Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder (NATO Security Through Science)

NOVEL APPROACHES TO THE DIAGNOSIS AND TREATMENT OF POSTTRAUMATIC STRESS DISORDER

NATO Security through Science Series This Series presents the results of scientific meetings supported under the NATO Programme for Security through Science (STS). Meetings supported by the NATO STS Programme are in security-related priority areas of Defence Against Terrorism or Countering Other Threats to Security. The types of meeting supported are generally “Advanced Study Institutes” and “Advanced Research Workshops”. The NATO STS Series collects together the results of these meetings. The meetings are co-organized by scientists from NATO countries and scientists from NATO’s “Partner” or “Mediterranean Dialogue” countries. The observations and recommendations made at the meetings, as well as the contents of the volumes in the Series, reflect those of participants and contributors only; they should not necessarily be regarded as reflecting NATO views or policy. Advanced Study Institutes (ASI) are high-level tutorial courses to convey the latest developments in a subject to an advanced-level audience Advanced Research Workshops (ARW) are expert meetings where an intense but informal exchange of views at the frontiers of a subject aims at identifying directions for future action Following a transformation of the programme in 2004 the Series has been re-named and reorganised. Recent volumes on topics not related to security, which result from meetings supported under the programme earlier, may be found in the NATO Science Series. The Series is published by IOS Press, Amsterdam, and Springer Science and Business Media, Dordrecht, in conjunction with the NATO Public Diplomacy Division. Sub-Series A. B. C. D. E.

Chemistry and Biology Physics and Biophysics Environmental Security Information and Communication Security Human and Societal Dynamics

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Sub-Series E: Human and Societal Dynamics – Vol. 6

ISSN: 1574-5597

Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder

Edited by

Michael J. Roy Division of Military Internal Medicine, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

Amsterdam • Berlin • Oxford • Tokyo • Washington, DC Published in cooperation with NATO Public Diplomacy Division

Proceedings of the NATO Advanced Research Workshop on Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder Cavtat, Croatia 13–16 June 2005

© 2006 IOS Press. All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without prior written permission from the publisher. ISBN 1-58603-590-8 Library of Congress Control Number: 2006920943 Publisher IOS Press Nieuwe Hemweg 6B 1013 BG Amsterdam Netherlands fax: +31 20 687 0019 e-mail: [email protected] Distributor in the UK and Ireland Gazelle Books Falcon House Queen Square Lancaster LA1 1RN United Kingdom fax: +44 1524 63232

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LEGAL NOTICE The publisher is not responsible for the use which might be made of the following information. PRINTED IN THE NETHERLANDS

Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder M.J. Roy (Ed.) IOS Press, 2006 © 2006 IOS Press. All rights reserved.

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Preface We believe that this Advanced Research Workshop has given participants an opportunity to foster essential international collaborative research on the diagnosis and treatment of posttraumatic stress disorder, a common and disabling consequence of war, terrorism, and natural disasters. As a result, it represents an important piece in efforts to help soldiers and civilians of NATO and partner nations in the face of future international conflicts. This publication contains the full papers corresponding to the relevant presentations provided at the workshop. This text is organized so as to provide a coherent picture of the work and thoughts of participants in the ARW, rather than necessarily following the exact order of the presentations as they were provided in Cavtat, although this summary conveys to the reader the manner in which presentations and working groups were conducted. Appropriate financial support was vital for the successful organization and implementation of the workshop. Grateful acknowledgments for generosity go to the primary sponsor, the NATO Security through Science Programme, as well as to a number of Croatian donors, who recognized the importance of this event. As a token of our appreciation, the logos of all sponsors are included here. The workshop was organized and this accompanying publication was assembled by joint dedication and efforts from the members of Uniformed Services University of the Health Sciences (USUHS), Bethesda, MD, and University of Zagreb, Faculty of Electrical Engineering and Computing (FEEC), Croatia. Professor Michael Roy of USUHS, the NATO-country program co-director and organizing co-director, conceived the overall design of the workshop, and with the assistance of his research assistant Patricia Kraus, wrote and submitted an application to NATO. Dr. Roy selected and invited the majority of the speakers and participants, and he and Ms. Kraus edited each of the chapters incorporated in this publication. Professor Kresimir Cosic, the organizing co-director and a member of FEEC, coordinated financial aspects of the ARW, solicited additional funding from Croatian donors, invited representatives of the Government of Croatia, and promoted the workshop within international politico-military circles. He coordinated coverage of the workshop with Croatian Radiotelevision, and organized meals as well as a boat trip to Dubrovnik for participants. Professor Dragica Kozaric Kovacic, the partner-country program co-director and a member of University Hospital Dubrava in Zagreb, Croatia, extended invitations to several international speakers, further improving the quality of the workshop. Assistant Professor Miroslav Slamic, a member of FEEC, handled accreditations, the purchase of consumable supplies, and designed such items as the workshop poster, program cover, and the appearance of compact disks (CDs) of presentations and pictures for participants. He was also the workshop photographer. Sinisa Popovic, a member of FEEC, was the “glue” that held together the planning and smooth running of the workshop, coordinating travel, lodging and meal arrangements, precise estimation of expenses, assembling of workshop materials, and other arrangements with the conference site. Marko Cosic designed

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the gala dinner menu and coupons, and assisted Mr. Popovic with local arrangements and assembling of workshop materials, handled some on-site financial matters, etc. Workshop CDs were made possible through the joint efforts of Miroslav Slamic, Sinisa Popovic, Marko Cosic, and Patricia Kraus. Dr. Roy also gratefully acknowledges the many hours of assistance Ms. Kraus provided in reviewing the manuscripts for this text.

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Program Co-directors Michael Roy, USA

Dragica Kozaric Kovacic, Croatia

Organizing Co-directors Kresimir Cosic, Croatia

Michael Roy, USA

Speakers Amy Adler, USA Randy Boddam, Canada Tim Brennen, Norway Kresimir Cosic, Croatia Paul Emmelkamp, The Netherlands Elke Geraerts, The Netherlands Jamie Hacker Hughes, UK Louis Jehel, France Tanja Jovanovic, Croatia Ivica Kostovic, Croatia David Lam, USA Nela Pivac, Croatia Ronald Poropatich, USA Barbara Rothbaum, USA Charles van der Mast, The Netherlands Brenda Wiederhold, USA

Mariano Alcaniz, Spain Cristina Botella, Spain Gianluca Castelnuovo, Italy JoAnn Difede, USA Azucena Garcia Palacios, Spain John Gruzelier, UK Neven Henigsberg, Croatia Naomi Josman, Israel Ivica Klapan, Croatia Dragica Kozaric Kovacic, Croatia George Naneishvili, Georgia Sinisa Popovic, Croatia Albert “Skip” Rizzo, USA Michael Roy, USA Zoltan Vekerdi, Hungary Joseph Zohar, Israel

