Handbook of Clinical Neurology, Vol. 106 (3rd series)Neurobiology of Psychiatric DisordersT.E Schlaepfer and C.B. Nemeroff, Editors# 2012 Elsevier B.V. All rights reserved

Chapter 18

Biological and clinical framework for posttraumatic

stress disorder

ERIC VERMETTEN1 * AND RUTH A. LANIUS2

1Department of Psychiatry, University Medical Center; Rudolf Magnus Institute of Neurosciences, Utrecht, The Netherlands2University of Western Ontario, London, Ontario, Canada

INTRODUCTION

Overview

The study of the psychological and emotional conse-quences of traumatic stress has become a burgeoningand important field in psychiatric research and treat-ment. In fact, the diagnosis of posttraumatic stressdisorder (PTSD) is now so frequently made that onewonders how we once got by without it. PTSD is of par-ticular interest in the 21st century, when the entire worldis filled with the specter of terrorism – a stressor of greatmagnitude that can strike any time and anywhere. It isalso a time when we again have many young soldiersreturning from yet another war: the treacherous combatexperience in Iraq and Afghanistan. Moreover, societyis increasingly affected by various other types of humanviolence, including killing, rape, robberies, assault, aswell as other psychological traumas, such as large-scalenatural disasters (hurricanes, floods), man-made dis-asters, and train, plane and other accidents. These eventscan leave the individual with intense terror, fear, andparalyzing helplessness.

About 60% of men and 50% of women have experi-enced one of these psychological traumas (defined asthreat to life of self or significant other) at some timein their lives. As many as 39% of these individualsexposed to a traumatic event will develop PTSD. Thelifetime prevalence of PTSD in the USA is estimatedat 7.8% and is twice as common in women as in men.This is more than twice the prevalence of bipolar disor-der or schizophrenia. For the Netherlands the lifetimeprevalence of exposure to any potential trauma was80.7%, and the lifetime prevalence of PTSD was 7.4%.

*

Correspondence to: Eric (H.G.J.M.) Vermetten, MD, PhD, HeadHealth, Ministry of Defense, Assoc. Prof. Psychiatry, University

Lundlaan 1, 3584 EZ Utrecht, The Netherlands. Tel: þ31 30 250259

Similar to the US data, women and younger personsshowed higher risk of PTSD (de Vries and Olff,2009). Despite events that qualify as traumagenic, a rel-ative minority of those exposed will develop PTSD.Many questions have emerged to explain the factorscontributing to the risk for the disorder as well as factorsthat contribute to resilience. This chaper will focus onthe disorder and the current state of knowledge.

The conditional probabilities for PTSD after experi-encing traumas, risk factors and comorbidity patternsare quite similar in different populations (Perkonigget al., 2000). The highest risk of PTSD is associated withassaultive violence (20.9%); the trauma most oftenreported as the precipitating event among persons withPTSD is sudden unexpected death of a loved one.Women are still at higher risk of PTSD than men, con-trolling for type of trauma (Breslau et al., 1998). Acrossstudies PTSD is strongly comorbid with other lifetimepsychiatric disorders. More than one-third of peoplewith an index episode of PTSD fail to recover even aftermany years (Kessler et al., 1995). PTSD is most oftenrecognized as being related to wartime experiences,and only relatively recently has it been recognized asbeing associated with other types of trauma (Weisaethand Eitinger, 1993; Wilson, 1994; Saigh and Bremner,1999). PTSD is increasingly recognized as being presentin diverse cultures (Kleber et al., 1995; Allen, 1996)where, for example, Latino patients typically view theirsymptoms as impairing health and functioning,and describe their symptoms as being sad, anxious,nervous, or fearful (Eisenman et al., 2008).

The diagnosis of PTSD was first included in the thirdedition of the Diagnostic and Statistical Manual of

of Research Military Mental Health, Staff Military MentalMedical Center, Rudolf Magnus Institute of Neuroscience,

1, Fax: 31 30 2502282, E-mail: e.vermetten@umcutrecht.nl

Table 18.1

Comparison of International Classification of Diseases

(ICD) and Diagnostic and Statistical Manual of MentalDisorders (DSM) diagnoses of traumatic stress

Year ICD DSM

1948 ICD-6

Acute situationalmaladjustment

1952 DSM-ITransient situational personality

disturbanceGross stress reactionAdult situational reaction

Adjustment reaction of infancy,childhood, adolescence, orlate life

1968 ICD-8Transientsituational

disturbance

DSM-IIAdjustment reaction of infancy,childhood, adolescence, or late

life1977 ICD-9

Acute reaction tostress with

predominantdisturbance ofemotions,

consciousnessorpsychomotor

disturbance, ormixed

1980 DSM-IIIPosttraumatic stress disorder

1987 DSM-IIIRPosttraumatic stress disorder

1992 ICD-10

Acute stressreaction

Posttraumatic

stress disorderEnduring

AND R.A. LANIUS

Mental Disorders (DSM-III) in 1980 (American Psychi-atric Association (APA), 1980), where it was, and in theupdated version of this manual in 1994 (DSM-IV), stillis, categorized as an anxiety disorder. Its first appear-ance in the International Classification of Diseases(ICD) is of more recent date (WHO, 1992)(Table 18.1). For DSM-V, due to be released in 2013,the classification may still the same; however, propo-sals have been made to group the disorder with othertrauma-based disorders in a trauma or stress spectrumclassification (Kinzie and Goetz, 1996; Moreau andZisook, 2002).

Over the last three decades there has been an expan-sion of studies on PTSD, resulting in a significantincrease in our knowledge of the prevalence, phenome-nology, and neurocircuitry of PTSD (Ursano et al., 1994;Vermetten and Bremner, 2002a, b; Nutt et al., 2009;Jovanovic and Ressler, 2010). The literature on thisdiagnosis is now vast. It goes far beyond the descriptivepsychopathology upon which the original DSM-IIIdefinition was based. There is a multitude of papers cov-ering topics such as neural mechanisms as revealed inimaging studies, risk factors, prevalence, comorbidity,symptom patterns, and outcome. Over 15 000 scientificpapers have been published on PTSD in the last 40 years,as well as numerous books and dissertations. The Amer-ican Journal of Psychiatry has shown the greatest inter-est in PTSD overall, publishing over 200 papers on thisdisorder in the last 10 years alone, by far more than anyother journal in the field of general psychiatry. Biolog-ical Psychiatry has also shown a marked increase inpublications of papers focusing on PTSD in recentyears. In addition, the Journal of Traumatic Stress isa specialty journal that started in 1987 and deals withall PTSD-related issues. In 2010 a new specialty journalemerged carrying the name psychotraumatology in it:the European Journal of Psychotraumatology. Thischapter will highlight these findings in PTSD and givea comprehensive overview on the history, diagnosis, ep-idemiology, and treatment of the disorder.

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personality

changes aftercatastrophicexperience

1994 DSM-IV

Acute stress disorderPosttraumatic stress disorder

2013 DSM-V (proposed)

Acute stress disorderPosttraumatic stress disorderComplicated grief

Developmental trauma disorder2015 ICD-11

(scheduled)

The one conditional probability of PTSD isexposure to extreme threat

Both acute stress disorder (ASD) and PTSD are the onlypsychiatric conditions whose definition demands that aparticular stressor precede their appearance. ASD willnot be discussed in detail here; suffice to say thatthe majority of people who develop PTSD do not initiallymeet the criteria for ASD, leading to the conclusionthat ASD is not a predictor of chronic PTSD (Bryantet al., 2008).

PTSD is characterized by specific symptoms thatdevelop following exposure to psychological trauma,

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defined as a situation in which a person experienced,witnessed, or was confronted with an event or eventsthat involved actual or threatened death or seriousinjury, or a threat to the physical integrity of self orothers, and where the person’s response involved intensefear, helplessness, or horror. According to DSM-IV(APA, 1994), PTSD can result from a variety of trau-matic stressors (Table 18.2), interpreted by the subjectiveexperience of the individual: military, violent personalassault (sexual, physical assault, criminal assault, rob-bery, mugging), being kidnapped, being taken hostage,terrorist attack, torture, incarceration as a prisoner of

BIOLOGICAL AND CLINICAL FRAMEWORK

Table 18.2

Types of extreme stressors – A criterion events

A1: The stressor must beextreme, not just severe

The event involved actual orthreatened death, serious

injury, rape, or childhoodsexual abuse. Would notinclude many frequentlyencountered stressors that

are severe but not extreme(e.g., losing a job, divorce,failing in school, expected

death of a loved one)A2: The stressor causespowerful subjective

responses

The person experienced intensefear, helplessness, or horror

Type of stressor Examples

Serious accident Car, plane, boating, or

industrial accidentNatural disaster Tornado, hurricane, flood, or

earthquake

Criminal assault Being physically attacked,mugged, shot, stabbed, orheld at gunpoint

Military Serving in an active combattheater

Sexual assault Rape or attempted rape

Child sexual abuse Incest, rape, or sexual contactwith an adult or much olderchild

Child physical abuse or

severe neglect

Beating, burning, restraints,

starvation

Hostage/imprisonment/

torture

Being kidnapped or taken

hostage, terrorist attack,torture, incarceration as aprisoner of war or in a

concentration camp,displacement as a refugee

Witnessing or learningabout traumatic events

Witnessing a shooting ordevastating accident,

sudden unexpected death ofa loved one

war or in a concentration camp, or natural or man-madedisasters (severe automobile accidents, being diagnosedwith a life-threatening disease, or other threat to life).

Over time the events qualifying for extreme threathave been extensively debated and have stretched from“outside the range of human experience” to exposure tothe threat, as expressed in DSM-IV (APA, 1994). PTSDmay be induced by observing events such as the seriousinjury or unnatural death of another person due to vio-lent assault, accident, war, or disaster, or unexpectedlywitnessing a dead body or body parts (Zisook et al., 1998;Ursano et al., 1999). Sexually traumatic events may in-clude developmentally inappropriate sexual experienceswithout threatened or actual violence (Davidson et al.,1989). Traumatization can also occur where theindividual receives information about the stressfulexperiences of others such as personal assault, seriousaccident, or serious injury experienced by a family mem-ber or a close friend, or learning that one’s child has alife-threatening disease, if this is associated with intensefear, helplessness, or terror. Psychological trauma mayoccur as a single episode or repetitive ongoing trauma(such as sexual or physical abuse). It must be notedhere that prior and cumulative effects of trauma are aparticularly important determinant of risk for PTSD(Breslau et al., 2008).

EPIDEMIOLOGY

Prevalence

When the prevalence of traumatic events was systemat-ically examined, it became apparent that trauma wassurprisingly commonplace. Several studies have sinceinvestigated the overall prevalence of traumatic eventsin the general population, looking at community-basedpopulations (Bronner et al., 2009; Kaltman et al., 2010),populations of individuals at high risk for trauma or ex-posed to events such as natural disasters (Acierno et al.,1999), or the elderly (Spitzer et al., 2008). In a study byResnick et al. (1993), 4008 adult women randomly se-lected from a US nationwide sampling were interviewedover the phone. Prevalence of crime and noncrime civil-ian traumatic events, lifetime PTSD, and PTSD in thepast 6 months were assessed by telephone interview.The authors found a lifetime exposure to any type oftraumatic event of 69%, whereas exposure to crimesthat included sexual or aggravated assault or homicideof a close relative or friend occurred among 36%. Over-all sample prevalence of PTSD was 12.3% lifetime and4.6% within the past 6 months. The rate of PTSD wassignificantly higher among crime versus noncrimevictims (25.8% versus 9.4%). Norris (1992) assessedthe frequency and impact of 10 potentially traumaticevents in a sample of 1000 men and women drawn from

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four southeastern US cities. Over their lifetimes, 69% ofthe sample experienced at least one traumatic event,while 21% experienced a traumatic event in the past yearalone. The 10 events varied in importance, with tragicdeath occurring most often, sexual assault yieldingthe highest rate of PTSD, and motor vehicle accidentpresenting the most adverse combination of frequencyand impact. Numerous differences were observed inthe prevalence of these events across demographicgroups. Lifetime exposure was higher among whitesand men than among blacks and women; past-yearexposure was highest among younger adults. When im-pact was analyzed as a continuous variable (perceivedstress), black men appeared to be most vulnerable tothe effects of events, and young people showed thehighest rates of PTSD.

Kessler et al. (1995) reported a landmark study in alarge national sample of 5877 individuals aged15–54 years. This study obtained information on esti-mated lifetime prevalence of trauma and PTSD, thekinds of trauma that were most often associated withPTSD, sociodemographic correlates, the comorbidityof PTSD with other lifetime psychiatric disorders, andthe duration of an index episode. The estimated lifetimeprevalence of PTSD was found to be 7.8%. Prevalencewas elevated among women and the previously married.The traumas most commonly associated with PTSDwere combat exposure and witnessing of violenceamong men, and rape and sexual molestation amongwomen. PTSD was strongly comorbid with other life-time DSM-IIIR disorders. Survival analysis showedthat more than one-third of people with an index episodeof PTSD failed to recover even after many years.

Another study by Breslau et al. (1999a) involved 2181individuals in the USA, aged 18–45 years, who wereinterviewed by telephone to assess the lifetime history oftraumatic events and PTSD. PTSD was assessed using amodified version of the DSM-IV and ICD-10 criteria.The risk of PTSD following exposure to trauma was9.2%. The highest risk of PTSD was associated with as-saultive violence (20.9%). The traumamost often reportedas the precipitating event among individuals with PTSD(31% of all PTSD cases) was sudden unexpected deathofa lovedone,anevent experiencedby60%of the sample,and with a moderate risk of PTSD (14.3%), indicating theimportance of traumatic grief. Women were at higherrisk for PTSD than men, controlling for type of trauma.Although recent research had focused on combat, rape,and other assaultive violence as causes of PTSD, suddenunexpected death of a loved one was considered a farmore important cause of PTSD in the community,accounting for nearly one-third of PTSD cases.

Spitzer et al. (2008) assesssed PTSD in 3170 adultsliving in a German community and divided them into

294 E. VERMETTEN

three age groups: young (44 years and younger;n ¼ 997), middle-aged (45–64 years; n ¼ 1322), andelderly (65 years and older; n ¼ 851). At least onetrauma was reported by 54.6%, and the odds for traumaexposure were almost fourfold in the elderly comparedto the younger age groups. Among those who were trau-matized, the lifetime and 1-month prevalence rates ofPTSD in the elderly were 3.1% and 1.5%, respectively,and did not differ from the rates in the young andmiddle-aged adults. PTSD is certainly not rare in theelderly and a lifetime diagnosis of PTSD is associatedwith symptoms of depression and anxiety. Assessmentof trauma and PTSD should be integrated into routineexaminations of the elderly to improve managementand treatment provisions. These studies led to the conclu-sion that PTSD ismore prevalent thanpreviously believedand that PTSD often persists throughout the lifespan.

In summary, exposure to traumatic events is com-monplace. Most studies report prevalence twice as highin females compared to males. The majority of exposedsubjects are resilient, as this is still the rule rather thanthe exception.

ETIOLOGY

Multiple variables play a role in the development oftrauma-related psychopathology. Models of PTSD takeinto account genetic constitution, prestressor factors(defined as vulnerability), peritraumatic factors (charac-teristics of stress, of length of dissociative response),and poststressor factors in the development of PTSD(for a review, see Bremner et al., 1995a) (Fig. 18.1).

Genetic contribution

Early genetic contributions to PTSD have been studiedusing monozygotic twins. Goldberg et al. (1990) studiedthe impact of military service during the Vietnam era(1965–1975) on PTSD using a sample of 2092 male–male, monozygotic, veteran twin pairs. In 715 monozy-gotic twin pairs who were discordant for military servicein South-East Asia (SEA), PTSD was found to bestrongly associated with military service in SEA. Theprevalence of PTSD was 16.8% in twins who served inSEA compared with 5.0% in cotwins who did not servein SEA. There was a ninefold increase in the prevalenceof PTSD comparing twins who experienced high levelsof combat with their cotwin who did not serve in SEA(Goldberg et al., 1990). True et al. (1993) followed upon this and looked at effects of heredity, shared environ-ment, and unique environment on the liability for 15 self-reported PTSD symptoms, studying 4042 Vietnam-eraveteran monozygotic and dizygotic male twin pairs.Quantitative genetic analysis revealed that inheritancehad a substantial influence on liability for all symptoms.

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Behavior and Emotional ChangeBiological Alterations

Trauma orDaily LifeEvents inAdulthood

Vulnerability to Stress and LifeEvents

- HPA-axis/CRF systemhyperactivity- NE system hyperactivity- Impaired neurogenesis in HC- Neurotoxicity in HC- Altered GR

Vulnerable Phenotype

Early Life StressGenetic Predisposition

- Stress regulation - Memory impairment - Emotion regulation intrusion - Avoidance - Hyperarousal - Alterations in cognition and mood

PTSD represents a stress-sensitized, fear-conditioned clinical phenotype characterizedby a high allostatic load

Fig. 18.1. Diagrammatic presentation of pathways of posttraumatic stress disorder (PTSD) development. HPA, hypothalamic–

pituitary–adrenal axis; CRF, corticotropin-releasing factor; NE, norepinephrine; HC, hippocampus; GR, glucocorticoid receptor.

BIOLOGICAL AND CLINICAL FRAMEWORK FOR POSTTRAUMATIC STRESS DISORDER 295

The field of genetics has developed very rapidly.Although twin studies suggest that genetic influencesaccount for substantial variance in PTSD risk, more pro-gress needs to be made in identifying variants in specificgenes that influence liability to PTSD (Koenen et al.,2009). Identification of liability genes would representa major advance in understanding the pathophysiologyof the disorder. Such understanding could also advancethe development of new pharmacological agents forPTSD treatment and prevention.

Yet, the complex etiology of PTSD, for which experi-encing a traumatic event forms a necessary condition,makes it difficult to identify specific genes that substan-tially contribute to the disorder. Gene-finding strategiesare difficult to apply. Interactions between differentgenes, and between them and the environment, probablymake certain people vulnerable to developing PTSD.Gene–environmental studies are needed that focus morenarrowly on specific, distinct endophenotypes and oninfluences from environmental factors (Broekmanet al., 2007; Koenen et al., 2008).

Recently reported genetic association studies indi-cate that these effects may be mediated, in part, bygene–environment interactions involving polymor-phisms within two key genes, CRHR1 and FKBP5.Data suggest that these genes regulate hypothalamic–pituitary–adrenal (HPA) axis function in conjunctionwith exposure to child maltreatment or abuse. In addi-tion, a large and growing body of preclinical researchsuggests that increased activity of the amygdale–HPAaxis induced by experimental manipulation of theamygdala mimics several of the physiological and be-havioral symptoms of stress-related psychiatric illnessin humans. Notably, interactions between the developingamygdala and HPA axis underlie critical periods foremotional learning, which are modulated by develop-mental support and maternal care. These translationalfindings are leading to an integrated hypothesis: highlevels of early-life trauma lead to disease through thedevelopmental interaction of genetic variants with neu-ral circuits that regulate emotion, together mediatingrisk and resilience in adults (Gillespie et al., 2009).

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Early-life trauma

Epidemiological data suggest that early-life trauma ishighly prevalent, not only in the USA, but internation-ally. In fact, the public health burden of childhoodtrauma may be greatest in the developing world, partic-ularly in places that are experiencing ongoing conflictand violence. Childhood physical or sexual abuse is astrong predictor of PTSD later in life, and can be consid-ered a “hidden epidemic” (Lanius et al., 2010b). Studiesof both child and adult populations over the last 25 yearshave established that, in a majority of trauma-exposedindividuals, traumatic stress in childhood does not occurin isolation, but rather is characterized by co-occurring,often chronic, types of victimization and other adverseexperiences (Dong et al., 2004; van der Kolk et al., 2005;Anda et al., 2006). Despite the methodological chal-lenges to estimate the prevalence of specific types ofchildhood trauma, such as abuse and neglect, extantresearch has come to some consensus as to the individ-ual, family, and community-level factors that increaserisk of childhood trauma. A survey of 1699 childrenreceiving trauma-focused treatment across 25 networksites of the National Child Traumatic Stress Network(Spinazzola et al., 2005) showed that the vast majority(78%) were exposed to multiple and/or prolonged inter-personal trauma, with a modal 3 trauma exposure type;less than 25% met diagnostic criteria for PTSD. Fewerthan 10% were exposed to serious accidents or medicalillness. Most children exhibited posttraumatic sequelaenot captured by PTSD, yet at least 50% had significantdisturbances in affect regulation, attention and concen-tration, negative self-image, impulse control, aggres-sion, and risk-taking (Spinazzola et al., 2005).

There is consensus on the importance of attachmentfigures for very young children and on the fact that thetraumatization of mother or father can be as damagingfor an infant as direct exposure (Al-Turkait and Ohaeri,2008). In a review of 17 studies on the relational contextof PTSD in very young children, Scheeringa et al. (2005)consistently found a relation between psychopathologyin parents and maladaptive outcomes in children. Yetthere is a need to elucidate the mechanisms of the trans-mission of trauma in order to understand better theeffect of trauma on very young children. Informationon the pathways of influence of trauma on childrenwould provide new directions for the design and imple-mentation of prevention measures and early therapeuticinterventions (Heidenreich et al., 2010).

