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Sleep disturbances (SDs) are among the most distressing and commonly reported symptoms in posttraumatic stress disorder (PTSD). Despite increased attention on sleep in clinical PTSD research, SDs remain difficult to treat. In Phase 2 trials, 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has been shown to greatly improve PTSD symptoms. We hypothesized that MDMA-assisted psychotherapy would improve self-reported sleep quality (SQ) in individuals with PTSD and be associated with declining PTSD symptoms. Participants in four studies (n = 63) were randomized to receive 2-3 sessions of active MDMA (75-125 mg; n = 47) or placebo/control MDMA (0-40 mg, n = 16) during all-day psychotherapy sessions. The PSQI was used to assess change in SQ from baseline to the primary endpoint, 1-2 months after the blinded sessions. Additionally, PSQI scores were measured at treatment exit (TE) and 12-month follow-up. Symptoms of PTSD were measured using the CAPS-IV. At the primary endpoint, CAPS-IV total severity scores dropped more after active MDMA than after placebo/control (-34.0 vs. -12.4), p = .003. Participants in the active dose group showed more improvement in SQ compared to those in the control group (PSQI total score ΔM = -3.5 vs. 0.6), p = .003. Compared to baseline, SQ had improved at TE, p < .001, with further significant gains reported at 12-month follow-up (TE to 12-months ΔM = -1.0), p = .030. Data from these randomized controlled double-blind studies provide evidence for the beneficial effects of MDMA-assisted psychotherapy in treating SDs in individuals with PTSD., (© 2021 MAPS Public Benefit Corporation. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Epigenetic mechanisms play a role in the detrimental effects of traumatic stress and the development of post-traumatic stress disorder (PTSD). However, it is unknown whether successful treatment of PTSD restores these epigenetic marks. This study investigated longitudinal changes of blood-based genome-wide DNA methylation levels in relation to trauma-focused psychotherapy for PTSD in soldiers that obtained remission (N = 21), non-remitted PTSD patients (N = 23), and trauma-exposed military controls (N = 23). In an independent prospective cohort, we then examined whether these DMRs were also relevant for the development of deployment-related PTSD (N = 85). Successful treatment of PTSD was accompanied by significant changes in DNA methylation at 12 differentially methylated regions (DMRs) in the genes: APOB, MUC4, EDN2, ZFP57, GPX6, CFAP45, AFF3, TP73, UBCLP1, RPL13P, and two intergenic regions (p values < 0.0001 were confirmed using permutation and sensitivity analyses). Of the 12 DMRs related to PTSD symptom reduction, consistent prospective evidence was found for ZFP57 methylation changes related to changing PTSD symptoms (B = -0.84, t = -2.49, p = 0.014). Increasing ZFP57 methylation related to PTSD symptom reduction was present over and above the relation with symptoms, suggesting that psychological treatments exert biological effects independent of symptom reduction. Together, these data provide longitudinal evidence that ZFP57 methylation is involved in both the development and successful treatment of deployment-related PTSD. This study is a first step to disentangle the interaction between psychological and biological systems to identify genomic regions relevant for the etiology and treatment of stress-related disorders such as PTSD.

Background: Heart Rate Variability Biofeedback (HRVB) is a treatment in which patients learn self-regulation of a physiological dysregulated vagal nerve function. While the therapeutic approach of HRVB is promising for a variety of disorders, it has not yet been regularly offered in a mental health treatment setting., Aim: To provide a systematic review about the efficacy of HRV-Biofeedback in treatment of anxiety, depression, and stress related disorders., Method: Systematic review in PubMed and Web of Science in 2020 with terms HRV, biofeedback, Post-Traumatic Stress Disorder (PTSD), depression, panic disorder, and anxiety disorder. Selection, critical appraisal, and description of the Random Controlled Trials (RCT) studies. Combined with recent meta-analyses., Results: The search resulted in a total of 881 studies. After critical appraisal, nine RCTs have been selected as well as two other relevant studies. The RCTs with control groups treatment as usual, muscle relaxation training and a "placebo"-biofeedback instrument revealed significant clinical efficacy and better results compared with control conditions, mostly significant. In the depression studies average reduction at the Beck Depression Inventory (BDI) scale was 64% (HRVB plus Treatment as Usual (TAU) versus 25% (control group with TAU) and 30% reduction (HRVB) at the PSQ scale versus 7% (control group with TAU). In the PTSD studies average reduction at the BDI-scale was 53% (HRV plus TAU) versus 24% (control group with TAU) and 22% (HRVB) versus 10% (TAU) with the PTSD Checklist (PCL). In other systematic reviews significant effects have been shown for HRV-Biofeedback in treatment of asthma, coronary artery disease, sleeping disorders, postpartum depression and stress and anxiety., Conclusion: This systematic review shows significant improvement of the non-invasive HRVB training in stress related disorders like PTSD, depression, and panic disorder, in particular when combined with cognitive behavioral therapy or different TAU. Effects were visible after four weeks of training, but clinical practice in a longer daily self-treatment of eight weeks is more promising. More research to integrate HRVB in treatment of stress related disorders in psychiatry is warranted, as well as research focused on the neurophysiological mechanisms.

Only a few studies have investigated the welfare of animals participating in animal-assisted interventions (AAIs). Most of these studies focus on dogs in therapeutic settings. There are, however, also dogs-service dogs-that are employed to continuously support a single human. Because the welfare of these service dogs is important for the sustainability of their role, the aim of this study was to investigate their stress response to service dog training sessions. To do this, we took repeated salivary cortisol samples from dogs who participated in a training session ( n = 19). Samples were taken just after arrival at the training ground, before training, after training, and after a period of free play. Our results showed that mean cortisol levels in all samples were relatively low (between 1.55 ± 1.10 and 2.73 ± 1.47 nmol/L) compared to similar studies. Analysis further showed that samples taken before and after participation in the training's session did not differ from one another. Mean cortisol levels in both situations were additionally lower than those upon arrival at the training site and after a period of free play. This led to the conclusion that the dogs in our study did not seem to experience training as stressful.

Background: Firefighters, paramedics, specialized nurses working in Intensive Care Units (ICUs), Operating Rooms (OR), and Emergency Rooms (ER), police officers and military personnel are more frequently exposed to potentially traumatic events than the general population; they are considered high-risk professionals. To reduce the risk of traumatization it is of great importance to be embedded in a social environment with supportive relationships. Methods: We performed a systematic review (based on the PRISMA-Guidelines) looking for social connections within the environment in which high-risk professionals are embedded (work, home, community), to obtain evidence on the impact of these connections on the risk of traumatization. Additionally, we aim to identify relevant supportive relationships in the professionals' environments. We identified the relevant scientific literature by searching, without time, and language restriction, five electronic bibliographic databases: MEDLINE, PsycINFO, Sociological Abstracts, CINAHL, and Web of Science. These databases were last searched in January 2019. Results: A qualitative analysis of the 89 eligible (out of 9,047 screened) studies shows that for firefighters, paramedics, and emergency nurses social connections in their work environment are predominantly supportive relationships and may protect them against traumatization. In other occupations (OR-nurses, ICU-nurses, police officers), however, social connections at work are not only a source of support but are also a source of stress. For military personnel study results are inconclusive as to whether their social connections at work or at home support them against traumatization. In so far as connections are supportive, their sources vary greatly from one occupational group to another; they differ between work vs. home as well as within work between peers vs. supervisor. Conclusions: Being embedded in a social environment, i.e., having social connections, is important but not always sufficient to protect high-risk professionals against traumatization. For, while these connections may be the antecedents of supportive relationships, they can also be the antecedents of damaging relationships. Additionally, the sources of supportive relationships differ among groups. This suggests that knowledge of how the social structures of the occupational groups differ may increase our understanding of the impact of social connections and relationships, including socialization, on the risk of traumatization of high-risk professionals., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Geuzinge, Visse, Duyndam and Vermetten.)

