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NC-PTSD Clinical Quarterly

Fall 1997, Volume 7, Issue 4, ISSN-1052-7168

Post traumatic Stress Disorder

(PTSD), marked by symptoms of

reexperiencing, avoidance, and

arousal, was officially delineated in

1980 as a clinical diagnosis within

the category of anxiety disorders.

Although initial delineation and

characterization of PTSD represents

a major advance, the diagnostic

criteria continue to emphasize

factors mainly dependent on patient

self-reporting. The DSM-III-R

includes physiologic reactivity and

exaggerated startle as diagnostic

STARTLE RESPONSE

IN INDIVIDUALS WITH PTSD

veteran subjects with PTSD. Yet some investigators felt that the

presentation of identical stimuli to all subjects did not permit

an accurate assessment of what was uniquely stressful about a

particular individual traumatic experience. It was thought that

without the possibility of eliciting an individual’s unique

response to a stressful event, the sensitivity and specificity of

psychophysiological testing could not improve.

As a result, several researchers have used script-driven

mental imagery as a means of provoking a more personalized

physiologic response in the laboratory. The scripts are recorded

narratives taken from a detailed description of the most

traumatic event experienced by the participant, then played

back to the participant in the laboratory. Each participant is

asked to listen to the recording and to imagine the events

portrayed. While the participant does this, heart rate, skin

conductance and electromyogram activity of the left frontalis

are recorded. This technique has successfully demonstrated

significantly larger physiological responses during personal

The idea of an objective test for

PTSD remains extraordinarily

appealing to many clinicians and

forensic specialists.

combat imagery compared with mentally healthy Vietnam

veterans (4), and Vietnam veterans with non-PTSD anxiety

disorders (5). Discriminant analyses of the physiologic measures

indicated that skin conductance successfully classified 73%,

EMG 67%, and HR 64% of the PTSD subjects (4). The convergent

elevation of these measures in the PTSD group is noteworthy

considering that concordance between physiologic measures

in research of this nature has generally been found to be low.

However promising, the above described

psychophysiology studies examined peripheral autonomic

reactivity and behavioral changes in order to make inferences

about brain function in PTSD. A number of investigators felt

continued on page 3

C. A. Morgan III, M.D., M.A.

C. A. Morgan III, M.D., M.A.

features of PTSD. The presence of psychophysiological

alterations accompanying a mental disorder has provided the

opportunity to obtain data that is more objective and more

readily quantifiable than self-report data. While this article will

focus primarily on investigations of the startle response, a few

words are in order about psychophysiologic investigations.

Psychophysiology studies have attempted to assess the

symptoms of physiologic reactivity in individuals with PTSD

by measuring the heart rate (HR), electrodermal, and blood

pressure responses of veterans with PTSD and control subjects

when said subjects are exposed to recorded sights and sounds

of combat in the laboratory. In most of these studies, the

veterans with PTSD have shown greater autonomic arousal

when exposed to the combat stimuli than the comparison

subjects. The ability to discriminate PTSD from control subjects

using these physiologic measures has been thought impressive

and has ranged from 80%-95% (1-3). While these studies have

contained design flaws (such as group discrepancies in age,

educational level, and combat exposure; comparisons of

medicated and unmedicated subjects; differences in baseline

physiologic arousal), taken together, they have been perceived

by biological investigators as providing convincing evidence

of physiologic hyperreactivity to combat-related stimuli in

INSIDE THIS ISSUE

FROM THE EDITOR 66

NEUROIMAGING STUDIES IN PTSD 70

PRACTITIONER NETWORK 72

CLINICAL TRAINING PROGRAM 73

WOMEN AND TRAUMA: A CLINICAL FORUM 74

PHARMACOTHERAPY FOR PTSD: A STATUS REPORT 75

SITUATIONS OF THREAT 78

EDUCATION & SUPPORT SERVICES FOR

SPECIALIZED PTSD PROGRAMS 81

DISASTER MENTAL HEALTH/CRITICAL 

INCIDENT TRAINING UPDATE 82
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NC-PTSD Clinical Quarterly

In a recent overview of the biological themes in PTSD,

Pitman (1) noted that when PTSD first appeared as a diagnosis,

many people, lay and professional alike, thought it was a device

to appease forsaken and angry Vietnam veterans. In the early

1980’s, clinicians who believed in the validity of a post-traumatic

stress syndrome, founded their belief primarily on the collective

self-report of patients’ psychological symptoms. The validity of

a post-traumatic stress disorder has since become irrefutable

as several studies have indicated that neurobiological changes

(e.g., changes in the central nervous system) occur in individuals

who meet the diagnostic criteria for PTSD. These findings are

referenced in this issue of the Quarterly. This edition also

presents an update on pharmacotherapy as neurobiological

research is correspondingly broadening the possibilities for

pharmacological prevention and treatment. An article providing

an overview of the physiologic reactivity associated with PTSD,

a commentary on assessing and treating somatic symptoms

related to PTSD, and the third installment in a series addressing

specialized care for chronic complex PTSD round out this issue.

In addition to informing clinicians, we hope the articles serve

to help clinicians better educate their patients and clients about

the impact of having experienced or witnessed life threatening

events.

Julian Ford, Ph.D., Deputy to the Executive Director for

Clinical Networking and Education has accepted an offer to

become the Director of Behavioral Healthcare Outcomes

Research and Associate Professor in the University of

Connecticut Medical School Department of Psychiatry. Dr. Ford

will be developing clinical research initiatives in mental health

FROM THE EDITOR

primary care and mental health services research, with a special

focus on trauma and PTSD. A prodigious worker, Dr. Ford has

worked on several important projects since joining the National

Center in 1994, including clinical evaluation projects providing

early assessment and treatment for Persian Gulf veterans,

assessment and treatment of complex PTSD with veterans of

all eras, and education projects for VA clinicians in disaster

mental health and mental health primary care. In addition, Dr.

Ford has been a regular contributor to the Clinical Quarterly,

authoring the Practitioner Network column. We wish him

continued success and look forward to new collaborative

ventures.

In closing, we apologize for the delay in getting this issue

to you. We have addressed the problems resulting in the delay

and, as is typical of setbacks, used the opportunity to generate

new possibilities including making plans for the Clinical

Quarterly to be available on the Web. As always, your comments,

suggestions, or questions are appreciated and serve to guide

future issues. I can be reached via the following:

phone: 650-493-5000 Ext. 22494

email: bhh@icon.palo-alto.med.va.gov

postal: NC-PTSD, 795 Willow Road 352 (E117)

Menlo Park, CA 94025

Bruce H. Young, Editor

Reference

1. Pitman, R.K. (1997). Overview of biological themes in PTSD. Annals

of the New York Academy of Sciences, 821, 1-9. 

NATIONAL CENTER FOR PTSD

Executive Director

Matthew J. Friedman, M.D., Ph.D.

VAMC/ROC White River Junciton,

Vermont 05009

Clinical Laboratory & Education Division

Fred D. Gusman, M.S.W., Director

VAMC, Palo Alto, California 94304

Pacific Islands Division

Sarah Miyahira, Ph.D., Acting Director

Honolulu, Hawaii 96813

Behavioral Science Division

Terence Keane, Ph.D., Director

VAMC, Boston, Massachusetts 02130

Neuroscience Division

Dennis Charney, M.D., Director

VAMC, West Haven, Connecticut 06516

Women’s Health Science Division

Jessica Wolfe, Ph.D., Director

VAMC, Boston, Massachusetts 02130

Clinical Laboratory & Education Division

Robert Rosenheck, M.D., Director

VAMC, West Haven, Connecticut 06516

Editor

Managing Editor

Executive Editor

Associate Editor

Assistant Editor

Copy Editor

Graphic Designers

Bruce H. Young, M.S.W., L.C.S.W.

Joe Ruzek, Ph.D.

Fred D. Gusman, M.S.W.

Dudley D. Blake, Ph.D.

John Aboytes, B.A.

Annabel Prins, Ph.D.

Kristopher J. Morrow

Bruce H. Young, M.S.W., L.C.S.W.

Clinical Quarterly Staff

Please feel free to contact us at the Education Division: FTS 463-2673/2494; commercial number 650-493-5000 ext. 22673/22494; or E-mail: bhh @ icon.palo-alto.med.va.gov

Please address all correspondence to : Editor, National Center for PTSD Clinical Quarterly, VA Palo Alto Health Care System, 795 Willow Rd (323E117), Menlo Park, CA 94025
Volume 7 (4) Fall 1997

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NC-PTSD Clinical Quarterly

that a clearer understanding of central nervous system reactivity

and functioning might be afforded by using a more direct probe

of brain function that is sensitive to noradrenergic neuronal

reactivity, fear and alarm states. It was not without reason that

many believed that the acoustic startle reflex could fulfill such

a need.

Historical and contemporary records provide evidence

that an important symptom seen in combat veterans diagnosed

with Shell Shock, Combat Fatigue or Post Traumatic Stress

Disorder has been, and continues to be, an exaggerated startle

reflex (6-9). Clinical observations of exaggerated startle in

distressed combat veterans were so common by mid-century,

some psychiatric authorities argued that increased startle was

cardinal symptom of combat fatigue (10). While not considered

the cardinal symptom of PTSD today, exaggerated startle remains

tightly linked to trauma related psychological illness. In fact,

according to DSM-IV, PTSD is now the only anxiety disorder in

which hyperstartle is listed as a core symptom.

 Investigators have had various motivations for studying

the acoustic startle reflex in humans and especially in those

suffering from PTSD. Some have been interested in finding out

whether or not exaggerated startle is a marker (or sign)

indicating, or helping to provide a reliable diagnosis of PTSD.

The idea of an objective test for PTSD remains extraordinarily

Because the components of the basic startle response

are relatively small in number, the time it takes for a sound

stimulus to enter the ear and produce a corresponding eyeblink is rather short (21-75 milliseconds). This means that the

optimal time to measure the blink component of the startle

response is after 21 milliseconds and before 75 milliseconds.

Startle responses recorded before 21 milliseconds are

considered to be unrelated to the sound stimulus, while those

occurring after 75 are considered as potentially random or

consciously produced. Thus, it is possible to minimize the

likelihood of random and voluntary blink responses. While many

investigators have employed the methodology described above

(assessment of EMG activity of the orbicularis oculi muscle in

response to a sudden burst of white noise) they have not used

identical sound stimuli. Some investigations have used sound

stimuli of many different intensities and of very short duration

(30-40 milliseconds), whereas others have used a single sound

stimulus of a much longer duration (500 milliseconds). These

distinctions are important to notice when reading the literature

about startle for two main reasons: First, it makes it difficult to

directly compare studies conducted in one laboratory to those

from another; second, there is a great deal of evidence that

startle varies according to stimulus intensity, frequency and

duration. That the startle response may be directly enhanced

by the type and characteristics of the acoustic stimulus is

important and relevant to the issue of whether or not

exaggerated startle can be used as a marker for PTSD.

