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Treatment of Posttraumatic Stress Disorder: a State-of-the-art Review

Burback, Lisa; Brémault-Phillips, Suzette; Nijdam, Mirjam J; McFarlane, Alexander; Vermetten, Eric
This narrative state-of-the-art review paper describes the progress in the understanding and treatment of Posttraumatic Stress Disorder (PTSD). Over the last four decades, the scientific landscape has matured, with many interdisciplinary contributions to understanding its diagnosis, etiology, and epidemiology. Advances in genetics, neurobiology, stress pathophysiology, and brain imaging have made it apparent that chronic PTSD is a systemic disorder with high allostatic load. The current state of treatment yields a wide variety of pharmacological and psychotherapeutic approaches, of which many are evidence-based. However, the myriad challenges inherent in the disorder, such as individual and systemic barriers to treatment outcome, comorbidity, emotional dysregulation, suicidality, dissociation, substance use, and trauma-related guilt and shame often render treatment response suboptimal. These challenges are discussed as drivers for emerging novel treatment approaches, including early interventions in the Golden Hours, pharmacological and psychotherapeutic interventions, medication augmentation interventions, the use of psychedelics, as well as interventions targeting the brain and nervous system. All of this aims to improve symptom relief and clinical outcomes. Finally, a phase orientation to treatment is recognized as a tool to strategize treatment of the disorder, and position interventions in step with the progression of the pathophysiology. Revisions to guidelines and systems of care will be needed to incorporate innovative treatments as evidence emerges and they become mainstream. This generation is well-positioned to address the devastating and often chronic disabling impact of traumatic stress events through holistic, cutting-edge clinical efforts and interdisciplinary research.
PMID: 37132142
ISSN: 1875-6190
CID: 5544852

Get a Grip on Stress with Grippy! A Field Study to Understand Human-Wearable Partnerships in Stress Management

Li, Xueliang Sean; Rozendaal, Marco C.; Vermetten, Eric; Jansen, Kaspar; Jonker, Catholijn
Smart wearables are increasingly used to help people deal with stress. Still, a less explored area of research in this field concerns the partnerships that smart wearables can take on when engaging people in stress-coping activities. To facilitate further understanding of the human-wearable partnerships, we designed Grippy, a smart wearable system composed of a physical glove and a smartphone application to help the wearer actively explore and cope with stress in daily situations. We introduced Grippy, as a speculative probe, to six participants (four master students and two university employees) who wore it for five successive days. Participants were interviewed about their use experience of Grippy during and after these five days. Qualitative data collected from the interviews was interpreted regarding how Grippy could fit into people"™s stress-coping activities across different daily contexts and what kinds of partnerships with the smart wearable were perceived by the participants. In addition, we reflect on the design issues that led to the mismatch between our design intentions and people"™s actual use experiences. We discuss how these results have deepened our understanding of human-wearable partnerships in the context of stress management and the usability issues that might hinder the expression and acceptance of smart wearables designed as partners. We end the discussion by reflecting on the implications of smart wearables as partners in mental healthcare.
ISSN: 1991-3761
CID: 5408562

Enhancing Discovery of Genetic Variants for Posttraumatic Stress Disorder Through Integration of Quantitative Phenotypes and Trauma Exposure Information