Publicity Michael Roy, USA Dragica Kozaric Kovacic, Croatia

Kresimir Cosic, Croatia

Local Arrangements and Social Events Kresimir Cosic, Croatia Marko Cosic, Croatia

Sinisa Popovic, Croatia

Finances Michael Roy, USA Sinisa Popovic, Croatia

Kresimir Cosic, Croatia Marko Cosic, Croatia

Publication Michael Roy, USA Sinisa Popovic, Croatia

Patricia Kraus, USA Miroslav Slamic, Croatia

Workshop Materials and CDs Miroslav Slamic, Croatia Marko Cosic, Croatia

Sinisa Popovic, Croatia Patricia Kraus, USA

Secretary Sinisa Popovic, Croatia Photographer Miroslav Slamic, Croatia

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Croatian Radiotelevision Reportage Guests Kresimir Cosic, Croatia David Lam, USA Barbara Rothbaum, USA JoAnn Difede, USA Michael J. Roy, USA

Organizers

General Sponsor

Sponsors

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Key Speakers CANADA Randy Boddam Psychiatry and Mental Health, Rm 406, Health Care Centre, 1745 Alta Vista Drive, Ottawa, Ontario, Canada, K1A 0K6 CROATIA Kresimir Cosic University of Zagreb, Faculty of Electrical Engineering and Computing, Unska 3, 10000 Zagreb, Croatia Neven Henigsberg Department of Psychopharmacology, Croatian Institute for Brain Research, Medical School, University of Zagreb, Salata 12, HR-10000, Zagreb, Croatia Tanja Jovanovic Department of Psychiatry & Behavioral Sciences, Emory University School of Medicine, 1365 Clifton Road, Atlanta, GA 30322, USA Ivo Klapan Zagreb University School of Medicine, and Croatian Telemedicine Society of the Croatian Medical Association, HR-10000 Zagreb, Croatia Ivica Kostovic Croatian Institute for Brain Research, School of Medicine, Zagreb University Hospital Center Gojka Suska 12, HR-10000 Zagreb, Croatia Dragica Kozaric-Kovacic, MD, PhD University Hospital Dubrava, Department of Psychiatry, Referral Centre for the Stress-Related Disorders of the Ministry of Health of the Republic of Croatia Avenija Gojka Suska 6, 10000 Zagreb, Croatia Nela Pivac Division of Molecular Medicine, Rudjer Boskovic Institute, POBox 180, HR-10002 Zagreb, Croatia Sinisa Popovic University of Zagreb, Faculty of Electrical Engineering and Computing, Unska 3, 10000 Zagreb, Croatia FRANCE Louis Jehel Psychotraumatologiy Unit, Tenon, University Hospital, Ap-HP, Paris France, 4, rue de la Chine75020, Paris, France GEORGIA George Naneishvili M.Asatiani Research Institute of Psychiatry, 10 Asatiani St., Tbilisi 0177, Georgia

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HUNGARY Zoltan Vekerdi Operational Division, Medical Command, Hungarian Defence Forces, 1885 Budapest PO Box 25, Hungary ISRAEL Naomi Josman Department of Occupational therapy, University of Haifa, Mount Carmel, Haifa, 31905 Israel Joseph Zohar Chaim Sheba Medical Center Division of Psychiatry Tel-Hashomer, 52621 Israel ITALY Gianluca Castelnuova Applied Technology for Neuro-Psychology Istituto Auxologico Italiano, Casello Postale 1-2892, Intra (Verbania), Italy NORWAY Tim Brennen Department of Psychology, University of Oslo Box 1094 Blindern, Oslo 0317, Norway SPAIN Mariano Alcaniz Medical Image Computing Laboratory. Technical University of Valencia. Camino vera s/n. 46022 Valencia, Spain Cristina Botella Department of Psychology, Universitat Jaume I, Campus de Riu Sec, Avda. Sos Baynat s/n, 12071 Castellon, Spain Azucena Garcia-Palacios Department of Psychology, Universitat Jaume I, Campus de Riu Sec, Avda. Sos Baynat s/n, 12071 Castellon, Spain THE NETHERLANDS Paul Emmelkamp Department of Clinical Psychology, Roetersstraat 15, 1018 WB Amsterdam, The Netherlands Elke Geraerts Department of Experimental Psychology, Maastricht University, PO Box 616, 6200 MD, Maastricht, The Netherlands Charles van der Mast Delft University of Technology, Mekelweg 4, 2628 CD Delft, The Netherlands

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THE UNITED KINGDOM John Gruzelier Division of Neuroscience & Mental Health, Faculty of Medicine, Imperial College room 10 L17 Charing Cross Campus St., Dunstan’s Road, London, W6 8RP, England Jamie Hacker Hughes ACDMH, King’s College London, Weston Education Centre, 10 Cutcombe Road, London, England UNITED STATES Amy Adler US Army Medical Research Unit – Europe Nachrichten Kaserne, Karlsruher str. 144 Heidelberg 69126, Germany JoAnn Difede Department of Psychiatry, Weill Cornell Medical College 525 East 68th Street Box 200, New York, New York 10021, USA David Lam University of Maryland Medical School and U.S. Army Telemedicine and Advanced Technology Research Center PSC 79, BOX 145 APO AE 09714, USA Ronald Poropatich US Army Medical Research & Materiel Command 504 Scott Street Fort Detrick Maryland 21702-5012, USA Albert Skip Rizzo University of Southern California Institute for Creative Technologies 13274 Fiji Way, Marina Del Rey, California 90292, USA Barbara Rothbaum Department of Psychiatry, Emory University School of Medicine, 1365 Clifton Road, Atlanta, Georgia 30322, USA Michael Roy Department of Medicine, Uniformed Services University, 4301 Jones Bridge Road, A3062, Bethesda, Maryland 20814, USA Brenda Wiederhold Interactive Media Institute, 6160 Cornerstone Court East, Suite 161, San Diego, CA 92121, USA

