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Posttraumatic stress disorder (PTSD) is a chronic, often debilitating mental health disorder that may develop after a traumatic life event. Fortunately, effective psychological treatments for PTSD exist. In 2017, the Veterans Health Administration and Department of Defense (VA/DoD) and the American Psychological Association (APA) each published treatment guidelines for PTSD, which are a set of recommendations for providers who treat individuals with PTSD. The purpose of the current review article is to briefly review the methodology used in each set of 2017 guidelines and then discuss the psychological treatments of PTSD for adults that were strongly recommended by both sets of guidelines. Both guidelines strongly recommended use of Prolonged Exposure (PE), Cognitive Processing Therapy (CPT) and trauma-focused Cognitive Behavioral Therapy (CBT). Each of these treatments has a large evidence base and is trauma-focused, which means they directly address memories of the traumatic event or thoughts and feelings related to the traumatic event. Finally, we will discuss implications and future directions.

Rationale 3,4-Methylenedioxymethamphetamine (MDMA) persistently improves symptoms of post-traumatic stress disorder (PTSD) when combined with psychotherapy. Studies in rodents suggest that these effects can be attributed to enhancement of fear memory extinction. Therefore, MDMA may improve the effects of exposure-based therapy for PTSD, particularly in treatment-resistant patients. However, given MDMA’s broad pharmacological profile, further investigation is warranted before moving to a complex clinical population. Objectives We aimed to inform clinical research by providing a translational model of MDMA’s effect, and elucidating monoaminergic mechanisms through which MDMA enhances fear extinction. Methods We explored the importance of monoamine transporters targeted by MDMA to fear memory extinction, as measured by reductions in conditioned freezing and fear-potentiated startle (FPS) in mice. Mice were treated with selective inhibitors of individual monoamine transporters prior to combined MDMA treatment and fear extinction training. Results MDMA enhanced the lasting extinction of FPS. Acute and chronic treatment with a 5-HT transporter (5-HTT) inhibitor blocked MDMA’s effect on fear memory extinction. Acute inhibition of dopamine (DA) and norepinephrine (NE) transporters had no effect. 5-HT release alone did not enhance extinction. Blockade of MDMA’s effect by 5-HTT inhibition also downregulated 5-HT 2A -mediated behavior, and 5-HT 2A antagonism disrupted MDMA’s effect on extinction. Conclusions We validate enhancement of fear memory extinction by MDMA in a translational behavioral model, and reveal the importance of 5-HTT and 5-HT 2A receptors to this effect. These observations support future clinical research of MDMA as an adjunct to exposure therapy, and provide important pharmacological considerations for clinical use in a population frequently treated with 5-HTT inhibitors.

Posttraumatic stress disorder (PTSD) is a debilitating syndrome with substantial morbidity and mortality that occurs in the aftermath of trauma. Symptoms of major depressive disorder (MDD) are also a frequent consequence of trauma exposure. Identifying novel risk markers in the immediate aftermath of trauma is a critical step for the identification of novel biological targets to understand mechanisms of pathophysiology and prevention, as well as the determination of patients most at risk who may benefit from immediate intervention. Our study utilizes a novel approach to computationally integrate blood-based transcriptomics, genomics, and interactomics to understand the development of risk vs. resilience in the months following trauma exposure. In a two-site longitudinal, observational prospective study, we assessed over 10,000 individuals and enrolled >700 subjects in the immediate aftermath of trauma (average 5.3 h post-trauma (range 0.5–12 h)) in the Grady Memorial Hospital (Atlanta) and Jackson Memorial Hospital (Miami) emergency departments. RNA expression data and 6-month follow-up data were available for 366 individuals, while genotype, transcriptome, and phenotype data were available for 297 patients. To maximize our power and understanding of genes and pathways that predict risk vs. resilience, we utilized a set-cover approach to capture fluctuations of gene expression of PTSD or depression-converting patients and non-converting trauma-exposed controls to find representative sets of disease-relevant dysregulated genes. We annotated such genes with their corresponding expression quantitative trait loci and applied a variant of a current flow algorithm to identify genes that potentially were causal for the observed dysregulation of disease genes involved in the development of depression and PTSD symptoms after trauma exposure. We obtained a final list of 11 driver causal genes related to MDD symptoms, 13 genes for PTSD symptoms, and 22 genes in PTSD and/or MDD. We observed that these individual or combined disorders shared ESR1, RUNX1, PPARA, and WWOX as driver causal genes, while other genes appeared to be causal driver in the PTSD only or MDD only cases. A number of these identified causal pathways have been previously implicated in the biology or genetics of PTSD and MDD, as well as in preclinical models of amygdala function and fear regulation. Our work provides a promising set of initial pathways that may underlie causal mechanisms in the development of PTSD or MDD in the aftermath of trauma.

