Psychoneuroendocrinology (2015) 51, 441—443

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New findings from prospective studies 1. Background: the conference The first biomarker in the military conference, which was a broad discussion of issues in a panel format, was held on September 14, 2012 in New York, NY. The research that was presented is summarized in a paper that includes criteria for biomarkers for PTSD, but with no specific study findings available yet (Lehrner and Yehuda, 2014). This special section covers talks presented at the second military biomarker conference that was held as a satellite to the 43rd meeting of the annual meeting of the Society of Psychoneuroendocrinology. The conference, entitled ‘Biomarkers in the Military’ was held at the Royal Marine Base in Amsterdam August 23, 2013. The aim of the satellite was to bring together researchers supported by Departments of Defense, Veterans Administrations, National Institutes of Health, and other agencies around the world engaged in study of biomarkers in the military. This special section, the first to assemble new findings focused on biomarker discovery, presents work of researchers from a number of North Atlantic Treaty Organization (NATO) partners collaborating in the International Security Assistant Force (ISAF). While one paper is a pre-clinical study relevant to biomarker discovery, most are clinical. The work, as described below, includes original contributions from the gold-standard study design, prospective longitudinal studies as well as from cross-sectional research.

2. Special section papers Schmidt et al. provide a literature review and conceptual framework for prospective longitudinal studies. They review progress in the search for PTSD risk and resiliency biomarkers in both civilian and military studies. Despite a significant increase in the number of prospective trials over last couple of years and some promising results, Schmidt et al. address the need for well-designed pre-post studies. In their rigorous selection of over 8,000 papers targeting PTSD biomarker research they could only include 9 imaging and 27 molecular studies that hold power for biomarker identification. They 0306-4530/© 2014 Published by Elsevier Ltd.

underscore the increasing evidence that polymorphisms of HPA axis associated genes interact with early life stress to enhance the vulnerability for adulthood PTSD. Yet, none of the proposed PTSD risk markers is currently clinically applicable since all proposed markers lack PTSD specificity. Nievergelt and colleagues present the first ever genomewide association study (GWAS) in a military cohort. This cohort, the Marine Resiliency Study (MRS) cohort was designed as a prospective study to determine risk and resilience genes by analyzing genes from active duty personnel about to deploy to Iraq and Afghanistan (Baker et al., 2012). Because the intention was to follow nearly 3500 troops when they returned from combat, the study offered the possibility to determine whether information about GWAS and other markers predicted short- and longterm post-combat mental and physical outcomes. The study by Nievergelt et al. is also noteworthy for being the first multi-ethnic/racial GWAS of PTSD, and thus highlights the potential to increase power through meta-analyses across ancestry groups. In this initial analysis of the data, Nievergelt and colleagues identified the phosphoribosyl transferase domain containing 1 gene (PRTFDC1) as a genome-wide significant PTSD locus, with a similar effect across ancestry groups. Another key finding of the paper is that a cross-disorder polygenic analysis shows the existence of common SNPs between posttraumatic stress disorder and bipolar disorder. By seeking data from other studies to locate replication cohorts, the study also highlights important strategies for interpreting similarities and differences between military and other samples. Another paper, by Tylee et al. presents data from the same cohort, the MRS study, building upon earlier work (Glatt et al., 2013). It provides preliminary results of proof-of-principle findings for a diagnostic blood-based mRNA-expression biomarker panel in PTSD based on geneexpression levels in peripheral blood samples. The authors present a prospective study in 50 U.S. Marines (25 eventual PTSD cases and 25 non-PTSD comparison subjects) with data gathered prior to their deployment overseas to war-zones in Iraq or Afghanistan, and again upon return. Their panel of biomarkers in peripheral blood cells of eventual PTSD cases

