PTSDLooking Back & Looking Ahead:

Progress and Challenges

Matthew J. Friedman, MD, Ph.D.Executive Director

National Center for PTSD

Validity of PTSD is Well-Established

PTSD has proven to be a very useful and valid diagnosis after 25 years of clinical use

Although there have been minor revisions to the diagnostic criteria the core concept has withstood the test of time

The PTSD Concept

Inability to cope with overwhelming stress may be followed by a distinctive pattern of symptoms

It does not presume that this is the only possible psychiatric outcome

Research Supports the PTSD Concept

PTSD and PTSD symptoms rank among the most common new onset post-traumatic clinical problems

Before DSM-III, there was no way to identify people so affected

The PTSD Hypothesis Made it Possible to:

Predict how affected people react to traumatic reminders

Differentiate them from non-affected people or those with depression or other anxiety disorders

Develop unique therapeutic approaches (e.g. CBT & medication) that could not have been envisioned without the PTSD model

PTSD is a Disorder of Reactivity

Its alterations are best revealed by responses to psychological or pharmacological probes

In contrast, depression is a shift in basal state, alterations are best revealed by measurement of tonic activity

PTSD has a Wealth of Animal Models Unequaled in Psychiatry Traumatic stress can be operationalized as

uncontrollable or unpredictable stress

Laboratory-induced physiological and neurohormonal alterations resemble those seen in PTSD

Brain systems affected by uncontrollable stress and fear conditioning resemble those affected in PTSD

PTSD has Provided a New and Powerful Tool for

Translational Research

Translation of important clinical observations into rigorous experimental protocols

Translation of laboratory findings into testable clinical approaches

Is PTSD the Only Post-Traumatic Outcome?

No

Prospective studies show that people may develop new-onset depression, other anxiety disorders, alcoholism or behavioral alterations

without PTSD

But that is not what we are here to discuss today

Prevalence of PTSD in the General Population

Large national probability sample of US adults (Ns > 5000)

National Comorbidity Survey (1995) National Comorbidity Survey-Replication (2005) Benchmark for prevalence of mental disorders in

US

Lifetime PTSD prevalence 6.8% (NCS-R) 10% women (NCS) 5% men (NCS)

Combat Exposure in the NCS

Any combat veteran’s lifetime PTSD prevalence = 39%

Male combat > all other male trauma Lifetime PTSD prevalence Delayed onset Unresolved symptoms Functional impairment (unemployment, being fired,

divorce or separation, spousal abuse)

Changes in the PTSD Diagnostic Criteria

Symptom clusters: Symptoms expanded from DSM-III to III-R

and IV

Added duration and distress/impairment

Revised stressor criterion

Biological Profile

The diagnosis has distinguished people with a unique set of biological abnormalities.

These include: psychophysiological reactivity neurohormonal profiles EKG abnormalities structural and functional brain imaging

alternations

The Stress System

The stress system coordinates the generalized stress response which takes place when a stressor of any kind exceeds a threshold

The main components are:• HPA system• LC/NE system• Immunological system

Are there structural brain abnormalities associated

with PTSD?

Hippocampal Volume in PTSD(% DIFFERENCE BETWEEN PTS AND Controls)(% DIFFERENCE BETWEEN PTS AND Controls)

-6

0 1-3

7

-7.9

-2.9-4.8

21.9--18

1%-3%

-1%7%

4%- 5%-

12%-

-26%

13%-

Schuff 1997

Bonne 2001

De Bellis 2001

Bremner 1995

Bremner 1997

Vythlingam2001

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Are there functional brain abnormalities associated

with PTSD?