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.

Background Exposure to a traumatic event leads to posttraumatic stress disorder in 10% to 20% of exposed individuals. Predictors of risk are needed to target early interventions to those who are most vulnerable. The objective of the study was to test whether a noninvasive mobile device that measures a physiological biomarker of autonomic nervous system activation could predict future posttraumatic stress disorder symptoms. Methods Skin conductance response was collected during a trauma interview in the emergency department within hours of exposure to trauma in 95 individuals. Trajectories of posttraumatic stress disorder symptoms over 12-month posttrauma were identified using latent growth mixture modeling. Results Skin conductance response was significantly correlated with the probability of being in the chronic posttraumatic stress disorder trajectory following trauma exposure in the emergency department (r = 0.489, p < 0.000001). Lasso regression with elastic net was performed with demographic and clinical measures obtained in the emergency department, demonstrating that skin conductance response was the most significant predictor of the chronic posttraumatic stress disorder trajectory (p < 0.00001). Conclusions This study is the first prospective study of posttraumatic stress disorder showing skin conductance response in the immediate aftermath of trauma predicts subsequent development of chronic posttraumatic stress disorder. This finding points to an easily obtained, and neurobiologically informative, biomarker in emergency departments that can be disseminated to predict the development of posttraumatic stress disorder.

Dropout rates and factors contributing to dropout in drug and placebo groups in pharmacotherapy trials for posttraumatic stress disorder (PTSD) are not well understood. This study aimed to examine differences in all-cause study dropouts between drug and placebo groups, using conventional meta-analysis and an exploratory predictor analysis of individual participant data from three trials. We included randomized controlled trials (RCTs) of adults with PTSD, comparing drug monotherapy with placebo. Forty-three RCTs (  = 4829) were included in a conventional meta-analysis. Additionally, we conducted a small exploratory predictor analysis including participant-level data from three RCTs (  = 246). In the conventional meta-analysis, study dropout was marginally lower in the drug relative to the placebo group, but the difference was not significant, RR = 0.92, 95% CI [0.83, 1.02],  = .099. Drug class, dosing regimen, population, study duration, or gender were not related to dropout.In the exploratory predictor analysis, study dropout did not differ significantly between drug and placebo groups  = .617). In the drug group, gender was a significant predictor for dropout, with males having higher dropout rates (  = .046). When controlling for baseline PTSD symptom severity, gender was no longer a statistically significant predictor (  = .051). None of the other predictors in group analyses were significant in predicting drop-out. This study demonstrated that study dropout rates in monotherapy pharmacotherapy RCTs for PTSD do not significantly differ between drug and placebo groups. These findings underscore the need for further research to identify the factors contributing to dropout in PTSD pharmacotherapy trials and to develop tailored treatment adherence strategies. Additionally, they highlight the importance of pooling participant-level data to facilitate more comprehensive and granular analyses in future research.

Major depressive disorder is associated with considerable morbidity, disability, and risk for suicide. Treatments for depression most commonly include antidepressants, psychotherapy, or the combination. Little is known about predictors of treatment response for depression. In this study, 681 patients with chronic forms of major depression were treated with an antidepressant (nefazodone), Cognitive Behavioral Analysis System of Psychotherapy (CBASP), or the combination. Overall, the effects of the antidepressant alone and psychotherapy alone were equal and significantly less effective than combination treatment. Among those with a history of early childhood trauma (loss of parents at an early age, physical or sexual abuse, or neglect), psychotherapy alone was superior to antidepressant monotherapy. Moreover, the combination of psychotherapy and pharmacotherapy was only marginally superior to psychotherapy alone among the childhood abuse cohort. Our results suggest that psychotherapy may be an essential element in the treatment of patients with chronic forms of major depression and a history of childhood trauma.

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