Background: Symptoms of post-traumatic stress disorder (PTSD) can manifest several years after trauma exposure, and may impact everyday life even longer. Military deployment can put soldiers at increased risk for developing PTSD symptoms. Longitudinal evaluations of PTSD symptoms in deployed military personnel are essential for mapping the long-term psychological burden of recent operations on our service members, and may improve current practice in veterans' mental health care., Methods: The current study examined PTSD symptoms and associated risk factors in a cohort of Dutch Afghanistan veterans 10 years after homecoming. Participants (N = 963) were assessed seven times from predeployment up to 10 years after deployment. Growth mixture modeling was used to identify distinct trajectories of PTSD symptom development., Results: The probable PTSD prevalence at 10 years after deployment was 8%. Previously identified risk factors like younger age, lower rank, more deployment stressors, and less social support were still relevant 10 years after deployment. Four trajectories of PTSD symptom development were identified: resilient (85%), improved (6%), severely elevated-recovering (2%), and delayed onset (7%). Only the delayed onset group reported increasing symptom levels between 5 and 10 years postdeployment, even though 77% reported seeking help., Conclusions: This study provides insights into the long-term burden of deployment on the psychological health of military service members. It identifies a group of veterans with further increasing PTSD symptoms that does not seem to improve from currently available mental health support, and underlines the urgent need for developing and implementing alternative treatment opportunities for this group.

Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.

Objective: Military servicemen deployed to war zones are at increased risk of developing posttraumatic stress disorder (PTSD) and successful adaptation to stress is important. Epigenetic alterations in response to trauma have been identified as mechanism of adaptation and may therefore predict deployment-related PTSD symptoms. To date, human studies of epigenetic marks for traumatic stress have been largely constrained by short-term analyses of one or two time points., Method: This study in a prospective Dutch military cohort (N ​= ​125) examined longitudinal changes of DNA methylation profiles before, as well as one and six months after deployment-related combat exposure in relation to the development of PTSD symptoms over a period of up to five years after deployment. We investigated the predictive value of specific methylation changes for immediate and delayed-onset PTSD symptoms and recovery. This epigenetic prediction was compared to polygenic risk score predictions obtained from the currently available largest genome-wide association study of PTSD., Results: A total of fourteen genomic regions were identified in which PTSD symptom levels were associated with methylation changes over time (pre-deployment, one, and six months post-deployment). Of these regions, four were significant determinants of longitudinal development of PTSD symptoms. In addition, we observed that, together with risk level during deployment (operating inside or outside the military base) and physical childhood trauma, post-deployment decreases in methylation at a genomic region in EP300 / miRNA1281 was associated with a delayed onset of PTSD compared to a resilient profile. Polygenic risk, in contrast, was related to PTSD onset within six months after deployment but was not associated with long term outcomes., Conclusion: The present study suggests predictive utility of changes in DNA methylation for the subsequent development of PTSD symptoms and showed that the currently available measure of polygenic risk is primarily related to non-delayed disease onset., Competing Interests: 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., (© 2020 The Authors.)

In recent years, there has been an increased interest in the use of hypnosis and hypnotic suggestions in the treatment of complaints such as pain and anxiety during medical procedures, irritable bowel syndrome, and headaches. Traditionally, hypnosis has been used in patients with psychiatric problems like posttraumatic stress, conversion, and dissociative disorders. Misconceptions about the nature of hypnosis, caused by the association with stage or show hypnosis, seems to prevent a wider integration in medicine. In this article, we try to shed more light on the nature of hypnosis and the evidence for its use in several medical disorders. Moreover, we discuss the use of hypnotic suggestions as a way to increase placebo effects.

Background: Hypothalamic-pituitary-adrenal axis functioning has been related to treatment outcome in posttraumatic stress disorder (PTSD). Previous studies have primarily focused on cortisol levels before and after a course of therapy and findings have not been fully consistent. This study investigated session-related cortisol levels in veterans with treatment-resistant PTSD over the course of a novel motion-assisted virtual reality exposure therapy and aimed to determine whether cortisol levels were related to changes in PTSD symptom severity., Methods: Veterans (N = 22) received six exposure sessions during which salivary cortisol samples were collected pre-session, post-session and in the late afternoon following sessions. PTSD symptom severity was assessed by structured clinical interviews at pre- and post-treatment. Average cortisol levels were compared between responders and non-responders. Linear regression analyses were conducted with PTSD symptom change as criterion variable, average cortisol levels as predictor, and timing of sampling and baseline PTSD symptoms as covariates., Results: Responders to treatment tended to have higher average cortisol levels at pre-session (p = 0.064) and post-session (p = 0.050) compared to non-responders. Higher average pre-session and post-session cortisol levels predicted greater PTSD symptom improvement (pre: b = -1.83, p = 0.009; post: b = -3.57, p = 0.004)., Conclusion: This study provides preliminary evidence for session-related cortisol as biomarker of response to exposure-based therapies for PTSD. Higher cortisol levels may have facilitated fear extinction and reconsolidation, and may indicate increased physiological stress activation necessary for appropriate treatment engagement. Further work involving comparable methodology is encouraged to establish session-related cortisol as biomarker and to determine the mechanisms through which it interacts with treatment outcome., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: A novel intervention, Multi-modular motion-assisted memory desensitization and reconsolidation (3MDR), aims to reduce avoidance and improve engagement for patients with posttraumatic stress disorder (PTSD) who did not sufficiently respond to previous treatments. It has been found to effectively reduce PTSD symptoms for veterans with treatment-resistant PTSD. Symptomatic measures alone might not capture all treatment effects, and addition of qualitative outcomes may provide deeper understanding of treatment processes and treatment-induced changes. Objective: To study the perspectives of veterans with treatment-resistant PTSD on 3MDR treatment processes and effects and explore the relation of their experiences to PTSD symptom improvement. Method: A convergent parallel mixed methods design was applied. For the qualitative part, open-ended question interviews were conducted until data saturation was reached (N = 10). Thematic analysis, rooted in grounded theory, was performed. Quantitative data included pre- to posttreatment responder status based on a structured clinical interview for PTSD. Results: Treatment processes endorsed by the veterans were engaging, regulating distress, feeling supported, facing traumatic memories, allowing emotions, associating, and disengaging from trauma. In terms of effects, veterans reported positive changes following 3MDR, including openness, new learning, self-understanding, closure, and reintegration. High comparability across themes was observed for responders and non-responders, except for the themes closure and reintegration, which were reported more often or more in depth by responders. Conclusions: Veterans indicated 3MDR treatment processes that complied with its aims of breaking through avoidance and increasing engagement, thereby facilitating traumatic memory retrieval and processing. However, this did not necessarily translate into PTSD symptom improvement for all veterans. Walking towards trauma-related pictures was highlighted as unique component of 3MDR and connected to specific treatment processes and effects. Positive changes following 3MDR were experienced outside the domain of PTSD symptom improvement, implicating that 3MDR may beneficially impact veterans beyond symptom changes alone., Competing Interests: No potential conflict of interest was reported by the authors., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Military members are at elevated risk of operational stress injuries, including posttraumatic stress disorder (PTSD) and moral injury. Although psychotherapy can reduce symptoms, some military members may experience treatment-resistant PTSD. Multimodular motion-assisted memory desensitization and reconsolidation (3MDR) has been introduced as a virtual reality (VR) intervention for military members with PTSD related to military service. The 3MDR intervention incorporates exposure therapy, psychotherapy, eye movement desensitization and reconsolidation, VR, supportive counselling, and treadmill walking., Objective: The objective of this study is to investigate whether 3MDR reduces PTSD symptoms among military members with combat-related treatment-resistant PTSD (TR-PTSD); examine the technology acceptance and usability of the Computer Assisted Rehabilitation ENvironment (CAREN) and 3MDR interventions by Canadian Armed Forces service members (CAF-SMs), veterans, 3MDR clinicians, and operators; and evaluate the impact on clinicians and operators of delivering 3MDR., Methods: This is a mixed-methods waitlist controlled crossover design randomized controlled trial. Participants include both CAF-SMs and veterans (N=40) aged 18-60 years with combat-related TR-PTSD (unsuccessful experience of at least 2 evidence-based trauma treatments). Participants will also include clinicians and operators (N=12) who have been trained in 3MDR and subsequently utilized this intervention with patients. CAF-SMs and veterans will receive 6 weekly 90-minute 3MDR sessions. Quantitative and qualitative data will be collected at baseline and at 1, 3, and 6 months postintervention. Quantitative data collection will include multiomic biomarkers (ie, blood and salivary proteomic and genomic profiles of neuroendocrine, immune-inflammatory mediators, and microRNA), eye tracking, electroencephalography, and physiological data. Data from outcome measures will capture self-reported symptoms of PTSD, moral injury, resilience, and technology acceptance and usability. Qualitative data will be collected from audiovisual recordings of 3MDR sessions and semistructured interviews. Data analysis will include univariate and multivariate approaches, and thematic analysis of treatment sessions and interviews. Machine learning analysis will be included to develop models for the prediction of diagnosis, symptom severity, and treatment outcomes., Results: This study commenced in April 2019 and is planned to conclude in April 2021. Study results will guide the further evolution and utilization of 3MDR for military members with TR-PTSD and will have utility in treating other trauma-affected populations., Conclusions: The goal of this study is to utilize qualitative and quantitative primary and secondary outcomes to provide evidence for the effectiveness and feasibility of 3MDR for treating CAF-SMs and veterans with combat-related TR-PTSD. The results will inform a full-scale clinical trial and stimulate development and adaptation of the protocol to mobile VR apps in supervised clinical settings. This study will add to knowledge of the clinical effectiveness of 3MDR, and provide the first comprehensive analysis of biomarkers, technology acceptance and usability, moral injury, resilience, and the experience of clinicians and operators delivering 3MDR., Trial Registration: ISRCTN Registry 11264368; http://www.isrctn.com/ISRCTN11264368., International Registered Report Identifier (irrid): DERR1-10.2196/20620., (©Chelsea Jones, Lorraine Smith-MacDonald, Antonio Miguel-Cruz, Ashley Pike, Marieke van Gelderen, Liana Lentz, Maria Y Shiu, Emily Tang, Jeffrey Sawalha, Andrew Greenshaw, Shawn G Rhind, Xin Fang, Adrian Norbash, Rakesh Jetly, Eric Vermetten, Suzette Brémault-Phillips. Originally published in JMIR Research Protocols (http://www.researchprotocols.org), 29.10.2020.)