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Participants CROATIA Mirjana Grubisic-Ilic University Hospital Dubrava, Department of Psychiatry, Referral Centre for Stress-related Disorders of the Ministry of Health of the Republic of Croatia Avenija Gojka Suska 6 10 000 Zagreb, Croatia Tihana Jendricko University Hospital Dubrava, Department of Psychiatry, Referral Centre for Stress-related Disorders of the Ministry of Health of the Republic of Croatia Avenija Gojka Suska 6 10 000 Zagreb, Croatia Zeljka Mihajlovic University of Zagreb, Faculty of Electrical Engineering and Computing Department of Electronics, Microelectronics, Computer and Intelligent Systems Unska 3 10000 Zagreb, Croatia Dorotea Muck-Seler Division of Molecular Medicine, Ruđer Bošković Institute, PO Box 180, HR-10002 Zagreb, Croatia Miroslav Slamic University of Zagreb, Faculty of Electrical Engineering and Computing, Unska 3, 10000 Zagreb, Croatia CZECH REPUBLIC Pavel Kral Central Military Hospital Prague U Vojenske nemocnice 1200 169 02, Praha 6 Czech Republic Vlastimil Tichy Central Military Hospital Prague U Vojenske nemocnice 1200 169 02, Praha 6 Czech Republic SLOVENIA Robert Donicar NATO COMEDS WG MP ZDRAVSTVENI CENTER MORS, STULA B.S. 1000 Ljubljana, Slovenia Zdravko Strnisa OPK-H. Bracica 2 2000 Maribor, Slovenia

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UNITED STATES Patricia Kraus Department of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, A3056, Bethesda, Maryland 20814, USA

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Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder Michael J. ROY, MD, MPH, FACP 1 Director, Division of Military Internal Medicine, Professor of Medicine Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA

Background Terrorist events, natural and man-made disasters, and intra- and international conflicts over the past 10–15 years have led to increased attention to the prevalence and adverse health consequences of posttraumatic stress disorder (PTSD). PTSD has an estimated 2–5% point prevalence and 8–12% lifetime prevalence in the general population, with higher rates in primary care settings, and even more so in combat veterans [1–9]. It is especially common after terrorism and natural disasters: for example, 60% of those who sought care after terrorist sarin release still met PTSD criteria 6 months later [10], as did 41% of victims of a terrorist bombing in a Paris subway [11]. Likewise, 43% of earthquake survivors in Turkey were diagnosed with PTSD [12]. With 24-hour television news coverage, such events impact an entire society; after the terrorist attacks in the U.S. on September 11, 2001, one in six adults nationwide had persistent distress 2 months later, and this was associated with poorer function at work, avoiding public places, greater worries, and greater use of alcohol and drugs. [13–14] Persistent PTSD has in turn been implicated in reduced societal resistance, delayed communal recovery, and lesser income earned by the individuals with PTSD [15–18]. Preventing persistence of PTSD may help to alleviate these symptoms of distress that impact every corner of a society after war, terrorism, or disasters, and should materially increase the speed of societal recovery from these insults. PTSD unfortunately often goes undiagnosed, and available diagnostic instruments tend to be either cumbersome and time-consuming, or insensitive. PTSD is associated with a variety of somatic symptoms, markedly higher rates of depression and other psychological conditions, poorer physical health, missing work, impaired function at work and at home, and significantly higher healthcare costs. [15–18] PTSD is not only associated with significant adverse impact on quality of life, but it has also proven to be relatively persistent, and it has been difficult to produce durable, full responses to therapy. Selective serotonin reuptake inhibitors result in improvement for many individuals, but remission is sometimes only partial, and there is a sizeable percentage of patients who do not respond or do not continue with pharmacotherapy due to side effects. Cognitive behavioral therapy that incorporates imaginal exposure elements has been found to be effective in multiple clinical trials, and recent expert consensus treatment guidelines characterize it as the non-pharmacologic treatment of choice. [19–20] Re1

Corresponding Author: LTC Michael Roy. Uniformed Services University of the Health Sciences, Department of Medicine, 4301 Jones Bridge Road, A3062. Bethesda, Maryland, 20814, USA. Telephone: (301) 295 9601; Fax: (301) 295 3557; Email: [email protected].

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cent technologic advances make it possible for virtual reality (VR) scenarios to be realistic enough to effectively confront individuals with stimuli associated with their traumatic experience through progressively more intense exposure, neutralizing behavioral cues. In recent years, virtual reality technology has been utilized to help patients overcome a variety of phobias, anxiety disorders and PTSD. In uncontrolled studies, small numbers of Vietnam War veterans and World Trade Center survivors with PTSD have each been reported to improve through the use of progressively more realistic and intense virtual reality exposures. Investigators in multiple nations have published case reports, as well as trials comparing therapeutic approaches that incorporate VR with usual care or waiting list controls, describing success with the use of VR to treat a variety of psychiatric disorders. There have not yet been studies that clearly define the added benefit that VR might provide when used in addition to pharmacotherapy or other approaches with demonstrable efficacy but still large numbers who have inadequate or incomplete responses. PTSD was first defined in veterans of the Vietnam War, but the symptoms that constitute this disorder have been reported from many nations through centuries of warfare. PTSD and other psychologic sequelae often persist long after physical wounds have healed, preventing the return of sizeable numbers of military service members to the battlefield, and thus impairing readiness. Moreover, persistent PTSD often evolves into, or is accompanied by, depression and other psychiatric conditions, resulting in lower response rates once treatment is initiated, and consequently greater morbidity. Undiagnosed and/or untreated PTSD impairs the resilience of military service members both while they remain on active duty, and when they return to society at large. In 1998, the annual cost of PTSD and related anxiety disorders was estimated at $63 billion dollars (50 billion Euros), in the United States alone, with PTSD representing the most significant healthcare utilization and work limitations of all the anxiety disorders. [21–22]

1. Cavtat, June 13–16, 2005 In June, 2005, in the town of Cavtat on the Adriatic coast of Croatia, we brought together many of the leading researchers in the use of VR therapy in psychological disorders. The purpose of this NATO-sponsored Advanced Research Workshop (ARW) was to give these groundbreaking researchers an opportunity to share their experiences and expertise, to achieve consensus on the best methods for incorporating VR in the treatment of veterans of war and terrorism, and to foster multinational collaborative studies in this regard. To achieve this, invited experts shared the most salient findings of recent research with which they have been involved. We then divided all workshop participants into working groups to focus on four key elements of the challenges faced in utilizing VR and other new technologies in the treatment of PTSD: • • • •

Diagnostic and epidemiologic concerns with PTSD Technological challenges in the use of VR Integration of cognitive behavioral therapy and virtual reality approaches Outcomes measurement and issues in follow up

Each working group drafted a consensus document, which the group leader then presented to all ARW attendees. Feedback was solicited to ensure a general consensus