Rauch 96 (combat scripts) Shin 99 (CSA scripts)

Liberzon 99(combat sounds) Bremner 99 (CSA scripts)

Shin 97 (CSA scripts) Bremner 99 (combat slides

Rauch ‘00 (masked faces) & sounds)

Semple ’00 (auditory CPT)

Bremner 2001 (unpub, fear conditioning)

HIPPOCAMPUS

Bremner 99

MEDIAL PFC & Ant Cingulate

Bremner 99 Lanius ’00 (scripts)

Bremner 99 Shin ’01 (emotional stroop)

Shin 97 Semple ’00

Shin 99

AMYGDALA

OFC

Semple 93

Shin 99

Rauch 96

Increased Blood Flow with Fear Acquisition versus Control in Abuse-

Related PTSD

Yellow areas represent areas of relatively greater increase in blood flow with paired vs. unpaired US-CS in PTSD women alone, z>3.09; p<0.001

Orbitofrontal CortexSuperior Temporal Gyrus

Left Amygdala

Medial prefrontal & Orbitofrontal Cortex

Fusiform, inferior temporal gyrus

Left hippocampus

Retrieval ofWord pairs like“blood-stench”

Decreased Blood Flow During Recall Of Emotionally Valenced Words In Abuse-Related PTSD

Psychological and Biological Mechanisms

We know that: a number of psychological mechanisms such as

negative cognitions, threat appraisal, coping behaviors, information/memory processing and cognitive strategies predict PTSD;

animal models of fear conditioning and neurobiological models concerning the human stress response provide a useful context for understanding acute distress and PTSD; and

exposure to stress during crucial developmental periods may produce stable abnormalities in stress response systems.

PTSD Treatment Options

PharmacologicalTCAs

MAOIs SSRIs

Mood StabilizersAnti-anxiety Agents

PsychosocialExposure TherapyCognitive Therapy

Anxiety ManagementDesensitizationHypnotherapy

-40

-30

-20

-10

0

0 1 2 3 4 6 8 10 12

Weeks

Placebo (N=90) Sertraline (N=93)

Sertraline Flexible-Dose PTSD StudySertraline Flexible-Dose PTSD Study

Adjusted Mean Change

in CAPS-2Total Score

* p < .001 at week 12Mean dose for completers = 151.3 mgBrady K et al. JAMA. 2000;283:1837-1844.

*

LOCF dataset* p < 0.001 vs placebo

Marshall RD, Beebe KL, Oldham M, et al. Am J Psychiatry 2001;158:1982-1988.

Week

*

*

-40

-35

-30

-25

-20

-15

-10

-5Paroxetine 40 mgParoxetine 20 mg

Placebo

-45

0

4 8 12

*

**

*

Adjusted Mean

Change in CAPS-2

Total Score

Paroxetine Fixed-Dose PTSD Study

0

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35

Week 0 Week 5 3 Months 6 Months

PE/SIT

PT

SD

Sym

pto

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(PS

S-I

)

PSS-I = Post Traumatic Stress Disorder Symptom Scale—Interview; Foa et al, 1999b

Prolonged Exposure (PE) Therapy, Stress Inoculation Training (SIT) and Their Combination

for Female Assault Victims with PTSD (9 Sessions)

PESIT

Wait-list control

Controversy #1 PTSD is not a Legitimate

Diagnosis Battle still wages after 25 years

Being fought in the media as well as scientific journals

Institute of Medicine hearings in U.S. PTSD’s dubious parentage

Emerged from converging social (feminist, veteran) movements rather than traditional scientific and clinical sources

Controversy #1 (continued) Legitimacy of PTSD diagnosis

Criticism & negative reception has spurred an outpouring of rigorous research

Clinical phenomenology, cognition, brain imaging, personal dynamics

Factor analysis of PTSD symptom clusters has generally validated construct

People with PTSD exhibit significant differences from non-affected individuals

Controversy #2 PTSD Needlessly

Pathologizes Normal Reactions to Abusive ViolenceThis argument fails to acknowledge that some people cope successfully with traumatic events and manifest normal distress while others exhibit clinically significant symptoms

The purpose of any diagnosis is to inform treatment decisions - not to “pathologize”

Controversy #3PTSD is a Euro-American Culture-Bound Syndrome

PTSD has been documented throughout the world1,2 Comparable PTSD prevalence in Nairobi embassy

and Oklahoma City bombings3

Men: 26% Nairobi, 20% Oklahoma City Women: 35% Nairobi, 34% Oklahoma City

Although there may be culture-specific idioms of distress, PTSD appears to encompass a pattern of universal post-traumatic distress

