonly associated symptoms (e.g., depression, substance use) will be examined. The proposed study has the potential to make a significant public health impact by advancing knowledge on the link between sexual assault and co-occurring PTSD and AUD and informing early intervention efforts for this high-risk population.

Consultation competencies in prolonged exposure therapy for posttraumatic stress disorder.

INTRODUCTION: The Emory University Prolonged Exposure (PE) Consultant Training Program seeks to develop a national network of competent PE consultants. Comprehensive training in empirically supported treatment (EST), such as PE, includes a didactic training followed by a period of experiential learning through consultation during real-world clinical practice (Karlin & Cross, 2014). Expert consultants are needed to meet demand as ESTs are disseminated. METHOD: The Emory program has developed a training model to develop 18 consultation skills within five competency domains: the consultation relationship, general psychotherapy skills, PE-specific skills, trainee barriers to delivery, and implementation. RESULTS: The current article outlines these domains and discusses their theoretical background and applied value for PE consultant training, drawing on examples from the Emory program. DISCUSSION: Just as manualizing therapy has allowed for EST dissemination, the operationalizing of consultation competencies can provide a first step in disseminating evidence-based consultation practice. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neighborhood Poverty Prospectively Predicts PTSD Symptoms Six-Months Following Trauma Exposure.

Introduction: Individuals living in areas with high rates of poverty are disproportionately affected by posttraumatic stress disorder (PTSD). Despite this association, little is known about how neighborhood poverty rates impact risk for PTSD development. In the current prospective study, we determined the relationship between neighborhood poverty rate and PTSD symptoms six-months after experiencing a traumatic event in a sample of varied race, gender, and socioeconomic status. Methods: Participants (N=252) were enrolled in a hospital emergency department after experiencing a traumatic event. Demographic information (including zip code of residence), baseline PTSD symptoms, and baseline trauma history was assessed in the emergency department. PTSD symptoms were again assessed six-months post-trauma. Neighborhood poverty rate was determined using the American Community Survey. Results: Correlation analyses revealed that neighborhood poverty was significantly associated with baseline PTSD symptoms (r=.181, p=.004) and PTSD symptoms six-months post-trauma (r=.163, p=.009). A regression analysis controlling for baseline trauma exposure, clinician-rated trauma severity, and individual socioeconomic status demonstrated that neighborhood poverty predicted PTSD symptoms six-months post-trauma (R2= 0.099, B= 0.15, p=0.04), but this relationship was no longer significant when baseline PTSD symptoms was added as an additional covariate (R2=.304, B= 0.07, p>0.05). Conclusion: Overall, results suggest that neighborhood poverty generally increases PTSD symptom severity, and the context in which an individual lives should be considered when conceptualizing risk for PTSD.

Prevention of posttraumatic stress during inpatient rehabilitation post spinal cord injury: Study protocol for a randomized controlled trial of Brief Prolonged Exposure Therapy (Brief PE).

Background: Scant research has focused on posttraumatic stress disorder (PTSD) in the SCI population, despite high prevalence estimates. Fortunately, prolonged exposure therapy (PE) is a well-researched and highly effective treatment for PTSD. Our recent clinical trial showed that standard 12-session PE was effective for PTSD treatment among inpatients with SCI. Early intervention with brief PE (3-sessions) delivered in the emergency department has also been effective for PTSD prevention, but has not been tested among people post-SCI. Thus, we aim to conduct the first test of the Brief PE intervention to prevent PTSD among patients with SCI. Methods: Adults who have experienced a SCI (N = 200) will be randomly assigned during inpatient rehabilitation to either: (a) 3 60-min sessions of Brief PE (intervention group) or (b) treatment as usual (control group). Results: The primary outcome measure (PTSD symptoms measured by the PSSI-5) and secondary outcome measures (depression, anxiety, pain, quality of life, sleep disturbance, and resilience) will be assessed at baseline, 1-month, 3-months, and 6-months. Hierarchical linear modeling (HLM) will be used to evaluate the effectiveness of the PE intervention on PTSD and secondary outcomes. Descriptive statistics will examine feasibility and will include the number of participants enrolled, the number of sessions completed, fidelity of Brief PE delivery, and average scores for difficulty and helpfulness of the intervention scales for those randomized to intervention. Conclusions: Successful completion of this study will provide an evidence-based program to alleviate posttraumatic distress post spinal cord injury and prevent long-term development of PTSD.