Importance: First responders are at risk for developing symptoms of posttraumatic stress disorder (PTSD). Little is known about the risk factors for developing PTSD during a years-long period after complex mass disasters., Objective: To explore the long-term course of PTSD symptoms and to identify risk factors and their relative association with PTSD among first responders dispatched to the 2011 Japanese earthquake, tsunami, and nuclear disaster., Design, Setting, and Participants: This 6-year, large, prospective cohort study was part of a continuous longitudinal study of Japan Ground Self-Defense Force first responders. The data were collected at 1, 6, 12, 24, 36, 48, 60, and 72 months after mission completion from 2011 to 2017. Of approximately 70 000 eligible participants, 56 388 were enrolled in this study. Data were analyzed from 2017 to 2020., Exposures: Stress exposures owing to personal or professional disaster experience (eg, duties with body recovery or radiation exposure risk) and working conditions (eg, deployment length, postdeployment overtime work)., Main Outcomes and Measures: The Impact of Event Scale-Revised score assessed PTSD symptoms; scores of at least 25 were defined as probable PTSD. Cox proportional hazards regression models assessed the risk factors for incidence of probable PTSD., Results: Among the 56 388 participants, 97.1% were men, and the median age at enrollment was 34 (range, 18-63) years. A probable PTSD rate was 2.7% at 1 month and showed a downward trend in the first year and a subsequent plateau. The cumulative incidence of probable PTSD was 6.75%. The severity of PTSD symptoms demonstrated a high degree of rank-order stability over time. Rather than professional disaster experience, sociodemographic factors and working conditions were independently associated with the incidence of probable PTSD: personal experience of the disaster (hazard ratio [HR], 1.96; 95% CI, 1.72-2.24), deployment length of at least 3 months (HR vs <1 month, 1.75; 95% CI, 1.52-2.02), increased age (HR for ≥46 vs ≤25 years, 2.28; 95% CI, 1.79-2.92), and postdeployment overtime work of at least 3 months (HR vs little to none, 1.61; 95% CI, 1.39-1.87)., Conclusions and Relevance: Given these findings, in the future, first responders' PTSD symptoms might be mitigated by shortening deployment length, avoiding postdeployment overtime work, and paying special attention to the needs of personnel with personal experience of the disaster or older age. Efforts to alleviate responders' initial symptoms will be required.

Introduction: Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders., Objective: To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients' accounts, and elucidating how these affect the treatment process., Methods: We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP)., Results: Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses., Conclusions: This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.

Mild traumatic brain injury (mTBI, also known as a concussion) as a consequence of battlefield blast exposure or blunt force trauma has been of increasing concern to militaries during recent conflicts. This concern is due to the frequency of exposure to improvised explosive devices for forces engaged in operations both in Iraq and Afghanistan coupled with the recognition that mTBI may go unreported or undetected. Blasts can lead to mTBI through a variety of mechanisms. Debate continues as to whether exposure to a primary blast wave alone is sufficient to create brain injury in humans, and if so, exactly how this occurs with an intact skull. Resources dedicated to research in this area have also varied substantially among contributing NATO countries. Most of the research has been conducted in the US, focused on addressing uncertainties in management practices. Development of objective diagnostic tests should be a top priority to facilitate both diagnosis and prognosis, thereby improving management. It is expected that blast exposure and blunt force trauma to the head will continue to be a potential source of injury during future conflicts. An improved understanding of the effects of blast exposure will better enable military medical providers to manage mTBI cases and develop optimal protective measures. Without the immediate pressures that come with a high operational tempo, the time is right to look back at lessons learned, make full use of available data, and modify mitigation strategies with both available evidence and new evidence as it comes to light. Toward that end, leveraging our cooperation with the civilian medical community is critical because the military experience over the past 10 years has led to a renewed interest in many similar issues pertaining to mTBI in the civilian world. Such cross-fertilization of knowledge will undoubtedly benefit all. This paper highlights similarities and differences in approach to mTBI patient care in NATO and partner countries and provides a summary of and lessons learned from a NATO lecture series on the topic of mTBI, demonstrating utility of having patients present their experiences to a medical audience, linking practical clinical care to policy approaches., (Copyright © 2020 Robinson-Freeman, Collins, Garber, Terblanche, Risling, Vermetten, Besemann, Mistlin and Tsao.)