One final comment is in order regarding methodology:

Some authors have used different definitions than those

described here when referring to the startle response (such as

the heart rate response to a startling sound) while others have

used a tactile stimulus (a puff of air). These distinctions are not

minor in that the neuroanatomical pathways invoked in the

responses are not entirely overlapping

Theoretically, there are a number of ways that

exaggerated startle and PTSD might be associated. Investigators

interested in whether or not hyperstartle might be a marker in

individuals with PTSD know that in healthy subjects, startle

shows large variability across individuals, but high consistency

within subjects over time. Therefore, it is conceivable, that

people who eventually develop PTSD might be those who had

high levels of startle prior to the development the disorder.

Rather than being caused by exposure to trauma (and/or the

development of PTSD) exaggerated startle might be a reflection

of a stable trait. At this present time, no studies have measured

the startle response in individuals prior to, and after exposure

to intense trauma to test out this possibility.

A second possibility is that exaggerated startle in PTSD

reflects a persistent sensitization (or heightened responding)

of the startle reflex caused by exposure to trauma induced

psychological stress. While there is some evidence from animal

studies that do support the idea that intense stress may increase

the overall startle response, the increased responding tends to

be fairly brief in duration and is not thought to be directly related

to the reports of chronic and exaggerated startle in humans

with PTSD. Nevertheless, there are a number of startle studies

in humans with PTSD documenting heightened startle which

Startle Response In Individuals with PTSD

appealing to many clinicians and forensic specialists. It is felt

that such a test would enhance discrimination between

individuals who do and who do not have PTSD.

For other investigators, startle has been less interesting

as test for PTSD, and more interesting as a probe in examining

central nervous system reactivity in individuals with PTSD.

Because so much is known about the neuroanatomical

pathways of, and neurotransmitters involved in the startle reflex, several studies have used startle to gain an understanding

of neurohormonal functioning in PTSD. Finally, several

investigators have used startle as an objective measure of the

emotional states of anxiety and fear and have used startle as a

tool to elucidate the neural mechanisms involved in the learning

and extinction of fear and anxiety.

The startle reflex is one that is shared by very nearly all

animals. In basic terms, it is the rapid motor twitch or jump

that occurs when an animal or human is exposed to a sudden

stimulus (such as a touch, a noise, or a visual image or light).

The term acoustic startle reflex refers to the startle response

to loud or sudden sounds. In humans, the most consistent and

easy way to measure the acoustic startle reflex is to record the

speed and intensity of the eye-blink that occurs after someone

hears the noise. Technically this is done by recording the

electromyographic (EMG) activity of the orbicularis oculi

muscle. This method provides information about the intensity

(amplitude and the speed (latency) of the eye-blink in response

to the sound stimulus.

There is a great deal of evidence that

startle varies according to stimulus

intensity, frequency, and duration.
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NC-PTSD Clinical Quarterly

have invoked the stress sensitization hypothesis (or increased

unconditioned responding) to explain the finding (11-15).

Importantly, there are a number of studies which have not found

exaggerated, but normal (16-18) or reduced startle in individuals

with PTSD (19). Some authors reviewing the startle literature

have wondered whether or not exaggerated startle in

individuals with PTSD might be reflective of a classically

conditioned response. It is reasoned that the sudden bursts

of noise might be reminiscent of the sounds of the battlefield

or of gun fire and thereby produce an exaggerated (fearconditioned) startle response. This idea however, has lost

considerable explanatory power given the evidence for

exaggerated startle in victims of non-combat, non-firearm related

trauma who suffer from PTSD.

An alternative way of viewing exaggerated startle in PTSD

is to consider the increased startle as an acute state of

conditioned fear or anxiety rather than as a conditioned

response unique to a specific sound or object. It is possible

that exaggerated startle is seen in individuals with PTSD when

they are in a state of heightened emotional arousal produced

by stress or reminders of their traumatic experiences. Support

for this idea comes from several sources.

First, it is well known that startle can be elevated under

conditions that are emotionally salient (20). Second, we have

examined startle in Vietnam veterans with PTSD in three studies

(17, 21-22). In one study, startle was investigated during periods of shock anticipation (threat condition) and during periods

when no shocks were administered (safe condition) (21). In

the second investigation, subjects were administered placebo

and yohimbine on alternative days (22). Startle was elevated in

the PTSD patients throughout both experiments. Because

startle was elevated in the safe condition of the shock

experiment and in the placebo condition of the

pharmacological challenge study, we argued that the stress of

the experimental context was responsible for the elevated

startle. Additional support for this idea came from our third

investigation in Vietnam veteran subjects who, when tested

under non-stressful conditions did not show exaggerated startle

compared to healthy and combat control subjects (17). What

these data suggest is that the laboratory conditions affect the

emotional state of the subjects participating in startle testing

and that anxious or fearful states produce an increase in the

startle response.

Support for the idea that exaggerated startle in PTSD is

associated with a particular emotional state, rather than a trait

(or marker), can also be found in studies which have used the

startle response as a measure of central nervous system neuronal

reactivity. Because the startle reflex is sensitive to fear/alarm

responses, and modulated by CNN noradrenergic

neurotransmission, it is an ideal means of assessing these

elements in PTSD. In a pharmacological challenge study

involving the administration of yohimbine and placebo on

alternative days, Vietnam veterans with PTSD demonstrated

significantly greater startle responses to yohimbine compared

to placebo and compared to combat controls (22). Startle

frequency and startle threshold were respectively increased

and reduced by yohimbine. Taken together, the data from this

investigation provided evidence that the exaggerated startle

seen in individuals with PTSD is, in part, a manifestation of

heightened noradrenergic responding.

Finally, startle has been used as a tool to study the learning and extinction of conditioned fear in healthy subjects and

in individuals with PTSD. Using a laboratory procedure that

involves exposing subjects to stressful electric shocks while

they view a series of lights, we have recently completed a 2-

day study of conditioned fear in Gulf War Veterans with PTSD

(23). On the first day startle was measured before, during and

after subjects were exposed to light/shock training trials.

During the training trials, only one of the two lights was paired

with electric shocks to the subject wrists. This procedure

permitted an assessment of whether, and to what degree, startle

would increase in the presence of the light that was paired

with the electric shocks, an indication that the subjects had

learned that the bluelight was linked with an unpleasant shock.

At the conclusion of the first day, we disconnected the shock

electrodes and measured startle in the presence of each light.

We repeated the same procedures on the second test day one

week later. Several things happened: First, on the initial day of

testing, the PTSD patients showed exaggerated startle to the

threat light and the safe light, but not the dark; Second, overall

startle responses were noted to be increased prior when the

subjects came into the lab on the second day. These data suggest

that Gulf War veterans with PTSD learn what to be fearful of,

but cannot make use of their intellectual knowledge about the

safe light to inhibit their fear. Second, they exhibit increased

fear to the context, or room where the testing occurred.

These findings are important because animal studies

suggest that different brain systems mediate fear to explicit

cues —such as a light indicating shock— and contextual fear

—fear of place where the shocks were experienced (24-27).

Lesions of a areas of the brain called the hippocampus (25-26)

or the BNST (24) block context conditioning, but not explicit

cue conditioning, whereas lesions of the amygdala block both.

In addition, inactivation of the BNST, but not the central nucleus

of the amygdala, blocks the potentiation of startle by another

type of contextual stimulus (such as sustained bright lights (28).

These data suggest that the hippocampus and the BNST may

be especially important in contextual fear or anxiety, compared

to explicit cue fear which is dependent upon the amygdala.

The results of the above described study point to a dysfunction

of the hippocampus and/or the BNST.

So, what have we actually learned about the startle

response in PTSD? Within recent years, a growing number of

studies have reported on the startle response in individuals

with PTSD. The majority of these studies have been conducted

on male combat veterans, however, there are a few studies

involving children and civilian women with PTSD. The startle

studies that have been conducted under relatively non-stressful

conditions have provided contradictory evidence as to whether

startle is increased, decreased, or normal in persons with PTSD.

By contrast, the studies that have included threat of shock or

an I.V. have consistently demonstrated exaggerated startle.

Also, it is clear that a person’s age, the length of time since

trauma, and testing conditions all affect the startle response.

Startle Response In Individuals with PTSD
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NC-PTSD Clinical Quarterly

Startle provides a means of studying fear and anxiety

states, as well as the learning of fear and anxiety states in

individuals with and without PTSD. Since the neural pathways

of the startle reflex are well understood, the findings of such

studies of the human startle response in individuals with PTSD

have provided information that may be of benefit to both

patients and clinicians. First, the evidence supports the idea

that exaggerated startle can be a long-lasting symptom in some

individuals with PTSD. Clinicians might educate patients about

this possibility so that both parties in the treatment setting

might have realistic appraisal of the severity of the condition.

Second, it may be helpful for clinicians to remember that

increased startle may occur even in the absence of reminders

of the traumatic events. For example, studies show quite

clearly that startle may be increased by background noise. This

may provide a clue as to why some patients find that their

startle is increased in a mall, or a grocery store, even when

they are unable to find anything that is “setting” them off.

Related to this, patients will often complain that in addition to

increased startle they feel rattled, agitated and restless. Third,

threatening situations or fearful experiences have a powerful

augmenting influence on the startle response. The research

has clearly shown that the very best way to detect exaggerated

startle is to test for it under stressful test conditions. Within

the clinical realm, this stress may take the form of anxiously

anticipating an unwanted event such as a bill, compensation &

pension examination, or after discussing PTSD-related traumatic

events. Clinicians and patients can explore together ways of

reducing exposure (when possible) to environments that are

likely to produce increases in startle. While there are no well

controlled studies examining the effects of medication on the

startle response in individuals with PTSD, the animal literature

suggests that medications such as buspirone or clonidine may

provide some relief.

References

1. Blanchard, E.B., Kolb, L.C., Pallmeyer, T.P., & Gerardi, R.J. (1982).

A psychophysiological study of posttraumatic stress

disorder in Vietnam veterans. Psychiatry Quarterly, 54,

220-229.

2. Malloy, P.F., Fairbank, J.A., & Keane, T.M, (1983). Validation of

a multimethod assessment of posttraumatic stress

disorder in Vietnam veterans. Journal of Consulting &

Clinical Psychology, 51, 488-494.

3. Pallmeyer, T.P., Blanchard, E.B., & Kolb, L.C. (1986). The

psychophysiology of combat induced PTSD in Vietnam

veterans. Behavioral Research Therapy, 24, 645-652.

4. Pitman, R.K., Orr, S.P., Forgue, D.F., deJong, J.B., & Claiborn,

J.M. (1987). Psychophysiological assessment of post

traumatic stress disorder in Vietnam combat veterans.

Archives General Psychiatry, 44, 940-975.

5. Orr, S.P. (1990). Psychophysiologic studies of posttraumatic

stress disorder. In E.L. Giller (Ed)., Biological assessment

and treatment of posttraumatic stress disorder (pp. 135-

157). Washington, DC: American Psychiatric Press.

6. Grinker, R.R., & Spiegle, J.P. (1945). War neuroses. Philidelphia:

Blakiston.

7. Southard, E.E. (1919). Shell shock and other neuropsychiatric

problems presented in 589 case histories from the war

literature, 1914-1918. Boston: W.M. Leonard.

8. Southwick, S.M., Morgan, C.A., Nagy, L.M., Bremner D.,

Nicolaou, A., Johnson, D.R., Rosenheck, R., & Charney, D.S.

(1993). Trauma-related symptoms in veterans of

Operation Desert Storm: A preliminary report. American

Journal of Psychiatry, 150, 1524-1528.