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and the working group leaders incorporated this into the documents that comprise the final four chapters of this book. The workshop opened with a welcome from several Croatian hosts, including Dr. Dragica Kozaric-Kovacic, Professor Kresimir Cosic, and Deputy Prime Minister Jadranka Kosor. Among other things, they emphasized the magnitude of the problem that PTSD poses for Croatia. The best estimates are that there are 10,000 Croatian Homeland War veterans with PTSD, another 1500 veterans have committed suicide, and since the war was fought on their own soil, countless civilians also have been traumatized by the war. It is estimated that 15–40% of Croatian Homeland War veterans have PTSD, and that 50–90% of them have comorbid psychiatric conditions such as depression. Deputy Prime Minister Kosor emphasized that it is also well-recognized that many veterans have delayed manifestations of disability, which is why the Croatian Parliament agreed to render compensation available to those veterans displaying effects within 10 years after the end of the war. Dr. John Gruzelier of Imperial College, London, reviewed the significance of theta waves on electro-encephalograms (EEGs), emphasizing their association with survival behavior, memory, and anatomical areas of the brain that are thought to be of particular importance in PTSD, such as the hippocampus. He also noted the significance of theta waves in autobiographical positive memories as well as flashbacks. Later in the first day of the conference, Dr. Kostovic, Director of the Croatian Institute for Brain Research, expanded upon this to detail the central role of the amygdala and limbic system in pathways that are central in PTSD. In addition, Dr. Nela Pivac from the Rudjer Boskovic Insitute in Croatia reviewed work on the neurobiologic basis for PTSD, particularly associated changes in various neurotransmitter levels. Dr. Dragica Kozaric-Kovacic, Professor of Psychiatry, Director of the Referral Center for Stress-Related Disorders at the University of Zagreb School of Medicine, Croatia, documented that up to 40% of Croatian Homeland War veterans with PTSD had psychotic symptoms. These symptoms were quite well-circumscribed, representing hallucinations specifically related to their combat exposure, rather than the more bizarre hallucinations characteristic of schizophrenia. She also noted that Croatian veterans completing the Minnesota Multiphasic Personality Inventory, Version 2 (MMPI-2) had their highest average scores on scale 8, unofficially known as the “schizophrenia” scale. She believes that those with psychotic symptoms represent a more severe form of PTSD, and it is her experience that treatment with antipsychotic medication is beneficial to these individuals. Finally, Dr. Kozaric also emphasized the high rate of comorbid psychiatric conditions, upwards of 60%, in those with PTSD; alcohol abuse was the single most common comorbid condition. Dr. Tim Brennen, professor of psychology at the University of Norway, and Elke Geraerts, a doctoral candidate at the University of Maastricht in the Netherlands, reviewed their work on the cognitive processes underlying PTSD, as well as their efforts to model what occurs cognitively after traumatization. They described some fascinating work on the effects of PTSD on memory, utilizing lists of words that included both trauma-related and unrelated terms, then asking PTSD and control patients what they were able to remember. Dr. Brennen documented that those with PTSD have greater difficulty forgetting words associated with their trauma, even when asked to try to do so. He also reported that combat veterans with PTSD are more likely than controls to think they heard trauma-related words that were not on the list, but there was no difference for unrelated words. Ms. Geraerts reported similar findings with women victims of sexual assault.

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Dr. Ronald Poropatich, Senior Advisor to the Telemedicine and Advanced Technology Research Center at the US Army Medical Research and Materiel Command, and Dr. Ivica Klapan, Professor of Otorhinolaryngology at the University of Zagreb, each discussed various applications of new technologies. Dr. Poropatich delineated the potential use of personal digital assistants, “smart dog tags” and other digital formats for storing and transmitting medical records information. He also displayed the wide range of applications for robotics to decrease the exposure of soldiers—including medical personnel—in far-forward areas of the battlefield, from detecting chemical weapons to performing surgery at distant sites. Since his talk was tangential to the subject of PTSD, Dr. Poropatich’s presentation is not covered in this book. Dr. Klapan discussed the application of three-dimensional modelling to increase the level of information available pre-operatively, improving surgical approaches. Dr. Michael Roy, Professor of Medicine at Uniformed Services University, provided vivid examples of the face of PTSD in primary care, drawing upon patients he has seen over the years at Walter Reed Army Medical Center. He outlined the challenges in faced in making the diagnosis in primary care, from competing demands to stigmatization, while emphasizing that similar issues are relevant to combat veterans. Dr. Roy noted the lack of validated diagnostic tools for PTSD in primary care, and the need to conduct studies to establish effective screening measures. In addition, he outlined plans to use the “Virtual Iraq” environment described later in the meeting by Dr. Rizzo, integrated with a cognitive behavioral therapy approach as described by Dr. Difede, to assess the added benefit of CBT/VR to pharmacotherapy in combat veterans. Provided that commensurate funding is obtained, current plans are for this study to begin in both Washington and Zagreb in late 2005, enrolling Operation Iraqi Freedom veterans in Washington, and Homeland War veterans in Zagreb. Mr. Sinisa Popovic of the University of Zagreb provided a presentation on behalf of collaboration with Drs. Kresimir Cosic and Miroslav Slamic. He focused on efforts to integrate physiologic measures of subjects, as well as Subjective Units of Distress (SUDs) scales, into software programs to facilitate guided progression of VR exposures, easing the pressure on the therapist to do so. Dr. Tanja Jovanovic of the University of Zagreb described psychophysiologic measures that could prove useful in supplementing or corroborating responses to questionnaires in diagnosing PTSD. These include cardiovascular (heart rate, heart rate variability, blood pressure) measures, respiratory rate, electromyography, electroencephalography, and skin conductance. Each measure adds something different in terms of the rapidity, duration, or other characteristics of the response, and they can be used to distinguish those with PTSD, in addition to later value in directing the progression of therapy. Dr. Louis Jehel reviewed the diagnostic instruments available for PTSD. He noted that the established gold standard, the Clinician Administered PTSD Scale (CAPS) is too lengthy and time-consuming to be used as a broad screening measure. An optimal cut-off score that has high sensitivity and specificity has not yet been established for the 17-item PTSD Checklist (PCL). Other available instruments still lack validation and/or have limitations. Dr. Brenda Wiederhold, Director of the Virtual Reality Medical Center in San Diego, California reviewed the track record of success that VR has had in treating anxiety disorders. She emphasized that one particular strength of VR is that it does not depend on patients’ ability to imagine scenarios, instead directly confronting the patient with the environment, which is especially valuable in conditions such as PTSD, where

