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Background: The 2023 VA/DoD Clinical Practice Guideline for the Management of PTSD recommends individual, manualized trauma-focused such as Prolonged Exposure (PE) over pharmacologic interventions for the primary treatment of PTSD. Unfortunately, clinical trials of trauma-based therapies in the military and veteran population showed that 30% to 50% of patients did not demonstrate clinically meaningful symptom change. Ketamine, an FDA-approved anesthetic with potent non-competitive glutamatergic N-methyl-d-aspartate antagonistic properties, has demonstrated to enhance the recall of extinction learning and decrease fear renewal without interference of extinction training in preclinical studies., Methods: We plan to conduct a single site RCT comparing three ketamine treatment vs. active placebo (midazolam) adjunct to PE therapy among Veterans with PTSD. Pharmacological phase will start simultaneously with PE session 1. Infusions will be administered 24 h. prior to PE session for the first 3 weeks. After PE is completed (session 10), patients will be assessed during a 3-month follow-up period at various time points. We estimate that out of 100 veterans, 80 will reach time point for primary outcome measure and will be considered for primary analysis. Secondary outcomes include severity of depression and anxiety scores, safety and tolerability of ketamine-enhanced PE therapy, cognitive performance during treatment and early improvement during PE related to the rate of dropouts during PE therapy., Discussion: Results of the proposed RCT could provide scientific foundation to distinguish the essential components of this approach, enhance the methodology, elucidate the mechanisms involved, and identify sub-PTSD populations that most likely benefit from this intervention., Competing Interests: Declaration of competing interest The authors report no financial relationships with commercial interests., (Published by Elsevier Inc.)

Background: Co-occurrence of posttraumatic stress disorder (PTSD) and substance use disorders (SUDs) is common and concurrent treatment is recommended. Relatively little is known about which evidence-based psychotherapies for PTSD are most effective for patients with varying substance use profiles. We aim to examine the comparative effectiveness of trauma-focused therapy (TFT) and non-trauma-focused therapy (NTFT) among Veterans with PTSD and SUD. TFT has been found to be effective among those with PTSD/SUD, though effects are smaller and rates of treatment non-completion are higher than in those without SUD. NTFTs suggested for the treatment of PTSD, such as Present Centered Therapy, (PCT) have not been examined among those with co-occurring SUD, despite lower rates of treatment dropout. We will also examine the comparative effectiveness of TFT and NTFT for patients with varying SUD severity, type of substances used, and patient treatment preference., Method: 420 Veterans with PTSD and SUD will be randomized in a prospective, pragmatic comparative effectiveness trial at 14 Veterans Health Administration facilities. Participants will receive either TFT (Prolonged Exposure or Cognitive Processing Therapy) or NTFT (PCT) after enrolling in concurrent SUD treatment-as-usual. Assessments will occur at baseline, posttreatment, 3- and 6 -months posttreatment. Main outcomes are PTSD symptom severity and PTSD treatment dropout. Clinician, patient, and leadership stakeholder panels advise study activities, and a process evaluation will identify strategies to enhance the implementation of evidence-based PTSD treatments in SUD care settings., Conclusions: Results will provide critical information to guide clinicians when recommending PTSD treatments to patients with comorbid SUD., Clinicaltrials: gov Identifier: NCT04581434., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Background: Posttraumatic stress disorder (PTSD) is heritable and a potential consequence of exposure to traumatic stress. Evidence suggests that a quantitative approach to PTSD phenotype measurement and incorporation of lifetime trauma exposure (LTE) information could enhance the discovery power of PTSD genome-wide association studies (GWASs)., Methods: A GWAS on PTSD symptoms was performed in 51 cohorts followed by a fixed-effects meta-analysis (N = 182,199 European ancestry participants). A GWAS of LTE burden was performed in the UK Biobank cohort (N = 132,988). Genetic correlations were evaluated with linkage disequilibrium score regression. Multivariate analysis was performed using Multi-Trait Analysis of GWAS. Functional mapping and annotation of leading loci was performed with FUMA. Replication was evaluated using the Million Veteran Program GWAS of PTSD total symptoms., Results: GWASs of PTSD symptoms and LTE burden identified 5 and 6 independent genome-wide significant loci, respectively. There was a 72% genetic correlation between PTSD and LTE. PTSD and LTE showed largely similar patterns of genetic correlation with other traits, albeit with some distinctions. Adjusting PTSD for LTE reduced PTSD heritability by 31%. Multivariate analysis of PTSD and LTE increased the effective sample size of the PTSD GWAS by 20% and identified 4 additional loci. Four of these 9 PTSD loci were independently replicated in the Million Veteran Program., Conclusions: Through using a quantitative trait measure of PTSD, we identified novel risk loci not previously identified using prior case-control analyses. PTSD and LTE have a high genetic overlap that can be leveraged to increase discovery power through multivariate methods., (Copyright © 2021 Society of Biological Psychiatry. All rights reserved.)