Introduction: Psychological stress is associated with sedentary behavior, which may impair exercise performance. The aim of our study was to examine the association between psychological stress and physical fitness in military personnel., Method: A military cohort of 4080 subjects in Taiwan was used for the analysis. The Brief Symptoms Rating Scale (BSRS-5) includes items of anxiety, depression, hostility, interpersonal sensitivity, and insomnia measured by a five-point Likert-type scale of 0-4. Psychological stress was defined as normal (n = 3657), slight (n = 314), and great (n = 109) by BSRS-5 score ≤5, 6-9, and ≥10, respectively. Aerobic fitness and anaerobic fitness were evaluated by the time of 3000-meter running and the numbers of 2-min sit-ups and 2-min push-ups, respectively. Multiple linear and logistic regression analyses were used to determine the relationship., Results: As compared with normal stress, slight and great stress were positive dose-dependently correlated with 3000-meter running time (β = 9.09 and 14.44; P = 0.0032 and 0.048, respectively) after adjusting for age, sex, service specialty, body mass index, systolic blood pressure, cigarette smoking, alcohol intake, hemoglobin levels, and exercise frequency. Similarly, those with slight stress were more likely to be the worst 10% performers in the 3000-meter run test relative to the normal individuals (odds ratio and 95% confidence intervals: 1.50, 1.00-2.24). By contrast, there was no relationship of psychological stress with the numbers of 2-min sit-ups and 2-min push-ups., Conclusions: Our findings suggest that the presence of higher psychological stress on military personnel may reduce their cardiorespiratory fitness but not affect the anaerobic fitness., (© Association of Military Surgeons of the United States 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To explore the potential efficacy of multi-modular motion-assisted memory desensitization and reprocessing (3MDR) in British military veterans with treatment-resistant service-related PTSD., Methods: Exploratory single-blind, randomized, parallel arm, cross-over controlled trial with nested process evaluation to assess fidelity, adherence and factors that influence outcome., Results: A total of 42 participants (all male) were randomized with 83% retention at 12 weeks and 86% at 26 weeks. The difference in mean Clinician-Administered PTSD Scale for DSM-5 scores between the immediate and delayed 3MDR arms was -9.38 (95% CI -17.33 to -1.44, P = 0.021) at 12 weeks and -3.59 (-14.39 to 7.20, P = 0.513) at 26 weeks when both groups had received 3MDR. The likely effect size of 3MDR was found to be 0.65. Improvements were maintained at 26-week follow-up. 3MDR was found to be acceptable to most, but not all, participants. Several factors that may impact efficacy and acceptability of 3MDR were identified., Conclusion: 3MDR is a promising new intervention for treatment-resistant PTSD with emerging evidence of effect., (© 2020 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Posttraumatic stress disorder (PTSD) is an often chronic condition for which currently available medications have limited efficacy. Medical cannabis is increasingly used to treat patients with PTSD; however, evidence for the efficacy and safety of cannabinoids is scarce. To learn more about patients' opinions on and experiences with medical cannabis, we organized a focus group discussion among military veterans (N = 7) with chronic PTSD who were treated with medical cannabis. Afterwards, some of their partners (N = 4) joined the group for an evaluation, during which they shared their perspective on their partner's use of medical cannabis. Both sessions were audio-recorded, transcribed verbatim, and analyzed by means of qualitative content analysis. Five overarching themes were identified. The first four themes related to the different phases of medical cannabis use - namely, 1) Consideration; 2) Initiation; 3) Usage; and 4) Discontinuation. The fifth theme related to several general aspects of medical cannabis use. Patients used medical cannabis to manage their symptoms and did not experience an urge to "get high." They used a variety of different cannabis strains and dosages and reported several therapeutic effects, including an increased quality of sleep. Furthermore, discussions about the experienced stigma surrounding cannabis generated insights with implications for the initiation of medical cannabis use. These results underscore the value of qualitative research in this field and are relevant for the design of future clinical trials on the use of medical cannabis for the treatment of PTSD., Competing Interests: Declaration of Competing Interest All authors declare that they have no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

There are few medications with demonstrated efficacy for the treatment of posttraumatic stress disorder (PTSD). Treatment guidelines have unequivocally designated psychotherapy as a first line treatment for PTSD. Yet, even after psychotherapy, PTSD often remains a chronic illness, with high rates of psychiatric and medical comorbidity. Meanwhile, the search for and development of drugs with new mechanisms of action has stalled. Therefore, there is an urgent need to explore not just novel compounds but novel approaches for the treatment of PTSD. A promising new approach involves the use of psychedelic drugs. Within the past few years, 2 psychedelics have received breakthrough designations for psychiatric indications from the US Food and Drug Administration, and several psychedelics are currently being investigated for the treatment of PTSD. This review discusses 4 types of compounds: 3,4-methylenedioxymethamphetamine, ketamine, classical psychedelics (e.g., psilocybin and lysergic acid diethylamide), and cannabinoids. We describe the therapeutic rationale, the setting in which they are being administered, and their current state of evidence in the treatment of PTSD. Each compound provides unique qualities for the treatment of PTSD, from their use to rapidly target symptoms to their use as adjuncts to facilitate psychotherapeutic treatments. Several questions are formulated that outline an agenda for future research., (© The Author(s) 2020. Published by Oxford University Press on behalf of CINP.)

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Disruption of persistent, stress-associated memories is relevant for treating posttraumatic stress disorder (PTSD) and related syndromes, which develop in a subset of individuals following a traumatic event. We previously developed a stress-enhanced fear learning (SEFL) paradigm in inbred mice that produces PTSD-like characteristics in a subset of mice, including persistently enhanced memory and heightened cFos in the basolateral amygdala complex (BLC) with retrieval of the remote (30-day-old) stress memory. Here, the contribution of BLC microRNAs (miRNAs) to stress-enhanced memory was investigated because of the molecular complexity they achieve through their ability to regulate multiple targets simultaneously. We performed small-RNA sequencing (smRNA-Seq) and quantitative proteomics on BLC tissue collected from mice 1 month after SEFL and identified persistently changed microRNAs, including mir-135b-5p, and proteins associated with PTSD-like heightened fear expression. Viral-mediated overexpression of mir-135b-5p in the BLC of stress-resilient animals enhanced remote fear memory expression and promoted spontaneous renewal 14 days after extinction. Conversely, inhibition of BLC mir-135b-5p in stress-susceptible animals had the opposite effect, promoting a resilient-like phenotype. mir-135b-5p is highly conserved across mammals and was detected in post mortem human amygdala, as well as human serum samples. The mir-135b passenger strand, mir-135b-3p, was significantly elevated in serum from PTSD military veterans, relative to combat-exposed control subjects. Thus, miR-135b-5p may be an important therapeutic target for dampening persistent, stress-enhanced memory and its passenger strand a potential biomarker for responsivity to a mir-135-based therapeutic.

Previous neuroimaging studies on resilience have generally compared resilience and psychopathology after stress exposure, which does not allow for conclusions regarding correlates specific to resilience. The aim of the present study was to investigate resilience-specific correlates in cortical thickness and/or cortical surface area and their correlations with psychometric measurements, using a three-group design that included a non-trauma-exposed control group in order to disentangle effects related to resilience from those related to psychopathology. Structural magnetic resonance imaging scans were acquired from 82 Dutch police officers. Participants were categorized into resilient (n = 31; trauma exposure, no psychopathology), vulnerable (n = 32; trauma exposure, psychopathology), and control groups (n = 19; no trauma exposure, no psychopathology). Specific regions of interest (ROIs) were identified based on previous studies that found the rostral and caudal anterior cingulate cortex (ACC) to be implicated in trauma-related psychopathology. Cortical thickness and surface area of the ROIs-the rostral and caudal ACC-and of the whole brain were examined. No significant differences in cortical thickness or surface area were found between the resilient group and other groups in the ROI and whole-brain analyses. Thus, the results of the present study provide no evidence of an association between resilience to traumatic stress and measures of thickness and surface area in cortical regions of the brain in a sample of Dutch police officers., (© 2020 The Authors. Journal of Traumatic Stress published by Wiley Periodicals, Inc. on behalf of International Society for Traumatic Stress Studies.)