1 de Jong et al., 2001; 2 Green et al., 2004; 3 North et al., 2005

Controversy #4PTSD primarily serves a litigious

rather than a clinical purpose Stressor Causality Liability Geometric rise in PTSD-related civil litigation

and disability claims Great concern about amount of money at stake

Big difference between challenging validity of PTSD as a clinical diagnosis and questioning the quality of forensic or disability evaluations

Controversy #5Traumatic Memories are not Valid

When external verification possible - most memories are accurate

Recovered Memory Controversy spurred much useful research

Accurate memories may be lost and later recovered Some traumatic memories are not accurate The veracity of any specific recovered memory must

be judged on a case-by-case basis

Controversy #6Verbal Reports are Unreliable

Excellent structured interviews and assessment tools have been developed

Reliability of retrospective self-report data among 260 Vietnam theater veterans was recently confirmed by archival records and other external sources

(Dohrenwend et al., (Dohrenwend et al., 2006)2006)

Looking Ahead #1Is PTSD a “Stress-Related Fear

Circuitry Disorder?”

Joint APA/WHO initiative being considered for DSM-V/ICD-11

Based on common neurocircuitry, cognitive alterations and neurohormonal changes

Would cluster PTSD with panic disorder, simple phobia and social phobia

Is PTSD a Fear Circuitry Disorder?

Neurocircuitry:

Disruption of restraining influence of medial prefrontal cortex (especially ACC)

Chain reaction brought about from activation of amygdala by fear stimuli1

1Vermetten & Bremner, 2002; Charney 2004)

Is PTSD a Fear Circuitry Disorder?

Cognitive / Behavioral:

PTSD as a model from Pavlovian Conditioning (Kolb, 1989), and Activated Fear Networks (Lang, 1977; Foa & Kozak, 1986).

Potential Non-Verbal Diagnostic Implications of Stress Related Fear

Circuitry Model Stimulus-driven paradigms: Auditory / Visual /

Narratives: CV / Electrodermal / Electromyographic/ Brain Imaging (Orr et al., 2004 / Kaufman et al., 2004) CSFP (Geracioti et al 2006)

Pharmacological probes: Super suppression on DST: (Yehuda et al., 1997) Yohimbine (Southwick 1993; Bremner 1997)

Looking Ahead #1 (continued)Is PTSD a “Stress-Related Fear

Circuitry Disorder?” Other emotions besides fear also often present

Sadness, grief, anger, shame & disgust May not be a nosological problem since the goal is to

cluster diagnoses according to a common denominator

Would be a conceptual problem since clinical problems often extend beyond fear-based appraisals and reactions

Shame, anger, substance abuse, aggression, horror, helplessness without personal fear (e.g. medical personnel, graves registration, etc.)

Looking Ahead #2 (continued)Should PTSD be Considered a Dimensional Rather Than a

Categorical Disorder? Subsyndromal/partial PTSD

Chronic non-traumatic stress syndromes

Chronic stress-related medical disorders

Subsyndromal/Partial PTSDAffective Disorders:

DSM I, II, III (III-R) and IV

DSM-I DSM-II DSM-III/ DSM-IV

III-R BAD/Manic-DepressionBAD/Manic-Depression X X X XX X X XMDD/Psychotic DepressionMDD/Psychotic Depression X XX X X X X XDysthmia/Depressive NeurosisDysthmia/Depressive Neurosis X X X XX X X XCycolthymia/Affective PersonalityCycolthymia/Affective Personality XX X X X X X X

Involuntary MeloncholiaInvoluntary Meloncholia X X(Other) Mood Disorder NOS(Other) Mood Disorder NOS X X X XAtypical Bipolar/NOSAtypical Bipolar/NOS X X X XAtypical Depressive/NOSAtypical Depressive/NOS X X X X

Adj Disorder - DepressedAdj Disorder - Depressed X X X XAdj Disorder - Mixed Anx/DepAdj Disorder - Mixed Anx/Dep X X X X

PSSD - Post-Severe Stress Disorder

“Severe” vs. “Traumatic” StressAre there enduring psychiatric syndromes caused by acute or chronic non-traumatic but severe stress?

Divorce, failure, bankruptcy, illness, bereavement

Does PSSD differ from PTSD?