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avoidance is a primary feature of the disorder. Dr. Wiederhold noted that the incorporation of VR into a CBT approach has been shown to result in 33% faster response rates in the treatment of agoraphobia, for example. She also discussed the use of VR to conduct stress inoculation training (SIT), drawing parallels between SIT and treatment, with the former addressing peak performers while the latter focuses on the impaired. Dr. Azucena Garcia-Palacios of Valencia, Spain, expanded upon the data favoring the use of VR in phobias and related disorders. She emphasized the advantage of being able to provide exposures under controlled circumstances without the risks inherent in actual in vivo exposures. In fact, she reported data demonstrating that 81% of patients preferred VR over in vivo exposures. For social phobia and panic with agoraphobia, the medical literature documents superiority for VR over waiting list controls, and comparability with in vivo exposures. Dr. Garcia-Palacios also described more recent applications of VR in eating disorders, addictions, pathological grief, autism, and ADHD. She was followed by her colleague, Dr. Cristina Botella, who reviewed the experience of VR in the treatment of PTSD. Dr. Botella noted that therapists have historically underutilized the exposure component in the conduct of CBT, with one study indicating that only 17% of therapists were using it. She reviewed the historical precedents for VR, based upon PIE—proximity, immediacy, and expectancy, developed during and subsequent to the two world wars; this policy was based upon the belief that soldiers would have better outcomes with prompt return to combat, the exposure that was responsible for their symptoms. Dr. Botella also described the EMMA project, a computer-based interactive therapy modality that enables the patient to incorporate their own elements into the virtual environment, with both visual and auditory elements. Dr. Giancarlo Castelnuovo of Milan reviewed the experience of the VEPSY Updated project in the treatment of anxiety disorders, obesity and other eating disorders, and male sexual disorders. He reported that more than 50,000 individuals have accessed the open, free virtual environment they made available on the internet, and over 500 patients have been enrolled in certified controlled clinical trials. The VEPSY Updated project has made considerable gains in identifying the most effective treatment model for a variety of psychiatric disorders. Dr. Barbara Rothbaum from Emory University in Atlanta, Georgia emphasized that the problem with PTSD is one of extinction—trauma has an effect on everyone initially, but it wears off over the ensuing weeks for most, while it becomes disabling for those with PTSD. VR for the latter individuals provides the opportunity to relive the trauma under therapeutic circumstances until it is no longer traumatic. Dr. Rothbaum also reported some promising initial results with d-cycloserine in the augmentation of VR. Dr. Joann Difede of Weill Medical College at Cornell University in New York City described her use of CBT/VR with firefighters responding to the World Trade Center site on September 11, 2001. Dr. Difede reported that nearly 10% of firefighters met full criteria for PTSD, with almost 25% having subsyndromal PTSD. She then outlined the novel therapeutic approach that was initially used in those firemen who had difficulty complying with imaginal exposure in the course of CBT. A virtual environment was developed that incorporated computer-generated images of planes hitting the World Trade Centers with actual audio from newscasts from 9/11. After four sessions in which therapists used a CBT approach including psychoeducational efforts and the introduction of ujayi breathing techniques, VR was introduced and used over the course of another half-dozen or more 75-minute sessions. The use of VR in this manner had an impressively large effect size in comparison to waitlist controls.

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Dr. Naomi Josman of the University of Haifa, Israel, reviewed the added value of occupational therapy with virtual reality exposure therapy, with an examination of occupational performance before and after therapy. She also discussed the significance of “presence” as a measure of the investment of the patient in VR. Dr. Skip Rizzo of the Institute for Creative Technology at the University of Southern California reinforced Dr. Wiederhold’s comments regarding the ability of VR to ensure that those with PTSD are confronted with their virtual environment, so that they can not avoid it, as those with this disorder are often inclined to do. He emphasized the need for inter-institutional collaboration, and highlighted a series of additional investigators using VR in the treatment of PTSD, including Beck at the University of Buffalo for survivors of motor vehicle accidents, and researchers in Portugal treating combat veterans of wars in former Portuguese colonies in Africa in the 1970’s. In addition, Dr. Rizzo described the importance of sensory input other than vision in VR, noting the well-delineated importance of auditory input, as well as the added value of vibration through the use of a platform, and more recent work incorporating smells. He also introduced the concept of using exposure to a virtual environment as a screening tool after military deployment, identifying those with strong physiologic responses as individuals who might benefit from intervention.

2. Working Groups These presentations set the stage for the four working groups described earlier. All ARW attendees actively participated in the deliberations of the working groups, which were held for an entire afternoon on the second day of the ARW. Group leader presentations ensued the following morning, with active feedback provided from other ARW participants.

3. Special Presentation The following morning, a special presentation was provided by Dr. Joseph Zohar, a researcher with years of experience in the evaluation of PTSD in Israeli combat veterans, who reviewed the results of a large case-control study in which PTSD patients were compared to matched controls with regard to demographic and pre-draft cognitive and behavioral testing. In general, while some of these measures were successful in predicting whether one might develop schizophrenia, they were not useful predictors of the development of PTSD. However, those who appeared to have less resources, as evidenced by such measures as having less education, more siblings, reservist status, and immigrant status, were more likely to seek help for PTSD symptoms on the battlefront rather than waiting until after deployment. While their overall prognosis did not appear different, this information can prove useful in making appropriate resources available.

4. PTSD and NATO Operations The ARW was closed out by a special session examining PTSD and NATO operations. This was opened by a graphic presentation from Dr. Zoltan Vekerdi of the Hungarian

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Defense Force. Dr. Vekerdi detailed his eye-witness account of “Black Sunday” in Kabul in 2003, when four Germans and 2 Afghans were killed, while another 35 required medical treatment of injuries—the result of the suicide bombing of a German motorcade which had been headed to the airport to depart the country after completing a tour of duty. Dr. Amy Adler, a psychologist with the US Army Medical Research Unit— Europe, described the results of psychological screening of soldiers returning from deployment to Afghanistan and Iraq. Their results indicated that the 4-question screen known as the PC-PTSD performed as well in this population as the 17-item PTSD Checklist for Military Populations (PCL-M). The PC-PTSD was more desirable on the basis of its brevity, and it has been incorporated in a U.S. Department of Defense form that is routinely used to screen soldiers after deployment. Dr. Adler also highlighted data that indicate screening should be done at 3–6 months after deployment since many do not develop symptoms until that point, rather than immediately upon return. Dr. Randy Boddam, Chief of Psychiatry for the Canadian Defence Force, reiterated the importance of screening at the 3–6 month period, noting the “honeymoon” phenomenon that is associated with improved mood and other symptoms upon immediate return home. He also noted the value of taking care of family members, identifying a strong correlation between problems with family members at home and those of deployed soldiers. Dr. Boddam detailed the Canadian approach to the management of operational stress, which makes a significant attempt to be proactive, beginning with the recruitment process, and including an algorithm that addresses diagnosis and treatment. Dr. Jamie Hacker Hughes of Kings College in London described the workings of the NATO Research and Technology Group (RTG)-20. Their objective is to develop guidelines for military leaders on stress and psychological support to enhance effectiveness in modern military operations. They developed a report to describe fundamental areas of agreement between NATO members that addresses pre-, during, and postdeployment periods. Among the items agreed upon are that all military service members are responsible for monitoring their own mental health, and that the mental health of the unit will enhance—or detract from—the ability of the unit to carry out their mission. They are also conducting a survey of military line unit leaders to determine what they perceive their needs to be with regard to mental health support. Dr. David Lam ended the meeting on a positive note by describing NATO’s Security through Science Program, and the variety of potential funding categories available to researchers through this program. Since this information is available on the NATO website, it has not been included in this volume.