Background: Previous studies using candidate gene and genome-wide approaches have identified epigenetic changes in DNA methylation (DNAm) associated with posttraumatic stress disorder (PTSD)., Methods: In this study, we performed an EWAS of PTSD in a cohort of Veterans (n = 378 lifetime PTSD cases and 135 controls) from the Translational Research Center for TBI and Stress Disorders (TRACTS) cohort assessed using the Illumina EPIC Methylation BeadChip which assesses DNAm at more than 850,000 sites throughout the genome. Our model included covariates for ancestry, cell heterogeneity, sex, age, and a smoking score based on DNAm at 39 smoking-associated CpGs. We also examined in EPIC-based DNAm data generated from pre-frontal cortex (PFC) tissue from the National PTSD Brain Bank (n = 72)., Results: The analysis of blood samples yielded one genome-wide significant association with PTSD at cg19534438 in the gene G0S2 (p = 1.19 × 10 -7 , p adj  = 0.048). This association was replicated in an independent PGC-PTSD-EWAS consortium meta-analysis of military cohorts (p = 0.0024). We also observed association with the smoking-related locus cg05575921 in AHRR despite inclusion of a methylation-based smoking score covariate (p = 9.16 × 10 -6 ), which replicates a previously observed PGC-PTSD-EWAS association (Smith et al. 2019), and yields evidence consistent with a smoking-independent effect. The top 100 EWAS loci were then examined in the PFC data. One of the blood-based PTSD loci, cg04130728 in CHST11, which was in the top 10 loci in blood, but which was not genome-wide significant, was significantly associated with PTSD in brain tissue (in blood p = 1.19 × 10 -5 , p adj  = 0.60, in brain, p = 0.00032 with the same direction of effect). Gene set enrichment analysis of the top 500 EWAS loci yielded several significant overlapping GO terms involved in pathogen response, including "Response to lipopolysaccharide" (p = 6.97 × 10 -6 , p adj  = 0.042)., Conclusions: The cross replication observed in independent cohorts is evidence that DNA methylation in peripheral tissue can yield consistent and replicable PTSD associations, and our results also suggest that that some PTSD associations observed in peripheral tissue may mirror associations in the brain.

Background: Epigenetic mechanisms have been suggested to play a role in the development of post-traumatic stress disorder (PTSD). Here, blood-derived DNA methylation data (HumanMethylation450 BeadChip) collected prior to and following combat exposure in three cohorts of male military members were analyzed to assess whether DNA methylation profiles are associated with the development of PTSD. A total of 123 PTSD cases and 143 trauma-exposed controls were included in the analyses. The Psychiatric Genomics Consortium (PGC) PTSD EWAS QC pipeline was used on all cohorts, and results were combined using a sample size weighted meta-analysis in a two-stage design. In stage one, we jointly analyzed data of two new cohorts (N = 126 and 78) for gene discovery, and sought to replicate significant findings in a third, previously published cohort (N = 62) to assess the robustness of our results. In stage 2, we aimed at maximizing power for gene discovery by combining all three cohorts in a meta-analysis., Results: Stage 1 analyses identified four CpG sites in which, conditional on pre-deployment DNA methylation, post-deployment DNA methylation was significantly associated with PTSD status after epigenome-wide adjustment for multiple comparisons. The most significant (intergenic) CpG cg05656210 (p = 1.0 × 10 -08 ) was located on 5q31 and significantly replicated in the third cohort. In addition, 19 differentially methylated regions (DMRs) were identified, but failed replication. Stage 2 analyses identified three epigenome-wide significant CpGs, the intergenic CpG cg05656210 and two additional CpGs located in MAD1L1 (cg12169700) and HEXDC (cg20756026). Interestingly, cg12169700 had an underlying single nucleotide polymorphism (SNP) which was located within the same LD block as a recently identified PTSD-associated SNP in MAD1L1. Stage 2 analyses further identified 12 significant differential methylated regions (DMRs), 1 of which was located in MAD1L1 and 4 were situated in the human leukocyte antigen (HLA) region., Conclusions: This study suggests that the development of combat-related PTSD is associated with distinct methylation patterns in several genomic positions and regions. Our most prominent findings suggest the involvement of the immune system through the HLA region and HEXDC, and MAD1L1 which was previously associated with PTSD.

Background: There is a need for new, effective treatments for patients with (treatment-resistant) depressive disorders, anxiety disorders and obsessive-compulsive disorder (ocd). At the same time, there is renewed interest in psychedelics for the treatment of psychiatric disorders.
AIM: To provide an overview of results from past and current research into psychedelics in the treatment of depression, anxiety disorders and ocd.
METHOD: Literature search in Medline and PubMed databases, supplemented with cross-references and results from recent studies.
RESULTS: There is a considerable evidence base for the atypical psychedelic ketamine. Ketamine has a rapid, beneficial effect on depression and suicidality; longer-term effects are less clear. Research into classical psychedelics for the treatment of depression and anxiety disorders is currently limited to a few small (open label) studies, although positive outcomes are reported even after a single administration, with potentially longer lasting benefits. Studies must be repeated in larger and more diverse groups of patients.
CONCLUSION: Further research into efficacy, therapeutic mechanisms and intervention models is very worthwhile; for the benefit of patients, but also to provide a deeper insight into the psychotherapeutic and neurobiological mechanisms that play a role in (the treatment of) common mental disorders.

Background: After psychedelics were banned in 1968, the flourishing research on the use of psychedelics in patients with a mental disorder stopped abruptly. Recently, we see a renaissance of this research.
AIM: To present an overview of what is known about the treatment of addiction and psychosis with psychedelics.
METHOD: Literature study based on Medline en PubMed publications till December 2019.
RESULTS: Studies on the effectiveness of psychedelics in the treatment of addiction and psychosis is still very limited in size and methodological quality. Nevertheless, most studies show positive effects of both classical and atypical psychedelics in a variety of addictions on motivation, craving, reduced consumption, and abstinence often following a single dose and with long-lasting benefits (3-24 months). Use of ketamine in patients with a psychosis stabilized on an antipsychotic might reduce negative symptoms.
CONCLUSION: Before psychedelics can be used in standard clinical practice for the treatment of patients with an addiction or a psychosis, larger and methodologically better studies are needed. The use of psychedelics also creates an opportunity to better understand the shared underlying pathology of many different mental disorders.

Background: Veterans with posttraumatic stress disorder (PTSD) tend to benefit less from evidence-based treatments than other PTSD populations. A novel virtual reality and motion-assisted exposure therapy, called 3MDR, provides treatment in an immersive, personalized and activating context., Objective: To study the efficacy of 3MDR for veterans with treatment-resistant PTSD., Method: In a randomized controlled trial (n = 43) 3MDR was compared to a non-specific treatment component control group. Primary outcome was clinician-rated PTSD symptoms at baseline, after 3MDR, and at the 12-week and 16-week follow-up (primary end point). Intention-to-treat analyses of covariance and mixed models were applied to study differences between groups at the end point and over the course of intervention, controlling for baseline scores., Results: The decrease in PTSD symptom severity from baseline to end point was significantly greater for 3MDR as compared to the control group, with a large effect size (F[1, 37] = 6.43, p = 0.016, d = 0.83). No significant between-group difference was detected in the course of PTSD symptoms during treatment when including all time points. The dropout rate was low (7%), and 45% of the patients in the 3MDR group improved clinically. The number needed to treat was 2.86., Conclusions: In this trial, 3MDR significantly decreased PTSD symptoms in veterans with, on average, a history of 4 unsuccessful treatments. The low dropout rate may be indicative of high engagement. However, a lack of significant differences on secondary outcomes limits conclusions that can be drawn on its efficacy and underlines the need for larger phase III trials. These data show emerging evidence for 3MDR and its potential to progress PTSD treatment for veterans (Dutch Trial Register Identifier: NL5126)., (© 2020 The Author(s) Published by S. Karger AG, Basel.)