As stated earlier, early trauma in the form of child-hood physical or sexual abuse has been associated withadult psychopathology in the stress sensitizationmodel: prior stressors increase the risk for PTSD withre-exposure to stress (for reviews, see Bremner et al.,

1999a,b). Consistent with this, Vietnam veterans withPTSD had higher rates of childhood physical abuse thanVietnam veterans without PTSD (26% versus 7%). Theassociation between childhood abuse and PTSD per-sisted after controlling for the difference in level ofcombat exposure between the two groups. Patients withPTSD also had a significantly higher rate of total trau-matic events before joining the military than patientswithout PTSD. This supported the notion that childhoodphysical abuse may be an antecedent to the developmentof combat-related PTSD in Vietnam combat veterans(Bremner et al., 1993).

Disasters

The potential for disasters exists in all cultures and com-munities.The Buffalo Creek disaster of 1972 involvingthe collapse of a slag dam and subsequent flood in WestVirginia was one of the most extensively studied naturaldisasters of recent history, followed by the 11 September2001 terrorist attack on the World Trade Center in NewYork (9/11), the 2004 tsunami, and hurricane Katrina(Smith et al., 2009). The rate of disaster-related PTSDin this study was 7%, down from a postflood rate atfollow-up of 32%. There were no differences by agegroup in their current psychological status; however,women demonstrated more PTSD-related symptomsthan did men (Green et al., 1990, 1994). Initially, intru-sive symptoms, nightmares, and sleep disturbances werethe most frequent difficulties. An exaggerated startleresponse was somewhat more frequent than avoidanceand numbing symptoms, such as loss of interest andcaring (Green et al., 1994). Survivor guilt was a relativelyuncommon phenomenon in disaster-affected popula-tions and was possibly one of the reasons why it was leftout of the DSM-IV criteria for PTSD.

Longitudinal studies on earthquake survivors (Carret al., 1997; Goenjian et al., 2000) have found that initialearthquake experiences have an enduring mental healtheffect that is only partially ameliorated over time, andPTSD symptoms tend to persist for an extended periodof time following extreme earthquake trauma. In gen-eral, the first year was the time of peak symptomsand effects, and people did improve over time. Yet inmany studies symptoms lingered for months, evenyears, for a significant minority of participants(Norris, 2002).

Relatively few studies have followed cohorts ofexposed people to assess the long-term impact on bothphysical and psychological health combined in health-related quality of life. Beehler et al. (2008) performedin-person interviews in 381 men and women from twogeographical areas of differing radiation contaminationwithin Belarus, the area that was affected by the

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Chernobyl disaster. It was found that long-term psycho-logical distress in this group was better predicted bystress-moderating psychosocial factors present in one’sdaily life than by level of residential radiation contami-nation. Neria et al. (2008) followed up on mental healthconsequences in 929 persons who had 9/11-related lossand found that this was significantly related to extremepain interference, work loss, and functional impairment.McFarlane and Van Hooff (2009) reported on thefollow-up of 1011 adults recruited from an original sam-ple of 1531 people who had been exposed 20 years earlierto an Australian bushfire disaster, showing only a smalldirect impact of the fires on adult psychiatric morbidity.

North et al. (1999) reported on a follow-up on theterrorist Oklahoma City bombing in 1995, where a bombblast killed 168 people. In their sample of 182 participat-ing adults, 45% had a postdisaster psychiatric disorderand 34% had PTSD. The onset of PTSD was swift, with76% reporting same-day onset. The relatively uncom-mon avoidance and numbing symptoms virtuallydictated the diagnosis of PTSD (94% of subjects meetingavoidance and numbing criteria had full PTSD diagno-sis) and were further associated with psychiatric comor-bidity, functional impairment, and treatment received.Intrusive re-experiencing and hyperarousal symptomswere nearly universal, but by themselves were generallynot associated with other psychopathology or impair-ment in functioning (North et al., 1999).

The event with the greatest number of peer-reviewed,event-specific publications was 9/11. Interest in publish-ing medical disaster-related articles has increased tre-mendously since 9/11 (Kelen and Sauer, 2008). Mostrecent studies report variables that are necessary tomake an estimate of prevalence and to interpret therelevance in relation to the course of PTSD: nature ortype of the trauma, sample size, recruitment of studypopulation (help-seeking, mailing, or advertisement),method of assessment, interval between stress exposureand assessment, lifetime and current PTSD. However,better standardization is needed to compare betweenstudies (Smith et al., 2009).

Combat and other predictive and risk factors

Predicting who would develop PTSD in response to astressor can have many implications for the develop-ment of screening instruments, treatment strategies,and policy. Risk factors, such as prior trauma, prior psy-chiatric history, family psychiatric history, peritrau-matic dissociation, acute stress symptoms, the natureof the biological response, and autonomic hyperarousal,need to be considered when setting up models to predictthe course of the condition. These risk factors influencevulnerability to the onset of PTSD and its spontaneous

BIOLOGICAL AND CLINICAL FRAMEWORK

remission. In the majority of cases, PTSD is accompa-nied by another condition, such as major depression,an anxiety disorder, or substance abuse. This comorbid-ity can also complicate the course of the disorder andraises questions about the role of PTSD in other psychi-atric conditions (McFarlane, 2000).

The influence of Freud’s original and somewhat mis-leading “war neurosis” led the military to attempt to pre-dict vulnerability to combat stress based on premilitarydevelopmental variables, assuming they could be foundin conflicts in early development. In different epidemio-logical studies, prestressor factors in the developmentof combat-related PTSD are found to be age of traumati-zation, years of education,minority status, pretraumaandpsychiatricdisorder, substanceabuse,historyofchildhoodabuse, antisocial behavior, academicdifficulty, familyhis-tory of psychiatric disorders, family environment, andlack of social support. In civilian PTSD, a previous historyof stress and previous psychiatric disorders may increaseboth the risk of exposure to a traumatic stressor as well asthe development of PTSD. Factors in PTSD associatedwith combat veterans are severity and length of exposure,seeingotherskilledorwounded,participating inatrocities,anddissociationat timeof trauma.Apostmilitary risk fac-tor is lack of social support. Since most victims of civiliantrauma, suchasrapeorchildhoodsexualabuse,feel shameand guilt, which discourage them from talking openlyabout their feelings and seeking social support, this maycontribute to adecrease in social support analogous to thatof combat veterans with PTSD (for a review, see Bremneret al., 1995a, b).

In a study that compared 2362 veterans who devel-oped PTSD with an equal number of war veteranswho did not develop PTSD, the predictive factors weremostly nonspecific, such as cognitive functioning,education, rank, and position during the trauma, withlittle effect from training, leading to the conclusion thatcarefully structured predrafting psychological assess-ment of social and individual qualifications (includingmotivation) failed to identify increased risk factorsfor PTSD (Zohar et al., 2009).

In summary, gene–environmental studies are neededwith a focus on specific, distinct endophenotypes and oninfluences from environmental factors. Among theseare early-life experiences as well as various other expo-sure types, such as disasters or combat.

HISTORYANDNOSOLOGYOF PTSD

“Soldier’s heart,” sexual abuse, andthe contribution of Freud

Although the diagnosis of PTSD was established withthe release of DSM-III in 1980 (APA, 1980), it was pre-ceded by a long history of observations of the effects of

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traumatic stress on the individual (for a review, seeVermetten and Bremner 2002a, b). Much of the historyof stress and psychiatric diagnosis has been determinedby the ebb and flow of attention paid to this area witheach new major military conflict. During the AmericanCivil War, DaCosta (1871) first described a syndrome in-volving symptoms of exhaustion and increased physio-logical responsivity (“soldier’s heart” or DaCosta’ssyndrome) seen in soldiers exposed to the stress ofwar. DaCosta described the autonomic cardiac symp-toms of soldiers exposed to the horrors of the CivilWar and felt that this syndrome was a physical disorderinvolving the cardiovascular system that was caused bythe extreme stress of war. His approach was similar totheories of the time advanced by Kraepelin (1919),who also believed that schizophrenia had its basis inthe constitution, leading to abnormalities in the brainand physiology.

Brain-based explanations of psychiatric disordersleft the scene at the turn of the century with SigmundFreud. During the early 1900s, psychoanalysts observed“traumatic neurosis” that resulted from different formsof trauma. Freud originally believed that his famouscase of Anna O was a victim of exposure to traumaticsexual experiences in childhood and only later modifiedhis views into the theory that fantasies, and not only thereality of childhood sexuality, could lead to mentalillness in later life.

It is important to note here that the pervasive societaldenial of the importance of sexual abuse that persistedfor most of the 20th century has been attributed toFreud’s change of thought. Yet, throughout Freud’spublished writings until he died in 1939, he reassertedthe importance of sexual abuse and its etiological signi-ficance in mental illness. By making Freud the leadingintellectual figure in the cover-up of sexual abuse, adisservice is done to the truth, and it will be perverse,because Freud was the person who coined the term “psy-chic trauma,” clearly articulated the role of childhoodsensitivity to trauma, and described the defenses ofdenial of trauma, ascribed to him (Doidge, personalcommunication, 2010).

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Shellshock and traumatic neuroses

In World War I, “shellshock” was understood as a formof brain trauma caused by the terror induced by explod-ing shells. Also during the First World War, the largenumber of psychiatric casualties of combat forcedattention on the effects of the stress of war and led tothe description of “combat fatigue,” or “physioneuro-sis.” Experimental studies revealed intolerance in thesepatients to carbon dioxide and exaggerated psychologi-cal and physiological responses to epinephrine.

Psychiatrists described phenomena such as amnesia onthe battlefield, where soldiers forgot their name orwho they were. After the war, however, the effects ofcombat stress on the mind were soon forgotten. WithWorld War II, interest in the mental health effects ofthe stress of war was revived. Again, psychiatrists de-scribed amnesia and other dissociative responses totrauma (Sargent and Slater, 1941; Torrie, 1944). Studiesin Danish police interned in German concentrationcamps noted symptoms in the survivors, including re-current memories of the camps, feelings of detachmentand estrangement from others, sleep disturbance, andhyperarousal, as well as problems with memory and con-centration (Thygesen et al., 1970). Abraham Kardiner,who treated many casualties in World War II, whichhe described in The Traumatic Neuroses of War in1941, recognized a set of symptoms that underlie the cur-rent conceptualization of PTSD, a condition he referredto as “physioneurosis”:

1. preoccupation with the trauma

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2. constriction of personality

3. atypical dream life 4. startle response 5. irritability.

Survivors of death camps in this war were found to havesymptoms of anxiety, motor restlessness, hyperarousal,sleeping difficulties, nightmares, fatigue, feeling worsewith traumatic reminders, and a constant preoccupationwith recollections of persecutory experiences. Thesesymptoms became known as the “concentration campsyndrome.”

DSM-I: gross stress reaction

The diagnosis that came closest to what we know asPTSD in DSM-I (APA, 1952) was “gross stress reac-tion.” This diagnosis suggested that everyone had abreaking point and, given a severe enough trauma, itwould be relatively “natural” to have a severe reaction.This may have stemmed from the experience of militarypsychiatrists in the Second World War, who observedduring the war that many normal men were having men-tal breakdowns in the face of combat. However, grossstress reaction specified that the individual must havea normal prestressor personality and that the symptomsshould naturally resolve with time. This disorder did nottake into account the fact that individuals with pre-existing psychiatric disorders may develop a new disor-der that is specifically related to the stressor, or thatacute responses to stress can translate into long-termpathology. It is as if gross stress reaction was a responseto the reality that extreme stressors such as war can leadto psychiatric outcomes that are not secondary to “bad

FOR POSTTRAUMATIC STRESS DISORDER 299

personalities” (military psychiatrists in the SecondWorld War had tried in vain to find premilitary person-ality traits that would help them predict who was mostvulnerable to the stress of combat). Embodied in grossstress reaction was the ambivalence that has pervadedpsychiatry until the current time about whether stresshas merely transient effects or whether it can lead topermanent psychopathology.

For reasons that remain obscure but that perhaps re-flect the early links between military combat and thediagnosis of stress disorders, gross stress reaction wassomehow dropped from DSM-II in 1968 (APA, 1968).The USA was not engaged in major war during the timethat manual was written. The corresponding categorywas renamed “transient emotional or adjustment reac-tion,” which emphasized the temporary nature of thepsychological response to an overwhelming trauma.Oddly enough, this took place in the same year as themajor outburst of the Vietnam war. The classificationincluded acute reactions to overwhelming environmen-tal stress, but did not name any specific catastrophes,such as war, death camps, or Hiroshima. Combatcropped up in one line, as an example of the adult typeof adjustment reaction: “fear associated with militarycombat and manifested by trembling, running andhiding.” The important work of Kardiner (1941), TheTraumatic Neuroses of War, and of Grinker and Spiegel(1945), Men Under Stress, and the impressive follow-up studies conducted by Archibald and Tuddenham(1965) were overlooked by many. These studies sug-gested that the argument of pre-existing disorders asan explanation for traumatic stress disorders was largelyirrelevant.

It was only later, in the aftermath of the Vietnamwar, that the lasting effects of traumatic stress on themind were recognized. Researchers and clinicians suchas Robert Jay Lifton, Chaim Shattan, and Charles Figleyargued at that time that the stress of war itself ledto psychopathology as opposed to factors such as“bad character” (pre-existing and preceding the war)(Figley, 1978). This was the background leading to theinclusion of PTSD (with both acute and chronic types)as a disorder in DSM-III in 1980. In the DSM-III-basedcriteria for PTSD, there was fortunately resistance byNancy Andreasen (1985, 1995) and others to those whoargued against the uniqueness of individual traumas.For example, at the time, some advocated a “Vietnamsyndrome” which would describe a constellation ofsymptoms unique to Vietnam veterans, while othershave argued for “postrape syndrome” or specific child-hood sexual abuse syndromes (ideas for which there waslittle empirical evidence). This resistance may have beenindispensable to the scientific advancement of the studyof traumatic stress.

BIOLOGICAL AND CLINICAL FRAMEWORK

After the Vietnam war: towards DSM-III

DSM-III was crafted in the post-Vietnam era, a timewhenthe USA contained yet another wave of young men whohad been exposed to the trauma of combat. VeteransAffairs andmilitarypsychiatrists hadnoofficial diagnosisto give them, as long asDSM-IIwas the official diagnosticmanual. DSM-I and DSM-II followed the view that, ifpatients had good adaptive capacity, their symptoms usu-ally receded as the stress diminished. Both DSM-I andDSM-II added that, if the symptoms persisted “after thestress was removed, the diagnosis of another mental dis-order was indicated.” A neurotic or psychotic labelreplaced the diagnosis of stress disorder or adjustmentreaction. Stress disorders were held to be transient andreversible, with no rubric for the continuance of stress-induced symptoms as such. With DSM-III-based PTSD(APA, 1980), there was finally a diagnosis that recognizedthe lasting pathological effects of traumatic stress. DSM-IIIalsofoundaplace for code308.33,delayedcatastrophicstress disorder following anasymptomatic interval (“incu-bation period”). This phenomenon was seen by manyclinicians. It resembleds an ongoing, chronic, low-grade,or latent subclinical disturbance that years later could betriggered into acute disorder by events that symbolizedor recaptured the original trauma (helicopters, smells,war inKosovo, Iraq, orAfghanistan), andwas best under-stood by a model of stress sensitization.

After the Vietnam war the concept of PTSD took off“like a rocket,” in ways that had not initially been antici-pated (Andreasen, 2004). Yet, several authors still notedgaps in the classification of PTSD in DSM-III. These wererelated to the etiology of the disorder, its natural history,and diagnostic specificity: how severe should the traumabe? What types of trauma could be considered causative?Would it make a difference if the trauma was inflictedby another human being, by an accident, or by a naturaldisaster? A demand was made for research in theoreticalissues and to collect empirical data in order to be moreprecise in later diagnostic descriptions and understanding(Green et al., 1985). DSM-IIIR (APA, 1987) included spec-ification of generic characteristics of traumatic stressors,clearerorganizationofsymptomsaroundthreedimensionsof stress response (re-experiencing, avoidance and numb-ing,andphysiological arousal), inclusionofsymptomsspe-cific to children, and specification of onset and duration ofthe disorder (Brett et al., 1988).

Definition of an event involving extremethreat: the A criterion

As was briefly pointed out in the introduction, one ofthe most vexing issues in the field of traumatic stresshas been the criterion A problem, or the definition ofpsychological trauma. Criterion A is a conditional

AN

prerequisite for diagnosis. In earlier versions of DSM,this centered on questions of how to define a traumaticevent andwhether experiencing a traumatic event shouldbe a requirement for aPTSDdiagnosis. CriterionArefersto the stressor criterion for PTSD and involves a numberof fundamental issues regarding the definition and mea-surement of psychological trauma. Criterion A rangesfrom war-related trauma, accidents, motor vehicleaccidents, exposure to human remains, violent crimes,medical causes, torture, child abuse, chronic exposurein high-risk population, to domestic violence, natural di-sasters and sexual trauma (not an exhaustive list). ForDSM-IV a two-part definition was developed, wherethe first part was a traumatic event, which distinguishestraumatic events fromordinary stressors (called criterionA1). The second part, criterionA2, required that, in ordertomeet the diagnosis, the person’s response at the time ofthe trauma involved intense fear, helplessness, or horror,recognizing the fact that an individual’s subjectiveresponse was an important dimension to be consideredwhen defining a traumatic event.

Let us focus on the variety of themes in the debate overcriterionA. Some argue that criterionA stipulated amono-causaletiologyof thedisorder, isautologous,andthereforeis dispensable. It was argued that it may bemore appropri-ate to define PTSD strictly on the basis of descriptive, phe-nomenological terms and to omit criterion A, in order toavoid useless confusions about causal attribution (Maier,2006). On the one hand, the broadening in DSM-IV ofthe concept of a traumatic event allowed clinicians and re-searchers to list several previously independently describedtypes of trauma reaction (e.g., soldier’s heart, battered-wife syndrome) under the unifying heading of PTSD(Weathers andKeane, 2007); on the other hand, a broaden-ing of the traumatic event construct might have a negativeimpacton thespecificityofstressdisordersandit is felt thatitmayultimatelyundermine the validity of the diagnosis ofPTSD (Spitzer et al., 2007).

Although the definition of psychological traumacontinues to be a matter of debate (Brewin et al., 2009;VanHooff et al., 2009), there appears to be a growing con-sensus that traumatic events can be distinguished fromor-dinary stressors and that the use of specific criteria forpsychological trauma serves a useful gate-keeping func-tion that preserves the meaningfulness of the disorderas a distinct diagnostic entity and prevents trivializationof the suffering of survivors of overwhelming stressors.

300 E. VERMETTEN

Different nosological system in psychiatry:DSM versus ICD

The International Statistical Classification of Diseases,Injuries, andCauses ofDeath (ICD)developed in parallelwith DSM over the past half-century. This classification

system was originally formalized as the 1892 BertillonClassification List of Causes of Death. ICD is meant tocover the worldwide classification of diseases and hasbeen used more in Europe than DSM. In 1948, the WorldHealth Organization (WHO) decided to include mentaldisorders in the sixth revision of the ICD (ICD-6;WHO, 1948), since many psychiatric hospitals weredealing with a nomenclature that did not appropriatelydescribe the majority of the cases handled. DSM, whichwas developed in the USA, has only focused on disordersof mental health.

The formulation of stress-related psychopathology inthe later ICD systems and in the DSM classification isbased upon attempts to describe posttraumatic psycho-pathology. The perspective that traumatic reactionswere short-lived responses in essentially normal individ-uals with no premorbid psychopathology can be origi-nally found in both the international and Americanclassifications. Prototypes of PTSD were called “acutesituational maladjustment” in ICD-6 and “transient sit-uational personality disturbance” in DSM-I. There wereno changes in the mental disorders section in ICD-7 (seeTable 18.1). In ICD-8 (WHO, 1968), there was a rephras-ing to “transient situational disturbance.” DSM-II wasmostly based on the mental disorder section of thiseighth edition of ICD. DSM-II focused on the diagnosis“adjustment reaction” and specified the phase in life towhich this was related. In DSM-III and ICD-9, therewere significant revisions of the conceptualization ofposttraumatic stress reactions, with the most importantchange being the notion that stress disorders were nolonger acute responses in healthy individuals. Traumaticstress was considered to cause chronic reactions, and re-sponses to stress were considered to occur with previousand simultaneous conditions. Another significantchange was the categorization of the diagnosis in theanxiety disorders section of DSM-III. ICD went alongthe same line; however, it also incorporated a variationof PTSD in its classification. In ICD, under sectionF62.0, there is a diagnosis named “enduring personalitychanges after catastrophic experience,” alluding tosome variation of a personality disorder. The Americanapproach was to consider anxiety a core phenomenon ofboth PTSD and obsessive-compulsive disorder (OCD),whereas the Europeans regarded anxiety as a commonand nonspecific feature of many disorders and locatedOCD and PTSD in their classification system in ICD onthe basis of other features.

The most recent version of ICD is ICD-10 (1992). Thisversion now consists of a three-volume work, with onesection on mental health. ICD-10 was field-tested in over100 institutions in 40 countries, making this book theproduct of a very large research effort. PTSD is codedas F43.1 and subsectioned under “neurotic stress-related

D R.A. LANIUS

Traumatic Event

Subjective Response

Criterion A Stressor

Cluster B Intrusion SymptomsCluster C Persistent Avoidance

Cluster D Negative Alterations in cognitions and mood Cluster E Alterations in arousal and reactivity

Functional Impairment

PTSD

Fig. 18.2. Proposed Diagnostic and Statistical Manual ofMental Disorders V classification of posttraumatic stress

disorder (each cluster is of more than 1 month’s duration).

