POSTTRAUMATIC STRESS DISORDER
From Cleveland Clinic’s Posttraumatic Stress Disorder Symposium
Steven M. Southwick, MD, PhD, Professor of Psychiatry, Yale Child Study Center, Yale University School of
Medicine, and Deputy Director, Clinical Neuroscience Division of the National Center for PTSD, Boston, MA
| SYMPTOMS, PREVALENCE, AND RISK
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| Definition: uncontrollable stress primary etiologic factor; criteria—exposure to traumatic event that involves actual
or threatened death or serious injury to self or others; witnessing or learning about traumatic event also may
initiate posttraumatic stress disorder (PTSD); response must include intense fear, helplessness, or horror;
chronic—symptoms last ≥3 mo (must be present ≥30 days); delayed onset—symptoms begin ≥6 mo after trauma
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| Symptom clusters: reexperiencing symptoms—intrusive distressing memories; recurrent nightmares; flashbacks;
intense psychologic and physiologic distress following reminders of trauma; arousal symptoms—inability to modulate
arousal causes sleep disturbance, irritability, and angry outbursts; individual often has difficulty concentrating;
hypervigilance, in attempt to regain feeling of safety, may become central to lifestyle; exaggerated startle
response; avoidance symptoms—person tries to avoid thoughts, feelings, conversations, activities, places, or people
associated with trauma or that arouse recollections of trauma; amnesia about aspects of traumatic event; decreased
interest in everyday activities; feeling detached or estranged from others; restricted range of emotions;
sense of foreshortened future; associated features—strained relationships; reduced ability to function in work environment;
changes in personality; altered world view; repetitive reenactments (in hope of changing outcome); survivor
guilt
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| Prevalence and comorbidity: rate of developing PTSD varies with type of trauma; 49% of rape victims, 23% of victims
of other forms of sexual assault, 15% of individuals who have been shot or stabbed, and ≈4% of survivors of natural
disasters develop PTSD; 8% lifetime prevalence; \>50% of people who develop PTSD still have symptoms 1 yr later;
psychiatric comorbidities—almost 50% of patients with PTSD also meet criteria for major depression; \>50% of men
and ≈27% of women with PTSD meet criteria for alcohol abuse
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| Risk factors: severity of stressor; accompanying physical injury; exposure to deliberate manmade trauma; exposure
to gross body disfigurement; severity of initial stress reaction (highly predictive; important for triage); younger age;
fewer social supports; history of trauma or abuse; personal or family history of psychiatric disorders
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| Neurobiology of stress response: broad array of stressors elicit similar neurobiologic responses; long-term stimulation
of stress response may cause health problems (eg, cardiovascular, immune); animals and stress—stress rarely
impacts health in animals, because response turns off once stress ends; anticipation, worry, and rumination often activate
(or perpetuate) stress response in humans; factors that increase likelihood of damage from stress response—
unremitting stress; inability to adjust or habituate to stress; failure to shut off stress response; insufficient stress response
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| Memory: vivid recollections (“flashbulb memories”) provide “now print,” that preserves biologically significant
events; emotion—emotionally arousing events or those that occur when alert, aroused, and responsive remembered
more strongly than neutral events (human and animal studies)
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| Neurobiology of fear: involves sympathetic nervous system; fight or flight response—epinephrine and norepinephrine
maximize mobilization and utilization of energy under conditions of extreme stress by shunting blood
to active muscle groups, rapidly mobilizing blood glucose, accelerating heart rate and increasing blood pressure
(BP); norepinephrine involved in orientation to novel stimuli, selective attention, and vigilance; long-term
memory—memory traces initially fragile; norepinephrine facilitates consolidation in dose-dependent way
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 | Animal studies: injecting rats with norepinephrine after they successfully negotiate maze enhances memory of
route; depends on dose, ie, too little or too much produces no effect; amygdala—brain center that assesses environment
and facilitates response to dangerous situations; fear response elicited by electric stimulation of
amygdala, blocked by lesion
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| Human studies: based on hypothesis that increasing norepinephrine in amygdala enhances memory; if true, pharmacologic
blockade of adrenergic systems should impair memory of emotional but not of neutral events; study (part
1)—subjects shown traumatic and neutral images; 1 wk later, traumatic slides remembered better than neutral ones,
presumably because increase of norepinephrine in amygdala enhanced consolidaiton; study (part 2)—subjects
given placebo or propranolol ( β-blocker; blocks release of norepinephrine) 1 hr before viewing slides; only subjects