Chronic Stress Syndrome

PSSD has medical consequences

PTSD also has medical consequences

Both affect HPA, cardiovascular, immunological, and other systems

Should “medical” illnesses precipitated by stress be included with PSSD/PTSD as “stress disorders?”

• Chronic Fatigue Syndrome• Fibromyalgia• Peripheral Vascular Disease• Endocrinopathies• etc

Looking Ahead #3New Directions for Psychosocial

Treatment

Despite success of CBT (PE, CT, CPT and EMDR) there is evidence for the efficacy of treatments that do not focus on traumatic material

SIT - focuses on symptom management rather than trauma processing

Present centered therapies have also been effective

SIT and PCT do better in recruitment and retention

Looking Ahead #3 (continued)New Directions for Psychosocial

Treatment

Need predictors of treatment outcome

Case matching - some may be better candidates for trauma processing and others for present-centered approaches or medication

Looking Ahead #3 (continued)New Directions for Psychosocial

Treatment

EMDR - How does it work? Is it CBT in disguise? Does it work through a unique mechanism?

Using brain imaging techniques might be a way to approach this issue

Looking Ahead #3 (continued)New Directions for Psychosocial

Treatment

Third Wave Influenced by Eastern & “mindfulness” approaches that emphasize acceptance

Little evidence of efficacy so far Comorbidity

Substance abuse (Seeking Safety) Traumatic brain injury

Technology Web based, virtual reality, telehealth

Looking Ahead #4New Directions for Biological

Research

Need to expand focus beyond serotonin and norepinephrine

CRF, NPY, GABA, glutamate, dopamine, etc.

Is PTSD a final common pathway (like fever or edema) that can be caused by different patterns of psychobiological alterations?

Genetic research on resilience and vulnerability

Looking Ahead #5New Directions for Pharmacotherapy

Current medications in use were all initially designed to treat other disorders (antidepressants, antihypertensives, anticonvulsants, antipsychotics, etc.)

Looking Ahead #5 (continued) New Directions for Pharmacotherapy

The need is for new medications that preferentially target abnormal psychobiological mechanisms associated with PTSD.

Medications to interrupt the cascade of stress-related alteratitons (e.g. CRF antagonists, NPY enhancers)

Medications to blunt fear conditioning (antiadrenergics, NMDA antagonists)

Medications to promote extinction of fear-conditioned reactions (e.g. cycloserine)

Medications to target dissociative symptoms (e.g. anticonvulstants such as lamotrigene)

Looking Ahead #5 (continued) New Directions for Pharmacotherapy

Combined treatment with CBT Need augmentation strategies for partial

responders Augmentation treatments with different

medications Effective and safe approaches for

children

Looking Ahead #6Using Neuroimaging to Understand Therapeutic Mechanisms of Action

Does CBT work “top-down” - (pre-frontal) cortical restraint of amygdala

Do medications work “bottom-up” - major targets are subcortical

Do different psychosocial approaches work in different ways? CBT vs. SIT or EMDR

Looking Ahead #7Major Challenges Regarding Memory and Dissociation: Might They Inform

Forensic Practice?

Studies of traumatic memory will need to be much more rigorous and inventive if they are to reflect the complexity of the processes that have already been demonstrated to occur. Neuroimaging methods will also assist in this understanding.

Looking Ahead #7 (continued)Major Challenges Regarding Memory and Dissociation: Might They Inform

Forensic Practice? Should draw more explicitly on concepts developed by

cognitive and experimental psychologists

Should utilize neuroimaging methods

Should distinguish between processing any trauma-specific information from processing information encoded in an emotional context

Should be designed to distinguish between ordinary autobiographical memories of trauma and involuntary flashbacks (which have a different neural basis)

Brewin, in pressBrewin, in press

Looking Ahead #8Developmental Challenges:

Children/Adolescents & the Elderly An approach that encompasses the dynamic

relationship between experience, neurological processing, and brain development, is necessary for understanding the problems of children who have experienced traumatic events

Such an approach must also address self-regulation from a developmental perspective since it has been noted to be a central problem for children with traumatic stress

Saxe et al., in press

Looking Ahead #8 (continued)Developmental Challenges:

Children/Adolescents & the Elderly

Are the psychological and biological effects of the same trauma (e.g. sexual, accident):

• different in children than adults• different in adults traumatized as children• different in adults traumatized as adults

Looking Ahead #8 (continued)Developmental Challenges:

Children/Adolescents & the ElderlyUnfortunately knowledge in the geriatric field is far from complete. More information is needed regarding the prevalence, symptom expression and course of trauma-related symptoms, particularly age-specific psychosocial and behavioral responses, mediators and moderators of negative and positive consequences, and assessment techniques. Many questions regarding treatment and delivery remain unexamined or only partially answered.