Background: Posttraumatic stress disorder (PTSD) is often a chronic condition, despite the availability of various evidence-based treatment options. Psychedelics offer new treatment opportunities.
AIM: An overview of the current evidence, therapeutic context, and possible mechanisms of action of different types of psychedelics in the treatment of PTSD.
METHOD: A scoping review of the available literature.
RESULTS: MDMA-assisted psychotherapy has shown to produce lasting reductions in PTSD symptoms in multiple RCTs. Based on a small number of studies, ketamine administration appears to lead to temporary symptom relief. Current studies are investigating whether the use of ketamine in combination with psychotherapy can lead to lasting reductions in PTSD symptoms. Classical psychedelics (such as psilocybin and LSD) induce psychoactive effects (on behavior or experience) that could contribute to the psychotherapeutic treatment of PTSD but have not yet been investigated in controlled studies. Reported positive effects extend beyond PTSD symptoms only.
CONCLUSION: Psychedelics may have potential to serve as a catalyst for the psychotherapeutic treatment of PTSD. Most evidence exists for MDMA-supported psychotherapy; relatively little research is available on ketamine and classical psychedelics. Future research needs to show whether the use of psychedelics can be integrated into available treatment options for PTSD.

Introduction: Soldiers have a higher risk for developing psychiatric disorders that require treatment; often with antidepressants. However, antidepressants as well as the psychiatric disorder, may influence military readiness in several ways. In the general population, early discontinuation of antidepressant treatment is often seen. It is yet unknown whether this occurs to a similar extent in soldiers. The objective of this study was to evaluate discontinuation of antidepressant use by Dutch soldiers in the first 12 months after start and determinants thereof., Materials and Methods: Data were obtained from the military pharmacy. All Dutch soldiers who started using an antidepressant between 2000 and 2014 were included. Kaplan-Meier curves were constructed to estimate the discontinuation rate over time and the influence of each determinant on discontinuation rate was estimated using Cox regression., Results: About 25.9% of de 2479 starters had discontinued their antidepressant use after 1 month; after 3 and 6 months this number increased to 52.7% and 70.3%, respectively. Early discontinuation was higher in soldiers who received their first prescription from a neurologist or rehabilitation specialist (HR 1.85, 95% CI 1.55-2.21, HR 2.66 95% CI 1.97-3.58) compared to soldiers with a first prescription from a general practitioner. In addition, early discontinuation was lower in soldiers who were prescribed serotonin reuptake inhibitors and other antidepressants (HR 0.57, 95% CI 0.51-0.60, HR 0.63, 95% CI 0.55-0.73) and in soldiers between 40 and 50 years of age (HR 0.79, 95% CI 0.70-0.89)., Conclusion: More than half of the soldiers discontinued their prescribed antidepressant within 3 months and after 6 months, only 30% were still on antidepressants., (© Association of Military Surgeons of the United States 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Exposure to traumatic stress increases the odds of developing a broad range of psychiatric conditions. Genetic studies targeting multiple stress-related quantitative phenotypes may shed light on mechanisms underlying vulnerability to psychopathology in the aftermath of stressful events. We applied a multivariate genome-wide association study (GWAS) to a unique military cohort (N = 583) in which we measured biochemical and behavioral phenotypes. The availability of pre- and post-deployment measurements allowed to capture changes in these phenotypes in response to stress. For genome-wide significant loci, we performed functional annotation, phenome-wide analysis and quasi-replication in PTSD case-control GWASs. We discovered one genetic variant reaching genome-wide significant association, surviving permutation and sensitivity analyses (rs10100651, p = 9.9 × 10 -9 ). Functional annotation prioritized the genes INTS8 and TP53INP1. A phenome-wide scan revealed a significant association of these same genes with sleeping problems, hypertension and subjective well-being. Finally, a targeted lookup revealed nominally significant association of rs10100651 in a PTSD case-control GWAS in the UK Biobank (p = 0.02). We provide comprehensive evidence from multiple resources hinting at a role of the highlighted genetic variant in the human stress response, marking the power of multivariate genome-wide analysis of quantitative measures in stress research. Future genetic and functional studies can target this locus to further assess its effects on stress mediation and its possible role in psychopathology or resilience., (Copyright © 2019. Published by Elsevier B.V.)

Posttraumatic stress disorder (PTSD) is a psychiatric disorder that can develop upon exposure to a traumatic event. While most people are able to recover promptly, others are at increased risk of developing PTSD. However, the exact underlying biological mechanisms of differential susceptibility are unknown. Identifying biomarkers of PTSD could assist in its diagnosis and facilitate treatment planning. Here, we identified serum microRNAs (miRNAs) of subjects that underwent a traumatic event and aimed to assess their potential to serve as diagnostic biomarkers of PTSD. Next-generation sequencing was performed to examine circulating miRNA profiles of 24 members belonging to the Dutch military cohort Prospective Research in Stress-Related Military Operations (PRISMO). Three groups were selected: "susceptible" subjects who developed PTSD after combat exposure, "resilient" subjects without PTSD, and nonexposed control subjects ( N = 8 per group). Differential expression analysis revealed 22 differentially expressed miRNAs in PTSD subjects compared to controls and 1 in PTSD subjects compared to resilient individuals (after multiple testing correction and a log2 fold-change cutoff of ≥|1|). Weighted Gene Coexpression Network Analysis (WGCNA) identified a module of coexpressed miRNAs which could distinguish between the three groups. In addition, receiver operating characteristic curve analyses suggest that the miRNAs with the highest module memberships could have a strong diagnostic accuracy as reflected by high areas under the curves. Overall, the results of our pilot study suggest that serum miRNAs could potentially serve as diagnostic biomarkers of PTSD, both individually or grouped within a cluster of coexpressed miRNAs. Larger studies are now needed to validate and build upon these preliminary findings., (Copyright © 2019 Snijders, Krauskopf, Pishva, Eijssen, Machiels, Kleinjans, Kenis, van den Hove, Kim, Boks, Vinkers, Vermetten, Geuze, Rutten and de Nijs.)

The risk of posttraumatic stress disorder (PTSD) following trauma is heritable, but robust common variants have yet to be identified. In a multi-ethnic cohort including over 30,000 PTSD cases and 170,000 controls we conduct a genome-wide association study of PTSD. We demonstrate SNP-based heritability estimates of 5-20%, varying by sex. Three genome-wide significant loci are identified, 2 in European and 1 in African-ancestry analyses. Analyses stratified by sex implicate 3 additional loci in men. Along with other novel genes and non-coding RNAs, a Parkinson's disease gene involved in dopamine regulation, PARK2, is associated with PTSD. Finally, we demonstrate that polygenic risk for PTSD is significantly predictive of re-experiencing symptoms in the Million Veteran Program dataset, although specific loci did not replicate. These results demonstrate the role of genetic variation in the biology of risk for PTSD and highlight the necessity of conducting sex-stratified analyses and expanding GWAS beyond European ancestry populations.

The inclusion of the dissociative subtype of post-traumatic stress disorder (PTSD-DS) in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) reflects the importance of assessing PTSD-DS. We developed the Dissociative Subtype of PTSD Interview (DSP-I). This clinician-administered instrument assesses the presence and severity of PTSD-DS (i.e., symptoms of depersonalization or derealization) and contains a supplementary checklist that enables assessment and differentiation of other trauma-related dissociative symptoms (i.e., blanking out, emotional numbing, alterations in sensory perception, amnesia, and identity confusion). The psychometric properties were tested in 131 treatment-seeking individuals with PTSD and histories of multiple trauma, 17.6 % of whom met criteria for PTSD-DS in accordance with the DSP-I. The checklist was tested in 275 treatment-seeking individuals. Results showed the DSP-I to have high internal consistency, good convergent validity with PTSD-DS items of the CAPS-5, and good divergent validity with scales of somatization, anxiety and depression. The depersonalization and derealization scales were highly associated. Moreover, the DSP-I accounted for an additional variance in PTSD severity scores of 8% over and above the CAPS-5 and number of traumatic experiences. The dissociative experiences of the checklist were more strongly associated with scales of overall distress, somatization, depression, and anxiety than scales of depersonalization and derealization. In conclusion, the DSP-I appears to be a clinically relevant and psychometrically sound instrument that is valuable for use in clinical and research settings.