442 was significantly enriched for immune genes, and achieved 70% prediction accuracy in an independent sample based on the expression of 23 full-length transcripts, and attained 80% accuracy in an independent sample based on the expression of one exon from each of five genes. From the same research group (Marine Resiliency Study II; Neurocognition project), Risbrough et al., analyzing data from Marines bound for Afghanistan prior to their deployment, uses a functional biomarker approach to assess the effectiveness of the fear potentiated startle paradigm in producing fear learning and extinction, and the association of performance with baseline psychiatric symptom classes. Comparison of four groups (Healthy, PTSD symptoms, Anxiety symptoms, and Depression symptoms) across the cohort shows differential patterns of fear conditioning and extinction, with the PTSD symptom group, in contrast to anxiety, depression and healthy showing reduced fear inhibition, consistent with the idea that safety signal discrimination is a relatively specific marker of PTSD. The researchers plan to follow up to determine if deficits in fear inhibition vs. exaggerated fear responding are separate biological ‘domains’ that might predict differential biological mechanisms and possibly treatment needs, as well as to pursue longitudinal analyses to examine whether poor safety signal learning provides a marker of vulnerability to develop PTSD or is specific to symptom state. Four papers are driven from data from a prospective longitudinal study in Dutch soldiers deployed to Afghanistan as part of ISAF, called Prospective Research in Stress related Military Operations (PRISMO). Acquisition of biological samples for this study started in 2005 and lasted until 2008 and included a total of 1032 soldiers. In the first 2 year follow-up prevalences of mental health symptoms do not differ much from those reported by other NATO partners (Reijnen et al., 2014). The design allows for identification of blood-based biomarkers, (epi)genetic analyses and symptom trajectories as this cohort is being followed up at multiple time points up to 10 years post deployment. A small group has been scanned with functional neuroimaging of the brain before and after deployment driving new findings e.g. on the role of the amygdala and glucocorticoid receptor number (Geuze et al., 2012; van Wingen et al., 2011). This special issue contains four studies by Boks et al., van Zuiden et al, Reijnen et al, and Smid et al., published from this cohort. The first, by Boks et al. focuses on epigenetic age. It has been suggested that traumatic stress has an impact on aging at the cellular level, which can be investigated by estimating epigenetic age based on DNA methylation profiles. While our prevailing understanding is that a telomere shortening is associated with PTSD or PTSD onset, Boks et al. found a remarkable acceleration of aging induced by combat exposure. Development of initial PTSD symptoms (at 6 months) was associated with telomere lengthening and reversed epigenetic aging which may be best understood to be linked to a dysfunctional compensatory cellular aging reversal in early stages of PTSD. The second paper, by Van Zuiden et al. followed up on prior findings of higher pre-deployment GR number in PBMCs in soldiers who developed high levels of PTSD symptoms after deployment. In the current analysis it was demonstrated that the differences in the peripheral GC-sensitivity persisted until at least 6 months after return from combat. This could indicate that in vitro GC-sensitivity of T-cells and

Editorial monocytes represents a persistent biological vulnerability factor for development of PTSD. The third paper, by Reijnen et al. added evidence for a role of the Hypothalamic Pituitary Gonadal (HPG) axis for the development of PTSD. The HPG axis parameter testosterone was analyzed in the total sample of deployed soldiers. Pre-deployment testosterone levels predicted the development of PTSD symptoms at 1 and 2 years post-deployment, with alterations in testosterone levels shortly after deployment not being predictive, but the pre-deployment testosterone levels at longer postdeployment timeframes being associated with PTSD. Lastly, Smid et al. followed up on earlier work on the model of stress sensitization that was previously validated in the PRISMO cohort (Smid et al., 2013). Especially in high combat exposed soldiers in the first 6 months after combat a higher T-cell chemokine production was associated with increases in PTSD symptoms. An interesting interaction between cytokines and stressful life effects at homecoming was associated with changes in PTSD symptoms. As mitogen-induced cytokine and chemokine production constitute markers of stress sensitization this finding may imply that efforts to prevent progression of posttraumatic distress should aim at creating a ‘comfort zone’, by keeping the highly exposed veterans in the first couple of months after homecoming safe, away from unnecessary stressors, thus preventing stress sensitization. In the only preclinical paper Rutten et al. studied the effects of 10 days of social defeat stress on behavior and Dnmt3a expression in relation to neurogenesis in the mouse hippocampus. Mice resilient to defeat stress show higher Dnmt3 expression compared to controls (non-defeat) as well as to susceptible groups. It is known that epigenetic modifications, such as DNA methylation, can occur in response to environmental influences to alter the functional expression of genes. This study adds preclinical evidence of the role of DNA methylation in susceptibility to severe stressors. These findings provide a pre-clinical scientific foundation for the assessment of the impact of trauma exposure on DNA methylation e.g. in prospectively followed military cohorts. Two additional papers used a cross-sectional approach. In a search for the relation between inflammatory markers and brain integrity O’Donovan et al. looked at a large cohort of Gulf war veterans for associations between peripheral inflammatory markers and brain integrity, in particular hippocampal volume. Specific inflammatory signaling proteins (sTNF-RII, but not IL-6) were significantly associated with reduced hippocampal volume and PTSD symptoms. In a small sample Yehuda et al. presented results of a new developing method of DTI tractography data from 20 Gulf War veterans. Their observations are consistent with a functional model that converges on the concept of increased amygdala responsivity in association with anterior cingulate modulation in PTSD. Another set of two papers focuses on the endocannabinoid system. It is only recently that researchers embrace the old notion that cannabis has qualities that are favored by PTSD patients. Neumeister et al. reviewed translational evidence for a role of endocannabinoids in the etiology and treatment of PTSD. Multiple studies are reviewed that report reduced endocannabinoid availability and elevated cannabinoid type 1 (CB1) receptor availability in PTSD and its link