5. Summary This was an effective, valuable meeting, enabling many of the leading researchers in the application of VR to the treatment of PTSD to come together to share their experiences and ideas. It will undoubtedly spur greater international collaboration to further improve the diagnosis and treatment of this challenging disorder that continues to afflict more soldiers from NATO member nations on a daily basis. VR has tremendous potential that is only beginning to be realized, and it is critical to maintain international collaboration as valuable research is being conducted at many different sites. The historical response rate of PTSD to conventional therapy is poor enough to warrant the

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earliest application of novel therapies as they are proven to provide added value. Future meetings should build upon the spirit of collaboration that was fostered in Cavtat in order to further improve the health of those who defend our nations’ borders.

References [1] JRT Davidson, D Hughes, D Blazer, LK George. Posttraumatic stress disorder in the community epidemiological study. Psychol Med 21 (1991), 1–19. [2] RC Kessler, A Sonnega, E Bromet, M Hughes, CB Nelson. Posttraumatic Stress Disorder in the National Comorbidity Survey. Arch Gen Psychiatry 52 (1995), 1048–60. [3] HS Resnick, DG Kilpatrick, BS Dansky, BE Saunders, CL Best. Prevalence of civilian trauma and posttraumatic stress disorder in a representative national sample of women. J Consult Clin Psychol 61 (1993), 984–91. [4] MB Stein, JR Walker, AL Hazen, DR Forde. Full and partial posttraumatic stress disorder: findings from a community survey. Am J Psychiatry 154 (1997), 1114–9. [5] AY Samson, S Bensen, A Beck, D Price, C Nimmer. Posttraumatic stress disorder in primary care. J Fam Pract 48 (1999), 222–7. [6] MB Stein, JR McQuaid, P Pedrelli, R Lenox, ME McCahill. Posttraumatic stress disorder in the primary care medical setting. Gen Hosp Psychiatry 22 (2000), 261–9. [7] N Breslau, GC Davis, P Andreski, E Peterson. Traumatic events and posttraumatic stress disorder in an urban population of young adults. Arch Gen Psychiatry 48 (1991) 216–22. [8] N Breslau, R Kessler, RC Chilcoat, LR Schultz, GC Davis, P Andreski. Trauma and posttraumatic disorder in the community: the 1996 Detroit area survey of trauma. Arch Gen Psychiatry 55 (1998), 626–32. [9] JRT Davidson, HM Tharwani, KM Connor. Davidson Trauma Scale (DTS): normative scores in the general population and effect sizes in placebo-controlled SSRI trials. Depress Anxiety 15 (2002), 75–8. [10] S Ohbu, A Yamashina, N Takasu, et al. Sarin poisoning on Tokyo subway. Southern Med J 90 (1997), 587–593. [11] L Jehel, C Duchet, S Paterniti, SM Consoli, JD Guelfi. [Prospective study of posttraumatic stress in victims of terrorist attacks] (French). Encephale 27 (2001), 393–400. [12] M Basoglu, E Salcioglu, M Livanou. Traumatic stress responses in earthquake survivors in Turkey. J Trauma Stress 15 (2002), 269–76. [13] S Galea, J Ahern, H Resnick, D Kilpatrick, M Bucuvalas, J Gold, D Vlahov. Psychologic sequelae of the September 11 terrorist attacks in New York City. N Engl J Med 346 (2002), 982–7. [14] MA Schuster, BD Stein, LH Jaycox, et al. A national survey of stress reactions after the September 11, 2001, terrorist attacks. N Engl J Med 345 (2001), 1507–112. [15] SE Ullman, JM Siegel. Traumatic events and physical health in a community sample. J Trauma Stress 9 (1996), 703–20. [16] Kessler RC. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry 61, Suppl 5 (2000), 4–14. [17] AW Wagner, J Wolfe, A Rotnitsky, SP Proctor, DJ Erickson. An investigation of the impact of posttraumatic stress disorder on physical health. J Traum Stress 2000;13:41–55. [18] EA Walker, W Katon, J Russo, P Ciechanowski, E Newman, AW Wagner. Health care costs associated with posttraumatic stress disorder symptoms among women. Arch Gen Psychiatry 60 (2003), 369–74. [19] EB Foa, JRT Davidson, A Frances, R Ross. Expert consensus treatment guidelines for posttraumatic stress disorder: a guide for patients and families. J clin Psychiatry 60, suppl 16 (1999), 1–8. [20] RJ Ursano, C Bell, S Eth, et al. Practice Guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry 161, suppl 11 (2004), 1–57. [21] PE Greenberg, T Sisitsky, RC Kessler, et al. The economic burden of anxiety disorders in the 1990s. J Clin Psychiatry 60 (1999) 427–35. [22] RC Kessler. Posttraumatic stress disorder: the burden to the individual and to society. J Clin Psychiatry 61, Suppl 5 (2000), 4–14.

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Contents Preface Key Speakers Participants Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder Michael J. Roy

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Section I. Epidemiology and Pathophysiology of PTSD Biological Markers in Croatian War Veterans with Combat Related Posttraumatic Stress Disorder Nela Pivac, Dragica Kozarić-Kovačić and Dorotea Mück-Šeler Theta Synchronisation of Hippocampal and Long Distance Circuitry in the Brain: Implications for EEG-Neurofeedback and Hypnosis in the Treatment of PTSD John Gruzelier

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Limbic Circuitry and Posttraumatic Stress Disorder Ivica Kostović and Miloš Judaš

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Investigating Cognitive Abnormalities in Posttraumatic Stress Disorder Elke Geraerts and Tim Brennen

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Psychotic Features of Combat Related Chronic Posttraumatic Stress Disorder and Antipsychotic Treatment Dragica Kozarić-Kovačić and Nela Pivac

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Section II. Diagnosis and Screening Efforts to Improve the Diagnosis and Treatment of Posttraumatic Stress Disorder Michael J. Roy and Patricia L. Kraus

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Assessment of Available Diagnostic Instruments for Posttraumatic Stress Disorder Louis Jehel and Kathleen Dullea