9. Southwick, S.M., Morgan, C.A., Nicholau, A., Darnell, A., &

Charney, D.S. (1995). Trauma-related symptomatology in

Desert Storm Veterans: Two year follow-up. American Journal

of Psychiatry, 152, 1150-1155.

10. Kardiner A. (1941). The traumatic neurosis of war. New

York: Paul Hoeber.

11. Butler, R.W., Braff, D.L., Rausch, J.L., Jenkins, M.A., Sprock, J.,

& Geyer, M.A. (1990). Physiological evidence of

exaggerated startle response in a subgroup of Vietnam

veterans with combat related PTSD. American Journal of

Psychiatry, 147, 1308-1312.

12. Morgan, C.A., Grillon, C., Southwick, S.M., Davis, M., &

Charney, D.S. (1996). Exaggerated acoustic startle in Gulf

War Veterans with PTSD. American Journal of Psychiatry,

153, 64-68.

13. Morgan, C.A., Grillon, C., & Southwick, S.M. (1997). Startle

abnormalities in women with sexual assault related PTSD.

American Journal of Psychiatry, 154, 1076-1080.

14. Orr, S.P., Pitman, R.K., & Shalev, A.Y. (1995). Physiologic

responses to loud tones. Journal Abnormality Psychology,

104, 75-82.

15. Shalev, A.Y., Orr, S.P., Peri, T., Schreiber, S., & Pitman, R.K.

(1992). Physiologic response to loud tones in Israeli

patients with posttraumatic stress disorder. Archives

General Psychiatry, 49, 870-875.

16. Cuthbert, B.N., Drobes, D.J., Patrick, C.J. and Lang, P. J. (1994).

Autonomic and startle responding during affective

imagery among anxious patients. Psychophysiology,31, v. 1,

S35.

17. Grillon, C., Morgan, C.A., Southwick, S.M., Davis, M., &

Charney, D.S. (1996). Baseline Startle amplitude and

prepulse inhibition in Vietnam veterans with

posttraumatic. Psychiatry Research, 64, 169-178.

18. Orr, S.P., Solomon, Z., Peri, T., Pitman, R. K. & Shalev, A.Y.

(1996). Physiologic responses to loud tones in Israeli

veterans of the 1973 Yom Kippur War. Biological

Psychiatry, 41, 319-326.

19. Ornitz, E.M., & Pynoos, R.S. (1989). Startle modulation in

children with posttraumatic stress disorder. American

Journal Psychiatry, 146, 866-870.

20. Lang, P.J., Bradley, M.M., & Cuthbert, B.N. (1990). Emotion,

attention, and the startle reflex. Psychology Review,97,

1-19.

21. Morgan, C.A., Grillon, C., Southwick, S.M., Davis, M., &

Charney, D.S. (1995). Fear potentiated startle in PTSD.

Biological Psychiatry,38, 378-385.

22. Morgan, C.A., Grillon, C., Southwick, S.M., Nagy, L.M., Davis,

M., & Charney, D.S. (1995). Yohimbine facilitated acoustic

startle in combat veterans with PTSD. Psychopharmacology,

117, 466-471.

23. Grillon C., & Morgan, C.A. (In review). Fear-potentiated startle

conditioning to explicit and contextual cues in Gulf War

veterans with posttraumatic stress disorder.

24. Davis, M., Gewirtz, J. C., McNish, K. A., & Kim, M. (1995). The

roles of the amygdala and bed nucleus of the stria

terminalis (BNST) in the acquisition of fear potentiated

startle using both explicit and contextual cues. Society

for Neuroscience Abstracts, 21, 1224.

25. Kim, J.J., & Fanselow, M.S. (1992). Modality-specific retrograde

amnesia off ear. Science, 256, 675-677.

26. Phillips, R.G., & LeDoux, J.E. (1992). Differential contribution

of amygdala and hippocampus to cued and contextual fear

conditioning. Behavioral Neuroscience, 106, 274-285.

27. Wilkinson, L. S., Humby, T., Robbins, T. W. & Everitt, B. J. (1995).

Differential effects of forebrain 5-hydroxytryptamine

depletions on Pavlovian aversive conditioning to discrete

and contextual stimuli in the rat. European Journal of

Neuroscience, 7, 2042-2052.

28. Walker, D.L. (1996). AMPA receptor blockade in the bed nucleus

of the stria terminalis (BNST) but not the central nucleus of

the amygdala (CNA) disrupts light-enhanced startle: A novel

paradigm for the assessment of anxiety in rats. Society for

Neuroscience Abstract, 22, 1117.

C. A. Morgan III is Associate Professor of Psychiatry and Research Affiliate,

History of Medicine Yale University School of Medicine and Associate

Director, Post Traumatic Stress Disorder Program, VA Connecticut Healthcare

System, Neuroscience Division of the National Center for PTSD.

Startle Response In Individuals with PTSD
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NC-PTSD Clinical Quarterly

With the growing appreciation for

the biological basis of posttraumatic

stress disorder (PTSD) there has

been an increase in interest in

neuroimaging studies of patients

with PTSD. Neuroimaging studies

include all studies which take

advantage of radiological techniques

to provide information about the

structure and function of the brain.

The first radiologic studies in trauma

patients used pneumoencephalography, which involves the

injection of air into the

measured by the Wechsler Memory Scale-Logical Component,

percent retention, were associated with decreased right

hippocampal volume in the PTSD patients (r=0.64; p<0.05) (2).

Multivariate analyses performed to control for differences in

alcohol abuse and education not completely controlled for by

the matching strategy showed significant differences after

controlling for these variables. Gurvits et al (3) found a

significant reduction in hippocampal volume bilaterally in males

with combat-related PTSD. Our group found a statistically

significant 12% decrease in left hippocampal volume in 17

patients with a history of PTSD related to severe childhood

physical and sexual abuse, in relationship to 17 controls

matched on a case-by-case basis with the patients (4). Stein et

al (5) found a reduction in left hippocampal volume in women

with childhood sexual abuse compared to women without

childhood sexual abuse. Reduced hippocampal volume correlated

with dissociative symptomatology in this study (r=-0.73).

Positron emission tomography (PET) can be used to

provide a measure of brain function, measured with brain blood

flow and metabolism. Glucose is the primary energy source of

the brain, and when there is an increase in firing of the neurons

in a specific brain region, there is an increase in glucose uptake

in that region to meet the demand. Similarly, with increased

glucose demand there is an increase of brain blood flow to

that region. With a regional increase in neuronal activity (for

instance, in the visual cortex following exposure to a bright

light), there is a shunting of blood flow with accompanying

drop in glucose toward that region which can be measured

with PET as a “real time” measure of brain function.

The radioactive substances used in PET can be prepared

in an on site cyclotron and injected immediately into the patient

for imaging. Brain blood flow is measured with radioactive

water H2[O-15], and brain metabolism with radioactive glucose

([18F]2 fluoro-2-deoxyglucose, or FDG). These substances emit

positrons in the course of radioactive decay, which collide with

electrons in the brain, creating two beams of light which travel

away from each other and are “detected” by the camera.

Computers then use this information to reconstruct an image

of the brain’s metabolism or blood flow patterns.

We used PET and FDG in the measurement of cerebral

glucose metabolic rate following administration of yohimbine

and placebo in Vietnam combat veterans with PTSD and healthy

controls. Increased noradrenergic function has been

hypothesized to underlie many of the symptoms of PTSD, and

administration of the alpha-2 antagonist, yohimbine, which

stimulates brain norepinephrine release, to patients with PTSD

results in increased PTSD symptoms and anxiety.

Norepinephrine has a U-shaped curve type of effect on brain

function, with lower levels of release causing an increase in

metabolism, while very high levels of release actually cause a

decrease in metabolism. We hypothesized that yohimbine would

cause a relative decrease in metabolism in patients with PTSD in

cortical brain areas which receive noradrenergic innervation.

NEUROIMAGING STUDIES IN PTSD

J. Douglas Bremner, M.D.

cerebrospinal space, and imaging with the use of simple Xrays. This technique was applied to concentration camp

survivors from World War II seeking compensation for disability.

The authors reported “[cerebral] atrophy of varying degrees

and “ diffuse encephalopathy” in up to 81% of cases, based on

their visual interpretation, although no quantitative measures

of atrophy were performed (1).

Magnetic resonance imaging (MRI) is a technologically

more advanced method of imaging than X-ray based techniques

such as pneumoencephalography. MRI uses a powerful

magnetic to throw the electrons and protons which make up

brain tissue out of their normal patterns, and measures the

time it takes for them to return to their normal resting state.

This relaxation time says something about the content of the

tissue, which can be used to create an image of the brain. MRI

images are obtained of successive slices which move through

the entire volume of the brain a few millimeters at a time. With

specialized image processing software on the computer, the

outline of individual brain regions in successive slices can be

traced using a mouse driven cursor, and the volume within the

outlines quantitated and converted to real brain volume. These

techniques have been shown to be highly reliable in the hands

of well trained operators, and have provided a wealth of

information about brain structure in psychiatric disorders in

general, and more recently in the field of PTSD.

Studies using MRI in PTSD have measured volume of the

hippocampus, a brain structure involved in learning and

memory. This line of research was prompted by studies in

animals showing that high levels of cortisol seen in stress are

associated with damage to the hippocampus. We compared

hippocampal volume measured with MRI in Vietnam combat

veterans with PTSD and healthy subjects matched for factors

which could affect hippocampal volume, including age, sex,

race, years of education, height, weight, handedness, and years

of alcohol abuse. Patients with combat-related PTSD had an 8%

decrease in right hippocampal volume in comparison to

controls (p<0.05), but no significant decrease in volume of

comparison structures including temporal lobe, amygdala or

caudate. Deficits in free verbal recall (explicit memory) as

J. Douglas Bremner, M.D.
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Consistent with this hypothesis, yohimbine resulted in a relative

decrease in metabolism in orbitofrontal, temporal, parietal, and

prefrontal cortex in PTSD patients relative to controls (6). These

findings are consistent with an increased release of

norepinephrine in the brain following yohimbine in PTSD.

Studies have begun to use PET to identify brain regions

which mediate traumatic remembrance and physiological

reactivity to traumatic cues. These studies have typically started

from the hypothesis that an increase in activity of limbic brain

regions involved in emotion following exposure to traumatic

cues is characteristic of PTSD. Three studies to date have

used varying behavioral protocols, consequently the results

are slightly different. Rauch et al (7) used PET and H20[150] to

look at blood flow during exposure to traumatic and neutral

scripts in a group of PTSD patients. Exposure to traumatic

scripts resulted in an increase in brain blood flow in limbic

regions (right amygdala, insula, orbitofrontal cortex, and anterior

cingulate) and decreased blood flow in middle temporal and

left inferior frontal cortex. Our group studied Vietnam veterans

with and without PTSD during exposure to combat-related and

neutral slides and sounds. Vietnam veterans with combat-related

PTSD demonstrated a relative failure of activation of

orbitofrontal cortex with combat-related slides and sounds in

comparison to Vietnam combat veterans without PTSD.