Frequency and correlates of suicidal ideation and behaviors in treatment-seeking Post-9/11 Veterans.

OBJECTIVE: Post-9/11 U.S. veterans and servicemembers are at increased risk for suicide, indicating an important need to identify and mitigate suicidal ideation and behaviors in this population. METHOD: Using data modeling techniques, we examined correlates of suicidal ideation and behavior at intake in 261 Post-9/11 veterans and servicemembers seeking mental health treatment. RESULTS: Our sample endorsed high rates of suicidal ideation and behavior. Approximately 40% of our sample scored in a range on the Suicide Behaviors Questionnaire-Revised (SBQ-R), indicating high clinical risk for suicide. Results from multivariate analyses indicate that greater state and/or trait depression severity, greater anger and anger expression, less impulse control, and lower rank were consistently associated with suicidal ideation and behavior across our models. Negative posttraumatic thoughts about the self, gender, and military branch of service were also significantly associated with suicidal ideation and behavior. CONCLUSIONS: Suicidal ideation and behaviors are common in veterans seeking mental health treatment. State and/or trait depression, anger and impulse control were predictors of increased risk for suicidal ideation and behavior across models. Consistencies and differences across models as well as limitations and practical implications for the findings are discussed.

Sex-dependent risk factors for PTSD: a prospective structural MRI study.

Female individuals are more likely to be diagnosed with PTSD following trauma exposure than males, potentially due, in part, to underlying neurobiological factors. Several brain regions underlying fear learning and expression have previously been associated with PTSD, with the hippocampus, amygdala, dorsal anterior cingulate cortex (dACC), and rostral ACC (rACC) showing altered volume and function in those with PTSD. However, few studies have examined how sex impacts the predictive value of subcortical volumes and cortical thickness in longitudinal PTSD studies. As part of an emergency department study completed at the Grady Trauma Project in Atlanta, GA, N = 93 (40 Female) participants were enrolled within 24 h following a traumatic event. Multi-echo T1-weighted MRI images were collected one-month post-trauma exposure. Bilateral amygdala and hippocampal volumes and rACC and dACC cortical thickness were segmented. To assess the longitudinal course of PTSD, the PTSD Symptom Scale (PSS) was collected 6 months post-trauma. We investigated whether regional volume/thickness interacted with sex to predict later PTSD symptom severity, controlling for PSS score at time of scan, age, race, and trauma type, as well as intracranial volume (ICV) for subcortical volumes. There was a significant interaction between sex and rACC for 6-month PSS, such that right rACC thickness was positively correlated with 6-month PSS scores in females, but not in males. In examining PTSD symptom subtypes and depression symptoms, greater rACC thickness in females predicted greater avoidance symptoms, while smaller rACC thickness in males predicted greater depression symptoms. Amygdala and hippocampus volume and dACC thickness showed no main effect or interaction with sex. The current findings provide evidence for sex-based differences in how brain volume predicts future PTSD severity and symptoms and supports the rACC as being a vital region regarding PTSD. Gender differences should be assessed in future longitudinal PTSD MRI studies for more accurate identification of future PTSD risk following trauma.

Long-term effectiveness of a prolonged exposure-based intensive outpatient program for veterans with posttraumatic stress disorder.