The Monash Dog-Owner Relationship Scale (MDORS) is a questionnaire that is used to evaluate the perceived relationship between humans and their dog. This questionnaire was originally only formulated and validated in English, which limits its use among non-English speaking individuals. Although a translation could be made, the translation of questionnaires without additional validation often impairs the reliability of that questionnaire. Therefore, the aim of this study was to validate a translation of the MDORS that is suitable for use among native Dutch speakers. To achieve this, a Dutch translation of the MDORS was made and checked for spelling/grammar mistakes, readability, feasibility, and clarity. A test-retest comparison was subsequently performed on the translation together with a calculation of Cronbach's alpha score and principal component analysis (PCA). Through the PCA, we found that the three-factor model of the original MDORS was also largely present in the Dutch translation. However, deviations were also found, as several questions did not achieve high PCA scores in their original factor. Therefore, we propose that these questions are excluded from the Dutch MDORS.

Purpose: The Prospective Research in Stress-Related Military Operations (PRISMO) study was initiated to gain a better understanding of the long-term impact of military deployment on mental health, and to map the different biological and psychological factors that contribute to the development of stress-related mental health symptoms., Participants: The PRISMO cohort consists of a convenience sample of Dutch military personnel deployed to Afghanistan between 2005 and 2008. Baseline data collection resulted in the recruitment of 1032 military men and women. Combat troops as well as non-combat support troops were recruited to increase the representativeness of the sample to the population as a whole., Findings to Date: The prevalence of various mental health symptoms increases after deployment in PRISMO cohort members, but symptom progression over time appears to be specific for various mental health symptoms. For post-traumatic stress disorder, we found a short-term symptom increase within 6 months after deployment (8.2%), and a long-term symptom increase at 5 years after deployment (12.9%). Several biological vulnerability factors associated with the development of stress-related conditions after deployment were identified, including predeployment glucocorticoid receptor sensitivity and predeployment testosterone level. Thus far, 34 publications have resulted from the cohort., Future Plans: Various analyses are planned that will include the prevalence of mental health symptoms at 10 years postdeployment, as well as trajectory analyses that capture the longitudinal development of symptoms. Furthermore, we will use a machine learning approach to develop predictive and network models for several mental health symptoms, incorporating biological, psychological and social factors., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Exposure to trauma strongly increases the risk to develop stress-related psychopathology, such as post-traumatic stress disorder (PTSD) or major depressive disorder (MDD). In addition, liability to develop these moderately heritable disorders is partly determined by common genetic variance, which is starting to be uncovered by genome-wide association studies (GWASs). However, it is currently unknown to what extent genetic vulnerability and trauma interact. We investigated whether genetic risk based on summary statistics of large GWASs for PTSD and MDD predisposed individuals to report an increase in MDD and PTSD symptoms in a prospective military cohort (N = 516) at five time points after deployment to Afghanistan: one month, six months and one, two and five years. Linear regression was used to analyze the contribution of polygenic risk scores (PRSs, at multiple p-value thresholds) and their interaction with deployment-related trauma to the development of PTSD- and depression-related symptoms. We found no main effects of PRSs nor evidence for interactions with trauma on the development of PTSD or depressive symptoms at any of the time points in the five years after military deployment. Our results based on a unique long-term follow-up of a deployed military cohort suggest limited validity of current PTSD and MDD polygenic risk scores, albeit in the presence of minimal severe psychopathology in the target cohort. Even though the predictive value of PRSs will likely benefit from larger sample sizes in discovery and target datasets, progress will probably also depend on (endo)phenotype refinement that in turn will reduce etiological heterogeneity., (Copyright © 2018. Published by Elsevier B.V.)

This paper reviews the military context of exposure to combat and deployment in Dutch soldiers. It does so by reviewing war victims and military psychiatry after WWII in the Netherlands, and describes Dutch deployments from the late 1970s to the present. 'Who is the Dutch soldier' is asked to articulate the mental load on the individual soldier before, during, and after deployment. The narrative review of this paper allows one to review how the armed forces personnel is challenged in relation to their specific assignment and in what respect the psychological dimensions are addressed and met in the face of risk and adversity. Finally, some critical considerations for future veterans care programmes are raised.

Background : Childhood trauma and combat-related trauma are both associated with decreased psychosocial functioning. Coping strategies play an important role in the adjustment to traumatic events. Objective : The present study examined childhood trauma and the mediating role of coping strategies in adult psychological symptoms in a non-clinical military population after deployment to Afghanistan. Additionally, the moderating role of coping strategies in vulnerability to combat events was explored. Method : Participants ( N = 932) were drawn from a prospective study assessing psychological complaints (SCL-90), early trauma (ETISR-SF), combat-related events and coping strategies (Brief COPE). Mediation analyses via joint significance testing and moderation analyses were performed. Results : Childhood trauma is related to adult symptoms of general anxiety, depression and problems concerning interpersonal sensitivity through the mediation of self-blame as a coping strategy. Some evidence was found that self-blame moderated vulnerability to combat-related events resulting in psychological complaints, specifically symptoms of anxiety and depression. Conclusions : Military personnel should be made aware of self-criticizing maladaptive belief systems when dealing with aversive events. Negative beliefs about oneself and distorted trauma-related cognitions may have a basis in childhood events. Self-blame cognitions may be a potential mechanism of change in empirically supported trauma interventions such as cognitive processing therapy.

Dissociative experiences have been associated with increased disease severity, chronicity, and, in some cases, reduced treatment response across trauma-related and other psychiatric disorders. A better understanding of the neurobiological mechanisms through which dissociative experiences occur may assist in identifying novel pharmacological and non-pharmacological treatment approaches. Here, we review emerging work on the dissociative subtype of posttraumatic stress disorder (PTSD), and other trauma-related disorders providing evidence for two related overarching neurobiological models of dissociation, the defense cascade model of dissociation and Mobb's threat detection model. In particular, we review neuroimaging studies highlighting alterations in functional connectivity of key brain regions associated with these models, including connectivity between the prefrontal cortex, the amygdala and its complexes, the insula, and the periaqueductal gray. Work implicating the kappa-opioid and endocannabinoid systems in trauma-related dissociative experiences is also reviewed. Finally, we hypothesize mechanisms by which pharmacological modulation of these neurochemical systems may serve as promising transdiagnostic treatment modalities for individuals experiencing clinically significant levels of dissociation. Specifically, whereas kappa-opioid receptor antagonists may serve as a pharmacological vehicle for the selective targeting of dissociative symptoms and associated emotion overmodulation in the dissociative subtype of posttraumatic stress disorder and transdiagnostically, modulation of the endocannabinoid system may reduce symptoms associated with emotional undermodulation of the fight or flight components of the defense cascade model.