Exposure to combat slides resulted in a relative increase in blood

flow in two limbic regions, lingual gyrus (posterior

parahippocampus) and mid-cingulate. There were also

activations in several nonhypothesized regions, including

parietal and motor cortex, and dorsal pons. Shin et al (8) used

PET and H20[150] during induction of combat trauma-related

and neutral mental imagery in patients with PTSD and healthy

controls. This study found a relative failure of orbitofrontal

cortex activation, increased blood flow in two hypothesized

limbic regions, right amygdala and anterior cingulate, as well

as decreased blood flow in middle temporal and left inferior

frontal cortex in PTSD patients (but not controls) during

exposure to mental imagery (8).

A failure of extinction to fear is an important part of the

presentation of PTSD. The neural mechanism of extinction to

fear involves orbitofrontal cortex inhibition of amygdala

function. Reexposure to the unconditioned-conditioned

stimulus pairing results in a rapid return of the conditioned

fear response, which suggests that the information was present

in the amygdala but merely inhibited by orbitofrontal cortex

inhibition. Exposure of PTSD patients to trauma-related material,

or traumatic imagery, results in an increase in fearfulness in

response to stimuli which were not truly life threatening,

possibly due to a failure of orbitofrontal function. In our study,

combat veterans without PTSD (unlike the PTSD patients) were

able to view combat slides and not have an increase in

fearfulness, which we hypothesized is due to active orbitofrontal

inhibition of amygdala function. Shin et al (8) also found a

relative failure of orbitofrontal activation with traumatic

imagery. Our prior PET yohimbine study (6) showed a failure

of orbitofrontal cortex with pharmacologic stress in PTSD.

Rauch et al (7) found increased orbitofrontal activation with

traumatic scripts with their PTSD patients, although this study

did not involve a control group, so it is not possible to determine

whether a greater increase in orbitofrontal blood flow would

be seen in subjects without PTSD. All of these PET studies

found a relative decrease in middle temporal blood flow with

combat slides and sounds in PTSD patients. The middle

temporal cortex also plays a role in the extinction to fear

through inhibition of amygdala function.

The parahippocampus was also found to activate with

traumatic reminders across groups. In our study, it involved a

posterior portion of the parahippocampus, the lingual gyrus,

which has been specifically implicated in visual processing.

The cingulate was found to activate in all studies, an area of

mid-cingulate in our subjects, and anterior cingulateis in the

other groups. Cingulate is a limbic region involved in memory,

emotion, and attention in the service of selection for action.

The fact that some brain regions did not show activation in all

of the studies reviewed above is not surprising, considering

the differences in tasks involved in each study. Future research

may show that traumatic exposure involves specific regions,

regardless of the task, while other regions are task specific. For

instance, other groups (but not our group) found activation in

amygdala and a decrease in left inferior frontal gyrus activity

with traumatic exposure. These findings were seen only with

traumatic imagery, however, and not with presentation of

traumatic pictures (8). It may be that a decrease in activity in

this area (as well as activation of the amygdala) is specific to

the generation of mental images of the traumatic event, and is

not seen during presentation of pictures of traumatic events

or with exposure to the combination of traumatic pictures and

sounds.

Several studies are ongoing in the rapidly expanding area

of functional imaging in PTSD. Semple and colleagues at Case

Western Reserve are studying brain correlates of attention in

patients with PTSD and comorbid substance abuse. Engdahl

and colleagues at the University of Minnesota are using single

photon emission computed tomography (SPECT) to study brain

correlates of script driven imagery in PTSD. Liebowitz and

colleagues at the University of Michigan are looking at brain

activation with SPECT following exposure to combat-related

sounds in PTSD patients and controls. Results of some of these

studies have been presented at scientific meetings.

References

1. Thygesen, P., Hermann, K., & Willanger, R. (1970).

Concentration camp survivors in Denmark: Persecution,

disease, disability, compensation. Danish Medical Bulletin,

17, 65-108.

2. Bremner, J.D., Randall, P.R., Scott, T.M., Bronen, R.A., Delaney,

R.C., Seibyl, J.P., Southwick, S.M., McCarthy, G., Charney,

D.S., & Innis, R.B. (1995). MRI-based measurement of

hippocampal volume in posttraumatic stress disorder.

American Journal of Psychiatry, 152, 973-981.

3. Gurvits, T.G., Shenton, M.R., Hokama, H., Ohta, H., Lasko, N.B.,

Gilbertson, M.W., Orr, S.P., Kikinis, R., Jolesz, F.A., McCarley,

R.W., & Pitman, R.K. (1996). Magnetic resonance imaging

study of hippocampal volume in chronic, combat-related

posttraumatic stress disorder. Biological Psychiatry, 40,

1091-1099. continued on page 9
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NC-PTSD Clinical Quarterly

Post-traumatic psychosocial impairment (PTPI) is not limited

to post-traumatic stress disorder (PTSD). It is also associated

with comorbid psychiatric disorders, affect and identity

dysregulation (1) and conflictual or isolative interpersonal

relationships, vocational and financial stressors, physical health

complaints and illnesses, addiction, and homelessness (2).

Therapeutic and rehabilitative care for PTPI requires a

continuum of coordinated multidisciplinary services ranging

from preventive screening, counseling, and referral to intensive

outpatient and inpatient PTSD treatment. Moreover, intensive

psychosocial case management can be utilized to prevent

chronic deterioration by providing a framework for facilitating

community reintegration.

The Madison model of intensive community-based

psychiatric case management (3) has been adapted and refined

in VA’s Intensive Psychiatric Community Care (IPCC) program

to assist severely mentally ill VA patients to use outpatient and

community resources rather than inpatient crisis services (4).

Several elements from the IPCC model are applicable to PTPI

rehabilitation:

• Frequent regular contact with the client in situ, rather

than only by sparsely scheduled visits to a medical center clinic

or inpatient hospital treatment. Provider visits to home, work,

school, employment office, or neighborhood milieus makes

possible clinical observation of the physical and social

environments that make up a client’s “real life.” Clinician

modeling and coaching of “real-time” social problem solving

can help the client to incorporate symptom-management skills

related to anticipating and coping with anniversary periods,

symbolic trauma cues, or flareups of interpersonal conflict and

hypervigilance. In addition, community visits enable the

clinician to assess and monitor a client’s skills.

• Individualized constructive life planning and fulfillment

of responsibilities: An empathic therapeutic relationship and

therapeutic narrative reconstruction of trauma and its sequelae

are twin cornerstones of posttraumatic treatment, but they do

not guarantee that the client has the requisite commitment,

skills, and resources to actively take responsibility for her or

his life. Posttraumatic avoidance, isolation, hypervigilance, and

fear of loss of control become retraumatizing replications of

the original traumatic helplessness, terror, and hopelessness if

not counterbalanced by present-day fulfillment of personally

significant responsibilities. Thus, frequent in situ problem

solving can be conceptualized as an essential in vivo

component of posttraumatic therapy. Case management is an

opportunity not just for practical problem solving and symptom

management, but for exploration of the spiritual and moral

dilemmas catalyzed by trauma and PTSD (e.g., loss of purpose

or goals). Case management can help the veteran with linkage

to resources that can assist him or her in regaining a sense of

purpose and productivity in day-to-day life (e.g., religious

advisors, vocational counselors).

• Development of a stable safe dwelling, (e.g., transitional

community residences) to reduce the severe strain of

homelessness. As many as one in twelve Vietnam veterans are

homeless or sufficiently itinerant to have no real home (5).

Homelessness among veterans is associated with war

traumatization, and can profoundly exacerbate chronic PTSD

via social isolation, comorbid psychiatric disorders, and

addiction (5). Being homeless exposes the individual to high

risk for additional traumatization (e.g., assault, robbery,

accidents), to stressors that exacerbate trauma and PTSD (e.g.,

malnutrition, malevolent environments, social rejection), and

to many direct and symbolic reminders of past trauma (e.g.,

lack of access to safety). Even the risk of homelessness—which

may be a nagging worry for veterans with compromised work,

financial, and family situations—is a debilitating stressor that

can catalyze and intensify PTSD. Case management makes

residential security and stability a primary focus as a preventive

and therapeutic intervention in its own right.

Granted the potential value of case management, where

can PTSD providers and programs find the resources to provide

such time-intensive care? Innovative inpatient and outpatient

VA PTSD programs across the country are developing models

for retaining their traditional clinic or hospital services while

adding a complementary case management component. Pilot

community outreach programs are being developed as VA

programs ally with one another and with community programs

specializing in social assistance and advocacy. For example,

demonstration projects providing community outreach to

severely disabled veterans with chronic PTSD are being jointly

funded and staffed by the former Psychiatry, Psychology, and

Social Work services in reorganized mental health product lines.

Personnel dollars, although always scarce, have been targeted

to fund several BA or MA level case manager positions

supervised by experienced staff clinicians. Alliances have been

forged between specialized PTSD programs, specialized

Substance Abuse programs, and homeless Domiciliaries to

establish case management services for veterans with chronic

PTSD who are graduating from Domiciliary to community

transitional living placements. Supplemental sponsorship of

part or all of these case management programs has been

undertaken by Veterans Service Organizations. Although no

simple answer exists to the administrative and fiscal challenges

of developing case management services for veterans with

chronic PTSD, the clinical and fiscal viability of this model make

it an idea whose time rapidly appears to be coming.

PRACTITIONER NETWORK

Specialized Care for Chronic Complex

PTSD, Part III: Extended Care Options

Julian Ford, Ph.D.

Deputy Executive Director for Education and Clinical Networking
Volume 7 (4) Fall 1997

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NC-PTSD Clinical Quarterly

CLINICAL TRAINING

PROGRAM

POST TRAUMATIC

STRESS DISORDER

The Education and Clinical Laboratory Education Division

for the National Center for Post Traumatic Stress Disorder

at the Palo Alto CA VAMC, in collaboration with the VA

Employee Education System offers an on-site clinical

training program in the treatment of Post Traumatic Stress.

The training program is approved for categor y 1

continuing medical education credit.

Psychiatrists, psychologists, social workers, nurses,

readjustment counselors, clinical nurse specialists,

occupational and recreational therapists combine to

provide a comprehensive treatment program and an

education experience for the mental health professional

seeking to expand his or her understanding of psychic

trauma and its treatment. The Clinical Training Program

offers a broad range of educational activities including:

* Lectures

* Clinical research observation

* Supervised clinical activities

* Use of multimedia materials

* Group discussions facilitated by staff

Specific training activities include warzone trauma

group treatment, treatment of women veterans, treatment

of sexual assault related PTSD, relapse prevention, cross

cultural treatment issues, assessment and treatment of

families, disaster mental health services, cognition and

PTSD, assessment of PTSD, and observation of psychiatric

assessment.

Training programs are scheduled for a minimum of

one week, though longer programs are available if the

applicant can justify an extended stay. Programs are

scheduled nine times per year, generally on the third week

of the month.

At present time, funding for attendance is not

available from the National Center. There is no fee for the

training program itself, but participants are responsible for

providing their own transportation, lodging, and meals.

Interested applicants are encouraged to explore funding

options through their local medical centers or VA Employee

Education System. For further information, please call

FTS 700-463-2673 or commercial number 650-493-5000,

extension 22673.