Empirically-supported psychotherapies for posttraumatic stress disorder (PTSD) are highly effective and recommended as first-line treatments, yet dropout rates from standard outpatient therapy are high. Intensive outpatient programs (IOPs) that provide these therapies in condensed format with complementary interventions show promise, as they have demonstrated similar efficacy and higher retention rates. The current study examined initial and long-term outcomes up to 12-months following a 2-week PTSD IOP involving daily prolonged exposure therapy (PE) and adjunctive interventions for veterans and military service members. Participants (N = 376) demonstrated high retention (91%) and large effect size reductions in self-reported PTSD and depression symptoms after two weeks. Small increases in symptoms occurred after 3 months but these stabilized and large reductions compared to baseline were maintained up to 12 months. Piecewise multilevel modeling indicated that demographic variables did not predict PTSD or depression symptom trajectories. Higher PTSD and depression severity at intake predicted higher symptomatology across timepoints and larger relative gains during treatment. Greater alcohol use prior to treatment was associated with higher PTSD symptomatology but did not affect the magnitude of gains. A history of childhood sexual abuse was associated with greater reduction in depression symptoms over treatment, although this effect faded over follow-up. Together these findings underscore the long-term effectiveness of a PE-based IOP across a diverse range of veterans and service members.

Enhancing exposure therapy for posttraumatic stress disorder (PTSD): a randomized clinical trial of virtual reality and imaginal exposure with a cognitive enhancer.

Posttraumatic stress disorder (PTSD) is a significant public health issue. Yet, there are limited treatment options and no data to suggest which treatment will work for whom. We tested the efficacy of virtual reality exposure (VRE) or prolonged imaginal exposure (PE), augmented with D-cycloserine (DCS) for combat-related PTSD. As an exploratory aim, we examined whether brain-derived neurotrophic factor (BDNF) and fatty acid amide hydrolase (FAAH) moderated treatment response. Military personnel with PTSD (n = 192) were recruited into a multisite double-blind randomized controlled trial to receive nine weeks of VRE or PE, with DCS or placebo. Primary outcome was the improvement in symptom severity. Randomization was stratified by comorbid depression (MDD) and site. Participants in both VRE and PE showed similar meaningful clinical improvement with no difference between the treatment groups. A significant interaction (p = 0.45) suggested VRE was more effective for depressed participants (CAPS difference M = 3.51 [95% CI 1.17-5.86], p = 0.004, ES = 0.14) while PE was more effective for nondepressed participants (M = -8.87 [95% CI -11.33 to -6.40], p < 0.001, ES = -0.44). The main effect of DCS vs. placebo was not significant. Augmentation by MDD interaction (p = 0.073) suggested that depressed participants improved more on placebo (M = -8.43 [95% CI -10.98 to -5.88], p < 0.001, ES = -0.42); DCS and placebo were equally effective for nondepressed participants. There was an apparent moderating effect of BDNF Val66Met polymorphism on DCS augmentation (ES = 0.67). Met66 allele carriers improved more on DCS (ES = -0.25). FAAH 385 A carriers improved more than non-carriers (ES = 0.33), particularly those with MDD (ES = 0.62). This study provides a step toward precision therapeutics for PTSD by demonstrating that comorbid MDD and genetic markers may help guide treatment selection.ClinicalTrials.gov Identifier: NCT01352637.

Acquisition, extinction, and return of fear in veterans in intensive outpatient prolonged exposure therapy: A fear-potentiated startle study.

Prolonged exposure (PE) therapy is a first-line treatment for posttraumatic stress disorder (PTSD) and involves repeated presentation of trauma-related cues without aversive outcomes. A primary learning mechanism of PE is fear extinction (new learning that a dangerous cue is now safe) and its retention (maintaining this new learning over time). Extant research suggests extinction is impaired in PTSD patients. In this study, we employed an established fear-potentiated startle-based paradigm to examine fear acquisition, extinction learning and retention before and after completion of intensive outpatient treatment. First, PTSD patients undergoing PE (n = 55) were compared to trauma-exposed patients without PTSD (n = 57). We identified excessive fear in PTSD patients during acquisition and extinction before treatment compared to non-PTSD patients. At post-treatment, we examined the return of fear after extinction in PTSD patients showing high or low treatment response to PE (≥50% change in PTSD symptom severity vs. < 50%). High PE responders maintained fear extinction learning whereas low PE responders showed significant return of fear at post-treatment. These results replicate and extend previous findings of impaired extinction in PTSD and provide support for the proposed theoretical link between fear extinction and PE response.