FOR POSTTRAUMATIC STRESS DISORDER 301

and somatoform disorders” and further under “otheranxiety disorders and reactions to severe stress,” whereit is grouped with “acute stress reaction,” “adjustmentdisorders,” “other reactions to severe stress,” and “reac-tion to severe stress unspecified.” PTSD is defined asfollows:

A mental disorder characterized by a preoccupa-tion with traumatic events beyond normal humanexperience; events such as rape or personal as-sault, combat, violence against civilians, naturaldisasters, accidents or torture precipitate thismental disorder; patients suffer from recurringflashbacks of the trauma and often feel emotion-ally numb, are overly alert, have difficulty remem-bering, sleeping or concentrating, and feel guiltyfor surviving.

ICD-10 defines the A criterion “beyond normal humanexperience,” whereas DSM-IV is more stringent. Al-though an essential criterion, the A criterion does notpredict PTSD or the course of PTSD. As stated earlier,the latest revision of ICD-10 has a wider variety of diag-noses for traumatic reactions, with the inclusion ofenduring personality changes after catastrophic experi-ence (F62.0) (WHO, 1992). In their latest releases, bothclassification systems seem to be more in line in theirdescription of PTSD.

However, in a comparison 12-month prevalence ofPTSD using ICD-10 and DSM-IV criteria, Peters et al.(1999) found that, using the ICD criteria, the prevalencewas more than doubled (3% using DSM-IV and 7%using ICD-10 criteria). Almost half of the discrepanciesbetween the classification systems could be explained bythe F criterion in DSM-IV requiring clinically significantdistress or impairment in social, occupational, or otherimportant areas of functioning. Another factor thataccounted for 18% of the discrepancies was the C crite-rion in DSM-IV (Lundin and Lofti, 1996).

BIOLOGICAL AND CLINICAL FRAMEWORK

Towards DSM-V

The imminent redefinition of DSM-V criteria for PTSDshould reflect new advances in the science and concep-tualization of the disorder, and address the need ofpatients. The A1 criterion was criticized regarding thedefinition of “traumatic.”A new definition intends totighten up the A1 criterion to make a better distinctionbetween “traumatic events” and events that are distres-sing but which do not exceed the “traumatic” threshold.New findings do not support the inclusion of A2 asa diagnostic requirement for DSM-V, so this will belikely left out of the new definition (O’Donnell et al.,2010). A new diagnostic cluster dividing C criterion willbe introduced based on confirmatory factor analytical

studies in: (1) persistent avoidance of stimuli associatedwith the traumatic event(s) (that began after the trau-matic event(s)); and: (2) negative alterations in cogni-tions and mood that are associated with the traumaticevent(s) (that began or worsened after the traumaticevent(s)) (Hinton and Lewis-Fernandez, 2010; Friedmanand Castel, 2011) (Fig. 18.2). It is increasingly understoodand recognized that PTSD is a heterogeneous disorder,perhaps with subtypes, and different types of complex-ity, yet this may not be fully captured in its classificationin DSM-V.

In summary, these developments demonstrate thatPTSD is a young disorder that started to be properly un-derstood only from 1980 with incorporation in DSM-III,in which it was acknowledged that exposure to traumaticevents can lead to long-term psychopathology. The Acriterion expressed the traumatic event, after whichthe symptom clusters are based on intrusions, avoid-ance, and irritability.

THECLINICAL FRAMEWORK:DIAGNOSTIC FEATURESOF PTSD

Diagnostic categories: vignette

When Carol and her friend were on a Christmas vaca-tion, on December 25, 2005, they had no idea that theirlives would become so affected because of the eventsthat happened one day later when they almost drownedin the waves of the tsunami that hit the coastline ofSouth-East Asia. Both survived and had nearly no inju-ries. It was almost a year later that Carol went down into

AN

a basement where she was following a yoga course.When the firealarm went off by accident she panicked,wanted to run away, but restrained herself. She startedcrying and relived the event again as if it were the firsttime. This event woke her up again and triggered her toseek therapy. She acknowledged that over the last yearafter the tsunami she had become fearful, irritable, andhad frequent dreams about the tsunami. She had givenup much of her social life and stopped engaging in asmany activities as she used to do. She catastrophizedevents, and had nearly become phobic. She was afraidof dying and often felt numb. Her friend is OK, butshe feels depressed and thinks that she will contractan illness so that she cannot raise her little daughter.

For DSM-V the proposed symptoms of PTSD aredivided into five discrete and different categories:

A. Definition of the traumatic event

302 E. VERMETTEN

B. Intrusion symptoms associated with the traumatic

event(s) (that began after the traumatic event)

C. Persistent avoidance of stimuli associated with the

traumatic event(s) (that began after the traumaticevent(s)

D. Negative alterations in cognitions and mood that

are associated with the traumatic event(s) (thatbegan or worsened after the traumatic event

E. Alterations in arousal and reactivity associated with

the traumatic event(s) (that began or worsened afterthe traumatic event.

At least one symptom of re-experiencing is required forthe diagnosis, including recurrent and intrusive distres-sing recollections of the event, recurrent distressingdreams of the event, acting or feeling as if the traumaticevent were recurring, intense psychological distress atexposure to internal or external cues that resemble anaspect of the traumatic event, or physiological reactivityupon exposure to internal or external cues that symbolizean aspect of the traumatic event. One avoidance symp-tom is required, including thoughts, feelings, or physicalsensations that arouse recollections of the traumaticevent(s); activities, places, physical reminders, or times(e.g., anniversary reactions) that arouse recollectionsof the traumatic event(s); and people, conversations, orinterpersonal situations that arouse recollections of thetraumatic event. The third cluster consists of negativealterations in cognitions and mood with inability to re-member an important aspect of the traumatic event(s)(typically dissociative amnesia; not due to head injury,alcohol, or drugs); persistent and exaggerated negativeexpectations about one’s self, others, or the world (e.g.,“I am bad,” “no one can be trusted,” “I’ve lost my soulforever,” “my whole nervous system is permanentlyruined,” “theworld is completely dangerous”); persistentdistorted blame of self or others about the cause or

consequences of the traumatic event(s); pervasive nega-tive emotional state, for example fear, horror, anger,guilt, or shame; markedly diminished interest or parti-cipation in significant activities; feeling of detachmentor estrangement from others; and persistent inability toexperience positive emotions (e.g., unable to have lovingfeelings, psychic numbing).

At least two of these symptoms are required, includ-ing difficulty falling or staying asleep, irritability or out-bursts or anger, difficulty concentrating, hypervigilance,or an exaggerated startle response. The duration of thedisturbance needs to bemore than 1 month and the symp-toms must be associated with significant distress orimpairment in social, occupational, or other areas offunctioning. DSM categorized three subtypes of thedisorder: acute, chronic, and a subtype with delayed on-set. PTSD is described as delayed onset if the symptomsappear more than 6 months after the event has passed.

When the time course of PTSD symptoms is consid-ered, the re-experiencing cluster peaks early but thenstarts to decline (Schell et al., 2004). Hyperarousalsymptoms tend to precede and strongly predict subse-quent emotional numbing (Bremner et al., 1996a, b; Litzet al., 1997; Weems et al., 2003). It has been hypothesizedthat emotional numbing is the patient’s response to pro-longed hyperarousal leading to emotional exhaustionand the depletion of cognitive and emotional resources(Weems et al., 2003). In fact, there is evidence that thelevel of hyperarousal is a strong predictor of all threeother symptom clusters, and of a lack of improval ofPTSD symptoms in the long term (Schell et al., 2004).Hyperarousal also appears to play a major role in theattention and memory deficits found in PTSD patients(Vasterling et al., 1998; Bremner et al., 2004), and inthe explosive anger that is readily triggered in male com-bat veterans with PTSD (Chemtob et al., 1997). Interest-ingly, in traumatized motor vehicle accident victims whoinitially met PTSD criteria, avoidance and numbingsymptoms had significantly declined after 6 months,when half of the patients no longer met full PTSDcriteria, whereas hyperarousal symptoms had not de-clined (Blanchard et al., 1995).

D R.A. LANIUS

Delayed-type PTSD: incubation time?

Recent studies have indicated that delayed-onset PTSD(i.e., the development of PTSDmore than 6months post-trauma) is generally characterized by subsyndromaldiagnoses within the first 6 months. Clinicians shouldconsider subthreshold diagnoses as potential risk factorsfor delayed-onset PTSD (Carty et al., 2006).Typically,two phenomena can be seen: (1) patient’s delay and (2)doctor’s delay. The patient’s delay can be due to denial,overcompensation, or shame. Patients can engage in

F

self-medication, work many hours, and get used to an-other social life. The doctor’s delay typically occurswhen the consultation is focused on one symptom,and there is no track record or relation to precedingevents. In 2001 in a Dutch sample of veterans the totaldelay was 9 years, and the ratio of patient’s to doctor’sdelay was 3:1. Typcially in this sample it was a partner,spouse, or mother who urged the patient to seektreatment.

Symptoms of PTSD generally become evident withinthe first months following the trauma; sometimes ASDdevelops into PTSD. ASD is a rather similar disorder toPTSD that may occur immediately after traumatic stressexposure andmay last from 2 days to 4 weeks. ASD alsoincludes symptoms of dissociation, such as derealiza-tion and depersonalization, as well as one symptomfrom each of the PTSD symptom clusters. Both theoccurrence of dissociative symptoms at the time oftrauma and their duration afterward predict later PTSD,as well as dissociative reactions to subsequent trauma(Bremner and Brett, 1997; Classen et al., 1998). Brewinet al. (1999) found that ASD diagnosis predicts 83% ofcases of PTSD at 1 year. This study also found that re-experiencing and hyperarousal (but not avoidance) wereequally adept at predicting the development of chronicPTSD. Most individuals who, shortly after trauma, ex-press symptoms of PTSD recover within 1 year of theirtraumatic experiences (Kulka et al., 1990). In contrast,those who remain ill for 1 year rarely recover completely(Freedman et al., 1999). In many individuals, PTSD canbe a chronic disorder that they take with them to thegrave, putting a burden on physical and mental healthand also on health providers (Blank, 1993; Friedmanand Schnurr, 1995; Solomon and Davidson, 1997).

BIOLOGICAL AND CLINICAL FRAMEWORK

Comorbid conditions associated with PTSD

Psychological trauma can have more consequences thanthe current PTSD criteria would suggest. PTSD isfrequently comorbid with other psychiatric disorders,such as depression, substance abuse, and anxiety disor-ders. These comorbid disorders may predate PTSD, maybe related to traumatic stress, or may be a reflection ofinadequacies of our diagnostic schema. For example,data from the National Vietnam Veterans ReadjustmentStudy (Kulka et al., 1990, 1991) show that 98% ofpatients with Vietnam combat-related PTSD have a co-morbid lifetime psychiatric disorder. Studies to dateshow an increased risk for comorbid anxiety disorders(agoraphobia, panic disorder, OCD, social phobia) aswell as major depressive disorder (MDD), somatizationdisorder, and substance-related disorder in PTSD (for areview, see Keane and Kaloupek, 1997; Weathers andKeane, 1999). Clinicians assessing victims of chronic

interpersonal trauma need to be particularly aware thatthe presentation may very well include many problemsother than the core symptoms of PTSD. Comorbiditymay also reflect a more general vulnerability to psycho-pathology that renders some individuals more suscepti-ble to developing a variety of disorders, including PTSD(Weathers and Keane, 1999).

Depression is one of the disorders that often occur inconjunction with PTSD (Momartin et al., 2004). Workersin the PTSD field have long been forced to explain thecomorbidity of depression in patients with PTSD. How-ever, Koren and colleagues (1999) have used a prospec-tive design in stress survivors, showing that depressionand non-PTSD anxiety disorders develop in conjunctionwith PTSD. This is consistent with other data, e.g., fromthe National Vietnam Veterans Readjustment Study andAustralian veterans from the Korean war, which showedthat rates of depression and anxiety disorders (as well asalcohol and substance abuse) are increased in combatveterans with PTSD (Kulka et al., 1990; Ikin et al., 2010).Zimmerman and Mattia (1999) investigated whether anassociation exists between psychotic subtyping of MDDand PTSD. They interviewed 500 psychiatric outpatientsusing the Structured Clinical Interview for DSM-IV. Al-most half of these patients had MDD (n ¼ 235). Nine-teen percent of this sample met criteria for PTSD. Theseresults indicate that the presence of psychosis in psy-chiatric outpatients with MDD is associated with con-current PTSD. Clearly, trauma results in a range ofoutcomes, and although PTSD patients may meet symp-tom criteria for other psychiatric disorders (e.g., majordepression), they may not be equivalent to nontrauma-tized patients with these disorders.

From a practical assessment perspective, comorbiddisorders complicate differential diagnosis and treat-ment planning. For example, PTSD and depression shareanhedonia, sleep disturbance, and impaired concentra-tion as core diagnostic criteria, and there is an arguableoverlap in terms of restricted range of affect, impair-ment in personal functioning, and guilt. Interestingly,there are no explicit exclusion criteria for PTSD as thereare for other Axis I disorders.

A close relationship also exists between PTSD, dis-sociation, somatization, and a variety of other medicalproblems (see below). Some authors have argued thatchronic interpersonal trauma, especially with childhoodonset, such as incest, physical abuse, torture, or neglect,leads to a much broader range of symptoms, often withdissociative features, described as complex PTSD(C-PTSD) (Herman, 1992; Van der Kolk et al., 1996;Van der Hart et al., 2005; Cloitre et al., 2009). C-PTSDtranscends current formulations of PTSD in three mainareas of disturbance: (1) complex symptom presenta-tions; (2) characterological issues; and (3) vulnerability

OR POSTTRAUMATIC STRESS DISORDER 303

AN

to repeated trauma. Individuals with PTSD may also ex-perience profound feelings of guilt and may blamethemselves for surviving when others did not, keepingthe guilt inside. This conflict, in its most acute presenta-tion, typically resembles an agitated depression and isdescribed as being associated with frequent dreams offriends dying (e.g., in battle) and by avoidance of inter-personal intimacy because they fear the other party mayabandon them or die (Glover, 1984; Henning and Frueh,1997). This can also cause phobic avoidance that inter-feres with daily activities and social interactions. Inter-personal stressors, such as childhood sexual abuse,domestic violence, or being held a hostage or a prisonerof war, may be associated with a constellation ofimpaired affect modulation, self-destructive and impul-sive behavior, dissociative symptoms, feelings of inef-fectiveness, difficulties in sexual involvement, shame,despair, or hopelessness. It may also led to feelingpermanently damaged, a loss of previously sustainedbeliefs, hostility, social withdrawal, feeling constantlythreatened, and impaired relationships with others, ormay induce a change away from the individual’s previ-ous personality characteristics (DSM-IV; APA, 1994).

304 E. VERMETTEN

Impact on general health

Besides psychiatric morbidity, traumatized individualsoften report poorer physical health, which can at leastpartially be confirmed after objective examination(Centers for Disease Control Vietnam ExperienceStudy, 1988; Schnurr et al., 1998). Conversely, peoplewho seek medical care for specific physical health prob-lems such as gastrointestinal disturbances often turn outto have a history of sexual and physical abuse or otherlifetime traumas (Leserman et al., 1998). Patients inwhom PTSD is formally diagnosed report more medicalconditions and poorer physical health and vitality result-ing in significant limitations in daily life, when com-pared both with normal controls and with patientswith other anxiety disorders or depression (Zayfertet al., 2002; Frayne et al., 2004). Using a global physicalhealth index, PTSD patients also have poorer physicalhealth than traumatized individuals without PTSD; thatis, most of the variance in physical health status follow-ing traumatic stress is mediated by PTSD (Schnurr andGreen, 2004). While increased physical health problemsin PTSD clearly reduce quality of life, it appears thatincreased mortality in veterans with PTSD is mainlyrelated to behavioral risk factors (Drescher et al.,2003). Most of the associations of physical health prob-lems with PTSD are still significant when controlled forage, socioeconomic status, intelligence, substanceabuse, hypochondriasis, or physical injury (Boscarino,1997; Weisberg et al., 2002). PTSD status has a stronger

association with these specific physical health problemsthan anxiety or depression (Boscarino, 1997; Andreskiet al., 1998; Weisberg et al., 2002), and, where a non-traumatized control group is included, PTSD is astronger predictor of physical health in multiple catego-ries than trauma alone (Weisberg et al., 2002). Physicalhealth problems also correlate with the intensity ofhyperarousal and avoidance symptoms (Woods andWineman, 2004).

D R.A. LANIUS

Dissociation and PTSD

A number of studies of individuals experiencing dangerand/or life threat have shown specific peritraumaticdissociative changes, including alterations in time sense,perception, attentional focus, and awareness of pain,among others (Morgan et al., 2001). In addition, deper-sonalization has been described in a significant percent-age of individuals facing acute threat to their life.Information related to the traumatic experiences is of-ten differently encoded in these altered states, resultingin decreased access to information about the traumaonce the person returns to their baseline state. Thismay give a subjective sense of “compartmentalization”of the traumatic experience and/or emotional detach-ment from the experience. The cost of this detachmentmay be avoidance of necessary cognitive and affectiveprocessing of traumatic experience in its aftermath(Spiegel and Cardena, 1991). Changes in one’s senseof time and place are common symptoms during a trau-matic event, as is altered spatial memory, where individ-uals describe feelings of “losing track of what is goingon around me” and of feeling “detached.” Altered senseof time, feeling that time either slowed down or sped up,is the most common peritraumatic dissociative symptomreported by individuals during or shortly after a trau-matic event (Noyes and Kletti, 1977; Terr, 1984; Cardenaand Spiegel, 1993; Shalev et al., 1996a).

There has been controversy about whether dissocia-tion is a normal psychological response or a pathologicalsymptom seen only in trauma survivors (Putnam et al.,1996). Part of this controversy relates to the overlap ofdissociation with other constructs, like hypnotizabilityand absorption. Both hypnotizability and absorption(e.g., the capacity to become intensely absorbed in amovie) are normal personality features that vary inthe general population. Absorption is described as atendency to become fully involved in a perceptual imag-inative or ideational experience. Individuals prone tothis type of experience are more highly hypnotizable(Tellegen and Atkinson, 1974).

The fact that the dissociative disorders are rarelyused in routine diagnosis highlights the limitations ofour current diagnostic schema for clinical practice.

F

Currently, PTSD is a rule-out for dissociative amnesia.It was found that symptom levels from different disso-ciative symptom areas (e.g., amnesia, depersonaliza-tion) are highly correlated with one another (Bremneret al., 1998), challenging the uniqueness of individualdissociative disorders. The somewhat artificial separa-tion of dissociative disorders such as dissociative amne-sia, dissociative fugue, and depersonalization disorder,however, contributes to the fact that they are not used inclinical practice. It remains to be seen to what extentdissociation is a predictor for therapeutic outcome inPTSD. Acute dissociative responses to psychologicaltrauma have been found to predict the developmentof chronic PTSD. Moreover, a chronic pattern of disso-ciation in response to reminders of the original traumaand minor stressors has been found to develop in per-sons who experience acute dissociative responses topsychological trauma. Some authors argue that thereis a specific dissociative subtype of PTSD, with neuro-biological features that distinguish it from nondisso-ciative PTSD (Lanius et al., 2010a).

BIOLOGICAL AND CLINICAL FRAMEWORK

Developmental trauma disorder

The availability of developmental trauma disorder hasbeen suggested as a diagnosis that would improve treat-ment for children suffering from the consequences ofinterpersonal trauma (van der Kolk, 2009). It has beenproposed that it would also reduce variability in childrendiagnosed with other disorders, such as attention-deficit/hyperactivity disorder and bipolar disorder. The disorderis based upon exposure to developmentally adverseinterpersonal trauma, maltreatment and neglect duringchildhood, and which includes the coherent set of devel-opmental trauma disorder symptoms, and should havethe potential to alert clinicians to the influential role ofchildhood trauma in psychopathology. It is proposed thatthe criteria for a diagnosis of developmental trauma dis-order include (Van Der Kolk and d’Andrea, 2010):

1. exposure to childhood interpersonal trauma, includ-

ing emotional abuse, neglect, and other disruptionsin caregiving

2. symptoms in the areas of: (a) affect and impulse

regulation; (b) attention, cognition, and conscious-ness; (c) self-perception and meaning; (d) inter-personal relationships; and (e) somatization andbiological dysregulation.

As long as the various symptoms suffered by trauma-tized individuals are relegated to seemingly discon-nected diagnoses such as PTSD, attention-deficit/hyperactivity disorder, bipolar illness, attachment dis-turbances, borderline personality disorder, and depres-sion, it may be very difficult systematically and

scientifically to study the full range of possible interven-tions to help human beings with a history of complextrauma gain control over their lives.

OR POSTTRAUMATIC STRESS DISORDER 305

Complex PTSD

Some authors argued that PTSD as now formulateddoes not go far enough in capturing the psychologicalresponse to traumatic events. The notion of “complexPTSD” is reviewed as an extension of the current formu-lations of PTSD (Ide and Paez, 2000; Dorahy et al.,2009). C-PTSD transcends current formulations ofPTSD in three main areas of disturbance:

1. complex symptom presentations

2. characterological issues 3. vulnerability to repeated trauma.

It is appreciated by clinicians that this disorder should beconsidered a superordinate diagnosis.