4. Bremner, J.D., Randall, P., Vermetten, E., Staib, L., Bronen,

R.A., Mazure, C.M., Capelli, S., McCarthy, G., Innis, R.B., &

Charney, D.S. (1997). MRI-based measurement of

hippocampal volume in posttraumatic stress disorder

related to childhood physical and sexual abuse: A

preliminary report. Biological Psychiatry, 41, 23-32.

5. Stein, M.B., Koverola, C., Hanna, C., Torchia, M.G., & McClarty,

B. (1997). Hippocampal volume in women victimized by

childhood sexual abuse. Psychological Medicine,27, 951-

959.

6. Bremner, J.D., Innis, R.B., Ng, C.K., Staib, L., Duncan, J., Bronen,

R., Zubal, G., Rich, D., Krystal, J.H., Dey, H., Soufer, R., &

Charney, D.S. (1997). PET measurement of central

metabolic correlates of yohimbine administration in

posttraumatic stress disorder. Archives of General

Psychiatry, 54, 246-256.

7. Rauch, S.L., van der Kolk, B.A., Fisler, R.E., Alpert, N.M., Orr,

S.P., Savage, C.R., Fischman, A.J., Jenike, M.A., Pitman, R.A.

(1996). A symptom provocation study of posttraumatic

stress disorder using positron emission tomography and

script driven imagery. Archives of General Psychiatry,

53, 380-387.

8. Shin, L.M., Kosslyn, S.M., McNally, R.J., Alpert, N.M., Thompson,

W.L., Rauch, S.L., Macklin, M.L., & Pitman, R.K. (1997).

Visual imagery and perception in posttraumatic stress

disorder: A positron emission tomographic investigation.

Archives of General Psychiatry, 54, 237-233.

J. Douglas Bremner is a research physician at VA Connecticut

Healthcare System, National Center for PTSD Neuroscience

Division at West Haven. Dr. Bremner is also Director, Trauma

Assessment Unit, Yale Psychiatric Institute and an Assistant

Professor of Diagnostic Radiology and Psychiatry at Yale

University School of Medicine.

NEUROIMAGING STUDIES IN PTSD

References (continued from page 7)

References

1. Herman, J. (1992). Trauma and recovery. New York: Basic

Books.

2. Friedman, M. J., & Rosenheck, R. (1996). PTSD as a chronic

disorder. In S. Soreff (Ed.), The seriously and persistently

mentally ill (pp. 369-389). Seattle: Hogrefe & Huber.

3. Drake, R, McHugo, G, Becker, D., & Anthony, W. (1996). The

New Hampshire study of supported employment for

people with severe mental illness. Journal of Consulting

and Clinical Psychology, 64, 391-399.

4. Rosenheck, R, Neale, M, Leaf, P, & Milstein, R. (1995). Multisite

experimental cost study of intensive psychiatric

community care. Schizophrenia Bulletin, 21, 129-140.

5. Rosenheck, R., & Fontana, A. (1994). A model of

homelessness among male veterans of the Vietnam War

generation. American Journal of Psychiatry,151,421-427.
Volume 7 (4) Fall 1997

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NC-PTSD Clinical Quarterly

Recently, I received a request for consultation regarding

a 28-year-old woman seeking mental health treatment following

a serious procedural error during gynecological surgery. During

the course of the, operation, the surgeon sprayed an acidic rather

than saline solution on her cervix. The patient sustained second

degree burns and was hospitalized for several days. In the

ensuing months, she experienced intermittent pelvic pain and

burning sensations in her vagina. Moreover, she lost interest in

sex and no longer wanted her husband to see her undressed

because she felt deformed. The therapist assigned to the case

was bewildered by these symptoms. He thought the patient

might be suffering from a delusional disorder related to her

beliefs about being deformed and what he viewed as tactile

hallucinations. A colleague with whom he discussed the case

suggested referring the patient to our trauma clinic.

Additional inquiry determined that the woman was experiencing nightmares about the burns, preoccupation about

whether she could function sexually and whether she could

have a successful pregnancy. These and other symptoms

confirmed a diagnosis of PTSD. The initial difficulty in providing

an accurate diagnosis reflects the ongoing struggle

within general psychiatric settings to educate mental health

providers about PTSD and its pertinence following physical

trauma. While general practitioners are beginning to link assault

victimization (e.g., child abuse, rape, muggings, etc.) to PTSD,

there seems to be less consideration of traumatic induced stress

when physical injury occurs, especially those occurring in a

medical setting. This may be because, as an interpersonal event,

there is no intention to do wrong. In this particular case, the

referring therapist viewed the patient as having an unusual

reaction to an event that lacked malice, an event he believed

was mildly distressful. Minimizing the patient’s injury and being

unable to recognize her reactions, he missed PTSD Criteria A

through D, concluding erroneously that she was delusional.

Fortunately, the woman was re-diagnosed and treated

accordingly. Admittedly, accurate diagnoses can be a problem

when the most salient symptom is somatic re-experiencing of

the trauma, particularly when the patient has not yet achieved

a full or the maximum physical recovery. The vital question in

this case was whether or not the woman’s chronic pain had a

partial or substantial organic source.

Both therapist and client need to determine as best as

possible the extent to which somatic symptoms derive from

physical injuries (e.g., pain related scar tissue). Identifying the

source of a physical problem is a prerequisite to identifying

effective treatment for physical recovery. Furthermore,

identifying that some pain is not “just in her head,” may help

the traumatized woman regain a sense of control via an

appropriate health plan. It also reduces uncertainty about her

subjective experiences and delimits the domains of problems

targeted for psychological intervention.

Women who have been traumatized in a medical setting

are typically anxious about returning to a doctor and will need

encouragement and support to do so. Ideally, therapists will

have a referral network of reliable and sensitive physicians, some

of whom may specialize in working with traumatized

individuals. Encouraging the client to bring a friend to the

doctor’s office or having a friend be present during the

evaluation and exam may help reduce the client’s anxiety. The

friend can be an additional “information processor” as the

client’s anxiety may not allow her to assimilate the medical

information being presented. In the case of the burn patient,

the traumatized woman wanted information about the risks

her injuries presented to future pregnancy, but was too upset

to find a doctor to whom she could make these inquiries.

Once accurate information about the client’s physical

condition has been obtained, client and therapist can

realistically assess potential problems and plan ways for coping

with the physical sequelae of the injuries. Coping strategies

should aim to speed physical recovery and enhance the client’s

sense of physical integrity (e.g., exercising regularly,

taking prescribed medications) as well as to increase client’s

sense of predictability and control over her injuries.

Interventions related to the psychological sequelae of the

physical trauma should be considered in tandem with the plan

for physical recovery.

It may be difficult for the client and the therapist to

discriminate somatic symptoms directly related to the injury

from psychosomatic symptoms related to the re-experiencing

phenomenon. However, standard PTSD interventions such as

the emotional processing of the trauma can be implemented

with the expectation that such work will reduce reexperiencing as well as other symptoms, such as nightmares

and intrusive thoughts. In addition, these treatments tend

to reduce generalized anxiety and depression. Thus, there may

be a complementary process in which increased psychological

well-being facilitates physical recovery and physical recovery

reinforces the psychotherapeutic aims of treatment. Lastly, the

therapist should encourage the client to work collaboratively

in an ongoing fashion with the physician. This will help keep

the client and therapist up-to- date with the changing physical

health picture and help the client re-establish a positive working

relationship with physicians.

Marylene Cloitre, Ph.D. is Director of the Anxiety and

Traumatic Stress Programs at Payne Whitney Clinic, New York

Hospital-Cornell Medical Center.

WOMEN AND TRAUMA: A CLINICAL FORUM

Marylene Cloitre, Ph.D.

Somatic Symptoms Associated with

PTSD: Assessment and Intervention
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NC-PTSD Clinical Quarterly

The majority of the initial

randomized trials were published

between 1987-1991 after which

there was a hiatus in research on

drug therapy for PTSD. These early

investigations focused primarily on

tricyclic anti-depressants (TCAs) and

monoamine oxidase inhibitors

(MAOIs). Despite some very

promising leads from these early

trials, results were inconsistent and

too modest to stimulate further

research until selective serotonin

reuptake inhibitors (SSRIs) became

available in recent years.

Trazadone and Nefazadone

Trazadone and nefazadone are serotonergic antidepressants

with both SSRI and 5-HT2 blockade properties. They also exert

alpha-adrenergic blockade and strong sedative effects. Trazadone

has received renewed attention, recently, because of its capacity

to reverse the insomnia caused by SSRI agents such as fluoxetine

and sertraline. A recent open trial (6) indicated that trazadone

may be an effective drug in its own right. Nefazadone is closely

related to trazadone with respect to mechanism of action but

appears to have greater potency. Multi-site trials with nefazadone

are currently in progress.

Monoamine Oxidase Inhibitors (MAOIs)

Phenelzine produced excellent reduction of PTSD

symptoms during an eight week randomized clinical trial, in

two open trials, and in several case reports. It was less effective

than placebo in a four week crossover study and one recent

negative open trial with phenelzin (see 8 for references).

 Southwick et al. (9) reviewed all published findings

(randomized trials, open trials and case reports) concerning

MAOI (phenelzine) treatment for PTSD. They found that MAOIs

produced moderate to good global improvement in 82% of all

patients, primarily due to reduction in reexperiencing

symptoms such as intrusive recollections, traumatic nightmares

and PTSD flashbacks. Insomnia also improved. No

improvement was found, however, in PTSD avoidant/numbing,

PTSD hyperarousal, depressive or anxiety/panic symptoms.

In summary, most published reports show that MAOIs

effectively reduce PTSD symptoms. In practice, however,

most clinicians appear reluctant to prescribe these agents

because of concerns about the risk of administrating these drugs

to patients who may ingest alcohol or certain illicit drugs or

who may not adhere to necessary dietary restrictions.

Tricyclic Antidepressants (TCAs)

There have been three randomized clinical trials with

tricyclic antidepressants involving 124 patients as well as

numerous case reports and open trials (see 10 for references).

Results have been mixed and generally modest in magnitude.

In their analysis of fifteen randomized trials, open trials and

case reports involving TCA treatment for PTSD, Southwick and

associates (9) found that 45% of patients showed moderate to

good global improvement following treatment whereas MAOIs

produced global improvement in 82% of patients who received

them. As with MAOIs, most improvement was due to reductions

in re-experiencing rather than avoidant/numbing or arousal

symptoms. It also appeared that a minimum of 8 weeks of

treatment with either TCAs or MAOIs was necessary to achieve

positive clinical results. Because of their relative lack of potency,

their side effects and their failure to reduce avoidant/numbing

symptoms, TCAs have been replaced by SSRIs as first-line 

drugs in PTSD treatment.

PHARMACOTHERAPY FOR PTSD:

A STATUS REPORT

Matthew J. Friedman, M.D., Ph.D.

Antiadrenergic agents: Propranolol, Clonidine and

Guanfacine

Although it is well established that adrenergic

dysregulation is associated with chronic PTSD (see 1, 2 for

details and references), there has been little research and no

randomized clinical trials with either the beta adrenergic

antagonist, propranolol, or with the alpha-2 agonist, clonidine

despite the fact that positive findings with both drugs were

Matthew J. Friedman,

M.D., Ph.D.