Right inferior frontal gyrus and ventromedial prefrontal activation during response inhibition is implicated in the development of PTSD symptoms.

Background: Inhibition is a critical executive control process and an established neurobiological phenotype of PTSD, yet to our knowledge, no prospective studies have examined this using a contextual cue task that enables measurement of behavioural response and neural activation patterns across proactive and reactive inhibition. Objective: The current longitudinal study utilised functional magnetic resonance imaging (fMRI) to examine whether deficits in proactive and reactive inhibition predicted PTSD symptoms six months after trauma. Method: Twenty-three (65% males) medical patients receiving emergency medical care from a level 1 trauma centre were enrolled in the study and invited for an MRI scan 1-2-months post-trauma. PTSD symptoms were measured using self-report at scan and 6-months post-trauma. A stop-signal anticipation task (SSAT) during an fMRI scan was used to test whether impaired behavioural proactive and reactive inhibition, and reduced activation in right inferior frontal gyrus (rIFG), ventromedial prefrontal cortex (vmPFC), and bilateral hippocampus, were related to PTSD symptoms. We predicted that lower activation levels of vmPFC and rIFG during reactive inhibition and lower activation of hippocampus and rIFG during proactive inhibition would relate to higher 6-month PTSD symptoms. Results: No significant associations were found between behavioural measures and 6-month PTSD. Separate linear regression analyses showed that reduced rIFG activation (F1,21 = 9.97, R2 = .32, p = .005) and reduced vmPFC activation (F1,21 = 5.19, R2 = .20, p = .03) significantly predicted greater 6-month PTSD symptoms; this result held for rIFG activation controlling for demographic variables and baseline PTSD symptoms (ß = -.45, p = .04) and Bonferroni correction. Conclusion: Our findings suggest that impaired rIFG and, to a lesser extent, vmPFC activation during response inhibition may predict the development of PTSD symptoms following acute trauma exposure. Given the small sample size, future replication studies are needed. HIGHLIGHTS: Impaired inhibition may be an important risk factor for the development of PTSD following trauma, with less right inferior frontal gyrus and ventromedial prefrontal cortex activation during response inhibition predicting PTSD development.

Antecedentes: La inhibición es un proceso de control ejecutivo crítico, y un fenotipo neurobiológico establecido del TEPT, sin embargo, en nuestro conocimiento no hay estudios prospectivos que hayan examinado esto usando una tarea con claves contextuales que permita medir la respuesta conductual y los patrones de activación neuronal en la inhibición proactiva y reactiva.Objetivo: El siguiente estudio es de diseño longitudinal y utilizó resonancia magnética funcional (fMRI por sus siglas en inglés) para examinar si los déficit en inhibición proactiva y reactiva predijeron los síntomas de TEPT 6 meses después del trauma.Método: 23 pacientes (65% hombres) que recibieron cuidado médico de emergencia en un centro de trauma nivel 1 se enrolaron en el estudio y se les invitó a una RNM (resonancia nuclear magnética) 1­2 meses después del trauma. Los síntomas de TEPT se midieron usando auto-reporte al momento de la exploración y 6 meses después del trauma. Se uso una tarea de anticipación de señal de parada (SSAT por sus siglas en inglés) durante la RNM funcional para evaluar si la alteración en la inhibición proactiva y reactiva, y la reducción de la activación en el giro frontal inferior derecho (rIFG por sus siglas en inglés), la corteza prefrontal ventromedial (vmPFC por sus siglas en inglés), y el hipocampo bilateral, estuvieron relacionadas a los síntomas de TEPT. Predijimos que niveles bajos de activación de vmPFC y rIFG durante la inhibición proactiva se relacionaría con mayores síntomas de TEPT a los 6 meses.Resultados: No se encontraron asociaciones significativas entre medidas conductuales y TEPT a los 6 meses. Los análisis de regresión lineal separados mostraron que una activación reducida de rIFG (F1,21 = 9.97, R2 = .32, p = .005) y una activación reducida de vmPFC (F1,21 = 5.19, R2 = .20, p = .03) predijeron significativamente mayores síntomas de TEPT a los 6 meses; este resultado fue corroborado para la activación de rIFG controlando para variables demográficas y síntomas basales de TEPT (ß = −.45, p = .04) y para la corrección de Bonferroni.Conclusión: Nuestros hallazgos sugieren que una rIFG deficiente y, en menor grado, la activación del vmPFC durante la inhibición de la respuesta pueden predecir el desarrollo de síntomas de TEPT tras la exposición a un trauma agudo. Dado lo pequeño de la muestra, se requieren futuros estudios de replicación.