Herman (1992), pioneer in C-PTSD, coined the termin her landmark book, Trauma and Recovery, and hasmade proposals for its criteria and inclusion in DSM-V. Herman’s proposed criteria for adult C-PTSD are:

1. Restricted or constricted impulses and exhibited be-

haviors,which include facial expressions andvocal in-flection expressing emotions. Theremay be problemswith regulating emotions, including chronic sadness,suicidal ideation, and hidden or explosive anger.

2. Variations in consciousness, such as repressing, sup-

pressing, or reliving traumatic events or dissocia-tion, detachment from mental or physical processes

3. Alterations in self-perception, including feelings of

helplessness, shame, guilt and/or being differentfrom others.

4. Differences in relationshipswith others, which can be

isolating, looking for a rescuer, and/or mistrust.People with C-PTSD may view the perpetrator asall-powerful or be obsessed with the relationship,and thismay be accompanied by thoughts of revenge.

5. Somatization, a subconscious process in which psy-

chologicaldistress isexpressedasphysical symptoms.One of themost common examples is a tension head-ache when stress is manifested physically.

6. Changes in systems of meaning, which can be felt

as a loss of faith, despair, and/or hopelessness.

People who develop C-PTSD after being held hostagemay also develop the Stockholm syndrome. Hostagesmay exhibit signs of loyalty to their captors, despite risksor dangers in which they were placed. The syndromeis named after the bank robbery in Norrmalmstorg,Sweden, when the thieves held employees hostage for6 days. The victims became emotionally attached to theircaptors and defended them after they were released.

306 E. VERMETTEN AN

Complicated grief

At present, grief is not recognized as a mental disorderin DSM-IV or ICD-10. Bereavement is a universalexperience, and its association with excess morbidityand mortality is well established. Nevertheless, griefbecomes a serious health concern for a relative few.For such individuals, intense grief persists, is distressingand disabling, and may meet criteria as a distinct mentaldisorder. Bereavement or traumatic grief (involving apathological reaction to loss of a loved one) could beargued to be subsumable under PTSD using currentcriteria, since loss of a loved one can be included under“threat to life of self or a loved one,” although it wouldnot be under previous criteria of an event “beyond therange of human experience” (Prigerson et al., 2009).Murphy et al. (1999) studied the prevalence of PTSDamong parents bereaved by the violent deaths of their12–28-year-old children. A community-based sampleof 171 bereaved mothers and 90 fathers was followedfor 2 years. Both parents’ gender and children’s causesof death significantly affected the prevalence of PTSDsymptoms: twice as many mothers and fathers whosechildren were murdered met PTSD caseness (full diag-nostic criteria) compared with accident and suicidebereavement; symptoms in the re-experiencing domainwere the most commonly reported. PTSD symptomspersisted over time, with 21% of the mothers and 14%of the fathers who provided longitudinal data stillmeeting caseness criteria 2 years after the deaths.

Towards trauma spectrum disorders?

Perhaps no other diagnostic category has gone throughasmany alterations and permutations as has PTSD. Untilrecently, many investigators and clinicians consideredPTSD a product of malingering or a form of personalitydisorder (Davidson and Foa, 1991). Over the last 10 or soyears, however, the validity of PTSD has become wellestablished and it is currently considered one of the mostprevalent and disabling psychiatric disorders in civilianand military populations. It is still not clear whetherPTSD, as currently conceptualized, is a distinct andhomogeneous category or whether it would be moreaccurate to think of PTSD as being part of one or moredimensions or spectra. PTSD is rarely found alone; it isoften comorbid with several other psychiatric diagnoses,which calls into question the use of the current catego-rization of PTSD. Comorbidity patterns also suggestthat, when PTSD is associated with other psychiatricillness, diagnosis is more difficult and the overall sever-ity of PTSD is considerably greater.

With regard to a stressor criteria spectrum, the diag-nostic nomenclature initially only recognized severe

forms of trauma personally experienced. In DSM-IV,the person’s subjective response and events occurringto loved ones were included. This has greatly broadenedthe stressor criteria by leading to an appreciation of therange of precipitating stressors and the potential impactof “low-magnitude” events. Some argue that, given thatresponses to trauma vary considerably, a possible spec-trum includes trauma-related conditions. Traumaticgrief, somatization, ASD and dissociation, personalitydisorders (borderline personality disorder), depressivedisorders, and other anxiety disorders all have signi-ficant associations with PTSD. Consideration of theseverity of symptoms and the range of stressors coupledwith the various disorders precipitated by trauma shouldgreatly influence scientific research (Moreau andZisook, 2002).

To conclude, PTSD is a disorder that is often accom-panied by comorbid disorders, such as depression, otheranxiety disorders, as well as drug and alcohol abuse anddependence. The disorder can be viewed as heteroge-neous, sometimes with complex features that focus onemotional dysregulation, a developmental trauma per-spective in case of early-life trauma, and dissociativecomponents when there are feelings of derealizationand depersonalization. Complicated grief could alsobe part of the spectrum that increasingly is understoodas part of trauma spectrum disoders.

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DIAGNOSTIC INSTRUMENTS

Trauma measures vary widely in scope and format,ranging from self-report checklists assessing the pres-ence or absence of a limited range of potentially trau-matic events to comprehensive protocols assessing awide range of stressors through both self-report and in-terview (for an overview of psychological assessment inPTSD, the reader is referred to Wilson and Keane, 1997;for an overview of assessment of PTSD in children, seeDonnelly et al., 1999; on assessment in traumatizedadults, see Weathers and Keane, 1999; on forensic as-sessment, see Sparr and Pitman, 1999). Recommendedclinician-administered instruments with good reliabilityand validity include the following.

Structured Clinician Interview forDSM-IIIR and DSM-IV (SCID;

Spitzer et al., 1990)

The SCID is a comprehensive structured interview thatassesses all of the major Axis I disorders. A revisedmodule of the original DSM-III-R PTSD module isnow introduced in the DSM-IV section of the SCID. Thismodule appears to have adequate reliability and validity(Kulka et al., 1991).

BIOLOGICAL AND CLINICAL FRAMEWORK FOR POSTTRAUMATIC STRESS DISORDER 307

Diagnostic Interview Schedule(DIS; Robins et al., 1981)

The DIS is a highly structured, comprehensive interviewdesigned for use by lay interviewers in the context of ep-idemiological research. Like the SCID, the DIS providesa standard prompt question for each of the 17 PTSDsymptoms. Each symptom is scored dichotomously onits presence or its absence. The DIS was found to beone of the best predictors of a clinical diagnosis of PTSD(Kulka et al., 1991).

Clinician-Administered PTSD Scale(CAPS; Blake et al., 1995)

The CAPS is a comprehensive scale developed by the USNational Center for PTSD (Blake et al., 1995). It isintended to be used by clinicians and addresses someof the limitations of the other instruments. It assessesthe current (DSM-IV-based) 17 core symptoms forPTSD,aswell as associated symptoms, response validity, overallsymptom severity, and the impact of symptoms on socialand occupational functioning. The CAPS assesses thefrequency and intensity of each symptom on a five-pointscale, yielding continuous and dichotomous scores foreach symptom and across the 17 symptoms. The CAPSalso contains behaviorally anchored prompt questionsand rating scales to help increase the reliability of symp-tom inquiry and severity ratings. These are specificguidelines for assessing lifetime diagnostic status. Withits recent revision for DSM-IV, the CAPS is dividedinto CAPS-DX, for diagnostic assessment of currentand lifetime PTSD, and CAPS-SX, assessing a 1-weeksymptom status. TheCAPS takes significantlymore timeto administer than the other interviews.

PTSD Symptom Scale-Interview(PSS-I; Foa et al., 1993)

The PSS-I is a structured interview specifically designedto assess DSM-IIIR PTSD symptoms (Foa et al., 1993).It contains 17 items; interviewers rate the severity ofeach symptom over the past 2 weeks. The severity ofeach symptom is rated on a scale from 0 to 3, where0 is “not at all” and 3 “very much.” A PTSD diagnosisis obtained by considering symptom ratings of 1 orhigher as present and then following the DSM-III algo-rithm. The PSS-I has excellent psychometric properties.The advantages of this scale are that it yields continuousand dichotomous scores, is easy to administer, and hasgood reliability and validity. The disadvantages are thatit only uses one single prompt for each item, its ratinganchors are not explicitly defined, and it assessessymptoms over a 2-week rather than a 1-month period.The instrument lacks lifetime diagnostic status.

Structured Interview for PTSD (SI-PTSD;Davidson et al., 1989)

The SI-PTSD was originally designed to assess bothDSM-III and DSM-IIIR criteria for PTSD (Davidsonet al., 1989). Items consist of initial prompt questionsand follow-up questions that clarify the initial questionwith concrete behavioral samples. The severity is ratedon a five-point scale, both for the past month and forthe worst period since the trauma. Descriptors are givenfor scale anchors. A total severity score is obtained bysumming ratings of all 17 symptoms, and symptomsare counted if they are scored as 2 or higher.

PTSD Interview (PTSD-I; Watsonet al., 1991)

The PTSD-I is another structured interview for assessingthe DSM-IIIR criteria for PTSD (Watson et al., 1991).The scale follows the same course as the other scales ex-cept its recommended format for administration. Inter-viewers are instructed to give respondents a copy of therating scale, read the questions aloud, and ask respon-dents to rate themselves.

Life charting for PTSD (the PTSD-LCM;Osuch et al., 2001)

The life chart method is a way of illustrating the rela-tionship of life events and treatment interventions tothe longitudinal course of illness. It is a longitudinal,graphic approach to the symptoms of PTSD. Life chart-ing is of particular importance in PTSD because thisdisorder involves the long-term effect of life eventson a patient’s symptomatology, can wax and wane dra-matically over time, and frequently overlaps with co-morbid entities (other anxiety disorders, alcohol andsubstance abuse, affective disorders). Accurate depic-tion of course of illness may yield clues about thenatural history, underlying neurobiology, and phase-related responses to treatment. Life events are recordedand scored for subjective impact, ranging from stronglypositive (þ4) to strongly negative (–4). Severity of eachpatient’s “positive” and “negative” symptoms of PTSD(analogous to positive and negative symptoms of schizo-phrenia or mania and depression in bipolar disorder)are graphically recorded. The symptoms of PTSD weresimplified into these two general categories to facilitaterecall and rating of their severity. PTSD symptomsare subjectively reported as mild, moderate, or severein retrospective charting.

Life charting can be used in two ways: prospectiveand retrospective. Retrospective life charting has theliabilities of depending on patients’ recall and beingtime-consuming. Nevertheless, the utility of such a

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detailed approach is suggested as part of the initialphases of intake and therapy. Once completed, a lifechart provides a concise longitudinal condensationfrom which to consider psychotherapeutic and pharma-cotherapeutic options. Prospective life charting is astructured, daily, self-report instrument and dependson the patient’s ability to assess a variety of symptomseverities that do not have precisely delineated cutoffs,and to report them accurately (Osuch et al., 2001).

Breslau et al. (1999b) reported a short screening scaleconsisting of seven screening symptoms for use incomputer-assisted telephone interviews. They chose fiveof the symptoms from the avoidance and numbinggroup, and two from the hyperarousal group. A scoreof 4 or greater on this scale defined positive cases ofPTSD with a sensitivity of 80%, a specificity of 97%,a positive predictive value of 71%, and a negative predic-tive value of 98%, showing that this short screeningscale can be an efficient method to screen for PTSDin epidemiological and clinical studies with limited bur-den on respondents (Breslau et al., 1999b).

308 E. VERMETTEN

Early-life trauma assessment

In order to assess traumatic events that may account forlater-life PTSD, we developed a semistructuredinterview (Early Trauma Inventory, ETI; Bremneret al., 2000, 2007). This assesses traumatic life eventsin the first 18 years of life. The questionnaire gives a com-posite score of four domains of early trauma: natural di-sasters, emotional trauma, physical trauma, and sexualtrauma. The interview combines narrative and structuredapproaches to inquiring about childhood emotional,physical, and sexual abuse aswell as nonabusive traumas.Each subsection begins with an open-ended format inwhich subjects are asked in a general way about theirexperiences related to that domain and are allowed totell their story in their own words. Following this initialintroduction, subjects are assessed using a series of struc-tured questions within that particular domain. The ETIassesses a wide range of abuse experiences, includingphysical abuse items, such as a more common “wereyou ever spanked with a hand?” as well as less commonevents, such as “were you ever locked in a closet?” TheETI has a range of sexual abuse items, including “wereyou ever exposed to someone flashing?” and “wereyou ever forced to have anal sex against yourwill?” Emo-tional abuse items range from “were you often shoutedat?” to “did your parents or caretakers fail to understandyour needs?” The general trauma component assessesevents ranging from parental loss and natural disasterto criminal victimization. Data show excellent interraterreliability. Test–retest studies performed in a patientand nonpatient population show excellent reliability

(Bremner et al., 2007). For a review of childhood traumainstruments, see Pietrini et al. (2010).

There have been considerable controversies about thevalidity of recall of childhood abuse. There have beenstudies that reported long-term correlates of abuseevents that were documented at the time they occurred(Chu et al., 1999). The relationship between reportedabuse and the historical accuracy of abuse events isnot fully known. Our findings of a strong level of agree-ment between test and retest administration of ETI,however, supports the stability of recalled memoriesof abuse and other traumas over time. Regardless ofthe controversy surrounding the accuracy of reportedabuse, the development of standardized instrumentsfor the assessment of reported abuse and other traumas,with demonstrated reliability and validity, will bebeneficial in furthering careful research in this area(Bremner et al., 1999a).

Several validated trauma assessments are availablethat allow quantification of trauma symptomatology.Special emphasis is for the early trauma assessment,as there have been controversies surrounding theaccuracy of reported abuse.

THEBIOLOGICALFRAMEWORKINFEARPROCESSINGANDSTRESSREGUALTION:

BRAIN, NEUROHORMONAL, ANDTRANSMITTERREGULATION

Animal experimental models

The development of animal models for PTSD is animportant part of advancing our neurobiological under-standing of the disease process as well as recovery,resilience, and possible therapeutic targets. Animalmodels that are characterized by long-lasting condi-tioned fear responses as well as generalized behavioralsensitization to novel stimuli following short-lasting butintense stress have a phenomenology that resemblesthat of PTSD in humans. These models include briefsessions of shocks, social confrontations, and a shortsequence of different stressors. The paradigm of mater-nal deprivation or exposure to inescapable stress hasbeen highly relevant to our understanding of PTSD,e.g., in the model of inescapable stress, animals areexposed to repeated stressors, such as electric footshock or being forced to swim in cold water. Thesestressors result in an acute release of stress-relatedneuropeptides, hormones, and transmitters, includingcorticotropin-releasing factor (CRF), which activatesthe HPA axis to cause release of adrenocorticotropichormone (ACTH) and cortisol, norepinephrine, benzo-diazepines, serotonin (5-HT), dopamine, and opiates.Subgroups of animals with different behavioral traitsor coping styles during stress exposure show a different

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FOR POSTTRAUMATIC STRESS DISORDER 309

degree or pattern of long-term sensitization. Weeks tomonths after the trauma, treated animals on averagealso show a sensitization to novel stressful stimuli ofneuroendocrine, cardiovascular, and gastrointestinalmotility responses as well as altered pain sensitivityand immune function. Animals exposed to chronicstressors typically show potentiated release of transmit-ters with exposure to subsequent stressors. These neuro-chemical changes are also accompanied by behavioralchanges (sometimes referred to as “learned helpless-ness”) that are similar to human anxiety, includingincreased defecation and avoidance of novel stimulisuch as an open field. Functional neuroanatomical andpharmacological studies in these animal models haveprovided similar evidence for involvement of amygdalaand medial prefrontal cortex, and of brainstem areasregulating neuroendocrine and autonomic functionand pain processing. They have also generated a numberof neurotransmitter and neuropeptide targets that couldprovide novel avenues for treatment in PTSD (Stam,2007). Thus chronic stress results in long-term abnor-malities in the neurochemical systems that are necessaryfor appropriately coping with stressful situations. Spe-cific brain areas that play an important role in a varietyof types of memory are preferentially affected by stress(and mediate the stress response), including amygdala,hippocampus, hypothalamus, thalamus, medial pre-frontal and parietal cortex, visual association cortex,and cingulate (Vermetten and Bremner, 2002a, b)(Fig. 18.3). These long-standing alterations in biologicalstress response systems may underlie symptoms of PTSD(Charney and Bremner, 2000).

BIOLOGICAL AND CLINICAL FRAMEWORK

Medial Prefrontal

Cortex

Anterior cingulate,orbitofrontal,subcallosal gyrusplanning, execution,inhibition of responses,extinction of fearresponse,contextualization

Amygd

Emotional v

Posterior Cingulate, Parieta

Visuospatial processing and a

Motor responses, peripheral sympath

Fig. 18.3. Functional neuroanatomy of posttraumatic stress disor

Brain circuitry

Based on animal research and current work in clinicalneuroscience of PTSD, a model for a neural circuitryof anxiety and fear that is also applicable to PTSD hasbeen described (Charney and Bremner, 2000; VermettenandBremner, 2002a,b;Stam,2007;ShinandHandwerger,2009). The model explains how information related toa threatening stimulus (e.g., you are being robbed bytwo men with knives in a dark alley) enters the primarysenses (sight, smell, touch, hearing), is integrated intoa coherent image that is grounded in space and time,activates memory traces of previous similar experienceswith the appropriate emotional valence (necessary in orderto evaluate the true threat potential of the stimulus),and subsequently triggers an appropriate motor response.Specific brain circuits that mediate these responsesmake up the neural circuitry of anxiety and fear and canbe adapted to the field of traumatic stress (Fig. 18.3).Critical processes in these circuits include failure ofinhibition, stress sensitization, and fear condition. Thecritical brain structures are hippocampus, amygdala,and orbitifrontal cortex.

In the developmental trajectory of human fear oranxiety, afferent sensory input enters through the eyes,ears, nose, sense of touch, the body’s own visceral infor-mation, or any combination of these. These sensory in-puts are relayed through the dorsal thalamus to corticalbrain areas, such as primary visual (occipital), auditory(temporal), or tactile (postcentral gyrus) cortical areas.Olfactory sensory input, however, has direct inputs tothe amygdala and entorhinal cortex (Turner et al.,

Thalamus

Sensory gateway

Hippocampus

Memoryala

alence

Sensoryinputs

Cerebellum

l and Motor Cortex

ssessment of threat

etic and cortisol response

der.

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1978). Input from peripheral visceral organs is relayedin the brainstem to the locus ceruleus, the site of themajority of the brain’s noradrenergic neurons, and fromhere to central brain areas.

These brain areas have projections to multiple areas,including amygdala, hippocampus, entorhinal cortex,orbitofrontal cortex, and cingulate, that are involvedin mediating memory and emotion (Vogt and Miller,1983). Cognitive appraisal of potential threat is also animportant aspect of the stress response. The cognitiveresponse to threat involves placing the threatening object(man/knife) in space and time. Specific brain areasare involved in these functions (such as localizing anobject in space, visuospatial processing, memory, cogni-tion, action, or planning). The anterior cingulate gyrus(Brodmann area 32) is involved in selection of responsesfor action as well as emotion (Devinsky et al., 1995). Thisarea and other medial portions of the prefrontal cortex,including area 25 and orbitofrontal cortex, modulateemotional and physiological responses to stress andare discussed in more detail below.

Another important aspect of the stress response isincorporation of a person’s previous experience (mem-ory) into the cognitive appraisal of stimuli. For example,if you are approached in a potentially threatening situa-tion, it will be important to determine whether the faceof the person is someone known to you or is a strangerwho may be more threatening. In addition, it is impor-tant to place the situation in time and place. Enteringa dark alleyway may trigger prior memories of beingrobbed, with associated negative emotions and physio-logical arousal. These memories may have survivalvalue, in that the individual will avoid the situationwhere the previous negative event took place. Finally,it is critical to lay down effectively memory tracesrelated to a potential threat in order to avoid this typeof threat in the future.

310 E. VERMETTEN

HIPPOCAMPUS

The hippocampus, which is particularly vulnerable tostress, plays an important role in memory. The hippo-campus and adjacent cortex mediate declarative mem-ory function (e.g., recall of facts and lists) and havebeen hypothesized to play an important role in integra-tion of memory elements at the time of retrieval and inassigning significance for events within space and time(Squire and Zola-Morgan, 1991). The hippocampus alsoplays an important role in mediating emotionalresponses to the context of a stressor, e.g., in animalstudies, lesions of the hippocampus disrupted the for-mation of emotional memories of the context (i.e., thebox) where the stressor (i.e., electric footshock) tookplace (Kim and Fanselow, 1992; Phillips and LeDoux,

1992). High levels of glucocorticoids released duringstress were also associated with damage to the CA3region of the hippocampus (Uno et al., 1989; Sapolskyet al., 1990) as well as related deficits in memory(McEwen et al., 1992; Arbel et al., 1994; Luine et al.,1994; reviewed in more detail below).

With long-term storage, memories are felt to beshifted from hippocampus to the neocortical areas,where the initial sensory impressions take place (Squireand Zola-Morgan, 1991). The shift in memory storageto the cortex may represent a shift from conscious repre-sentational memory to unconscious memory processesthat indirectly affect behavior. “Traumatic cues” suchas a particular sight or sound reminiscent of the originaltraumatic event will trigger a cascade of anxiety andfear-related symptoms will ensue, often without con-scious recall of the original traumatic event. In patientswith PTSD, however, the traumatic stimulus is alwayspotentially identifiable. Symptoms of anxiety in panicor phobic disorder patients, however, may be related tofear responses to a traumatic cue (in individuals whoare vulnerable to increased fear responsiveness, througheither constitution or previous experience),where there isno possibility that the original fear-inducing stimuluswillever be identified.