In general, investigators have been

impressed by the capacity of SSRIs to

reduce the numbing symptoms of PTSD

since other drugs tested thus far, do

not seem to have this property.

reported as early as 1984 (3). It should be noted that positive

reports of open trials with both drugs continue to be published.

In addition, preliminary success has been achieved with the

adrenergic alpha-2 agonist, guanfacine which has a longer halflife (18-22 hours) than clonidine.

Selective Serotonin Reuptake Inhibitors

SSRIs have revolutionized pharmacotherapy and are

beginning to emerge as the first choice of clinicians treating PTSD

patients. In the only published randomized clinical trial of an

SSRI, fluoxetine produced a marked reduction in overall PTSD

symptoms, especially with respect to numbing and arousal

symptoms (4).

In addition, a number of open trials and case reports have

appeared concerning fluoxetine, sertraline, and fluvoxamine (see

5 for references). In general, investigators have been impressed

by the capacity of SSRIs to reduce the numbing symptoms of PTSD

since other drugs tested thus far, do not seem to have this property.
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NC-PTSD Clinical Quarterly

Benzodiazepines

Because of their proven anxiolytic potency,

benzodiazapines have been prescribed widely for PTSD patients

in some clinical settings. There are only four publications on

benzodiazepine treatment for PTSD. In a randomized clinical

trial (11) and two open label studies, alprazolam and clonazepan

were no better than placebo in reducing core PTSD symptoms

although modest reductions in generalized anxiety were

observed.

Anticonvulsants

It has been proposed that following exposure to

traumatic events, limbic nuclei become kindled or sensitized

so that, henceforth, they exhibit excessive responsivity to less

intense trauma-related stimuli (12). Arguing from this theoretical

perspective, there have been several open trials of

anticonvulsant/antikindling agents. In five studies carbamazepine produced reductions in reexperiencing and arousal

symptoms, while in three studies, valproate produced

reductions in avoidant/numbing and arousal (but not

reexperiencing) symptoms (see 13 for references).

most of these symptoms will respond to anti-adrenergic or

antidepressant drugs and that antipsychotic medications should

only be prescribed for the rare PTSD patient who exhibits frank

paranoid behavior, overwhelming anger, aggressivity, psychotic

symptoms, fragmented ego boundaries, self-destructive behavior

and frequent flashback experiences marked by auditory or

visual hallucinations of traumatic episodes (15).

Conclusions

Most drugs tested in PTSD were developed as

antidepressants and later shown to have efficacy against panic

and other anxiety disorders. Given high comorbidity rates

between PTSD and such disorders and given the symptomatic

overlap between PTSD, major depression, panic disorder and

generalized anxiety disorder (16), it seems reasonable to have

tested such drugs in PTSD. On the other hand, PTSD appears

to be distinctive in a number of ways. First, it seems to be

more complex than affective or other anxiety disorders; and

second, its underlying pathophysiology appears to be

qualitatively different. For example, abnormalities in the

hypothalamic-pituitary-adrenocortical axis (HPA) system are

markedly different than those present in major depressive

disorder despite similarities in clinical phenomenology. In short,

the time has come to develop and test drugs that have been

developed specifically for PTSD rather than to recycle

pharmacological agents that have been developed to treat

affective or other anxiety disorders.

From this perspective, promising future directions might

be to test drugs that antagonize the actions of Corticotropin

Releasing Factor (CRF), the substance that appears to play such

a central role in the stress response (17). Another promising

direction for future research might be to design drugs that can

reverse the dissociative and amnestic symptoms associated with

PTSD (18).

Finally, there is certainly a need for further research on

adrenergic alpha-2 agonists such as clonidine and guanfacine,

on SSRIs and other serotonergic agents, and on anticonvulsants

with anti-kindling/sensitization properties. It appears that we

have barely begun to explore a variety of exciting

pharmacotherapeutic approaches for PTSD. We can all look

forward to important research findings in the coming years.

References

1. Friedman, M.J., Charney, D.S., & Deutch, A.Y. (Eds). (1995).

Neurobiological and clinical consequences ofstress:From

normal adaptation to PTSD. Philadelphia: LippincottRaven Press.

2. Yehuda, R. & McFarlane, A.C. (Eds.). (1997). Psychobiology

of posttraumatic stress disorder. Annals of the NewYork

Academy of Sciences,821. New York: New York Academy

of Sciences.

The time has come to develop and test

drugs that have been developed

specifically for PTSD rather than to

recycle pharmacological agents that

have been developed to treat affective

or other anxiety disorders.

Narcotic Antagonists

There is growing evidence that the endogenous opioid

system is dysregulated in PTSD patients. Spurred by the

hypothesis that emotional numbing in PTSD might result from

excessive endogenous opioid activity, an open trial of the

narcotic antagonist, nalmefene, was conducted (14) in which

some Vietnam veterans with PTSD exhibited reduced numbing

whereas the others showed either no improvement or a

worsening of anxiety, panic and hyperarousal symptoms.

Antipsychotics

Before the empirical and conceptual advances achieved

during the past 15 years, PTSD patients were often considered

to have psychotic disorder by treating physicians. Indeed the

intense agitation, hypervigilance (that sometimes appeared to

be paranoid delusions), impulsivity, and dissociative states

seemed to call for neuroleptic treatment. It now appears that
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3. Kolb, L.C., Burris, B.C., & Griffiths, S. (1984). Propranolol

and clonidine in the treatment of the chronic posttraumatic stress disorders of war. In B.A. van der Kolk

(Ed.), Post-traumatic stress disorder: Psychological and

biological sequelae (pp.97- 107). Washington DC:

American Psychiatric Press.

4. van der Kolk, B.A., Dryfuss, D., Michaels, M. et al. (1994).

Fluoxetine in post-traumatic stress disorder. Journal of

Clinical Psychiatry, 55, 517-522.

5. Friedman, M.J. (1996). Biological alterations in PTSD:

Implications for pharmacotherapy. In E. Giller &

L.Weisaeth (Eds.), Bailliere’s clinical psychiatry:

International practice and research:Post-traumatic stress

disorder, Volume 2(2), 245-262. London: Bailliere Tindall.

6. Hertzberg, M.A., Feldman, M.E., Beckham, J.C. et al. (1996).

Trial of trazadone for posttraumatic stress using a multiple

baseline group design. Journal of Clinical Psychopharmacology, 16, 294-298.

8. DeMartino, R., Mollica, R.F., & Wilk, V. (1995). Monoamine

oxidase inhibitors in posttraumatic stress disorder.

Journal of Nervous and Mental Disease, 183, 510-515.

9. Southwick, S. M., Yehuda, R., Giller, E.L. et al. (1994). Use of

tricyclics and monoamine oxidase inhibitors in the

treatment of PTSD: A quantitative review. In M.M.

Murburg (Ed.), Catecholamine function in post-traumatic

stress disorder: Emerging concepts (pp. 293-305).

Washington, DC: American Psychiatric Press.

10. Ver Ellen P.& D.P. van Kammen. (1990). The biological

findings in post-traumatic stress disorder: a review.

Journal of Applied Social Psychology, 20(21,pt1), 1789-

1821.

11. Braun, P., Greenberg, D., Dasberg, H. et al. (1990). Core

symptoms of posttraumatic stress disorder unimproved

by alprazolam treatment. Journal of Clinical Psychiatry,

51, 236-238.

12. Post, R.M., Weiss, S.R.B., & Smith, M.A. (1995).

Sensitization and kindling: Implications for the evolving

neural substrate of PTSD. In M.J. Friedman et al. (Eds.),

Neurobiological and clinical consequences of stress:

From normal adaptation to PTSD (pp. 203-224).

Philadelphia: Lippincott-Raven Press.

13. Friedman, M.J. & S.M. Southwick. (1995). Towards

pharmacotherapy for PTSD. In M.J. Friedman et al. (Eds.),

Neurobiological and clinical consequences of stress:

From normal adaptation to PTSD (pp. 465-481).

Philadelphia: Lippincott-Raven Press.

14. Glover, H. (1993). A preliminary trial of nalmefane for the

treatment of emotional numbing in combat veterans with

post-traumatic stress disorder. Israel Journal of Psychiatry

Related Sciences, 30, 255-263.

15. Friedman, M.J. (1991). Biological approaches to the

diagnosis and treatment of post-traumatic stress disorder.

Journal of Traumatic Stress, 4, 67-91.

16. Friedman, M.J. & R. Yehuda. (1995). PTSD and co-morbidity:

Psychobiological approaches to differential diagnosis.

In M.J. Friedman et al. (Eds.), Neurobiological and clinical

consequences ofstress: From normal adaptation to PTSD

(pp. 429-446). Philadelphia: Lippincott-Raven Press.

17. Stout, S.C., Kilts, C.D., & Nemeroff, C.B. (1995).

Neuropeptides and stress: Preclinical findings and

implications for pathophysiology. In M.J. Friedman et al.

(Eds.), Neurobiological and clinical consequences of

stress: From normal adaptation to PTSD (pp. 103-123).

Philadelphia: Lippincott-Raven Press.

18. Krystal, J.H., Bennett, A., Bremner, J.D. et al. (1995). Toward

a cognitive neuroscience of dissociation and altered

memory functions in post-traumatic stress disorder. In

M.J. Friedman et al. (Eds.), Neurobiological and clinical

consequences ofstress:From normal adaptation to PTSD

(pp. 239-270). Philadelphia: Lippincott-Raven Press.

Matthew J. Friedman is a pharmacologist turned psychiatrist

who has been actively concerned about PTSD since 1974.

His current positions are Executive Director of the National

Center for PTSD and Professor of Psychiatry and

Pharmacology at Dartmouth Medical School. Throughout

his professional career, he has tried to combine strong

concerns about psychiatric care with a scientific commitment

to understand the etiology, diagnosis, and treatment of

clinical phenomena. As a result, his publications and

presentations span a variety of topics (in addition to PTSD)

such as biological psychiatry, psychopharmacology, and

clinical outcome research. Dr. Friedman was one of the first

to publicize research on the biological alterations associated

with PTSD and to clarify the implication of such research for

rational pharmacotherapy for this disorder. Lastly, Dr.

Friedman was President of the International Society of

Traumatic Stress Studies, 1995-96.
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During situations of life threat

animals and humans mobilize

multiple internal neurobiologic

resources so as to maximize their

chances of survival. Numerous brain

regions and neurotransmitter

systems become activated in parallel

when the organism attempts to deal

with danger. One of the most

important systems to become

activated during stress and threat is

the sympathetic or autonomic

nervous system. This system plays a

central role in the organism’s ability

of epinephrine and norepinephrine

in the urine of combat veterans with

PTSD compared to individuals with

other psychiatric diagnoses and with

normal controls, veterans with PTSD

excreted significantly more

adrenaline and noradrenaline.

Twenty years after combat, levels of

excreted epinephrine and

norepinephrine were still high.

Similar findings have been reported

in most but not all studies involving

urine catecholamines and

traumatized populations. In the first

SITUATIONS OF THREAT

Steve M. Southwick, M.D., and Rachel Yehuda, Ph.D.

to fight a danger or to flee from that danger — the classic fight/

flight response. In threatening situations the sympathetic

nervous system tends to discharge as a unit. Coordinated

sympathetic discharge accelerates heart rate and increases

blood pressure allowing for greater perfusion of muscles and

blood loss; and mobilizes blood glucose and oxidation of

various food products for the purpose of increasing energy

supply to skeletal musculature (1).