Background: Personality traits, such as the character traits self-directedness and cooperativeness, might play a role in the risk of developing post-traumatic stress disorder (PTSD) after deployment to a combat zone. However, it is unclear whether these traits are preexisting risk factors or if event-related changes might also be associated with PTSD symptoms over time. Therefore, the current aim was to assess if military deployment is associated with changes in cooperativeness and self-directedness and to study how these traits are related to PTSD symptom trajectories., Methods: In a large cohort of military personnel (N = 1007), measurements were performed before, at one and six months, and two and five years after deployment to Afghanistan. Linear mixed-effect models were used to assess the individual change in the traits over time and to study the relation with potential predictors., Results: Cooperativeness was found to remain stable, whereas self-directedness was found to slightly decrease over time. This decrease was related to the development of PTSD symptoms over time. Furthermore, lower levels of self-directedness were associated with the symptomatic trajectories of PTSD symptoms. Lower levels of cooperativeness were only associated with the recovered PTSD trajectory., Conclusions: So, not only do the findings confirm that lower levels of these character traits are associated with the development of PTSD symptoms, it was also shown that there are differences in the relation between these traits and the course of PTSD symptoms. Studying methods to promote the levels of these character traits might help to improve the resiliency of military personnel., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2018.)

[This corrects the article DOI: 10.1080/20008198.2018.1503523.].

The therapeutic application of human-animal interaction has gained interest recently. One form this interest takes is the use of service dogs as complementary treatment for veterans with Post-Traumatic Stress Disorder (PTSD). Many reports on the positive effect of PTSD Service Dogs (PSDs) on veterans exist, though most are indirect, anecdotal, or based on self-perceived welfare by veterans. They therefore only give a partial insight into PSD effect. To gain a more complete understanding of whether PSDs can be considered an effective complementary treatment for PTSD, a scoping literature review was performed on available studies of PSDs. The key search words were 'dog', 'canine', 'veteran', and 'PTSD'. This yielded 126 articles, of which 19 matched the inclusion criteria (six empirical studies). Recurrent themes in included articles were identified for discussion of methodology and/or results. It was found that results from most included studies were either applicable to human-animal interaction in general or other types of service animals. They therefore did not represent PSDs specifically. Studies which did discuss PSDs specifically only studied welfare experience in veterans, but used different methodologies. This lead us to conclude there is currently no undisputed empirical evidence that PSDs are an effective complementary treatment for veterans with PTSD other than reports on positive welfare experience. Additionally, the lack of development standardization and knowledge regarding welfare of PSDs creates risks for both human and animal welfare. It is therefore recommended that a study on the effect of PSDs be expanded to include evaluation methods besides self-perceived welfare of assisted humans. Future studies could include evaluations regarding human stress response and functioning, ideally conducted according to validated scientific methodologies using objective measurement techniques to identify the added value and mechanisms of using PSDs to assist treatment of PTSD in humans., (© 2018 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background: Recent studies examining the association between posttraumatic stress disorder (PTSD) and accelerated aging, as defined by DNA methylation-based estimates of cellular age that exceed chronological age, have yielded mixed results., Methods: We conducted a meta-analysis of trauma exposure and PTSD diagnosis and symptom severity in association with accelerated DNA methylation age using data from 9 cohorts contributing to the Psychiatric Genomics Consortium PTSD Epigenetics Workgroup (combined N = 2186). Associations between demographic and cellular variables and accelerated DNA methylation age were also examined, as was the moderating influence of demographic variables., Results: Meta-analysis of regression coefficients from contributing cohorts revealed that childhood trauma exposure (when measured with the Childhood Trauma Questionnaire) and lifetime PTSD severity evidenced significant, albeit small, meta-analytic associations with accelerated DNA methylation age (ps = 0.028 and 0.016, respectively). Sex, CD4T cell proportions, and natural killer cell proportions were also significantly associated with accelerated DNA methylation age (all ps < 0.02). PTSD diagnosis and lifetime trauma exposure were not associated with advanced DNA methylation age. There was no evidence of moderation of the trauma or PTSD variables by demographic factors., Conclusions: Results suggest that traumatic stress is associated with advanced epigenetic age and raise the possibility that cells integral to immune system maintenance and responsivity play a role in this. This study highlights the need for additional research into the biological mechanisms linking traumatic stress to accelerated DNA methylation age and the importance of furthering our understanding of the neurobiological and health consequences of PTSD., (Published by Elsevier Ltd.)

The field of treatment of posttraumatic stress disorder (PTSD) has been a pacesetter for the changing face of psychotherapy, as is illustrated in the introduction of Virtual Reality Exposure Therapy. This paper outlines a novel approach that builds on a cognitive-motor interaction in a virtual interactive environment. It is based on the theory of memory reconsolidation and the embodiment of cognition. The framework we envision allows the patient to 'step into the past' by using forward motion as an essential ingredient to augment the impact of exposure to traumatic events. The behavioural response of approaching that is the exact opposite from the avoidance usually applied by patients and the enhancement of divergent thinking are the most prominent hypothesized mechanisms of action. This can contribute to strengthening of personal efficacy and self-reflection that is generated by high emotional engagement, as well as a sense of accomplishment and enhanced recovery as illustrated by a clinical case example. We argue that innovations with personalized virtual reality and motion need to be further investigated and implemented in current therapy settings.

Despite an array of evidence-based psychological treatments for patients with a posttraumatic stress disorder (PTSD), a majority of patients do not fully benefit from the potential of these therapies. In veterans with PTSD, up to two-thirds retain their diagnosis after psychotherapy and often their disorder is treatment-resistant, which calls for improvement of therapeutic approaches for this population. One of the factors hypothesized to underlie low response in PTSD treatment is high behavioral and cognitive avoidance to traumatic reminders. In the current paper we explore if a combination of personalized virtual reality, multi-sensory input, and walking during exposure can enhance treatment engagement, overcome avoidance, and thereby optimize treatment effectiveness. Virtual reality holds potential to increase presence and in-session attention and to facilitate memory retrieval. Multi-sensory input such as pictures and music can personalize this experience. Evidence for the positive effect of physical activity on fear extinction and associative thinking, as well as embodied cognition theories, provide a rationale for decreased avoidance by literally approaching cues of the traumatic memories. A dual-attention task further facilitates new learning and reconsolidation. These strategies have been combined in an innovative framework for trauma-focused psychotherapy, named Multi-modular Motion-assisted Memory Desensitization and Reconsolidation (3MDR). In this innovative treatment the therapeutic setting is changed from the face-to-face sedentary position to a side-by-side activating context in which patients walk toward trauma-related images in a virtual environment. The framework of 3MDR has been designed as a boost for patients with treatment-resistant PTSD, which is illustrated by three case examples. The intervention is discussed in context of other advancements in treatment for treatment-resistant PTSD. Novel elements of this approach are activation, personalization and empowerment. While developed for veterans with PTSD who do not optimally respond to standardized treatments, this innovative framework holds potential to also be used for other patient populations and earlier stages of treatment for patients with PTSD.

In order to determine the impact of the epigenetic response to traumatic stress on post-traumatic stress disorder (PTSD), this study examined longitudinal changes of genome-wide blood DNA methylation profiles in relation to the development of PTSD symptoms in two prospective military cohorts (one discovery and one replication data set). In the first cohort consisting of male Dutch military servicemen (n=93), the emergence of PTSD symptoms over a deployment period to a combat zone was significantly associated with alterations in DNA methylation levels at 17 genomic positions and 12 genomic regions. Evidence for mediation of the relation between combat trauma and PTSD symptoms by longitudinal changes in DNA methylation was observed at several positions and regions. Bioinformatic analyses of the reported associations identified significant enrichment in several pathways relevant for symptoms of PTSD. Targeted analyses of the significant findings from the discovery sample in an independent prospective cohort of male US marines (n=98) replicated the observed relation between decreases in DNA methylation levels and PTSD symptoms at genomic regions in ZFP57, RNF39 and HIST1H2APS2. Together, our study pinpoints three novel genomic regions where longitudinal decreases in DNA methylation across the period of exposure to combat trauma marks susceptibility for PTSD.