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AMYGDALA

The amygdala is involved in memory for the emotionalvalence of events. The paradigm of conditioned fear hasbeen utilized as an animal model for stress-inducedabnormalities of emotional memory (Davis, 1992). Con-ditioned fear, in which pairing of a neutral (“condi-tioned”) stimulus to a fear-inducing (“unconditioned”)stimulus results in fear responses to the neutral (“condi-tioned”) stimulus alone, has been used as a probe ofamygdala function (LeDoux, 1993). Lesions of the cen-tral nucleus of the amygdala have been shown to blockfear conditioning completely (Hitchcock and Davis,1986; Hitchcock et al., 1989), while electrical stimulationof the central nucleus increases acoustic startle (Rosenand Davis, 1988). The central nucleus of the amygdalaprojects to a variety of brain structures via the striaterminalis and the ventral amygdalofugal pathway.One pathway is from the central nucleus to the brain-stem startle reflex circuit (nucleus reticularis pontiscaudalis). Pathways from the amygdala to the lateralhypothalamus affect peripheral sympathetic responsesto stress (Iwata et al., 1986). Electrical stimulation ofthe amygdala in cats resulted in peripheral signs ofautonomic hyperactivity and fear-related behaviors seenin the wild when the animal is being attacked or is attack-ing, including alerting, chewing, salivation, piloerection,turning, facial twitching, arching of the back, hissing,

F

and snarling, associated with an increase in catechol-amine turnover (Hilton and Zbrozyna, 1963). Electricalstimulation of the amygdala in human subjects resultedin signs and symptoms of fear and anxiety, including anincrease in heart rate and blood pressure, increasedmuscle tension, subjective sensations of fear or anxiety,and increases in peripheral catecholamines (Chapmanet al., 1954; Gunne and Reis, 1963). These findings dem-onstrated that the amygdala plays an important role inconditioned fear and emotional responding, as well asmodulating peripheral stress responses. There are alsoimportant connections between cortical associationareas, thalamus, and amygdala that are important inshaping the emotional valence of the cognitive responseto stressful stimuli (LeDoux et al., 1988; Ehrlich et al.,2009). In addition to thalamocortico-amygdala con-nections, there are direct pathways from thalamus toamygdala, which could account for fear respondingbelow the level of conscious awareness (Romanskiand LeDoux, 1992).

FRONTAL CORTEX

Frontal cortical areas modulate emotional responsive-ness through inhibition of amygdala function, and wehave hypothesized that dysfunction in these regionsmay underlie pathological emotional responses inpatients with PTSD and possibly other anxiety disorders.Medial prefrontal cortex (area 25) (subcallosal gyrus)has projections to the amygdala that are involved inthe suppression of amygdala responsiveness to fearfulcues. Dysfunction of this area may be responsible forthe failure of extinction to fearful cues, which is animportant part of the anxiety response (Morgan andLeDoux, 1995). This area is involved in regulation ofperipheral responses to stress, including heart rate,blood pressure, and cortisol response (Roth et al.,1988). Finally, case studies of humans with brain lesionshave implicated medial prefrontal cortex (includingorbitofrontal cortex, area 25, and anterior cingulate area32) in “emotion” and socially appropriate interactions(Damasio et al., 1994). Auditory association areas (tem-poral lobe) have also been implicated in animal studiesas mediating extinction to fear responding (Jarrellet al., 1987; Romanski and LeDoux, 1992). As reviewedlater, several studies found dysfunction of medial pre-frontal cortex and with traumatic reminders in PTSD(Francati et al., 2007).

OTHER BRAIN STRUCTURES

A final component of the stress response involves prep-aration for a response to potential threat. Preparationfor responding to threat requires integration betweenbrain areas involved in assessing and interpreting the

BIOLOGICAL AND CLINICAL FRAMEWORK

potentially threatening stimulus, and brain areas in-volved in response. For instance, prefrontal cortex andanterior cingulate play an important role in the planningof action and in holding multiple pieces of informationin “working memory” during the execution of a re-sponse (Goldman-Rakic, 1988). Parietal cortex and pos-terior cingulate are involved in visuospatial processing,which is an important component of the stress response.Motor cortex may represent the neural substrate ofplanning for action. The cerebellum has a well-knownrole in motor movement, which would suggest that thisregion is involved in planning for action; however,recent imaging studies are consistent with a role in cog-nition as well (Ashkoomoff and Courchesne, 1992).Connections between parietal and prefrontal cortexare required in order to permit the organism to executemotor responses to threat rapidly and efficiently. It istherefore not surprising that these areas have importantinnervations to precentral (motor) cortex, which is re-sponsible for skeletal motor responses to threat, whichfacilitate survival. The striatum (caudate and putamen)modulates motor responses to stress. The dense innerva-tion of the striatum and prefrontal cortex by the amyg-dala indicates that the amygdala can regulate both ofthese systems. These interactions between the amygdalaand the extrapyramidal motor system may be very im-portant for generating motor responses to threateningstimuli, especially those related to prior adverse experi-ences (McDonald, 1991a, b).

Central and peripheral neurohormonalregulation

NOREPINEPHRINE

Norepinephrine release in the brain represents an imp-ortant part of the stress response (for reviews, seeBremner et al., 1996a, b). The majority of noradrenergiccell bodies are located in the brainstem, in the locusceruleus region of the mesencephalon, with axons thatextend throughout the cerebral cortex and to multiplesubcortical areas. Neurons in the locus ceruleus areactivated in association with fear and anxiety states(Abercrombie and Jacobs, 1987; Redmond, 1987), andthe limbic and cortical regions innervated by the locusceruleus are those thought to be involved in the elabora-tion of adaptive responses to stress. Stressors such as acat seeing a dog result in an increase in firing of neuronsin the locus ceruleus (Levine et al., 1990) and enhancedlocus ceruleus region of the release in the hippocampus(Nisenbaum et al., 1991; Petty et al., 1993) and medialprefrontal cortex (Finlay et al., 1995).

Stress sensitization refers to a stressor-inducedincrease in behavioral, physiological, and biochemicalresponding to subsequent stressors of the same or lesser

OR POSTTRAUMATIC STRESS DISORDER 311

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magnitude. For example, chronically stressed animalshad increased norepinephrine release in hippocampuswith subsequent stressors (Abercrombie et al., 1989).Significantly greater behavioral, cardiovascular, andbiochemical responses to equivalent doses of yohimbinein combat veterans with PTSD compared with healthycontrols are an example of evidence supporting thismodel (Southwick et al., 1993, 1999). It has been pro-posed that multiple neurobiological systems, includingcatecholamine systems and the HPA axis, can becomesensitized over time by traumatic stress and as a resultcontribute to PTSD symptoms such as hypervigilance,poor concentration, insomnia, exaggerated startle re-sponse, and intrusive memories. It has been proposedthat this facilitation of memory is caused by endogenousneuromodulators, such as epinephrine and norepineph-rine, which are released during arousing and stressfulcircumstances. Overstimulation of these stress-relatedneuromodulators during traumatic events can causeoverconsolidation and deeply engraved memories forthe event.

312 E. VERMETTEN

DOPAMINE, SEROTONIN, BENZODIAZEPINES,AND NEUROPEPTIDES

The role of dopamine, 5-HT, benzodiazepines, andneuropeptides will not be reviewed here in detail.Readers are referred to findings in the dopaminergicinnervation of the medial prefrontal cortex, whichappears to be particularly vulnerable to stress (for areview, see Thierry et al., 1998). The effects of stresson 5-HT systems have been studied less thoroughly thanthose on noradrenergic systems. Although there are onlya limited number of early studies of serotonergic func-tion in PTSD (Davis et al., 1997; Southwick et al., 1997;Maes et al., 1999a), there is a large body of indirect ev-idence suggesting that this neurotransmitter may be im-portant in the pathophysiology of trauma-relatedsymptomatology. In humans, low 5-HT functioninghas been associated with aggression, impulsivity, andsuicidal behavior. Patients with PTSD are frequently de-scribed as aggressive or impulsive and often suffer fromdepression, suicidal tendencies, and intrusive thoughtsthat have been likened to obsessions. Endogenous benzo-diazepines also play an important role in the stress re-sponse and anxiety (for a review, see Guidotti et al.,1990). Benzodiazepine receptors are present throughoutthe brain with the highest concentration in cortical graymatter. Several neuropeptides also mediate the responseto stress. Cholecystokinin is an anxiogenic neuropeptidepresent in the gastrointestinal tract as well as the brainand has recently been suggested as a neural substratefor human anxiety. Stress is associated with an increasein endogenous opiate release (Madden et al., 1977;

Maier et al., 1981) with decreased density of mu-opiatereceptors (Stuckey et al., 1989), which may mediate theanalgesia associated with stress. Other neuropeptidesunder investigation that appear to play a role in the stressresponse are neuropeptide Y, somatostatin, and thyro-tropin. Stress also has important effects on theimmune system that are not reviewed here in detail.

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THE HYPOTHALAMIC–PITUITARY–ADRENAL AXIS

IN THE STRESS RESPONSE

The HPA axis is the most critical component of thestress response system. CRF is released from the para-ventricular nucleus (PVN) of the hypothalamus, causingrelease of ACTH from the pituitary, which stimulatesrelease of cortisol (the major stress hormone) fromthe adrenals. This axis is involved in a negative-feedbackloop that regulates cortisol release (as well as regulatoryfeedback with the noradrenergic system, which isdiscussed in more detail below).

Acute stress of many types results in release of CRFas well as ACTH and cortisol. The mechanism responsi-ble for transient stress-induced hyperadrenocorticismand feedback resistance may involve a downregulationof glucocorticoid receptors (GRs: Herman et al., 1984;Sapolsky and Plotsky, 1990). High glucocorticoid levels(such as those elicited by acute stress) decrease the num-ber of hippocampal GRs, resulting in increased cortico-sterone secretion and feedback resistance. Followingstress termination, when glucocorticoid levels decrease,receptor numbers are increased and feedback sensitivitynormalizes (Sapolsky et al., 1984a, b). The effects ofchronic stress on ACTH and corticosterone secretionvary depending on the experimental paradigm. It hasbeen reported that an adaptation to chronic stress mayoccur, resulting in decreased plasma ACTH and cortico-sterone levels compared with levels following a singlestressor (Kant et al., 1987). However, some early inves-tigations have also revealed enhanced corticosteronesecretion after chronic stressor regimens (Irwin et al.,1986). There is also ample evidence that the experienceof prior stress may result in augmented corticosteroneresponses to a subsequent stress exposure (Dallmanand Jones, 1973; Caggiula et al., 1989). It is not knownwhich factors determine whether adaptation or sensiti-zation of glucocorticoid activity will occur followingchronic stress (Yehuda et al., 1991). The HPA axis hasimportant functional interactions with the norepine-phrine system that facilitate a sophisticated range of re-sponses to stress. Glucocorticoids have shown to inhibitstress-induced activation of catecholamine synthesis inthe PVN (Pacak et al., 1993, 1995; Vetrugno et al.,1993). CRF increases activity of the locus ceruleus(Valentino and Foote, 1988), and CRF injected into the

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locus ceruleus intensified anxiety-related responses(Butler et al., 1990). These findings supported the notionthat CRF serves as an excitatory neurotransmitter in thelocus ceruleus, which may represent the pathway for thebehavioral effects of CRF.

Linkage with other neurobiological systems

Coordinated functional interactions between the HPAaxis and noradrenergic neuronal systems may be criticalin promoting adaptive responses to stress, anxiety, orfear. CRF increases locus ceruleus firing, resulting inenhanced norepinephrine release in cortical and subcor-tical areas throughout the brain. The PVN of the hypo-thalamus, the site of the majority of CRF-containingneurons in the hypothalamus, is an important site ineffecting cardiovascular and neuroendocrine responsesto stress. Norepinephrine increases CRF in the PVNof the hypothalamus. In chronically stressed animals,the locus ceruleus (as opposed to other norepinephrineneurons in the medulla) may be preferentially respon-sible for norepinephrine release in the PVN. IncreasedCRF release from the PVN resulted in stimulation ofACTH secretion from the pituitary and consequentlycortisol release from the adrenal gland. High levelsof circulating cortisol act through a negative-feedbackpathway to decrease both CRF and norepinephrinesynthesis at the level of the PVN. Glucocorticoid inhibi-tion of norepinephrine-induced CRF stimulation maybe evident primarily during stressor-induced cortisolrelease and not under resting conditions. High levelsof cortisol likely inhibit the effects of norepinephrineon CRF release from the PVN, serving to restrain thestress-induced neuroendocrine and cardiovasculareffects mediated by the PVN. Norepinephrine, cortisol,and CRF thus appear to be tightly linked in a func-tional system that offers a broad homeostatic/allostaticmechanism for coping with stress.

LONG-TERMALTERATIONS INNEUROBIOLOGICAL SYSTEMS IN PTSD

Introduction

An understanding of the biological basis of PTSDrequires an examination of the underlying neurobiologyof fear as well as the factors that might contribute to anunsuccessful termination of the fear response in someindividuals. Several factors may lead to an inadequatetermination of a stress response, and the failure to con-tain the biological alterations initiated by stress mayhave long-term adverse consequences on emotionregulation. In particular, a prolonged continuationof biological responses following stress may lead toan inappropriate pairing of the traumatic memory with

BIOLOGICAL AND CLINICAL FRAMEWORK

distress and may then initiate a cascade of secondarybiological alterations. In a landmark paper in 1993,Charney et al. wrote on the psychobiology of PTSDand described long-lasting alterations in three psycho-biological domains: (1) stress sensitization; (2) fear con-ditioning; and (3) failure in extinction.

Their conceptual notions called for clinical empiricalsupport, which has been provided now by excellent stud-ies, as several now illustrate. Second is the model thatMcEwen has proposed for the understanding of PTSD.He introduced the “allostasis” concept, i.e., maintaininghomeostasis through change (McEwen, 1998). In thismodel the cost of allostasis or allostatic load representedthe outcome of wear and tear of the organism. From thispoint of view PTSD is manifested, for example (as willbe described later in this chapter), in noradrenergichyperreactivity, dysregulation of the HPA axis (basalhypocortisolemia, reactive hypercortisolemia, alteredGR, increased responsiveness, or sensitivity tostressors), dysregulated responsiveness of amygdala,orbitofrontal dysfunction resulting in failure of extinc-tion, and in reduced hippocampal volume. The brain isthe key organ of allostatic regulation because its cogni-tive operations determine what is threatening and there-fore stressful and also how the physiological andbehavioral responses occur.

OR POSTTRAUMATIC STRESS DISORDER 313

Norepinephrine

PTSD is characterized by tonic autonomic hyperarousaland increases in autonomic system activity in responseto trauma-relevant stimuli. This increased activitygenerally is not observed under baseline or resting con-ditions but rather in response to a variety of stressors.It has been suggested that altered reactivity of nor-adrenergic neurons is associated with a variety of hyper-arousal and re-experiencing symptoms characteristic ofPTSD. Consistent elevations of heart rate, blood pres-sure, plasma norepinephrine, and plasma 3-methoxy-4-hydroxyphenylglycol (MHPG) have not been reportedat baseline in this population but generally have beenreported in response to neuroendocrine and psycholog-ical challenges. Increased responsivity of noradrenergicsystems is consistent with a sensitization model of PTSDwhere biochemical, physiological, and behavioral re-sponses to subsequent stressors increase over time. Ithas been suggested that sensitization of noradrenergicsystems contributes to arousal symptoms in PTSD, in-cluding hypervigilance, exaggerated startle, anger, andinsomnia. The most frequently used measures are elec-trodermal activity as presented by skin conductancelevels; skin temperature; responses such as heart rateand systolic and diastolic blood pressure; and electro-myographic (EMG) activity of various facial muscles.

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These variables reflect in part activity of the peripheralsympathetic system. Exposure to traumatic remindersand neutral scenes utilized in the psychophysiology par-adigm includes slides, sounds, or scenes similar to theoriginal trauma or reading scripts that describe whatactually happened during the original trauma. Compar-isons are made between exposure to trauma-relatedmaterial and both the baseline and/or the neutralexposures.

Over the past 20 years, a large number of psycho-physiological studies have reported heightened sympa-thetic nervous system activity in veterans with PTSD.Some studies proposed to use hormonal ratios or pro-files, in an effort to increase the diagnostic sensitivityof neuroendocrine criteria in the differential diagnosisof psychiatric disoders and in particular the assessmentof PTSD. Mason et al. (1988) described a diagnostic sen-sitivity of 78% and a specificity of 94% for correct clas-sification of PTSD in a clinical sample of PTSD patients(Mason et al., 1988). Their preliminary findings yieldedencouragement for exploring multivariate strategies.However, no later studies were reported that used thisapproach. Exaggerated increases have not been foundin combat veterans without PTSD, in combat veteranswith anxiety disorders other than PTSD, or in responseto generic stressors (such as the film of an automobileaccident) that have never been experienced by thetrauma survivor.

Studies on autonomic arousal show some variabilityin their reports. Many of the studies assessing physiolog-ical characteristics in PTSD have been conducted withveteran subjects and women with histories of childhoodsexual abuse (Prins et al., 1995; Carlson et al., 1997;Liberzon et al., 1999; Metzger et al., 1999). A commonfinding in these studies was that PTSD patients showedheightened responsivity to trauma-related cues, consis-tent with increased norepinephrine responsivity. Patientswith combat-related PTSD were found to have elevatednorepinephrine and epinephrine in 24-hour urine in com-parison with normal controls and patients with otherpsychiatric disorders (Mason et al., 1988; Spivak et al.,1999). Relative elevations of the norepinephrine metab-olite MHPG were found in nighttime samples in PTSD(Mellman et al., 1995). No differences were found, how-ever, in urinary norepinephrine between patients withcombat-related PTSD and combat-exposed non-PTSDsubjects (Pitman and Orr, 1990) or in baseline levelsof plasma norepinephrine in combat-related PTSDversus healthy subjects (for a review, see Murberg,1994). Women with PTSD secondary to childhood sexualabuse had significantly elevated levels of catechol-amines (norepinephrine, epinephrine, dopamine) andcortisol in 24-hour urine samples (Lemieux and Coe,1995). Sexually abused girls excreted significantly

314 E. VERMETTEN

greater amounts of catecholamine metabolites, meta-nephrine, vanillylmandelic acid, and homovanillic acidthan nonsexually abused girls (De Bellis et al., 1994)and increased in abuse-related PTSD (De Bellis et al.,1999a, b). Exposure to traumatic reminders in the formof combat films resulted in increased epinephrine andnorepinephrine release, and increased MHPG with phys-ical exercise has been found in Vietnam veterans withPTSD in comparison to healthy subjects (Hamner andHitri, 1992). Children with PTSD were found to haveincreased orthostatic heart rate response, suggestingnoradrenergic dysregulation (Perry, 1994).

Alterations in HPA axis

HYPO- VERSUS HYPERCORTISOLEMIA

A comprehensive review of HPA function, one of themost widely studied physiological response systems inPTSD, is beyond the scope of this chapter. Excellentrecent overviews of earlier literature can be found(Yehuda, 2001, 2002; de Kloet et al., 2006). While lowbasal plasma, urinary, or saliva cortisol was thought tobe an endocrinological hallmark of PTSD (Yehuda,2002; Oquendo et al., 2003; Luecken et al., 2004; Neylanet al., 2005), this concept can no longer be maintained inthe wake of more recent findings. Normal (Hawk et al.,2000;Bonne et al., 2003; Lipschitz et al., 2003;Young andBreslau, 2004a, b; Young et al., 2004; Otte et al., 2005) orhigher (Lemieux and Coe, 1995; Carrion et al., 2002;Lindley et al., 2004) basal levels of plasma, urinary, orsaliva cortisol have now also been repeatedly reported.

As well as elevated levels of corticotropin-releasinghormone (CRH) (Bremner et al., 1997a; Baker et al.,1999, 2005; Sautter et al., 2003; de Kloet et al., 2008a)and cortisol (Baker et al., 2005) in cerebrospinal fluid,and a flattened awakening salivary cortisol response(Rohleder et al., 2004; Neylan et al., 2005; Yehudaet al., 2005; Wessa et al., 2006; de Kloet et al., 2007),different challenge paradigms have been used to exploreHPA axis regulation in PTSD. To measure CRH recep-tor sensitivity in PTSD, studies assessed the ACTH andcortisol response to a CRH challenge (Smith et al., 1989;Rasmusson et al., 2001; Kellner et al., 2003; the resultshave been inconclusive, varying from attenuated re-sponse to an exaggerated response and one study alsoshowed a normal response.