Epinephrine (adrenalin) and norepinephrine

(noradrenalin) are two important sympathetic nervous system

neurotransmitters that have been studied extensively in

traumatized animals and humans. In addition to their

involvement in the above sympathetic nervous system

functions, these neurotransmitters play a central role in the

development of fear as well as the organism’s ability to turn its

attention toward a feared stimulus, selectively focus on it, and

then respond to it. Further, they appear to facilitate the

encoding and consolidation of memory for events that occur

during states of arousal and fear (2,3).

Heightened sympathetic nervous system arousal

repeatedly has been documented in combat veterans suffering

from chronic PTSD (4-6). When exposed to visual and auditory

reminders of combat (such as war movies or the sounds of gun

fire), veterans with PTSD, as a group, react with higher

increases in heart rate and blood pressure than non-exposed

controls and combat veterans who have anxiety disorders other

than PTSD (4). These physiologic responses occur in response

to stimuli that remind the veteran of his own traumatic

experiences but not in response to stimuli related to traumas

that have not been experienced personally. Thus, combat

veterans with PTSD show increased physiological responses

to films of combat but normal responses to films of automobile

accidents. These findings are consistent with a model of PTSD

stimuli present at the time of the trauma become conditioned

to fear so that even previously neutral stimuli now elicit

exaggerated behavioral and psychophysiological responses

(5,6). To investigate the neurochemical correlates of these

psychophysiologic reactions, a number of investigators have

studied EPI, NE and alpha adrenergic receptors in patients with

PTSD. Kosten et al. (7) was the first to observe increased levels

study to investigate the relationship between psychophysiologic

hyper-reactivity and adrenergic function, McFall et al. (8) found

a parallel rise in blood pressure, heart rate, subjective distress

and plasma epinephrine during and after the viewing of a

combat film suggesting that hyperreactive physiologic

responses were indeed related to elevations of circulating

epinephrine.

For epinephrine or norepinephrine to have a

physiological effect they must first attach to adrenergic

receptors. Once attached, a cascade of biochemical events is

initiated, ultimately leading to a specific reaction. In essence,

adrenergic receptors translate the biochemical message of

adrenalin. Perry et al. (9), in a study of adrenergic receptors on

the surface of platelets (circulating blood elements), found a

40% decrease in receptor number on the platelets of combat

veterans with PTSD compared to healthy controls. This decrease

was most likely a response to chronic elevation of circulating

epinephrine and norepinephrine.

 To directly assess adrenergic responsivity of the central

nervous system, Southwick et al. (10) administered IV

yohimbine to 20 Vietnam combat veterans and 18 healthy

controls. Yohimbine is an alpha-2 adrenergic receptor

antagonist that activates noradrenergic neurons by blocking

the alpha-2-adrenergic autoreceptor, thereby increasing the

release of norepinephrine. Yohimbine caused full blown panic

attacks in 70% and flashbacks in 40% of combat veterans with

PTSD. In contrast, none of the control subjects experienced

either a panic attack or a flashback. Additionally, subjects with

PTSD had greater increases in heart rate and a greater than

two-fold increase in MHPG, the breakdown product of

norepinephrine. These findings suggest that at least a subgroup

of patients with PTSD have increased sensitivity of the

noradrenergic system. The fact that equivalent doses of

yohimbine caused significantly greater increases in anxiety,

vigilance, arousal, intrusive traumatic memories, heart rate and

MHPG among the combat-traumatized subjects compared to

healthy controls is consistent with a behavioral sensitization

model of PTSD. Behavioral sensitization refers to an

enhancement of response magnitude following repeated

presentations of stress-related stimuli. In a sensitized system

Steve M. Southwick, M.D. Rachel Yehuda, Ph.D.
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NC-PTSD Clinical Quarterly

one would expect that the same stimulus, over time, would

produce responses of increasing magnitude or that lower grade

stimuli would sustain the system in a state of heightened

responsivity.

In summary, a relatively large number of physiologic and

biochemical studies now support the notion that a subgroup

of traumatized individuals with PTSD have increased

responsivity of the sympathetic nervous system that is most

easily detected when the individual is stressed. In other words,

for some individuals with PTSD the sympathetic nervous system

appears to over respond to a variety of stimuli even many years

after having experienced an overwhelming trauma. The

individual continues to act psychologically and biologically as

if the danger is still present even though the event may have

occurred in the distant past. It has been hypothesized that a

sensitized sympathetic nervous system may contribute to a

number of core PTSD symptoms including hypervigilance, poor

concentration, insomnia, irritability, exaggerated startle, and

perhaps even intrusive memories. Being irritable and on edge

makes it difficult to interact with family members, friends,

coworkers and employers. To quiet these symptoms of

hyperarousal, PTSD patients often withdraw emotionally and

some use substances, particularly central nervous system

depressants that suppress peripheral and central catecholamine

function. In addition to the sympathetic nervous system, the

hypothalamic-pituitary-adrenal axis (HPA) is a critical

component of the neurobiologic response to stress. However,

unlike epinephrine and norepinephrine which prepare the

organism for action, cortisol appears to serve a catabolic

restorative function. When the individual is stressed,

corticotrophin releasing factor (CRF) is secreted from the

hypothalamus. CRF then stimulates the release of

adrenocorticotropic hormone from the pituitary gland and

cortisol from the adrenal gland. Cortisol’s primary function is

to terminate the neural defensive reaction (e.g., including those

turned on by the catacholamines) that has been initiated by

stress (14).

Most animals and human paradigms of stress have

demonstrated increased levels of cortisol in response to

increased magnitude of stress. However, studies in traumatized

humans with PTSD have found low cortisol levels and other

HPA abnormalities suggestive of a heightened sensitivity of this

axis to stressful stimuli. Because these abnormalities typically

are absent in trauma survivors without PTSD, it appears that

PTSD may be a specific reaction to stress that differs from classic

or normal stress reactions.

The first HPA-axis studies in PTSD showed that the

amount of cortisol excreted in the urine over a 24-hour period

was lower in combat veterans with PTSD than in normal

controls or psychiatric patients with major depression,

schizoaffective disorder, bipolar disorder, or schizophrenia (15).

These 24-hour urine findings have been replicated in all but

two studies. Urine cortisol has been found to be low in combat

veterans regardless of comorbid diagnoses such as substance

abuse or major depression (16). Circulating cortisol levels in

the blood also has been reported as lower than normal in trauma

victims with PTSD. In an epidemiological study of over 2000

Vietnam veterans, the 293 with PTSD had lower morning plasma

cortisol levels than the remainder without PTSD (17). In a 24-

hour circadian study of plasma cortisol levels, Yehuda et al. (18)

recently reported significantly lower cortisol levels particularly

in the very early morning and late evening hours in combat

veterans with PTSD compared to depressed patients and normal

controls.

Like norepinephrine, cortisol must bind to receptors in

order to exert a physiological effect. Three studies of combat

veterans and one study of adult survivors of severe childhood

sexual abuse have found larger numbers of glucocorticoid

receptors in traumatized subjects than in non-traumatized

normal controls (18). Having a larger number of glucocorticoid

receptors allows more cortisol to bind to the receptor, least

hypothetically, and increases the sensitivity of the system.

Indeed, this possibility has been confirmed using the low-dose

dexamethasone suppression test. Dexamethasone is a synthetic

hormone that mimics the effects of cortisol. When

dexamethasone is administered, it binds to cortisol receptors,

and activates the negative feedback system. As a result, the

body’ s own cortisol levels become lower. In trauma survivors

with and without PTSD, cortisol levels following

dexamethasone have been reported as lower than normals and

other psychiatric diagnostic groups (19, 20). This lower cortisol

response reflects a more sensitive system where cortisol has

an exaggerated inhibitory effect on HPA-axis function. Thus,

HPA axis alterations in PTSD resemble catecholamine alterations

in that both systems appear to be sensitized (18).

For some individuals with PTSD the

sympathetic nervous system appears

to over respond to a variety of stimuli

even many years after having

experienced an overwhelming trauma.

The individual continues to act

psychologically and biologically as if

the danger is still present even though

the event may have occurred

in the distant past.

It is important to point out that the sensitivity of a system

cannot be measured simply by knowing whether ambient

hormone or neurotransmitter levels are high or low. This is

true of both the HPA and catecholamine systems. It is only by

provoking the system through experimental, environmental or

pharmacologic manipulations that one can truly know whether

a system is more sensitive or less sensitive. In almost every

such test that has been performed in PTSD, an increased

sensitivity has been observed. Thus, sensitization may involve

more neurochemical systems than those that have been

mentioned in this review.

There has been an intriguing observation in recent years

suggesting that the cortisol response in the acute aftermath of

trauma is actually lower — not higher — in the subset of trauma

survivors who go on to develop PTSD, or who are at greater

risk for the subsequent development of PTSD. McFarlane et al.

(20) demonstrated that motor vehicle accident victims who

had PTSD at 6 months following a trauma actually had lower

cortisol levels in the immediate aftermath of the accident

compared to those who did not develop psychiatric disorders
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NC-PTSD Clinical Quarterly

and those who developed a major depression at 6 months.

Resnick et al. (21) reported that women with a prior assault

history who were at greater risk for the subsequent

development of PTSD also showed an attenuated rather than

an exaggerated response to the rape. This means that the

behavioral sensitization that appears in chronic PTSD seems

to develop very early on, and may even be a predisposing risk

factor for those who subsequently develop a chronic disorder

in response to trauma.

It is of interest to speculate how the low cortisol levels

in the immediate aftermath of a traumatic event may affect the

catecholamine system. Quite simply, if cortisol’s function is to

shut down biological responses, but for some reason does not

do so immediately after the trauma then catecholamine levels

may remain elevated for too long during a critical time and go

on to affect memory, mood, and other psychological and

physiological processes. This is an exciting area of investigation

which should yield fruitful information in the years to come.

In this review of neuroendocrine alterations in PTSD we have

focused on catecholamines and the HPA-axis. It is important

to note that multiple other neuroendocrine systems also may

be affected by trauma. For example, in trauma victims with

PTSD there is some evidence for abnormalities in the

endogenous opiate, serotonin and thyroid systems. From a

neurobiological perspective PTSD appears to be a multisystem

disorder that effects numerous aspects of the organism’s

complex response to trauma (11, 12). As advances in biomedical technology are made, more sophisticated investigations

of the biology of PTSD will be possible. Further, with a better

understanding of the neuroendocrine underpinnings of PTSD,

it may be possible to develop more effective and specific

treatments for this often devastating disorder.

References

1. Mountcastle, Z.B. (1973). Medical physiology, 13th ed. St. Louis:

Mosbey Publishing.

2. Aston-Jones, G., Valentino, R., Van Bockstaele. (1994). Locus

coeruleus, stress, and PTSD: Neurobiological and clinical

parallels. In M. Murburg, (Ed.), Catecholamine function in post

traumatic stress disorder: Emerging concepts (pp. 17-62).

Washington, DC: APA Press.

3. McGaugh, J.L. (1990). Significance and remembrance: The role of

neuromodulatory systems. Psychological Science, # 15-25.