New findings from prospective studies to abnormal threat processing and anxious arousal symptoms. This study lays the foundation for a mechanism-based pharmacotherapy approach by Jetly et al. This group conducted a small randomized clinical trial (RCT) with a double placebo controlled cross-over design in a Canadian military personal suffering from PTSD. In a brief report they demonstrated good efficacy for Nabilone, specifically for trauma related nightmares, thus adding support for the potential use of synthetic cannabinoids. As the last paper in this special section, Yehuda et al. employed the model of exposure based ‘golden hour’ opportunities (Vermetten et al., 2014b) by augmenting psychological treatment with medication in veterans with PTSD. They performed a highly important pilot study investigating the potential therapeutic benefit of hydrocortisone augmentation of prolonged exposure therapy for combat veterans with PTSD. Hydrocortisone augmentation was associated with greater reduction in total PTSD symptoms compared to placebo. Moreover, the biological data demonstrated an impressive correlation between glucocorticoid sensitivity and CAPS total score in hydrocortisone recipients. Their finding of a significant baseline difference in glucocorticoid sensitivity between responders and non-responders is also very relevant for future investigations into the fundamental neurobiological mechanisms underlying the pathophysiology of PTSD.

3. Promises As the papers illustrate there has been an enormous effort to capture risk and resilience factors, as well as to identify biomarkers of expressed illness. Various Departments of Defense (DOD) around the world have, and continue to invest significant resources to augment force protection and security by seeking methods to optimize prevention and treatment strategies for behavioral and mental health problems. We are grateful for the military leadership in their foresight and support of this research that enables a wide range of researchers across the globe to collaborate and to move the field forward. Given the similarities in deployment-related mental health support across nations (Vermetten et al., 2014a), collaborative efforts can be entertained that can enable both replication as well as validation of biomarker findings. We are grateful for so much support in organizing this satellite, dissemination of this research and promoting that these efforts are sustained. Lastly, a special thanks to all the reviewers for this special section. We are advancing rapidly, but these efforts will need to be sustained over the next decades as we consolidate knowledge in the field.

References Baker, D.G., Nash, W.P., Litz, B.T., Geyer, M.A., Risbrough, V.B., Nievergelt, C.M., Team, M.R.S., 2012. Predictors of risk and resilience for posttraumatic stress disorder among ground combat Marines: methods of the Marine Resiliency Study. Prev. Chronic Dis. 9, E97.

443 Geuze, E., van Wingen, G.A., van Zuiden, M., Rademaker, A.R., Vermetten, E., Kavelaars, A., Heijnen, C.J., 2012. Glucocorticoid receptor number predicts increase in amygdala activity after severe stress. Psychoneuroendocrinology 37 (11), 1837—1844, Glatt, S.J., Tylee, D.S., Chandler, S.D., Pazol, J., Nievergelt, C.M., Woelk, C.H., Marine Resiliency Study I., 2013. Blood-based gene-expression predictors of PTSD risk and resilience among deployed marines: a pilot study. Am. J. Med. Genet. B: Neuropsychiatr. Genet. 162B (4), 313—326, Lehrner, A., Yehuda, R., 2014. Biomarkers of PTSD: military applications and considerations. Eur. J. Psychotraumatol., 5, Reijnen, A., Rademaker, A.R., Vermetten, E., Geuze, E., 2014. Prevalence of mental health symptoms in Dutch military personnel returning from deployment to Afghanistan: a 2-year longitudinal analysis. Eur. Psychiatry, Smid, G.E., Kleber, R.J., Rademaker, A.R., van Zuiden, M., Vermetten, E., 2013. The role of stress sensitization in progression of posttraumatic distress following deployment. Soc. Psychiatry Psychiatr. Epidemiol. 48 (11), 1743—1754, van Wingen, G.A., Geuze, E., Vermetten, E., Fernandez, G., 2011. Perceived threat predicts the neural sequelae of combat stress. Mol. Psychiatry 16 (6), 664—671, Vermetten, E., Greenberg, N., Boeschoten, M.A., Delahaije, R., Jetly, R., Castro, C.A., McFarlane, A.C., 2014a. Deploymentrelated mental health support: comparative analysis of NATO and allied ISAF partners. Eur. J. Psychotraumatol., 5, Vermetten, E., Zhohar, J., Krugers, H.J., 2014b. Pharmacotherapy in the aftermath of trauma; opportunities in the ‘golden hours’. Curr. Psychiatry Rep. 16 (7), 455,

Eric Vermetten a,b,c,∗ Department of Psychiatry, University of Leiden, Leiden, The Netherlands b Military Mental Health — Research, Department of Defense, Leiden, The Netherlands c Arq Psychotrauma Expert Group, Diemen, The Netherlands Dewleen Baker a,b a Department of Psychiatry, University of California at San Diego, La Jolla, CA, USA b VA Center of Excellence for Stress and Mental Health (CESAMH), VA San Diego Healthcare System, San Diego, CA, USA Rachel Yehuda a,b a James J. Peters Veterans Affairs Medical Center, Bronx, New York, NY, USA b Traumatic Stress Studies Division, Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA a

∗ Corresponding author at: Department of Psychiatry, Leiden University School of Medicine, Albiniusdreef 2, 2333 ZA Leiden, The Netherlands. Tel.: +31 30 2502591. E-mail address:[email protected] (E. Vermetten)

New findings from prospective studies.

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