HYPERREGULATION AND INCREASED FEEDBACK

SENSITIVITY

Studies using the low-dose dexamethasone suppressiontest (0.5 mg DST) in PTSD populations are more consis-tent and show enhanced cortisol suppression (forreview, see de Kloet et al., 2006). Yet, it is not clear if

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FOR POSTTRAUMATIC STRESS DISORDER 315

the enhanced suppression is a sign of psychopathology,or a response pattern of a stressed system, since intrauma controls the same enhanced suppression wasfound in a matched control study run on military sub-jects with PTSD (de Kloet et al., 2007). It could alsobe that the trauma controls had not developed PTSDsymptoms yet. Based on accumulation of the mostreported findings a hypothalamic overdrive or “hyper-regulation” in both upward and downward directioncan be suggested (Bremner et al., 1997b; Risbroughand Stein, 2006), as well as enhanced GR feedback in-hibition (Yehuda et al., 2005). While some of the vari-ability in basal cortisol may relate to measurementmethods (i.e., saliva versus plasma), collection time orperiod (Bremner et al., 2007), type of trauma or patientsubgroup, it has recently been suggested that there maybe no static hypo- or hypercortisolism in PTSD, but atendency of HPA tone to “hyperregulate.” Basal cortisolat any given moment could depend on the current stress-fulness of the living environment and the degree ofemotional engagement versus disengagement/with-drawal, i.e., coping strategy (Mason et al., 2001, 2002).

This hyperregulation is also reflected by increasedfeedback sensitivity of the HPA axis. A more consistentfinding than low basal cortisol in PTSD is a hypersup-pression of plasma cortisol and its main secretagogueACTH in response to a low dose of the synthetic gluco-corticoid dexamethasone (Heim et al., 1998; Yehuda,2002; Duval et al., 2004; Yehuda et al., 2004; de Kloetet al., 2007). Although normal dexamethasone suppres-sion of the HPA axis has also been reported (Lipschitzet al., 2003; Lindley et al., 2004), the salivary cortisolmeasures used in those studies may be less reliable inmeasuring subtle differences in feedback sensitivitythan cortisol measurement in blood samples (Reynoldset al., 1998). Enhanced suppression of basal HPA axis ac-tivity could depend on increased expression of the GR(Yehuda et al., 2004), which mediates the negative-feedback effects of cortisol, with mineralocorticoidreceptor function probably being normal (Kellner et al.,2002). Since dexamethasone probably does not reachsignificant receptor occupancy in the brain in humansafter peripheral administration (Cole et al., 2000), thedexamethasone hypersuppression seen in PTSD is proba-bly mediated on the level of the pituitary. This does notexclude the possibility that GR function on the level ofthe brain is also altered in PTSD (de Kloet et al., 2007).

Chronobiological analysis of basal plasma cortisollevels in PTSD also provides evidence for a tighter reg-ulation and greater circadian signal-to-noise ratio,reflecting sensitization, whereas depressed patientshave a less rhythmic, more chaotic pattern of cortisolrelease than controls, a pattern more consistent withdesensitization.

BIOLOGICAL AND CLINICAL FRAMEWORK

ROLE OF COMORBIDITY

Whether or not PTSD patients have comorbid, activedepression may not affect basal cortisol or dexametha-sone suppression, but comorbid depression does seem toaffect HPA axis responses to administration of theACTH secretagogue CRF. In female PTSD patients withpast, but not current, major depression, the plasmaACTH and cortisol response to exogenous CRF isgreater than that in controls (Rasmusson et al., 2001).In contrast, female PTSD patients with current majordepression show smaller ACTH and cortisol responsesto exogenous CRF and a slightly smaller cortisol re-sponse to exogenous ACTH (Heim et al., 2001). Interest-ingly, women with comorbid PTSD and chronic pelvicpain, without depression, also show a lower cortisolresponse to CRF (Heim et al., 1998). Thus, as far asresponsivity to CRF goes, the effect of comorbid activemajor depression or certain somatic complaints seems toprevail over that for PTSD alone.

SUBGROUPS IN DEX/CRH

We compared the response to a dexamethasone (DEX)/CRH test between male veterans with PTSD (n ¼ 26)and male veterans, who had been exposed to similartraumatic events during their deployment, withoutPTSD (n ¼ 23). Patients and controls were matchedon age, year, and region of deployment. Additionally,we compared the response of PTSD patients with(n ¼ 13) and without comorbid MDD (n ¼ 13). Wefound no significant differences in ACTH and cortisolresponse to the DEX/CRH test between patients andcontrols. Yet, PTSD patients with comorbid MDDshowed a significantly lower ACTH response comparedto patients without comorbid MDD (de Kloet et al.,2008b) (Fig. 18.4). Altered sensitivity of the CRH recep-tors at the pituitary or differences in arginine vaso-pressin secretion might explain these differences inresponse. It demonstrated the need to look into sub-groups of the disorder, since there may be heterogeneitywithin the biological response pattern. There may befundamental differences in basal HPA axis regulationbetween patients with depression alone and patients withPTSD with or without comorbid depression. In depres-sion without PTSD, higher basal plasma cortisol is morecommon, and dexamethasone suppression is generallyreduced rather than enhanced (dexamethasone resis-tance) (Parker et al., 2003).

OTHER STRESSFUL CHALLENGES

While literature on the basal regulation of the HPA axisin PTSD is abundant, surprisingly few studies haveexamined the response of the system to controlled,

25 8

PTSD – MDD

*p<0.05

PTSD + MDDPTSD – MDDPTSD + MDD

6

4

2

0

20

CRH CRH*

** *

*15

10

AC

TH

(pg

/ml)

cort

isol

(nm

ol/l)

5

03:00A B3:30 3:45

time

4:154:00 3:00 3:30 3:45

time

4:154:00

Fig. 18.4. Adrenocorticotropic hormone (ACTH) and cortisol responses to the dexamethasone (DEX)/corticotropin-releasing

hormone (CRH) test. The plasma ACTH and cortisol levels (t0) in response to 1.5 mg DEX were log-transformed and compared

using an independent sample t-test between posttraumatic stress disorder (PTSD) patients and controls, and between PTSD

patients (n ¼ 13) with (PTSD þ MDD) and without (n ¼ 13) current major depressive disorder (PTSD – MDD). Area under

the response curve (AUCr) and delta were compared using a nonparametric test (Mann–Whitney U) between groups. Data are

expressed as mean and standard error of the mean. (Reproduced from de Kloet et al., 2008b.)

316 E. VERMETTEN AND R.A. LANIUS

external stressful challenges. Two studies showing in-creased plasma cortisol compared to that in healthy con-trols after traumatic reminders (Elzinga et al., 2003) or acognitive challenge (Bremner et al., 2003) are compli-cated by the fact that cortisol levels are already higherbefore the stress challenge starts. The relative cortisolresponse to the challenges on top of the higher baselineis not different from controls, even though heart rate,skin conductance, and epinephrine and norepinephrineresponses to traumatic reminders are greater in thePTSD group (Elzinga et al., 2003). Similarly high initialplasma cortisol, as well as high plasma catecholamines,heart rate, and skin conductance, are found before ex-posure of veterans with PTSD to combat sounds (condi-tioned stimuli) (Liberzon et al., 1999). It is of coursepossible that this higher baseline masks differentialresponsivity to the following challenge, or that the actuallaboratory challenges used are too mild (do not matchthe intensity that was anticipated). It is also possible thatin those studies in which higher basal cortisol levels arereported this may be the result of increased reactivity todaily stressful experiences.

SUMMARY OF HPA AXIS

Taken together, there is evidence for a sensitizedfeedback regulation of the HPA axis in PTSD. Althoughincreased reactivity of the HPA axis to laboratorystressors in PTSD patients has not been conclusivelydemonstrated, increased “basal” plasma cortisol levelsbefore the stress challenge may reflect a form of antic-ipatory anxiety that is in itself a sign of generalizedsensitization. Animal models of maternal deprivation

have shown enhanced cortisol reactivity in later life,but in some models an initial hyporeactivity of cortisolsecretion at younger ages is also observed. The questionnow remains whether this is bad or good? There arequestions that remain unanswered: Is attenuated cortisolreactivity actually a predisposing factor for PTSD? Oris inadequate cortisol release unable to contain anexaggerated initial stress reaction?

Memory function

Numerous studies have demonstrated explicit andworking memory deficits related to PTSD. Descriptionsfrom all wars of the 20th century document alterationsin memory occurring in combat veterans during or afterthe stress of battle. These include the forgetting ofone’s name or identity and the forgetting of events thathad just taken place during the previous battle. Amnesticmemory disturbances should not be confused withdeficits in short-term memory. Explicit memory isexpressed on tests that require conscious recollectionof previous experiences (e.g., free recall). Implicit mem-ory is revealed when these experiences affectperformance on a test that does not require consciousrecollection (e.g., perceptual identification). PTSDpatients have been found to have alterations in bothexplicit and implicit memory (McNally, 1997).

Danish survivors of the concentration camps in theSecond World War were described to have persistentself-reported difficulties in memory after release frominternment (Thygesen et al., 1970). Korean prisoners ofwar have been found to have an impairment of short-term verbal memory measured by the logical memory

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component of the Wechsler Memory Scale in compari-son to Korean veterans without a history of containment(Sutker et al., 1991). The same was found in Persian GulfWar veterans (Vasterling et al., 1998). Deficits in short-term memory in Vietnam combat veterans with combat-related PTSD as well as in patients with abuse-relatedPTSD were found on the logical memory componentof the Wechsler Memory Scale and the visual and verbalcomponents of the Selective Reminding Test as well ason the Auditory Verbal Learning Test (Uddo et al., 1993)and the California Verbal New Learning (Yehuda et al.,1995). A decrease in IQ in combat veterans with PTSDrelative to controls may be due to an increased riskfor the development of PTSD with lower IQ or maybe a secondary effect of exposure to trauma (McNallyand Shin, 1995). We found that veterans with PTSDhad similar total IQ scores compared to controls, butdisplayed deficits of figural and logical memory. Vet-erans with PTSD also performed significantly loweron measures of learning and immediate and delayedverbal memory. Memory performance also accuratelypredicted current social and occupational functioning(Geuze et al., 2009). Other studies in patients with PTSDhave shown enhanced recall on explicit memory tasksfor trauma-related words relative to neutral words incomparison to controls (Zeitlin and McNally, 1991;McNally et al., 1998).

Moreover, recent qualitative review papers have indi-cated that verbal memory impairment was found to bethe most consistent cognitive impairment related toPTSD. Ameta-analysis of 28 studies confirmed that ver-bal memory impairment was present in adults withPTSD. The review resulted in medium effect sizes inpatients with PTSD compared to controls on verbalmemory across studies. Marked impairment was foundin the patient groups compared to healthy controls, whilemodest impairment was found compared to exposednon-PTSD controls. Meta-analyses found strongesteffects in war veterans compared to sexual and physicalassault-related PTSD (Johnsen and Asbjornsen, 2008).

Few studies have addressed longitudinal changes inmemory functioning in PTSD. There is some evidenceto suggest an interactive effect of PTSD and agingon verbal memory decline in Holocaust survivors(Yehuda et al., 2006). However, the longitudinal tra-jectory of neuropsychological functioning has not beeninvestigated in a younger population of aging traumasurvivors. Samuelson et al. (2009) reported of a studyin which this was done. They administered tests of visualand verbal memory, and working memory to derive dif-ferent dependent measures in veterans between the agesof 41 and 63, most of whom had served in the Vietnamwar. The PTSD group did not show a significant changein PTSD symptoms over time. Veterans with PTSD only

BIOLOGICAL AND CLINICAL FRAMEWORK

showed a greater decline in delayed facial recognition,and this decline was extremely subtle.

OR POSTTRAUMATIC STRESS DISORDER 317

Glucocorticoids and the hippocampus

Stress is associatedwith damage to hippocampal neurons(Joels et al., 2004). The work of Sapolsky andMcEwen isseminal in this respect. The hippocampus, a major targetorgan for glucocorticoids in the brain (McEwen et al.,1986), modulates the pituitary–adrenocortical responseto stress (Sapolsky and McEwen, 1988). Monkeys thatdied spontaneously following exposure to severe stresswere found on autopsy to have multiple gastric ulcers,consistent with exposure to chronic stress, and hyper-plastic adrenal cortices, consistent with sustained gluco-corticoid release. These monkeys also had damage to theCA3 subfield of the hippocampus (Uno et al., 1989).

Follow-up studies suggested that hippocampal dam-age was associated with direct exposure of glucocorti-coids to the hippocampus (Sapolsky et al., 1990). Earlystudies in a variety of animal species (Aus der Muhlenand Ockenfels, 1969) suggest that direct glucocorticoidexposure results in decreased dendritic branching(Wooley et al., 1990) and a loss of neurons (Unoet al., 1989) that are steroid- and tissue-specific(Packan and Sapolsky, 1990). Prenatal exposure to ele-vated levels of glucocorticoids also results in hippocam-pal damage (Uno et al., 1989). Glucocorticoids appear toexert their effect through disruption of cellular metab-olism (Lawrence and Sapolsky, 1994) and by increasingthe vulnerability of hippocampal neurons to a variety ofinsults, including endogenously released excitatoryamino acids (Sapolsky, 1986; Armanini et al., 1990).Glucocorticoids have also been shown to augmentextracellular glutamate accumulation (Stein-Behrenset al., 1994). Furthermore, reduction of glucocorticoidexposure prevents the hippocampal cell loss asso-ciated with chronic stress (Landfield et al., 1981; Meaneyet al., 1988). Differing strains of rats may have varyingglucocorticoid responses to stress, suggesting the possi-bility that constitutional factors may influence theglucocorticoid-mediated effects of stress on hippocam-pal neurons (Dhabhar et al., 1993). There are alsosubstantial gender differences in the concentrations ofGRs at baseline and in response to stress, suggestingthat studies related to this area that are performedexclusively in males will not be applicable to females(McCormick et al., 1994). In summary, findings to dateare consistent with the idea that stress results in damageto neurons of the hippocampus, possibly through theeffects of increased levels of glucocorticoids. Otherfactors besides glucocorticoids, suchasbrain-derivedneu-rotrophic factor (BDNF), trkB mRNA, and nerve growthfactor, which have a regulatory effect on neuronal

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morphology and proliferation, may also mediate stress-induced alterations in hippocampal morphology (Nibuyaet al., 1995, 1996; Smith et al., 1995;Murakamiet al., 2005).

Glucocorticoids also have other actions besides adamaging effect on hippocampal neurons. For instance,low levels of glucocorticoids following adrenalectomyresult in damage to neurons of the dentate gyrus ofthe hippocampus (Vaher et al., 1994). Glucocorticoidsalso have effects on brain function through modulationof gene expression and have a variety of effects on im-munity, reproduction, bone formation, and other phys-iological functions. These effects may have a protectiveeffect on the organism during certain situations ofstress, but in other situations the effects of glucocorti-coids may be damaging (McEwen et al., 1992). Hippo-campal damage may also play a role in other aspectsof the long-term dysregulation of brain functionassociated with stress. The hippocampus is in generalfelt to have an inhibitory effect on the HPA axis.Stress-induced damage has been shown to be associatedwith an increase in levels of CRF mRNA in the PVN ofthe hypothalamus (Herman et al., 1984) as well as adecrease in the sensitivity of rats to dexamethasonesuppression of HPA function (Feldman and Conforti,1980; Magarinos et al., 1987). Consistent with this, in-creased levels of CRF have been reported in the cere-brospinal fluid of patients with combat-related PTSDin comparison to controls (Bremner et al., 1997a), as wellas in plasma (de Kloet et al., 2008a).

318 E. VERMETTEN

Glucocorticoid receptor expression as a riskfactor for PTSD

The interaction between glucocorticoids and immunefunction has also been investigated. The inhibition bythe synthetic glucocorticoid dexamethasone of leuko-cyte lysozyme activity (Yehuda et al., 2004), of bacteriallipopolysaccharide-stimulated interleukin-6 and tumournecrosis factor-a production (Rohleder et al., 2004), andof the mononuclear leukocyte GR number per cell(Yehuda et al., 2002) is potentiated in PTSD versushealthy controls. Oddly though, the baseline GR numberis reduced in all lymphocyte subpopulations (Gotovacet al., 2003), making it more likely that the potentiateddexamethasone suppression depends on increased re-ceptor affinity or secondary mechanisms.

Altered GR expression in peripheral blood mononu-clear cells (PBMCs) has been found in PTSD. We foundsignificantly lower leukocyte GR density in veterans withand without PTSD compared to healthy controls, suggest-ing that trauma exposure is sufficient to induce changesin GR-binding characteristics. The altered glucocorticoidsensitivity in lymphocytes and other changes in measuresof immunity do not appear to be secondary to changes in

activity of the HPA axis, since there is no correlation be-tween ambient plasma cortisol levels in PTSD patientsand changes in lymphocyte GR number (Gotovac et al.,2003), plasma interleukin (IL)-1b (Spivak et al., 1997),IL-6 (Maes et al., 1999b; Gill et al., 2008), or C-reactiveprotein (S€ondergaard et al., 2004) levels.

Since it was thus far unclear whether differences inGR expression exist already prior to developmentof PTSD, and thus may constitute a risk factor, weundertook a prospective study to assess whether pre-deployment GR-binding capacity differed betweenmilitary personnel with and without PTSD symptomsafter deployment. In addition it was aimed to assesswhether GR binding was a predictor of PTSD symptomsafter deployment. We included soldiers who reportedhigh levels of PTSD symptoms 6 months after deploy-ment (n ¼ 34) and soldiers without high levels of PTSDor depressive symptoms (n ¼ 34). Our data showedthat, before deployment, GR expression in PBMCswas significantly increased in participants with highlevels of PTSD symptoms after deployment as com-pared to matched controls. The risk for a high level ofPTSD symptoms after deployment increased 4.8-foldwith each increase of 1000 GR-binding sites. There wereno group differences in mRNA expression of GR-a,GR-P, GR-b, and FKBP5. These results demonstratedthat increased pre-trauma GR-binding capacity ofPBMCs is a vulnerability factor for the subsequent de-velopment of PTSD symptoms (Van Zuiden et al., 2011).

Sleep dysfunction

Sleep dysfunction has been documented following acutestress and appears to be related to the development ofchronic PTSD (Mellman et al., 1995). Polysomnographicstudies examining sleep abnormalities in PTSD haveproduced inconsistent results. PTSD patients have morestage 1 sleep, less slow-wave sleep, and greater rapid-eye-movement density compared to people withoutPTSD (Ross et al., 1994a, b; Kobayashi et al., 2007). Theyalso have decreased total sleep time, and increased“microawakenings” relative to controls. These abnor-malities may play a role in nightmares and sleep distur-bance in PTSD patients, which, according to someauthors, can be considered to be the hallmark symptomsof PTSD (for a review, see Ross et al., 1989; Spoormakerand Montgomery, 2008; Mellman, 2009).

THELAST TWODECADES:NEUROIMAGINGSTUDIES

Preclinical and clinical investigations provide strong evi-dence for linking several brain structures to the signs andsymptoms of anxiety and fear associated with trauma.Chief among these are the amygdala, hippocampus,

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thalamus, periaqueductal gray, and orbitofrontal cortex.Although there were no published studies on imaging inPTSDas recently as 15 years ago, since that time there hasbeen a rapid growth of studies in this area. This is in partdue to a growing appreciation of the neurobiologicalcontributions to PTSD. Also, technical developmentshave enabled complex designs. Spatial resolution hasmuch improved, and structures that 10 years ago werenot able to be visualized, e.g., amygdala, have now ledto a new focus in many studies. It is predicted that thefield is becoming saturated in terms of demonstatingthe validity as well as the neural circuitry of the disorder,and that the focus in the next decade will be on longi-tudinal studies that enable phenotypical comparison withfunctional imaging findings.

Small hippocampal volume on structuralneuroimaging with magnetic resonance

imaging (MRI)

Over the last decade a significant number of studieshave reported smaller hippocampal volume in individ-uals with symptoms of PTSD relative to control groups(Geuze et al., 2005; Smith, 2005). This line of researchwas prompted by studies in animals showing that highlevels of cortisol seen during times of stress are associ-ated with damage to the hippocampus (reviewed above).These studies were first reported when spatial resolutionof MRI was still low. First studies were reported inveterans with PTSD (Bremner et al., 1995c), and femaleswith sexual abuse-related PTSD (Bremner et al., 1997c).It was interesting that the magnitude of the reduction inhippocampal volume was associated with magnitude ofdeficits in short-term verbal memory (Bremner et al.,1995d). Since then studies have improved accuracyand subject composition. The meta-analysis that Smith(2005) performed showed on average that PTSD pa-tients had a 6.9% smaller left hippocampal volumeand a 6.6% smaller right hippocampal volume comparedwith control subjects. These volume differences weresmaller when comparing PTSD patients with controlsubjects exposed to similar levels of trauma, and largerwhen comparing PTSD patients to control subjectswithout significant trauma exposure.

Functional neuroimaging with functionalMRI and positron emission tomography

The first decade of neuroimaging research producedsymptom provocation, cognitive activation, and func-tional connectivity studies that highlighted the role ofthe medial prefrontal cortex, amygdala, sublenticularextended amygdala, and hippocampus, in mediatingsymptom formation in PTSD. Functional neuroimagingstudies in PTSD encompass a number of different

BIOLOGICAL AND CLINICAL FRAMEWORK

imaging modalities, including single-photon emissiontomography (SPECT), positron emission tomography(PET), and functional MRI (fMRI). In addition, a num-ber of different types of imaging paradigm havebeen pursued, including symptom provocation studies,cognitive activation studies, as well as functionalconnectivity analysis.