Time of trauma prospectively affects PTSD symptom severity: The impact of circadian rhythms and cortisol.

A key feature of posttraumatic stress disorder (PTSD) is a disruption of hypothalamic-pituitary-adrenal (HPA) axis feedback sensitivity and cortisol levels. Despite known diurnal rhythmicity of cortisol, there has been little exploration of the circadian timing of the index trauma and consequent cortisol release. Stress-related glucocorticoid pulses have been shown to shift clocks in peripheral organs but not the suprachiasmatic nucleus, uncoupling the central and peripheral clocks. A sample of 425 participants was recruited in the Emergency Department following a DSM-IV-TR Criterion A trauma. The Zeitgeber time of the trauma was indexed in minutes since sunrise, which was hypothesized to covary with circadian blood cortisol levels (high around sunrise and decreasing over the day). Blood samples were collected M(SD)= 4.0(4.0) hours post-trauma. PTSD symptoms six months post-trauma were found to be negatively correlated with trauma time since sunrise (r(233) = -0.15, p = 0.02). The effect remained when adjusting for sex, age, race, clinician-rated severity, education, pre-trauma PTSD symptoms, and time of the blood draw (ß = -0.21, p = 0.00057). Cortisol levels did not correlate with blood draw time, consistent with a masking effect of the acute stress response obscuring the underlying circadian rhythm. Interactions between trauma time and expression of NPAS2 (punadjusted=0.042) and TIMELESS (punadjusted=0.029) predicted six-month PTSD symptoms. The interaction of trauma time and cortisol concentration was significantly correlated with the expression of PER1 (padjusted=0.029). The differential effect of time of day on future symptom severity suggests a role of circadian effects in PTSD development, potentially through peripheral clock disruption.

A randomized controlled trial of 3,4-methylenedioxymethamphetamine (MDMA) and fear extinction retention in healthy adults.

BACKGROUND: Fear conditioning and extinction are well-characterized cross-species models of fear-related posttraumatic stress disorder (PTSD) symptoms, and recent animal data suggest that 3,4-methylenedioxymethamphetamine (MDMA) enhances fear extinction retention. AIMS: This study investigated the effect of MDMA on fear learning, extinction training, and retention in healthy humans. METHODS: The study involved a randomized placebo-controlled, two-group, parallel design trial in a sample of healthy adults, age 21-55 recruited from a major metropolitan area. The experimental paradigm included a fear acquisition session followed by an extinction training session 24 hours later, and 2 hours after study drug administration. Fear extinction retention was measured 48 hours after extinction training. Participants (N = 34; 70.6% male and 29.4% female) were randomly assigned in 1:1 ratio to 100 mg MDMA or placebo. All randomized participants completed the trial and were included in primary analyses. Safety was monitored via adverse events and vital signs. MDMA was well-tolerated with no serious adverse events. RESULTS: Results indicated a significant main effect of session between extinction training and retention with no significant group differences. Significantly more participants in the MDMA group retained extinction learning compared to the placebo group (χ2 = 7.29, p = 0.007). CONCLUSION: Although we did not observe the hypothesized facilitation of extinction retention, the findings from this initial human trial provide compelling rationale to continue to explore the potential for MDMA to impact extinction retention.Clinical Trials Registry Name and Identifier: Evaluation of MDMA on Startle Response (NCT0318176) https://clinicaltrials.gov/ct2/show/NCT03181763?term = MDMA&draw = 2&rank = 9.