Maihofer, Adam X; Choi, Karmel W; Coleman, Jonathan R I; Daskalakis, Nikolaos P; Denckla, Christy A; Ketema, Elizabeth; Morey, Rajendra A; Polimanti, Renato; Ratanatharathorn, Andrew; Torres, Katy; Wingo, Aliza P; Zai, Clement C; Aiello, Allison E; Almli, Lynn M; Amstadter, Ananda B; Andersen, Soren B; Andreassen, Ole A; Arbisi, Paul A; Ashley-Koch, Allison E; Austin, S Bryn; Avdibegović, Esmina; Borglum, Anders D; Babić, Dragan; Bækvad-Hansen, Marie; Baker, Dewleen G; Beckham, Jean C; Bierut, Laura J; Bisson, Jonathan I; Boks, Marco P; Bolger, Elizabeth A; Bradley, Bekh; Brashear, Meghan; Breen, Gerome; Bryant, Richard A; Bustamante, Angela C; Bybjerg-Grauholm, Jonas; Calabrese, Joseph R; Caldas-de-Almeida, José M; Chen, Chia-Yen; Dale, Anders M; Dalvie, Shareefa; Deckert, Jürgen; Delahanty, Douglas L; Dennis, Michelle F; Disner, Seth G; Domschke, Katharina; Duncan, Laramie E; Džubur Kulenović, Alma; Erbes, Christopher R; Evans, Alexandra; Farrer, Lindsay A; Feeny, Norah C; Flory, Janine D; Forbes, David; Franz, Carol E; Galea, Sandro; Garrett, Melanie E; Gautam, Aarti; Gelaye, Bizu; Gelernter, Joel; Geuze, Elbert; Gillespie, Charles F; Goçi, Aferdita; Gordon, Scott D; Guffanti, Guia; Hammamieh, Rasha; Hauser, Michael A; Heath, Andrew C; Hemmings, Sian M J; Hougaard, David Michael; Jakovljević, Miro; Jett, Marti; Johnson, Eric Otto; Jones, Ian; Jovanovic, Tanja; Qin, Xue-Jun; Karstoft, Karen-Inge; Kaufman, Milissa L; Kessler, Ronald C; Khan, Alaptagin; Kimbrel, Nathan A; King, Anthony P; Koen, Nastassja; Kranzler, Henry R; Kremen, William S; Lawford, Bruce R; Lebois, Lauren A M; Lewis, Catrin; Liberzon, Israel; Linnstaedt, Sarah D; Logue, Mark W; Lori, Adriana; Lugonja, Božo; Luykx, Jurjen J; Lyons, Michael J; Maples-Keller, Jessica L; Marmar, Charles; Martin, Nicholas G; Maurer, Douglas; Mavissakalian, Matig R; McFarlane, Alexander; McGlinchey, Regina E; McLaughlin, Katie A; McLean, Samuel A; Mehta, Divya; Mellor, Rebecca; Michopoulos, Vasiliki; Milberg, William; Miller, Mark W; Morris, Charles Phillip; Mors, Ole; Mortensen, Preben B; Nelson, Elliot C; Nordentoft, Merete; Norman, Sonya B; O'Donnell, Meaghan; Orcutt, Holly K; Panizzon, Matthew S; Peters, Edward S; Peterson, Alan L; Peverill, Matthew; Pietrzak, Robert H; Polusny, Melissa A; Rice, John P; Risbrough, Victoria B; Roberts, Andrea L; Rothbaum, Alex O; Rothbaum, Barbara O; Roy-Byrne, Peter; Ruggiero, Kenneth J; Rung, Ariane; Rutten, Bart P F; Saccone, Nancy L; Sanchez, Sixto E; Schijven, Dick; Seedat, Soraya; Seligowski, Antonia V; Seng, Julia S; Sheerin, Christina M; Silove, Derrick; Smith, Alicia K; Smoller, Jordan W; Sponheim, Scott R; Stein, Dan J; Stevens, Jennifer S; Teicher, Martin H; Thompson, Wesley K; Trapido, Edward; Uddin, Monica; Ursano, Robert J; van den Heuvel, Leigh Luella; Van Hooff, Miranda; Vermetten, Eric; Vinkers, Christiaan; Voisey, Joanne; Wang, Yunpeng; Wang, Zhewu; Werge, Thomas; Williams, Michelle A; Williamson, Douglas E; Winternitz, Sherry; Wolf, Christiane; Wolf, Erika J; Yehuda, Rachel; Young, Keith A; Young, Ross McD; Zhao, Hongyu; Zoellner, Lori A; Haas, Magali; Lasseter, Heather; Provost, Allison C; Salem, Rany M; Sebat, Jonathan; Shaffer, Richard A; Wu, Tianying; Ripke, Stephan; Daly, Mark J; Ressler, Kerry J; Koenen, Karestan C; Stein, Murray B; Nievergelt, Caroline M
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.
PMID: 34865855
ISSN: 1873-2402
CID: 5079282

Epigenome-wide meta-analysis of PTSD symptom severity in three military cohorts implicates DNA methylation changes in genes involved in immune system and oxidative stress