4. Orr, S.P. (1997). Psychophysiologic reactivity to trauma-related

imagery in PTSD: Diagnostic and theoretical implications of

recent findings. In R. Yehuda & A.C. McFarlane (Eds.),

Psychobiology of posttraumatic stress disorder. Annals of the

NewYorkAcademy of Sciences, 821, 114-124. New York: New

York Academy of Sciences.

5. LeDoux, J.E. (1995). Setting stress into motion: Brain mechanisms

of stimulus evaluation. In M.J. Friedman et al. (Eds.),

Neurobiological and clinical consequences of stress: From

normal adaptation to PTSD (pp. 125-134). Philadelphia:

Lippincott-Raven Press.

6. Keane, T.M., Zimering, R.T., & Caddell, J.M. (1985). A behavioral

formulation of PTSD in Vietnam veterans. The Behavior

Therapist 8, 9-12.

7. Kosten, T.R., Mason, J.W., Giller, E.L., et al. (1987). Sustained

urinary norepinephrine and epinephrine elevation in posttraumatic stress disorder. Psychoneuroendocrinology,12, 13-20.

8. McFall, M., Murburg, M., Ko, G., et al. (1990). Autonomic response

to stress in Vietnam combat veterans with post-traumatic stress

disorder. Biological Psychiatry, 27, 1165-1175.

9. Perry, B.D., Giller, E.L., & Southwick, S.M. (1987). Altered

platelet alpha-2-adrenergic binding sites in post-traumatic

stress disorder. American Journal of Psychiatry,144, 1511-1512.

10. Southwick, S.M., Krystal, J.H., Morgan, A.C., et al. (1993).

Abnormal noradrenergic function in post-traumatic stress

disorder. Archives General Psychiatry, 50, 266-274.11.

11. Southwick, S.M., Yehuda, R., & Morgan, C.A. (1995). Clinical

studies of neurotransmitter alterations in Post-Traumatic

Stress Disorder. In M.J. Friedman et al. (Eds.), Neurobiological

and clinical consequences of stress: From normal adaptation

to PTSD (pp. 335-349). Philadelphia: Lippincott-Raven Press.

12. Charney D., Deutch A., Krystal, J. et al. (1993). Psychobiologic

mechanisms of posttraumatic stress disorder. Archives

General Psychiatry, 50, 294-305.

13. Murburg, M.M. (1994). Catecholamine function in posttraumatic

stress disorder:Emerging concepts. Washington, DC: APA Press.

14. Yehuda, R., Giller, E.L., Levengood, R.A., Southwick, S.M., & Siever,

L.J. (1995). Hypothalamic-pituitary-adrenal functioning in

post-traumatic stress disorder: Expanding the concept of the

stress response spectrum. In M.J. Friedman et al. (Eds.),

Neurobiological and clinical consequences of stress: From

normal adaptation to PTSD (pp. 351-365). Philadelphia:

Lippincott-Raven Press.

15. Mason, J.W., Giller, E.L., Kosten, T.R., Ostroff, R.B., & Podd, L.

(1986). Urinary-free cortisol levels in post-traumatic stress

disorder patients. Journal of Nervous & Mental Disease,

174, 145-159.

16. Yehuda. R., Southwick, S.M., Nussbaum, G., Giller, E.L., & Mason,

J.W. (1991). Low urinary cortisol excretion in PTSD. Journal

of Nervous & Mental Disease, 178, 366-369.

17. Boscarino, J.A. (1996). Posttraumatic stress disorder, exposure

to combat, and lower plasma cortisol among Vietnam veterans:

findings and clinical implications. Journal of Clinical &

Consulting Psychology, 64, 191-201.

18. Yehuda, R. (1997). Sensitization of the hypothalamic-pituitaryadrenal axis in posttraumatic stress disorder. In R. Yehuda &

A.C. McFarlane (Eds.), Psychobiology of posttraumatic stress

disorder. Annals of the New York Academy of Sciences, 821,

57-75. New York: New York Academy of Sciences.

19. Yehuda, R., Southwick, S.M., Krystal, J.M. et al. (1993). Enhanced

suppression of cortisol following dexamethasone

administration in combat veterans with posttraumatic stress

disorder and major depressive disorder. Archives General

Psychiatry, 50, 150-183.

20. McFarlane, A.C., Atchison, M., Yehuda, R. (1997). The acute stress

response following motor vehicle accidents and its relation to

PTSD. In R. Yehuda & A.C. McFarlane (Eds.), Psychobiology

of posttraumatic stress disorder. Annals of the New York

Academy of Sciences, 821,437-441. New York: New York

Academy of Sciences.

21. Resnick, H.S., Yehuda, R., & Acierno, R. (1997). Acute post-rape

plasma cortisol, alcohol use, and PTSD symptom profile among

recent rape victims. In R. Yehuda & A.C. McFarlane (Eds.),

Psychobiology of posttraumatic stress disorder. Annals of the

NewYorkAcademy of Sciences, 821, 433-436. New York: New

York Academy of Sciences.

Steve M. Southwick is an Associate Professor Psychiatry, Yale

University School of Medicine and Director of the Post

Traumatic Stress Disorder Program VA Connecticut

Healthcare System, Clinical Neuroscience Division of the

National Center for PTSD.

Rachel Yehuda is an Associate Professor Psychiatry, Mount

Sinai Medical School and Director of the Post Traumatic Stress

Disorder Program, Bronx, VA. 
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NC-PTSD Clinical Quarterly

NC-PTSD Clinical Training Program (Menlo Park)

The Menlo Park Education Team, in collaboration with the Employee Education Network, System offers a oneweek on-site advance PTSD Clinical Training Program. Training consists of lectures, workshops, group

observations, and individual meetings with clinicians.

Telephone (650) 493-5000 ext. 22673.

PTSD Assessment Library

Available upon request are selected instruments from our library of assessment and program evaluation tools

(with accompanying articles), together with templates describing over 100 trauma-related measures courtesy of

Beth Stamm, Ph.D., and Sidran Press. Telephone (650) 493-5000 ext. 22477.

PTSD Article Library

A helpful set of key articles on aspects of PTSD is available to VA or Vet Center clinicians free of charge.

Telephone (650) 493-5000 ext. 22673.

PTSD Video Library

The Menlo Park Education Team maintains a small videotape lending library exploring topics related to PTSD

diagnosis, evaluation, and treatment. Videotapes may be borrowed free of charge.

Telephone (650) 493-5000 ext. 22673.

PTSD Program Liaison and Consultation

The Menlo Park Education Team can help VA health care professionals locate needed resources. Services may

include assistance in locating relevant articles, locating resource persons, or problem-solving. Staff are available

to consult in the areas of PTSD Diagnosis and Treatment, Program Development and Design, Women and Trauma,

Relapse Prevention, and with other PTSD-related concerns. Telephone (650) 493-5000 ext. 22977.

National Center for PTSD Web Page

The NCPTSD Home Page provides up-to-the-minute description of activities of the National Center for PTSD and

other trauma related information. The world wide web address is:

http://www.dartmouth.edu//dms//ptsd/

PILOTS Database

PILOTS, the leading electronic index to the world’s literature on PTSD and other mental health consequences of

exposure to traumatic events, provides clinicians and researchers with the ability to conduct literature searches

on all topics relevant to PTSD. Telephone (802) 296-5132.

NC-PTSD Research Quarterly

The Research Quarterly reviews recent scientific PTSD literature. Telephone (802) 296-5132

for subscription information.

Disaster Mental Health Training and Consultation

Education staff provide training in disaster mental health services, including team development, interfacing with

other agencies, on-site and off-site interventions, debriefing, and psychoeducational and treatment interventions

with disaster survivors and workers. Telephone (650) 493-5000 ext. 22494 or email:

bhh@icon.palo-alto.med.va.gov

Conferences and Training Events

The Menlo Park Education Team provides consultative support for the development of training in PTSD. Services

include assistance in finding faculty and designing program content. Telephone (650) 493-5000 ext. 22673.

EDUCATION & SUPPORT SERVICES FOR

SPECIALIZED PTSD PROGRAMS
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DISASTER MENTAL HEALTH/CRITICAL

INCIDENT TRAINING UPDATE

To prepare VHA and RCS mental health providers to respond to local and national critical

incidents/disasters, the National Center for PTSD and Readjustment Counseling Service,

in collaboration with the Emergency Management Strategic Health Care Group, have been

providing a two day disaster mental health/critical incident training. To date, this Employee

Education Service sponsored training has taken place in Dallas, Boston/Providence

area (Norwood), Memphis, Denver, and Philadelphia. Training is scheduled for

Pittsburgh and Portland.

Participants who take the training will be able to:

• assess the impact of disaster/critical incidents on individuals,

workers, organizations, communities;

• assess the factors associated with adaptation to disaster and critical

incident-related trauma;

• identify at-risk groups and individuals in the wake of disaster and

critical incidents;

• target phase-specific interventions to match needs of specific atrisk groups and individuals;

• identify essential operational guidelines for applying DMH/critical

incident interventions;

• identify essential operational guidelines for DMH/critical incident

provider stress management;

• apply an overview knowledge of the federal response plan to

team or practitioner liaisons to other disaster response organizations.

Participants have been VA Medical Center, Clinic, or Vet Center mental health professionals

within a VISN who are or plan to be actively involved in acute mental health response to

critical incidents or disasters. Ideally, participants have experience in critical incident

response (e.g., hospital or community post-trauma debriefings) and a familiarity with

basic concepts of trauma, critical incident stress, and PTSD.

Course enrollment: Minimum 25, maximum 50 participants.

FOR FURTHER INFORMATION PLEASE CONTACT:

BRUCE H. YOUNG, LCSW

NC-PTSD DISASTER SERVICES COORDINATOR

(650) 493-5000 Ext. 22494

Email: bhh@icon.palo-alto.med.va.gov

FTS: 1-700-463-2494
Volume 7 (4) Fall 1997

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NC-PTSD Clinical Quarterly

ATTENTION READERS

(SUPERINTENDENT OF DOC)

Due to budget cutbacks, we are no longer able to provide free issues of National Center

for PTSD Clinical Quarterly to readers not employed by the federal government. You can,

however, continue to receive National Center for PTSD Clinical Quarterly at nominal cost

by using the Superintendent of Documents order form below.

This change will ensure we have the funds to continue keeping you informed about

trauma-related topics important in clinical practice, helping to bridge the gap between

scientists and practitioners. We will continue to report on progress in assessing and treating

post-traumatic stress disorder.

We also will continue the Clinical Quarterly’s regular columns exploring new directions

in the field, issues specific to women’s care, and clinical networking.

Federal employees will continue to receive the National Center for PTSD Clinical

Quarterly at no cost. If you’ve been dropped from our distribution list because your federal

agency isn’t included in your mailing address, send a note requesting reinstatement to John

Aboytes, Education Division, National Center for PTSD, VA Palo Alto Health Care System,

795 Willow Road (323E112), Menlo Park, CA 94025. Be sure to use your agency letterhead.

If you’re not employed by the federal government, make sure you don’t miss a single

issue of National Center for PTSD Clinical Quarterly. Just complete and return the order

form to begin your annual subscription today.
Volume 7 (4) Fall 1997

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NC-PTSD Clinical Quarterly