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Psychological Screening Validation with Soldiers Returning from Combat Paul D. Bliese, Kathleen M. Wright, Amy B. Adler and Jeffrey L. Thomas Psychophysiological Responses to Trauma-Related Stimuli in PTSD: Potential for Scenario Adaptation in VR Exposure Therapy Tanja Jovanović, Sinisa Popović and Dragica Kozarić-Kovačić

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87

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Section III. Management of Posttraumatic Stress Disorder Pharmacotherapy Research in Posttraumatic Stress Disorder Neven Henigsberg Canadian Forces Approach to the Identification and Management of Operational Stress Injuries Randy Boddam “Stress and Psychological Support in Modern Military Operations” NATO Human Factors and Medicine HFM081 Research Task Group RTG020 History, Status, Objectives and Achievements to Date Jamie G.H. Hacker Hughes, Amy Adler, Vlastimil Tichy and Yves Cuvelier

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111

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Section IV. Virtual Reality Therapy in the Treatment of Posttraumatic Stress Disorder and Related Psychiatric Conditions Scenario Self-Adaptation in Virtual Reality Exposure Therapy for Posttraumatic Stress Disorder Sinisa Popovic, Miroslav Slamic and Kresimir Cosic Advanced Technologies in Military Medicine Brenda K. Wiederhold, Alex H. Bullinger and Mark D. Wiederhold Indications Provided by the Eating Disorder Module of the VEPSY Updated Project: Towards a New Generation of Virtual Environments for Clinical Applications Gianluca Castelnuovo, Gianluca Cesa, Andrea Gaggioli, Fabrizia Mantovani, Mauro Manzoni, Enrico Molinari and Giuseppe Riva

135 148

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Treatment of Mental Disorders with Virtual Reality Azucena Garcia-Palacios, Cristina Botella, Hunter Hoffman, Rosa M. Baños, Jorge Osma, Verónica Guillén and Conxa Perpina

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Clinical Issues in the Application of Virtual Reality to Treatment of PTSD Cristina Botella, Soledad Quero, Nuria Lasso de la Vega, Rosa Baños, Verónica Guillén, Azucena García-Palacios and Diana Castilla

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Virtual Reality in the Treatment of Survivors of Terrorism in Israel Naomi Josman, Azucena Garcia-Palacios, Ayelet Reisberg, Eli Somer, Patrice L. (Tamar) Weiss and Hunter Hoffman

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Virtual Vietnam: Virtual Reality Exposure Therapy Barbara Olasov Rothbaum

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Developing a Virtual Reality Treatment Protocol for Posttraumatic Stress Disorder Following the World Trade Center Attack JoAnn Difede, Judith Cukor, Nimali Jayasinghe and Hunter Hoffman

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A Virtual Reality Exposure Therapy Application for Iraq War Military Personnel with Post Traumatic Stress Disorder: From Training to Toy to Treatment Albert Rizzo, Jarrell Pair, Ken Graap, Brian Manson, Peter J. McNerney, Brenda Wiederhold, Mark Wiederhold and James Spira

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Section V. Other Aspects of Military Healthcare Advanced 3D Computer-Assisted Technologies in Improving Patient Telecare Ivica Klapan, Ljubimko Šimičić and Sven Lončarić

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War Related Stress George Naneishvili, Nino Okribelashvili and Ketevan Gigolashvili

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PTSD – Hungarian Lessons Learned in Afghanistan and Iraq Zoltan Vekerdi and Laszlo Schandl

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Section VI. Working Groups Posttraumatic Stress Disorder --- Diagnostic and Epidemiological Concerns G. Naneishvili

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Technological Challenges in the Use of Virtual Reality Exposure Therapy Charles van der Mast, Sinisa Popovic, Dave Lam, Gianluca Castelnuovo, Pavel Kral and Zeljka Mihajlovic

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Novel Approaches for the Integration of Behavioural Therapy and Virtual Reality 296 Mariano R. Alcañiz, Carmen L. Juan, Beatriz S. Rey and José Antonio Q. Lozano Posttraumatic Stress Disorder: Assessment and Follow-Up Paul M.G. Emmelkamp

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Author Index

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Section I Epidemiology and Pathophysiology of PTSD

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Novel Approaches to the Diagnosis and Treatment of Posttraumatic Stress Disorder M.J. Roy (Ed.) IOS Press, 2006 © 2006 IOS Press. All rights reserved.

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Biological Markers in Croatian War Veterans with Combat Related Posttraumatic Stress Disorder Nela PIVAC a,1 , Dragica KOZARIû-KOVAýIû b and Dorotea MÜCK-ŠELER a a,1 Division of Molecular Medicine, Ruÿer Boškoviü Institute, Zagreb, Croatia b Referral Centre for the Stress Related Disorders of the Ministry of Health of the Republic of Croatia, Department of Psychiatry, Dubrava University Hospital, Zagreb, Croatia

Abstract. Posttraumatic stress disorder (PTSD) is a severe psychiatric illness associated with disturbances in diverse neurobiological systems. The evaluation of a variety of biomarkers might facilitate a goal of modern medicine, a proper treatment for an individual patient at a given stage of disease. This is especially important in PTSD, a disorder with a complex clinical picture, diverse symptoms, and frequent comorbidities. Biological markers (platelet serotonin, platelet monoamine oxidase, plasma lipid levels, plasma dopamine beta hydroxylase, plasma cortisol and serum levels of thyroid hormones) were determined, and clinical symptoms were evaluated, in 93 male war veterans with chronic combat related PTSD, using the Clinician Administrated PTSD Scale, Positive and Negative Syndrome Scale, and the Hamilton Rating scales for Depression and Anxiety. Platelet serotonin concentration and plasma dopamine beta hydroxylase activity were similar in PTSD subjects and healthy controls. Platelet monoamine oxidase activity, and plasma/serum levels of total and free triiodothyronine and cortisol were increased in war veterans with PTSD compared to controls, indicating that these biomarkers might be used as the trait markers in PTSD. Since a great proportion of our war veterans with chronic combat related PTSD had a severe form of PTSD, complicated with the presence of psychotic or depressive symptoms, further studies are underway to elucidate the association between biological markers and particular symptoms occurring in PTSD.