Symptom provocation studies were the first onesto provide replicable findings and still are the mostcommon in the neuroimaging literature on PTSD. Theyinvolve provoking symptoms while attempting to cap-ture the underlying neural substrates (as gleaned fromblood flow and/or blood oxygen level-dependenteffects) and employ trauma-related stimuli of an auto-biographical nature (e.g., narrative scripts of personaltrauma) or general nature (e.g., nonpersonalized pic-tures and sounds). The amygdala has been shown tobe a region implicated in rapidly assessing the salienceof emotion-related and especially threat-related stimuli(Davis andWhalen, 2001). Taken together, they lend ten-tative support to a neurocircuitry model that emphasizesthe role of dysregulation in threat-related processing inPTSD. According to this model, trauma exposure setsoff a cascade of neural changes that culminates ina state of amygdala hyperresponsivity to trauma-reminiscent and other threat-related stimuli. Amygdalahyperresponsivity is proposed to mediate symptoms ofhyperarousal and vigilance associated with PTSD.

Sophisticated techniques have also been developedfor the measurement of cerebral blood flow usingPET. H2[

15O] provides a good measure of cerebral bloodflow. Cerebral blood flow has been shown to be highlycorrelated with local cerebral glucose metabolism. Sinceneurons almost exclusively utilize glucose for cell pro-cesses, glucose utilization provides a measure of localneuronal activity. Studies in PTSD have begun to usePET during pharmacological and cognitive provocationof symptom states in order to identify neural correlatesof PTSD symptomatology and of traumatic remem-brance. In a classical study of combat-related PTSDusing PET and H2[

15O] measurement of cerebral bloodflow, 10 Vietnam veterans with PTSD and 10 Vietnamveterans without PTSD were studied during exposureto combat-related and neutral slides and sounds. Viet-nam veterans with combat-related PTSD (but not non-PTSD veterans) demonstrated a decrease in blood flowin the medial prefrontal cortex (Brodman’s area 25, orsubcallosal gyrus) and middle temporal cortex (auditorycortex) during exposure to combat-related slides andsounds. A failure of activation was found in anteriorcingulate (area 32 and 24), and increased activation inposterior cingulate, motor cortex, and lingual gyrus inPTSD veterans (Bremner et al., 1999c). In a similarstudy, cerebral blood flow correlates of exposure to

OR POSTTRAUMATIC STRESS DISORDER 319

AND R.A. LANIUS

personalized scripts of childhood sexual abuse werelooked at in women with histories of childhood abusewith (n ¼ 10) and without (n ¼ 12) PTSD. PTSDwomenshowed decreased blood flow in medial prefrontalcortex (area 25) and failure of activation in anterior cin-gulate, with increased blood flow in posterior cingulateand motor cortex (replicating findings in combat-relatedPTSD) and anterolateral prefrontal cortex. PTSDwomen also had decreased blood flow in right hippo-campus and parietal and visual association cortex(Bremner et al., 1999d). Other first studies of traumaticimagery in combat-related PTSD found alterations inorbitofrontal and temporal cortex in PTSD (Rauchet al., 1996; Shin et al., 1997, 1999).

PET and fluorodeoxyglucose was also used in themeasurement of cerebral glucose metabolic rate follow-ing administration of yohimbine and placebo in Vietnamcombat veterans with PTSD and healthy controls.Increased noradrenergic function has been hypothesizedto underlie many of the symptoms of PTSD. Adminis-tration of the a2-antagonist yohimbine, which stimulatesbrain norepinephrine release, resulted in increasedPTSD symptoms and anxiety in the PTSD group. Norepi-nephrine has a U-shaped curve type of effect on brainfunction, with lower levels of release causing an in-crease in metabolism, while very high levels of releaseactually cause a decrease in metabolism. It was hypoth-esized that yohimbine would cause a relative decrease inmetabolism in patients with PTSD in cortical brain areasthat receive noradrenergic innervation. Indeed, yohim-bine resulted in differences in metabolism in orbito-frontal, temporal, parietal, and prefrontal cortex inPTSD patients relative to controls, with PTSD patientsshowing a pattern of decreased and normal subjects apattern of increased metabolism in these areas. PTSDpatients (but not normal subjects) had decreasedhippocampal metabolism with yohimbine (Bremneret al., 1997b).

Another field is receptor imaging in PTSD. Based onfindings of decreased benzodiazepine binding in frontalcortex in animal models of stress, we measured benzo-diazepine binding with PET and found reduced [11C]flumazenil binding throughout most of the cortical area(Geuze et al., 2008). This was consistent with an earlier[123I]-iomazenil SPECT study in Vietnam veterans withPTSD (Bremner et al., 1999e). This may be indicativeof an a priori difference in subunit composition ofGABAA-benzodiazepine receptors, a lower expressionof the GABAA receptor in PTSD patients, or a disease-or trauma-induced modulation or downregulation of theGABAA receptor complex. These explanations are con-sistent with other clinical studies that have suggested al-tered GABAergic function in PTSD (Vaiva et al., 2004;Connor et al., 2006).

320 E. VERMETTEN

Heterogeneity of response to traumaticreminders

It was Bremner (1999a, b) who proposed the presence oftwo subtypes of acute trauma response that representunique pathways to chronic stress-related psychopathol-ogy. One is primarily intrusive and hyperaroused with aconcomitant increase in heart rate and can be seen as aform of emotional undermodulation. The other is pre-dominantly dissociative with no concomitant increasein heart rate and can be viewed as a form of emotionalovermodulation. Data from psychophysiological andneuroimaging studies have shown that two subtypesof response can persist in individuals with chronic PTSDand are associated with distinct neural and cardiovascu-lar correlates in response to recalling traumatic memo-ries (Orr and Roth, 2000; Lanius et al., 2001, 2002, 2005;Frewen and Lanius, 2006; Hopper et al., 2007; Keane,2008; McTeague et al., 2010).

Approximately 70% of patients in our own studies,for example, reported re-experiencing their traumaticevent in response to traumatic script-driven imageryconcomitant with psychophysiological hyperarousal(Lanius et al., 2001, 2002, 2005, 2006). In contrast,the remaining 30% of PTSD subjects experienced deper-sonalization, derealization, and a feeling of emotionaldetachment while evidencing no significant increase inheart rate (Lanius et al., 2002, 2005). We emphasizethe state-related nature of these response patterns, spe-cifically that individuals with PTSD may show bothtypes of response during different episodes or even dis-tinct time points within a single episode. Nevertheless,PTSD patients with histories of prolonged trauma, suchas childhood maltreatment or combat trauma, oftenshow a clinical syndrome that is characterized by chronicsymptoms of dissociation as opposed to patients whohave suffered from more acute traumatic experiencesduring adulthood.

Emotional undermodulation: failureof corticolimbic inhibition

PTSD individuals who re-experienced their traumaticmemory and showed concomitant psychophysiologicalhyperarousal exhibited abnormally low response in brainregions that are implicated in arousal modulation andemotion regulation, including the medial prefrontaland the rostral anterior cingulate cortex (reviewed byLanius et al., 2006). Consistent with impaired top-downcortical modulation, decreased response within theventromedial prefrontal cortex and increased responsewithin the limbic system, especially the amygdala, hasbeen one of the most replicated findings in individualswith PTSD after exposure to traumatic script-driven

FOR POSTTRAUMATIC STRESS DISORDER 321

imagery, as well as to masked fearful faces (reviewed byEtkin and Wager, 2007).

When taking a dimensional approach to individualdifferences in re-experiencing symptoms and asso-ciated neural response patterns in response to traumareminders, results have shown that severity of state re-experiencing was positively correlated with response inthe right anterior insula, a brain region that is involvedin the neural representation of somatic aspects of emo-tional states and interoception of feeling states. In con-trast, state re-experiencing was negatively correlatedwith response of the rostral portion of the anteriorcingulate cortex (BA 32) (Hopper et al., 2007). This find-ing further supports the top-down cortical modulationmodel because, as discussed above, rostral anteriorcingulate reactivity is a powerful modulator of regionsinvolved in conditioned emotional responses.

The findings described above are consistent with thephenomenology and clinical presentations of individualswith PTSD who exhibit pathological emotional under-modulation during re-experiencing states. Such re-experiencing states often also include a wide variety ofnegative emotional states, such as anger and guilt. Weconceptualized this group of individuals as experiencingemotional undermodulation in response to traumaticmemories leading to subjective reliving of experiencesof the traumatic events, such as experiencing a flashbackor acting or feeling as if the traumatic event was recur-ring. Re-experiencing/hyperarousal reactivity and relatedemotional states such as anger and guilt can therefore beviewed as a form of emotion dysregulation that involvesemotional undermodulation, mediated by failure of pre-frontal inhibition of limbic regions (Lanius et al., 2010a)(Fig. 18.5).

BIOLOGICAL AND CLINICAL FRAMEWORK

Fig. 18.5. Emotional over- and undermodulation in posttraumati

Emotional undermodulation and failure ofcorticolimbic inhibition: implications forgeneralized affective disturbance in PTSD

Neuroimaging studies in PTSD have begun to movebeyond solely focusing on fear-specific stimuli and sit-uations, and have begun to encompass other affectivedisturbances. Responses to recall imagery of nontrau-matic sad and anxious memories in PTSD were associ-ated with decreased response in the rostral anteriorcingulate cortex and thalamus similar to what was foundduring recall of traumatic memories (Lanius et al.,2002). A further study reported decreased ventromedialprefrontal cortex response and decreased amygdalaresponse during viewing of negatively valenced/aversivepictures (Phan et al., 2006). A recent study examiningdeliberate emotion regulation in PTSD showed thatdeliberate successful attempts to downregulate emo-tional responses to negative pictures was moresuccessful in nontraumatized healthy controls as com-pared to subjects with a history of sexual assault withand without PTSD, and that success was associated withincreased response of prefrontal regions in the nontrau-matized group (New et al., 2009). These studies there-fore not only provide support for failure of corticalinhibition during the processing of nontraumatic stim-uli, but also suggest that affective disturbances andemotion dysregulation extend to nontrauma-relatedstimuli in trauma-exposed individuals with and withoutPTSD. Future psychobiological research will have toexamine closely the neural correlates underlying grief,anger, guilt, and shame in PTSD and their relationshipto the neural circuitry involved in adaptive emotionregulation.

c stress disorder.

322 E. VERMETTEN AN

Emotional overmodulation: excessivecorticolimbic inhibition

In contrast to the re-experiencing/hyperaroused groupof chronic PTSD patients, the dissociative group exhib-ited abnormally high response in brain regions involvedin arousal modulation and emotional regulation, includ-ing the rostral anterior cingulate cortex and the medialprefrontal cortex. It is interesting to note that the medialprefrontal cortex cluster (peak Montreal NeurologicalInstitute (MNI) 4, 54, 12) that shows increased responseduring states of dissociation is in close proximity to themedial prefrontal cortex cluster (peak MNI 10, 52, 2)that was associated with decreased cerebral blood flowduring trauma imagery and found to be negativelycorrelated with amygdala response in a study by Shinand colleagues (2004). Consistent with the corticolimbicdisconnection model of depersonalization (Sierra andBerrios, 1998), the findings of increased medial pre-frontal cortex response during states of dissociation inPTSD may reflect medial prefrontal inhibition of theamygdala and other limbic activity. The dissociativePTSD patients can be conceptualized as experiencingemotional overmodulation in response to exposure totraumatic memories. This can include subjective disen-gagement from the emotional content of the traumaticmemory through depersonalization, derealization, andemotional numbness mediated by midline prefrontalinhibition of the limbic regions.

Dimensionally, dissociative responses to traumareminders are negatively correlated with right anteriorinsula response (Hopper et al., 2007). Interestingly,the right anterior insula positively correlated with statere-experiencing symptoms. Dissociative response posi-tively correlated with response in the medial prefrontalcortex and dorsal anterior cingulate cortex. The leftmedial prefrontal cortex cluster (peak MNI –12, 50, 4)that was positively correlated with state dissociativesymptoms is, aside from laterality, in very close pro-ximity to the right medial prefrontal cluster (peakMNI 10, 52, 2), previously negatively correlated withamygdala activity during script-driven imagery (Shinet al., 2004). This finding provides support for hypo-thesized hyperinhibition of limbic regions by medialprefrontal areas in states of pathological overmodulation;i.e., during dissociative states in response to trauma-related emotions.

A study by Felminghamet al. (2008) gives further sup-port to the corticolimbic inhibition model. Using fMRI,these investigators examined the impact of dissociationon fear processing in two groups of PTSD patients,onewith high, and the otherwith low, dissociation scores.Felmingham et al. compared brain response during theprocessing of consciously and nonconsciously perceived

fear stimuli. Patients with PTSD who experienced higherlevels of dissociation showed enhanced response inthe ventral prefrontal cortex during conscious fearprocessing, as compared to patients with PTSD andlow levels of dissociation. The authors suggest that thesedata support the theory that dissociation is a strategy in-voked to cope with extreme levels of arousal in PTSDthrough hyperinhibition of limbic regions, with this strat-egy most active during conscious processing of fear.

Additional evidence for hyperinhibition of the limbicsystem, including the amygdala, during dissociative statesstems from an examination of the neural correlates un-derlying pain processing in healthy and disease states.In a study examining healthy individuals, Roder et al.(2007) demonstrated decreased amygdala response inresponse to painful stimulation during hypnosis-inducedstates of depersonalization. These findings are alsoconsistent with amygdala deresponse in response tothermal pain stimuli in patients with PTSD as well as inpatients with borderline personality disorder and comor-bid PTSD, who generally show high levels of dissociationand analgesia to painful stimuli (Geuze et al., 2007;Schmahl et al., 2008; Kraus et al., 2009). A recent studyrevealed a similar pattern of increased mid-cingulateand insula response in patients with borderline personalitydisorder and comorbid PTSD in conjunction with reducedpain sensitivity during script-induced dissociative states(Ludascher et al., 2010). Future research will need toexamine to what extent hyperinhibition of limbic regionsunderlies reduced pain sensitivity/analgesia to painfulstimuli often observed in patients with PTSD (Pitmanet al., 1990; Geuze et al., 2007; Kraus et al., 2009).

D R.A. LANIUS

PHARMACOLOGICALTREATMENT

General considerations

Antidepressant medications are the mainstay of treat-ment and are the best studied in controlled clinicaltrials, but there are also reports in the literature ofalleviation of specific symptoms of PTSD with the useof other medications such as sympatholytic agents,mood stabilizers such as lithium and anticonvulsants,benzodiazepines, and drugs that affect the dopamine,opioid, and serotonergic system. Given the differentclusters of PTSD symptoms, the clinician may find onlypartial response in individual patients with a singlemedication and will find it necessary to consider addres-sing the multiple symptoms with a combination ofmedications. Such medications will be found in thefollowing groups: antidepressants, anxiolytics, adrener-gic inhibitors, mood stabilizers, and anticonvulsants(Table 18.3). The individual therapeutic dose range islisted for each drug.

Table 18.3

Pharmacotherapy in posttraumatic stress disorder

Class Group Generic name Standard dose (mg/day) RCTs

Antidepressants SSRI Citalopram 20–60 2Fluvoxamine 100–300Fluoxetine 20–80 �3

Paroxetine 20–60 �3Sertraline 50–200 �3

TCA Amitriptyline 50–300 1Imipramine 50–300 2

MAOI Phenelzine 15–90 2New antidepressants NaSSA Mirtazapine 15–45 1

SARI Nefazodone 200–600 2

Trazodone 50–400 -SNRI Venlafaxine 75–225 -

Anticonvulsants Carbamazepine 400–1000 -

Gabapentin 300–2400 -Lamotrigine 25–500 1Lithium 600–1800 -

Topiramate 50–400 -Valproate 250–2000 -

Antipsychotics SDA Olanzapine 5–20 1Quetiapine 25–300 -

RisperidoneAripiprazole

0,5–810–14

2

Anxiolytics Benzodiazepines Alprazolam 0.25–6

Clonazepam 0.5–45-HT1a-agonist Buspirone 15–60

Antiadrenergics a2-agonists Clonidine 0.2–0.6

a2-agonists Guanfacine 0.5–3a1-antagonists Prazosin 2–10 3

Antihistamine

(partial) NMDA antagonists

b-antagonists Propranolol CyproheptadineD-cycloserine

40–1608–12

50–500

2

SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; MAOI, monoamine oxidase inhibitor; NaSSA, noradrenergic-specific

serotonergic antidepressant; SARI, serotonin 2A-antagonist/reuptake inhibitor; SNRI, serotonin noradrenergic reuptake inhibitor; SDA, serotonin

dopamine antagonist; NMDA, N-methyl-D-aspartic acid; RCTs, number of positive randomized controlled trials.

BIOLOGICAL AND CLINICAL FRAMEWORK FOR POSTTRAUMATIC STRESS DISORDER 323

Pharmacotherapy

Evidence for neurobiological dysfunction in PTSD, suchas dysregulation of both main arms of the stressresponse system, the HPA axis and the locus coeruleus–norepinephrine system, as well as dysfunctional re-sponses of other neurotransmitter systems, includingserotonergic, GABA, and glutamate, suggest a rolefor pharmacotherapeutic interventions in the treatmentof PTSD; however, data obtained from RCTs suggestlimited efficacy (Stein et al., 2006). The magnitudeof positive effects on PTSD symptomatology observedin the RCTs has been small, that is, the relative effectsize measurement is <0.5, prompting some to recom-mend that drug treatments should not be used as

routine first-line treatments, but preferring trauma-focused psychological therapy. In contrast, a meta-analysis conducted by the Cochrane Collaboration ofexisting RCTs in individuals with PTSD concluded thatdrug treatments were superior to placebo in reducingthe severity of PTSD symptom clusters, as well ascomorbid depression and disability (Stein et al., 2006).

So, although the most effective treatment option forPTSD seems to be cognitive and behavioral therapy(Ursano et al., 2004; Bradley et al., 2005), pharma-cotherapy also plays an important role. Of the appro-ved pharmacotherapeutic options for PTSD, selectiveserotonin reuptake inhibitors (SSRIs: fluoxetine, sertra-line, paroxetine), tricyclic antidepressants (imipramine,

AN

desipramine, amitriptyline), and monoamine oxidaseinhibitors (phenelzine, brofaromine, moclobemide) havebeen extensively evaluated in placebo-controlled trials(Ursano et al., 2004). Their mechanisms of action arecomplex, affecting pre- and postsynaptic receptorlevels, and release and reuptake of both 5-HT andnorepinephrine in the brain (Hageman et al., 2001;Albucher and Liberzon, 2002; Schoenfeld et al., 2004).Although all of these are effective as antidepressants,and also show some anxiolytic and antipanic effects(Schoenfeld et al., 2004), it is important to realize thattheir effectiveness in PTSD is not simply mediatedthrough improvement in anxiety and depression, thatis, PTSD symptoms respond independently from theanxiolytic or antidepressant effect (Hageman et al.,2001). Tricyclic antidepressants have modestly benefi-cial effects on hyperarousal and re-experiencing, butnot on avoidance and numbing symptoms. Monoamineoxidase inhibitors appear somewhat more effective thantricyclics, and affect mainly intrusion/re-experiencingand sometimes avoidance symptoms. Both categoriesare associated with broad side-effect profiles anddrop-out rates are consequently high (Albucher and Lib-erzon, 2002; Schoenfeld et al., 2004). SSRIs have a morefavorable side-effect profile, also have some anxiolyticproperties, and are more effective in reducing all threePTSD symptom clusters. They therefore currently formthe first-line psychopharmacological treatment optionfor PTSD (Hageman et al., 2001; Albucher and Liberzon,2002; Schoenfeld et al., 2004). One possible mechanismthrough which SSRIs could improve PTSD hyperarousalsymptoms is by increasing serotonergic inhibition ofcentral nervous system norepinephrine release, as hasbeen reported for patients with panic disorder (Coplanet al., 1996).

Classical anxiolytics have not been as extensivelytested in PTSD. Benzodiazepines have not proved tobe very effective, but are also problematic because ofthe development of dependence and subsequent with-drawal symptoms, which may actually exacerbate PTSDsymptoms (Albucher and Liberzon, 2002; Schoenfeldet al., 2004). The anxiolytic 5-HT1A agonist buspirone,though, has been successfully used to reduce PTSDsymptoms in small, open-label trials (Albucher andLiberzon, 2002), and more extensive, double-blindedplacebo-controlled trials seem warranted.

Interestingly, antiadrenergic drugs (suchasa2-agonistsor beta-blockers) are receiving increasing attention inclinical trials, despite evidence for adrenergic dys-regulation in PTSD. Some authors recommended startingpharmacotherapy in new PTSD patients with an anti-adrenergic agent such as clonidine or propranolol earlyafter exposure (Pitman et al., 2002). Clonidine can be veryeffective in this respect, where the reduced adrenergic

324 E. VERMETTEN

activity isoftenaccompaniedbya reduction indissociativesymptoms. The advantage of clonidine or a beta-adrenergic agonist is that this medication can be titratedover the course of 1–2 weeks. We suggest switching toa drug with longer half-life if a clonidine responderappears to develop tolerance to the drug. If the symptomspersist, as they often do, after optimal titration, the nextdrug to add is an SSRI. Using another medication fromthe same class is not recommended if the first drug isnot effective. If patients develop insomnia or agitation,the best choice is nefazadone or trazodone at bedtime.If patients are still nonresponders after 8–10 weeks, adifferent class of medication (e.g., adrenergic inhibitors,anxiolytics, mood stabilizers, anticonvulsants) should beconsidered.

The importance of pharmacoeducation has neverbeen well studied, but every clinician knows or shouldknow the importance of this part of the treatment.