Objective: Recent clinical practice guidelines recommend the delivery of evidence-based psychotherapies for both substance use disorder (SUD) and posttraumatic stress disorder (PTSD) within the same treatment episode for patients with SUD/PTSD comorbidity. This randomized clinical trial evaluated the comparative effectiveness of integrating versus phasing evidence-based psychotherapies for SUD and PTSD among veterans with co-occurring SUD/ PTSD., Method: 183 veterans with DSM-IV PTSD and SUD at two VA Medical Centers were randomized to one of two psychotherapies during which Motivational Enhancement Therapy [MET] for SUD and Prolonged Exposure [PE] for PTSD were either phased or integrated throughout treatment. Primary outcomes as evaluated by blinded assessors were percent days with drug use or heavy drinking and PTSD symptomology. We hypothesized integrated MET/PE (n = 95) would yield better SUD and PTSD-related outcomes at posttreatment than phased MET/PE (n = 88)., Results: In intent-to-treat analyses (n=183), both treatment groups achieved clinically (d=0.46 - 1.06) and statistically significant reductions in SUD (p < 0.01) and PTSD (p < 0.01) symptomology; the time by treatment interactions were not significant. Post-hoc analyses could not confirm statistical non-inferiority; between-group effect sizes suggest a lack of clinically-meaningful differences between the two treatment approaches (d=0.08 - 0.27)., Conclusions: Our hypothesis that integrated MET/PE would result in better outcomes than phased MET/PE across a range of PTSD and SUD measures was not supported; both strategies for combining two single-disorder treatments for co-occurring SUD/PTSD yielded significant symptom reduction., (Published by Elsevier B.V.)

Research has increasingly focused on the role that social circumstances before, during, and after trauma exposure play in risk for posttraumatic stress disorder (PTSD). In this article, we provide an overview of conceptual and methodological challenges to the study of social context's role in PTSD and propose strategies that can mitigate these challenges. Throughout the article, we draw from the current literature to illustrate how attention to these issues can lead to advances in our knowledge of the role of social context in PTSD., (Published by Elsevier Ltd.)

While comorbidity between posttraumatic stress disorder (PTSD) and substance use disorders (SUD) is common among veterans, there is debate regarding how to best treat individuals suffering from both conditions. Despite data supporting the effectiveness of integrated treatments that simultaneously address both disorders, due to concerns that an early focus on trauma may increase dropout and reduce the likelihood of achieving SUD-related goals, providers continue to prefer a sequential approach, where the addiction is treated first and PTSD treatment is instituted following sustained abstinence or reduced use. This project is designed to directly examine these provider concerns by evaluating the benefits and harms of an integrated versus a sequential approach to treating comorbid PTSD and SUD. This paper reviews the study's methodology, treatment approaches, and baseline participant characteristics. In this randomized clinical trial, one hundred eighty-three veterans with co-occurring PTSD and SUD have been randomized to one of two psychotherapies that include the same treatment components for SUD and PTSD (Motivational Enhancement Therapy and Prolonged Exposure respectively), but differ by whether the components are delivered sequentially or are integrated such that PTSD and SUD symptoms are addressed concurrently. We hypothesize that veterans assigned to integrated treatment will show greater improvement in PTSD and SUD symptoms than veterans assigned to sequential treatment. If this hypothesis is supported, the findings have the potential to change clinicians' beliefs and challenge long-standing practice patterns that require participation in SUD treatment prior to initiating trauma-focused therapies for PTSD., (Published by Elsevier Inc.)

The assumption of specific etiology in posttraumatic stress disorder (PTSD) differentiates the disorder from most other psychiatric conditions. A 'risky test' of the assumption of specific etiology and resultant trauma-related symptom dimensions was conducted through structural modeling of PTSD symptoms in soldiers before (N=522) and after (n=423) a combat deployment to Iraq. If PTSD represents a discrete diagnostic entity that emerges after trauma exposure, we hypothesized either the number of latent classes should increase from pre- to post-deployment or symptom dimensions should qualitatively distinguish affected from unaffected classes following trauma exposure. Comparison of latent structural models revealed best fitting hybrid models for PTSD and depression with strong invariance of symptom dimensions across classes both before and after deployment and only quantitative (i.e., severity) differences between classes. These findings suggest PTSD is generally well-conceptualized as a dimensional syndrome worsened but not necessarily elicited by trauma exposure., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

There is growing evidence that disturbed sleep is a risk factor for the development of a number of psychiatric diagnoses including depression, PTSD and substance use. The goal of this study was to use a subset of participants from a larger prospective longitudinal study to examine whether preexisting daytime and nighttime sleep disturbances predict depression, PTSD and substance use in US National Guard Soldiers deployed to Iraq. Data on daytime and nighttime sleep complaints, baseline symptoms and personality variables were gathered prior to deployment to Iraq. Measures of psychopathology were collected at three time points post-deployment over the course of two years using both questionnaires and interviews. Multiple regressions were used to predict diagnoses and symptoms of depression, PTSD and substance use. Pre-deployment daytime and nighttime sleep complaints contributed significantly to the prediction of PTSD and depression up to two years after deployment, but not substance use. This study suggests that daytime and nighttime sleep complaints are a risk factor for internalizing disorders including PTSD and depression., (Published by Elsevier Ltd.)