Cook & Niederehe, in press

PTSD and RetirementPTSD and Retirement11

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51 53 55 57 59 61 63 65 67 69 71 73 75 77 79

Age

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Model for age 65 retirement

1Schnurr et al., 2005

N = 404 older veterans

Looking Ahead #9Challenges Regarding Gender

The development of testable conceptual models and hypotheses regarding the impact of gender on vulnerability and treatment outcomes in PTSD are sorely needed, as are efficacy trials that can formally assess the potential role of gender as a moderator of treatment efficacy.

Kimerling et al, in press

Looking Ahead #10Cross-Cultural Challenges

It is time for the fields of anthropology and mental health to end the debate about the validity of the PTSD diagnosis.

A culturally competent model of traumatic stress should address how culture is implicated in the process of appraisal of vulnerable or protective factors. Critical to this field is learning the language-the idioms of distress-that cultural groups use as acceptable means of communicating distress. Equally important is understanding the explanatory models, the attribution of illness and the culturally sanctioned local healing methods.

de Jong & Osterman, in press

Looking Ahead #10 (continued) Cross-Cultural Challenges

PTSD has been documented throughout the world1,2 Comparable PTSD prevalence in Nairobi embassy

and Oklahoma City bombings3

Men: 26% Nairobi, 20% Oklahoma City Women: 35% Nairobi, 34% Oklahoma City

Although there may be culture-specific idioms of distress, PTSD appears to encompass a pattern of universal post-traumatic distress

1 de Jong et al., 2001; 2 Green et al., 2004; 3 North et al., 2005

PTSD and Hazard of Physician-Diagnosed Disease in Older Veterans

(Schnurr, Spiro, & Paris, 2000)

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Cancer

Endocrine

Hypertension

Ischemic

Other Cardio.

Arterial

Pulmonary

Upper GI

Lower GI

Urinary

Dermatologic

Musculoskeletal

**

**

****

Hazard is expressed per 10-pt increase in PTSD sxs and is adjusted for age, BMI, smoking, and alcohol consumption

*p < .05

PTSD and Arterial Disorder in Older Veterans (Schnurr et al., 2000)

Years on Study403020100

1.0

.8

.6

.4

.2

0.0

Low

Moderate

High

Cumulative Probability of Arterial Disorder as a Function of PTSD Symptom Level

Odds of Cardiovascular Problems in Vietnam Veterans with PTSD(Boscarino & Chang, 1999)

0 1 2 3 4 5 6 7

Any ECG Abnornmality

Infarction

AVC Defect

Arrhythmias

VC Defect

ST/T Abnormality

Odds Ratio

PTSD

PTSD adj. for anxiety &depression

*

*

**

*

N = 4,462

Adjusted for demographic, military, and health risk covariates. *p < .05.

Looking Ahead #12Resilience & Prevention

Most people exposed to traumatic stress do not develop PTSD

It is important to understand resilience in order to promote it in the general population and to use such knowledge to inform the development of new treatments

Gene x Environment-1Gene x Environment-1

Plasma NPY:Plasma NPY:Baseline and Acute StressBaseline and Acute Stress

Looking Ahead #12 (continued)Resilience & Prevention

It is likely that stress-related risk and resilience factors have multiple determinants such as genetic makeup, developmental history, personality, coping style, social support, and history of exposure to traumatic events

Southwick et al., in press

Looking Ahead #12 (continued)Resilience & Prevention

A “wellness-oriented” preventive public health approach:

1. Prepare the population-at-large with the expectation of recovery but with the goal of accelerating recovery

• psychoeducation, public mental health strategies, foster resilience

2. Identity populations at risk and build capacity for early detection and intervention for those manifesting severe distress or psychiatric symptoms