D R.A. LANIUS

New developments in the treatment ofstress-related brain changes

The pharmacotherapy of PTSD has so far mainly beenbased on serendipity and trial and error. There has sofar been no approach from the rational neurobiology.Now the insights into the substrate will begin to increaseover time, more drugs can be found from a more ratio-nal approach. The pathophysiology of PTSD involves theinvolvement of many different neurotransmitter sys-tems and different neuroanatomical circuits. A carefuldelineation of the chemical, structural, and neuronalcircuits will take time. In the meantime it is importantto focus the examination on the clinical treatment andresearch of existing classes of psychotropic drugs basedon efficacy in the treatment of PTSD.

Studies in animals have demonstrated several agentswith potentially beneficial effects on the reversibility ofthe glucocorticoid-mediated hippocampal toxicity. It hasbeen found that phenytoin (Dilantin) reverses stress-induced hippocampal atrophy, probably through excit-atory amino acid-induced neurotoxicity. Agents suchas tianeptine and dihydroepiandrosterone have been de-scribed to produce similar effects (Watanabe et al.,1993). Neurons within the hippocampus were found tobe unique within the brain in showing the capacityto regenerate themselves (Gould et al., 1999). Since theseare in vitro studies that report on neurogenesis in thehippocampus through a regulation of BDNF and cyclicadenosine monophosphate (cAMP) by SSRIs, we hy-pothesized that the effects of SSRIs may play a rolein the reversibility of the accelerated aging process inhumans (Duman et al., 1997; Nibuya et al., 1999). Thereare findings indicating that a common action of antide-pressant treatments is through upregulation of cAMP

F

response element-binding (CREB) protein and that thismay lead to regulation of specific target genes. Suchtreatment effects on BDNF and trkB mRNA can havelong-term effects on brain function. In these studies,however, it is evident that chronic, but not acute, admin-istration of several different classes of antidepressant,including SSRIs and selective norepinephrine reuptakeinhibitors, increase the expression of CREB mRNA.

In a treatment study performed with paroxetine, wefound that 9-month treatment not only led to a reductionin PTSD symptoms, but was accompanied by an increasein hippocampal volume of 5.6%, an increase in declara-tive memory performance (Vermetten et al., 2003),as well as normalization of the stress response(Vermetten et al., 2006). Hippocampal atrophy may bea viable drug target for PTSD; however, it cannot bethe sole ingredient (DeCarolis and Eisch, 2010).

In almost all cases, pharmacotherapy was conductedalong the path of symptom clusters for PTSD, and willbe the first choice for a medium based on the symptomcluster in which most distress is experienced. This mayinclude sleep disorders (van Liempt et al., 2006).However, despite many trials showing the efficacy ofdifferent substances, there are few long-term studies(Vermetten et al., 2003), no information about the effec-tiveness of treatment in general clinical practice, andlack of data on treatment of therapy-resistant patients.Older products with a “new” application that arepromising and deserve attention are: propranolol(beta-adrenergic blocker), D-cycloserine (a partialN-methyl-D-aspartate (NMDA) antagonist, acting on theglycine site of glutamatergic NMDA receptor) and keta-mine (NMDA receptor anatagonist) (McGhee et al.,2008). These are important candidates for their specificimpact with regard to memory consolidation processes(Ravindran and Stein, 2009). In particular, propranololuse has been examined in three phases of memory:(1) acquisition, formation, and encoding; (2) emotionalresponse and consolidation; and (3) retrieval and reconso-lidation. Early research focused on acquisition andconsolidation with encouraging but inconsistent results,with more recent research directed towards memoryreconsolidation, and dissociation of emotion and fearfrom memories. Also cyproheptadine in treating night-mares, in addition to prazosin, has been described(Rijnders et al., 2000). New resources in the futurewill be targeted to CRF antagonists (Adamec et al.,2010) and GR antagonists (Kohda et al., 2007).

Advanced scientific techniques, including neuroim-aging and genetic analysis, will enhance understandingof rational pharmacotherapy. These studies may leadto the development of additional pharmacologicaloptions and have the potential to predict who will andwill not respond to a particular product. Gain can also

BIOLOGICAL AND CLINICAL FRAMEWORK

be achieved by timed administration of drugs in relationto psychotherapy (Marshall and Cloitre, 2000), exposureto traumatic events (propranolol, cortisol) and preced-ing or following a treatment aimed at extinction(D-cycloserine, ketamine). The current guideline forpharmacotherapy is largely analogous to the treatmentof depression, consisting of respectively two differentSSRIs, a tricyclic antidepressant (e.g., amitriptyline,imipramine), an anticonvulsant (e.g., lamotrigine) andfinally a MAOI (e.g., phenelzine). It is possible to optfor an atypical antipsychotic as an additive to an SSRI,where there are flashbacks and prepsychoticexperiences, or because of the light sedative effect. Thiscall of medication is also often chosen for the targetedtreatment of a single symptom, such as nightmares.Alpha1-adrenergic antagonists for this (prazosin, alfuzo-sin) have also been studied. This medication has beenused off-label and has been investigated in a few ran-domized controlled trials (Raskind et al., 2003; see alsoAurora et al., 2010).

The timely use of medication is a new approach in thetreatment of PTSD, e.g., the early start of medication toprevent PTSD after traumatic exposure (e.g., proprano-lol in the immediate phase) has been proposed andtrested in some studies, with promising effect (Pitmanet al., 2002). Another development is the use of medica-tion in conjunction with psychotherapy (in particularexposure) for the purpose of modification of memoryreconsolidation, and this has been the subject of investi-gations, e.g., D-cycloserine in relation to exposure(Heresco-Levy et al., 2002; Lehner et al., 2009). Anothernew line is the use of cortisol in the intensive careunit (de Quervain, 2008). These compounds have thepotential to reduce retrieval of aversive memories andenhance fear extinction.

OR POSTTRAUMATIC STRESS DISORDER 325

PSYCHOLOGICALTREATMENT

Expert consensus guidelines for PTSD treatment werefirst published in 1999. According to these guidelines(Foa et al., 1999a), current psychological treatmentsof PTSD include: (1) behavioral therapy (flooding, sys-tematic desensitization, eye movement desensitizationand reprocessing: EMDR); (2) cognitive-behavioral ther-apy; and (3) anxiety management training (stress inocu-lation training (SIT), biofeedback). These treatments aredescribed in detail by Meadows and Foa (1999). Eachintervention has its own merits, and all three can be veryuseful regardless of the stage of PTSD. It is recom-mended that patients should be seen in the acute situa-tion for 3 months, with booster sessions every2–4 weeks; in a chronic situation, the therapy can lastup to 6 months, with booster sessions every 2–4 weeks.Studies have been performed to assess the efficacy of

AND R.A. LANIUS

psychological interventions in PTSD (Foa et al., 1999b;Spiegel, 1999).

A Cochrane Report was published in 2007 on psycho-logical treatment (Bisson and Andrew, 2007). In the 33studies that had been included there was evidence infavor of individual trauma-focused cognitive-behavioraltherapy (TFCBT), EMDR, stress management, andgroup TFCBT being effective in the treatment ofPTSD. Other nontrauma-focused psychological treat-ments did not reduce PTSD symptoms as significantly.There was some evidence that individual TFCBT andEMDR are superior to stress management in the treat-ment of PTSD between 2 and 5 months followingtreatment, and also that TFCBT, EMDR and stress man-agement weremore effective than other therapies. Therewas insufficient evidence to determine whether psycho-logical treatment is harmful. Therewas some evidence ofgreater drop-out in active treatment groups. The consid-erable unexplained heterogeneity observed in thesecomparisons, and the potential impact of publication biason these data, suggest the need for caution in interpretingthe results of this review.

A concern that was reported in the Cochrane reviewis that nonresponse and drop-out rates in thesetreatments often are considered high. A review of thetreatment drop-out and nonresponse rates in 55 studiesof empirically supported treatments for PTSD showed awide range that depended, at least in part, on the natureof the study population. It was not uncommon tofind nonresponse rates as high as 50% (Schottenbaueret al., 2008).

326 E. VERMETTEN

Behavioral treatments

Exposure techniques involve confronting one’s fears.Exposure-based therapeutic regimens have had a longhistory in the treatment of anxiety-related disorders.

FLOODING

Flooding involves two essential steps: (1) the adminis-tration of multiple component assessment packages;and (2) the provision of imaginal flooding regimens.In the assessment phase, the goal is to identify the path-ological behaviors, determine the etiological variablesthat maintain distress, and establish baseline data todetermine treatment efficacy over time. Differentsources of information should be used. The interventionphase is presented in five basic steps, which should bepresented in sequential order: (1) education; (2) imagerytraining; (3) relaxation training; (4) presentation oftraumatic scenes; and (5) debriefing. Flooding is anaversive process in that PTSD symptoms may increaseduring the initial phases of therapeutic exposure.

SYSTEMATIC DESENSITIZATION

Systematic desensitization falls at the other end of thedimensions of exposure methods, using brief, imaginal,and minimally arousing exercises. Pioneered by Wolpe(1961), systematic desensitization was among the earliestbehavioral treatments studies for PTSD. It involves pair-ing imaginal exposure with relaxation, so that the anxi-ety elicited by the confrontation with the feared stimuliis inhibited by relaxation. First, the patient is instructedin muscle relaxation exercises. When a state of relaxa-tion is achieved, the feared stimuli are introduced, viaimagined scenarios, in a graded hierarchical manner,with the least anxiety-provoking scenarios presentedfirst. When the patient begins to feel anxious, the in-struction is given to erase the screen, focus on relaxa-tion, and begin again. The scenario is repeated until itno longer elicits anxiety, at which point the next scenariois introduced. This process continues until the stimuli onthe hierarchy no longer elicit anxiety. For example, atherapist may teach a patient to head off panic attacksby taking slow deep breaths. The therapist may gradu-ally expose the patient to images or sensations thatremind him or her of the trauma (battle photos, loudnoises, smells) and then help him or her deal with thefears that come up.

EYE MOVEMENT DESENSITIZATION AND REPROCESSING

EMDR is a form of imaginal exposure accompanied bysaccadic eye movements. It is conducted by having thepatient focus on a disturbing image or memory whilethe therapist moves a finger across the patient’s visualfield (Shapiro, 1989). The saccadic eye movements resultfrom the patient’s tracking of the therapist’s finger (forreviews, see Lohr et al., 1995; Lazrove et al., 1998;Cusack and Spates, 1999; Devilly and Spence, 1999; inchildren: see Rodenburg et al., 2009). Since its inception,EMDR has been the focus of much controversy, but inthe last decade it has resulted in a breakthrough in treat-ment of PTSD. In some studies prolonged exposureand EMDR did not differ significantly for change frombaseline to either posttreatment or follow-up measure-ment for any quantitative scale (Rothbaum et al.,2005; Seidler and Wagner, 2006). What remains unclearis the contribution of the eye movement component inEMDR to treatment outcome.

Cognitive therapy

Cognitive therapy was pioneered by Beck in 1972 andfurther developed by others to help patients modifydysfunctional cognitions. The basic assumption is thatdysfunctional thoughts drive negative emotional statessuch as fear or anger. In a given situation, this may lead

F

to different emotions depending upon the interpretationof the situation. Pathological emotions are generated bydistorted, dysfunctional thoughts. Typically, cognitiverestructuring aims to teach patients to identify dysfunc-tional thoughts, to evaluate their validity, to challengeerroneous or unhelpful thoughts, and to replace themwith more beneficial ones. Cognitive restructuringwould focus on identifying the thoughts that precedestrong emotions, such as “I am going to be assaulted.”Then the validity of this belief would be evaluated.Erroneous beliefs are replaced by rational ones, suggestedby the evidence reviewed in one of the previous steps.

Anxiety management therapies

The assumption that seems to underlie the rationale foranxiety management programs centers on the notionthat pathological anxiety stems from skill deficits. Thisimplies that providing patients with appropriate skillswould enable them to manage their anxiety. Skills suchas relaxation training, positive self-statements, breath-ing retraining, biofeedback, social skill training, anddistraction methods aim at managing the anxiety whenit occurs, rather than preventing pathological anxietyfrom occurring by correcting the supposedly underlyingmechanisms.

STRESS INOCULATION TRAINING

SIT was developed by Meichenbaum in 1974 as a treat-ment for anxious patients. The method was adopted byVeronen et al. (1979) for treatment of rape-relateddisturbances. This modified SIT includes psychoeduca-tion, muscle relaxation training, breathing training, roleplaying, covert modeling, guided self-dialogue, andthought-stopping. The three-component model of SITincludes patients beginning to see their responses inthe physiological, behavioral, and cognitive domains.SIT is one of the most commonly used anxiety manage-ment treatments for PTSD.

BIOFEEDBACK

Biofeedback is a procedure in which patients learn togain control over their physiological processes. Thiscontrol is achieved by having patients observe displaysor listen to tones of their physiological activity (EMGactivity) and then try to change the display or changethe tone.

As biofeedback is becoming more and more main-stream, unaware participants often misinterpret anadvantage that the machine alone provides as the solemechanism/modum of the therapy. Since the therapydoes not rely on face-to-face contact, this can contributeto more flexibility for the patient to plan interventions.

BIOLOGICAL AND CLINICAL FRAMEWORK

Graap and Freides (1998) were the first to introduce al-pha-theta feedback for the treatment of PTSD. Recentevidence has supported neurofeedback as being advanta-geous in exerting direct control over the body’s central ner-vous system, making it a valuable adjunct in the treatmentof several neuropsychiatric disorders (Batty et al., 2006).Acommon paradigm often applied in the treatment ofattention-deficit/hyperactivity disorder is to facilitate tha-lamic inhibitory mechanisms by decreasing activity in thetheta band and increasing activity in the beta band.Anotherapproach relies in increasing the sensorimotor rhythm(SMR) activity (Fox et al., 2005), as SMR is an oscillatorythalamocortical rhythm that may play a role in controllingmovement. SMR amplitude is strongly suppressed duringtheperformanceof contralateralmotoracts or evenduringmotor imagery, i.e., just by seeing the activity, and in-creasedwhenthe sensorimotor areasare lessactive.Periph-eral markers, as in heart rate variability, have alsodemonstrated promising new avenues for reduction ofPTSD symptoms (Zucker et al., 2009).

OR POSTTRAUMATIC STRESS DISORDER 327

Other therapeutic interventions andmodalities; development of computer-

assisted technologies

Several other therapeutic strategies and technologies arereported in PTSD. Shay and Munroe (1999) report on atreatment setting in which the encounter is the focus ofattention in therapy; other reports describe narrativeexposure therapy (Neuner et al., 2004), psychodramatherapy (Carbonell and Parteleno-Barehmi, 1999), psy-chodynamic approaches (Huller and Barash-Kishon,1998), or use of hypnosis (Kluft, 1992; Spiegel, 1992).

Most clinicians who treat PTSD have an eclecticapproach to treatment, and there is a push forevidence-based treatments (Bisson et al., 1997). Combin-ing biological, psychological, and psychosocial treat-ment may well yield best results. Rehabilitative goalsshould replace curative techniques in patientswith chronic PTSD (Shalev et al., 1996b). Even thoughempirical support is still lacking, the importance ofpsychoeducation should not be underestimated (Allenet al., 1997; Lubin et al., 1998; Wessely et al., 2008).

A potential new direction for PTSD treatment iscomputer-assisted technologies, e.g., online CBT, butalso virtual reality exposure therapies (VRET) and otherstrategies that are embedded in conventional CBT orEMDR. Knaevelsrud and Maercker (2010) exploredinternet-based CBT, and demonstrated large treatmenteffects, low drop-out rates, quality therapeutic relation-ships, and sustained effects for this type of intervention.VRET is another variation demonstrating potentialfor PTSD treatment (Difede et al., 2007; Reger andGahm, 2008). Such possibilities for remote therapy

AN

may improve treatment options for PTSD sufferers liv-ing in more isolated areas. Finally, other future interven-tions combine VRET exposure with physical interaction:patients are placed on a treadmill platform and walkthrough a three-dimensional environment, which en-ables them to interact with self-paced motion andcontrol.

The newer applications, like online therapies andneurofeedback, may be combined in future studies withtimed administration of medication.

328 E. VERMETTEN

CONCLUDINGREMARKS

Three decades of PTSD research have placed it well onthe map. Table 18.4 summarizes the key findings of thelast 30 years. This calls for an orientation for where newinvestment should go. A new direction in which the fieldhas moved is resilience. The cohorts of veterans whohave returned and will return from the wars in Iraqand Afghanistan have already confronted cliniciansand researchers with a new challenge. Since each newwar has a “signature” weapon and a “signature” injury,the challenge is to differentiate the impact of exposureto blast (signature weapon) to blast-related injuries(signature injury), the spectrum of traumatic brain

Table 18.4

Three decades of posttraumatic stress disorder research and p

Decade Field Developme

First decade: 1980–1990 Epidemiological PrevalenceBiological Validation o

inductionClinical Stress reduPharmacological Experiment

Second decade: 1990–2000 Epidemiological EpidemioloBiological Cross-sectio

Cross-sectio

“Decade ofClinical DevelopmePharmacological SSRIs

Third decade: 2000–2010 Epidemiological More speci

Biological Increased uAvailability

“decade

Clinical DevelopmePharmacological New drugs

Fourth decade: 2010– Longitudina

Increase inPrimary pre“Decade of

CBT, cognitive-behavioral therapy; SSRI, selective serotonin reuptake inh

mild traumatic brain injury; PFC, prefrontal cortex.

injury with PTSD. Especially difficult in this respect ismild traumatic brain injury (Bryant et al., 2009; Brenneret al., 2010).

Future studies will need to focus on estimatingage-at-onset distributions, cohort effects, and the condi-tional probabilities of PTSD from different types oftrauma. These epidemiological studies will also needto assess PTSD for all lifetime traumas rather thanfor only a small number of retrospectively reported“most serious” traumas. As for the neurobiology andtreatment of the disorder, the wealth of laboratory re-search and animal models has helped us understandits pathophysiology. It is for future studies to translatethese findings into optimal pharmacotherapeutic inter-ventions that can be combined with psychological treat-ments for alleviation of symptoms, reduction of medicalconsumption, and better quality of life for patients cur-rently suffering from PTSD.

With increased capabilities of imaging techniques, in-cluding improved spatial resolution but also increasedavailability of scanning equipment in smaller researchinstitutes, the knowledge of the altered brain functionin PTSD increases. Given the specific role of the prefron-tal cortex in (neuro)psychological functions in patientswith PTSD (i.e., attention and cognitive interference),

D R.A. LANIUS

rogress

nt

f the disorder; linking with experimental models of stress

ction, little availableal studies

gical studiesnal studiesnal interdisciplinary interest

hippocampus”nt of CBT, exposure

fic on cohort prevalences, targeted groups

nderstanding of neural circuitsand increased resolution neuroimaging:of the amygdala”

nt and introduction of EMDRbeyond SSRIsl studies

specificity of diagnostic accuracy, differentiate from mTBIventionPFC”?

ibitor; EMDR, eye movement desensitization and reprocessing; mTBI,

FOR POSTTRAUMATIC STRESS DISORDER 329

the interest in the role of the prefrontal cortexwill increasesignificantly. Increased multidisciplinary interaction withinclusion of genetics, endocrinology, immunology,(neuro)psychology, and psychopathology is essential tofindconsistencybetweenbiological, emotional, andcogni-tive dysfunction in PTSD. Related to this, longitudinalstudies are essential to assess the relationships betweenstress parameters and clinical phenotype of PTSD. Thisis true for DST supersuppression, stress reactivity, hypo-cortisolemia, and hippocampal (neurogenetic) changes,but also for memory function and neurocognitive mecha-nisms.Thedeploymentofnewandexistingdrugs inPTSD,including specific serotonergic agents such as 5-HT1A an-tagonists, norepinephrine blockers, CRF antagonists, GRantagonists, prazosin, and a1-adrenergic blocker s fornightmares, and the use of beta-blockers early aftertrauma exposure will need to be investigated. Treatmentoptions such as D-cycloserine and cortisol seem to offeropportunities to influence thememory of traumatic expe-riences, in timedand careful therapeutic dosage in relationto exposure. Finally, the mechanisms of exposure therapyand cognitive therapy in influencing neurobiologicalmarkers should be further investigated. The same goesfor emerging therapies such as EMDR, virtual reality ex-posure, internet therapy, and neurofeedback.

Although a variety of effecive psychological andpharmacological interventions canbeused to treat PTSD,no economic evaluations are known to exist. Healtheconomists are aware that there is an economic burdenassociated with PTSD, and treatments require the useof scarce resources. They will ultimately provide tools(including cost-effectiveness, cost–benefit, and cost–utility analyses) to ascertain the relative efficiency ofdifferent treatment options and plan the availability ofthese for the affected population. This is perhaps thebiggest challenge for the future evolution of the disorder.

Finally, one of the challenges for the courts andworkers’ compensation systems is the potential relation-ship between traumatic stress exposure and the emer-gence of psychopathology (McFarlane, 2010). Thesignificant body of research that has been reviewed herehas now provided valuable insights into the reality ofPTSD and the fact that it represents chronic and some-times progressive accumulation of symptoms in individ-uals over time. Intercurrent life stresses have also beenshown to play an important role, impacting upon the tra-jectory of an individual’s posttraumatic reactions. Theseeffects represent significant challenges in establishingcausality in legal settings. Furthermore, the statute oflimitations poses a particular challenge to plaintiffswhen there is a delay in the onset of their disorder out-side the prescribed window for taking legal action fol-lowing a potential compensable injury ofapproximately 3 years.

BIOLOGICAL AND CLINICAL FRAMEWORK

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