Katrinli, Seyma; Maihofer, Adam X; Wani, Agaz H; Pfeiffer, John R; Ketema, Elizabeth; Ratanatharathorn, Andrew; Baker, Dewleen G; Boks, Marco P; Geuze, Elbert; Kessler, Ronald C; Risbrough, Victoria B; Rutten, Bart P F; Stein, Murray B; Ursano, Robert J; Vermetten, Eric; Logue, Mark W; Nievergelt, Caroline M; Smith, Alicia K; Uddin, Monica
Epigenetic factors modify the effects of environmental factors on biological outcomes. Identification of epigenetic changes that associate with PTSD is therefore a crucial step in deciphering mechanisms of risk and resilience. In this study, our goal is to identify epigenetic signatures associated with PTSD symptom severity (PTSS) and changes in PTSS over time, using whole blood DNA methylation (DNAm) data (MethylationEPIC BeadChip) of military personnel prior to and following combat deployment. A total of 429 subjects (858 samples across 2 time points) from three male military cohorts were included in the analyses. We conducted two different meta-analyses to answer two different scientific questions: one to identify a DNAm profile of PTSS using a random effects model including both time points for each subject, and the other to identify a DNAm profile of change in PTSS conditioned on pre-deployment DNAm. Four CpGs near four genes (F2R, CNPY2, BAIAP2L1, and TBXAS1) and 88 differentially methylated regions (DMRs) were associated with PTSS. Change in PTSS after deployment was associated with 15 DMRs, of those 2 DMRs near OTUD5 and ELF4 were also associated with PTSS. Notably, three PTSS-associated CpGs near F2R, BAIAP2L1 and TBXAS1 also showed nominal evidence of association with change in PTSS. This study, which identifies PTSD-associated changes in genes involved in oxidative stress and immune system, provides novel evidence that epigenetic differences are associated with PTSS.
PMID: 34992238
ISSN: 1476-5578
CID: 5136862

Successful treatment of post-traumatic stress disorder reverses DNA methylation marks

Vinkers, Christiaan H; Geuze, Elbert; van Rooij, Sanne J H; Kennis, Mitzy; Schür, Remmelt R; Nispeling, Danny M; Smith, Alicia K; Nievergelt, Caroline M; Uddin, Monica; Rutten, Bart P F; Vermetten, Eric; Boks, Marco P
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.
PMID: 31645664
ISSN: 1476-5578
CID: 4175692

Neurophysiological Approach by Self-Control of Your Stress-Related Autonomic Nervous System with Depression, Stress and Anxiety Patients

Blase, Kees; Vermetten, Eric; Lehrer, Paul; Gevirtz, Richard
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.
PMID: 33804817
ISSN: 1660-4601
CID: 4895152

Do Service Dogs for Veterans with PTSD Mount a Cortisol Response in Response to Training?

van Houtert, Emmy A E; Endenburg, Nienke; Rodenburg, T Bas; Vermetten, Eric
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.
PMID: 33804470
ISSN: 2076-2615
CID: 4895142

Long-term development of post-traumatic stress symptoms and associated risk factors in military service members deployed to Afghanistan: results from the PRISMO 10-year follow-up

van der Wal, S J; Vermetten, E; Geuze, E
PMID: 33342444
ISSN: 1778-3585
CID: 4726672

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR

Smith, Alicia K; Ratanatharathorn, Andrew; Maihofer, Adam X; Naviaux, Robert K; Aiello, Allison E; Amstadter, Ananda B; Ashley-Koch, Allison E; Baker, Dewleen G; Beckham, Jean C; Boks, Marco P; Bromet, Evelyn; Dennis, Michelle; Galea, Sandro; Garrett, Melanie E; Geuze, Elbert; Guffanti, Guia; Hauser, Michael A; Katrinli, Seyma; Kilaru, Varun; Kessler, Ronald C; Kimbrel, Nathan A; Koenen, Karestan C; Kuan, Pei-Fen; Li, Kefeng; Logue, Mark W; Lori, Adriana; Luft, Benjamin J; Miller, Mark W; Naviaux, Jane C; Nugent, Nicole R; Qin, Xuejun; Ressler, Kerry J; Risbrough, Victoria B; Rutten, Bart P F; Stein, Murray B; Ursano, Robert J; Vermetten, Eric; Vinkers, Christiaan H; Wang, Lin; Youssef, Nagy A; Uddin, Monica; Nievergelt, Caroline M
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.
PMID: 33235198
ISSN: 2041-1723
CID: 4709812

Perceived treatment processes and effects of interactive motion-assisted exposure therapy for veterans with treatment-resistant posttraumatic stress disorder: a mixed methods study

van Gelderen, Marieke J; Nijdam, Mirjam J; Dubbink, G Elsemieke; Sleijpen, Marieke; Vermetten, Eric
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.
PMID: 33244364
ISSN: 2000-8066
CID: 4709822