Keywords. Combat related Posttraumatic Stress Disorder, War veterans, Blood Platelets, Serotonin, Monoamine Oxidase, Plasma Lipid Levels, Dopamine Beta Hydroxylase, Plasma Cortisol Levels, Free and Total Triiodothyronine

Introduction Posttraumatic stress disorder (PTSD) is a severe psychiatric disorder, classified as an anxiety disorder that occurs in some individuals exposed to a life-threatening traumatic event. PTSD is characterized by specific clusters of symptoms: reexperiencing the 1

Corresponding Author: Nela PIVAC, Division of Molecular Medicine, Rudjer Boškoviü Institute, POBox 180, HR-10002 Zagreb, Croatia, E-mail: [email protected]

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N. Pivac et al. / Biological Markers in Croatian War Veterans with Combat Related PTSD

trauma, numbing of responsiveness and avoidance, and hyperarousal. War trauma and combat experience result in a high prevalence of PTSD. The disorder is often chronic, frequently complicated with comorbid psychiatric diagnoses such as major depressive disorder, anxiety, mood and substance use disorders. Socio-cultural but also geographically specific comorbidities have been proposed [1,2]. In extensive studies using an ethnically homogenous population of Croatian war veterans with combatrelated PTSD [3], a high prevalence of comorbid diagnoses were found [4]. The most frequent comorbidities were depression, alcohol and drug abuse, panic disorder and phobia, psychosomatic disorder, psychotic disorders, and dementia [5,6]. Recent studies identified a specific, severe, psychotic subtype of PTSD, unresponsive to antidepressant treatment [5-10]. Biomarkers might be used for preclinical screening, diagnosis, disease staging, and monitoring of treatment, and their utility becomes especially important in PTSD, a disorder with a complex clinical picture, diverse symptoms, and variable course, that is complicated by various comorbidities. Disturbances in multiple neurobiological systems (e.g., GABA, glutamate, noradrenalin, dopamine, serotonin, acetylcholine, opioids, and the hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitarythyroid (HPT) axes), are responsible for the diverse clinical symptoms (avoidance, anxiety, flashbacks, nightmares, hyperarousal, numbing, anger, impulsivity, aggression) occurring in PTSD [11-14]. In the studies evaluating biological markers in Croatian war veterans with combat related PTSD, we investigated platelet serotonergic markers, i.e. platelet serotonin (5hydroxytryptamine, 5-HT) concentration [15,16], platelet monoamine oxidase (MAO) activity [16,17], plasma lipid levels [18], plasma dopamine beta hydroxylase (DBH) activity [19], plasma cortisol levels [20], and serum thyroid hormones [21].

1. Materials and methods 1. 1. Participants Ninety three subjects with combat related PTSD participated in the study. All participants were Croatian male war veterans, aged 28-48 years, all Caucasians, who were hospitalized at the Referral Centre for the Stress Related Disorders of the Ministry of Health of the Republic of Croatia, Regional Center for Psychotrauma, in the University Hospital Dubrava, Zagreb, Croatia, from 1999 to 2002. The diagnosis of current and chronic PTSD was conducted according to the Structured Clinical Interview based on DSM-IV(SCID). The subjects were asked to describe their traumatic experiences and were given enough time to talk about these and other psychiatric disturbances. Different clinical symptoms (trauma-related, psychotic, and depressive), occurring in this cadre of war veterans were assessed with the CAPS, the Positive and Negative Syndrome Scale (PANSS), and the Hamilton Rating Scales for Depression (HAM-D) and Anxiety (HAM-A). All patients were war veterans who had been on active duty in the Croatian armed forces (range of 1-4 years, most with 3 years of continuous combat experience), had similar social and cultural backgrounds, and the great majority were married. All were screened with a comprehensive multidisciplinary evaluation (conducted by 2 psychiatrists and a psychologist) prior to entry into inpatient treatment. Subjects were excluded from the study if they had a positive family

N. Pivac et al. / Biological Markers in Croatian War Veterans with Combat Related PTSD

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history of psychosis, or a history of schizophrenia, schizoaffective disorder or bipolar disorder, a serious concomitant medical condition, a history of seizures or misuse of alcohol or drugs (recent use of any psychotropic drugs within one month of baseline), clinically significant abnormalities in electrocardiogram or laboratory findings, or a serious risk of suicide. Combat-related symptoms included intrusive images of screaming soldiers, fire, bombing, rocketing, etc. Individuals taking cholesterollowering drugs were excluded. The procedures were fully explained and written informed consent was obtained from all patients. The local Ethics committee approved this protocol. The control group consisted of 124 healthy male volunteers, with no personal or family history of psychopathology, and receiving no medical treatment. None of the healthy subjects were receiving psychiatric or related treatment before the samples were selected. Groups were matched on age, gender, smoking, and other socio-demographic characteristics. The control subjects agreed, and provided written informed consent, to participate in the study and to provide a blood sample. 1.2. Biochemical determination A forearm vein was cannulated for blood sampling at 08.00 a.m., after an overnight fasting. Blood samples (8 ml) were drawn in a plastic syringe with 2 ml of acid citrate dextrose anticoagulant. Platelet-rich-plasma (PRP) was obtained by centrifugation (935 x g) for 70 s at room temperature. Platelets were sedimented by further centrifugation of PRP at 10,000 x g for 5 min. The platelet pellet was washed with saline and centrifuged again. Platelet 5-HT concentration was determined by the spectrofluorimetric method, as previously described [15,16,22]. Platelet MAO activity was determined spectrofluorimetrically using kynuramine as a substrate, as previously described [16]. Platelet protein levels were measured by the method of Lowry et al. [23]. Serum lipid levels—total cholesterol, high-density lipoprotein (HDL), and triglycerides (TG) levels—were determined by enzymatic color test, while serum lowdensity lipoprotein (LDL) levels were measured using an enzymatic clearance assay. Serum thyroid hormones: total and free triiodothyronine (T3) levels were assayed using an luminoimmunochemical assay kit (Johnson and Johnson Clinical Diagnostic Products, Amersham, UK). Plasma DBH activity was determined by a photometric assay, using tyramine as a substrate, by the method of Nagatsu and Udenfriend [24]. Cortisol levels were determined using a commercially available radioimmunoassay kit from Diagnostic Products Cooperation, CA, USA. 1.3. Data analysis All data (expressed as mean ± S.D.) were evaluated by one-way analysis of variance (ANOVA), followed by Tukey’s multiple comparison test. The level of significance was p0.05, one way ANOVA) was found between the age of war veterans (39.7 ± 8.5 years) and control subjects (38.4 ± 11.9 years).

Table 1. Mean scores in CAPS, PANSS, HAMD and HAMA scales and subscales in 93 war veterans with chronic combat related PTSD

Measures CAPS total PANSS total PANSS positive PANSS negative PANSS general psychopathology PANSS supplementary items HAMD HAMA

Scores (mean r SD) 81.2 84.3 16.9 12.4 45.8 9.2 21.5 24.4

r r r r r r r r

13.1 20.9 6.5 5.1 9.5 2.4 4.8 6.4

Platelet 5-HT concentration did not differ significantly (F=0.069, df=1,152 p=0.079, one way ANOVA) between war veterans with PTSD and control subjects (Figure 1). Plasma cortisol levels differed significantly between groups (Table 2). Plasma cortisol levels were significantly higher (p