given placebo remembered traumatic images better than neutral images (ie, propranolol appeared to block memory
enhancement associated with emotionally-charged images); yohimbine—α2 -receptor antagonist (briefly increases
norepinephrine) used instead of propranolol in similar study; found that increase in norepinephrine within 1 hr after
viewing slides led to enhanced memory of all slides (level of norepinephrine correlated with memory 1 wk later)
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| Conclusions: memory of emotional events can be enhanced or blocked by manipulating norepinephrine; proposed
mechanism—traumatic events stimulate release of epinephrine and norepinephrine, causing over-consolidation
of memory of traumatic event; deeply engraved traumatic memories may manifest as intrusive memories, recollections,
nightmares, and flashbacks
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| Stress sensitization: system sensitized by previous stress, resulting in increased synthesis and release of neurotransmitters
into presynaptic space and exaggerated stress response; evidence—patients with PTSD have exaggerated
increases in BP and heart rate when exposed to reminders of trauma (compared to individuals who
experienced trauma but did not develop PTSD); increased reactivity of epinephrine and norepinephrine systems evident
by elevated urinary excretion of epinephrine and norepinephrine over 24 hr and elevated levels of norepinephrine
in cerebrospinal fluid (CSF); elevations persist years after trauma; patients with PTSD have increased
sensitivity to yohimbine (induces PTSD symptoms, including intrusive memories)
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| State-dependent learning: recreation of physiologic state present when original event (and memory consolidation)
occurred facilitates retrieval of associated memories; yohimbine study suggests that people have intrusive
memories of trauma in response to increases in their epinephrine and norepinephrine because of induction of
physiologic state similar to state existing at time of trauma; this may explain why intense exercise can provoke
symptoms of PTSD
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| Neurologic response: imaging studies looking at effects of yohimbine in patients with PTSD and controls show decreased
blood flow in prefrontal cortex in PTSD patients; at moderate to moderately high levels, norepinephrine
increases focus, planning, and executive function, but at high levels, prefrontal cortex “offline,” and fight or
flight response dominates; prefrontal cortex normally inhibits amygdala, keeping fight or flight response in
check; result—fight or flight response stimulated easily and often in patients with PTSD, so these patients often
feel out of control
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| Fear conditioning: associative learning in which previously neutral stimulus becomes paired with fear-provoking
stimulus; fear subsequently occurs in response to neutral stimulus alone (Pavlovian response); conditioning rapid
and often permanent; PTSD may be viewed (in part) as profound version of fear conditioning
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| Encoding and retrieval: all sensory aspects of traumatic event (visual; olfactory; tactile; environmental; emotional)
encoded together; exposure to any part of original experience facilitates recall of traumatic event; recall enhanced
when retrieval cues closely match original encoding; unconscious cues (eg, similar weather, anniversary of
event) also may provoke memories; developing awareness of potential triggers helps anticipate and manage response;
positive feedback loop—memories further consolidated with recall, especially if patient emotionally
aroused during recall
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| Substance abuse: use of depressants (eg, alcohol, benzodiazepines) common; “self-medication” in attempt to suppress
alerting mechanisms of central nervous system (CNS); >50% of men with PTSD have substance abuse diagnosis
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| HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
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| Cortisol: hypothalamic-pituitary-adrenal (HPA) axis also may become sensitized; cortisol levels normally rise in response
to stress; persistently elevated levels during first 72 hr after traumatic event indicate increased risk for PTSD;
patients with PTSD have more variable dysregulated pattern of cortisol release, compared to controls; elevated levels of
corticotropin-releasing factor (CRF) present in CSF; animal studies—excess cortisol shown to damage hippocampus,
resulting in impaired ability to shut off stress response (hippocampus normally provides negative feedback for HPA
axis); chronic stress associated with neuronal changes and suppressed neurogenesis in hippocampus; reduced hippocampal
volume—occurs in patients with Cushing’s disease, recurrent major depression, and PTSD; hippocampus involved
in new learning and short-term memory, associative learning, and spatial and contextual memory; damage to
hippocampus may impair ability to understand context of fear, resulting in generalized fear response; human studies
show—people with PTSD have more activity in amygdala in response to threatenting stimuli than those without
PTSD; with high-stress stimuli, PTSD patients have less than normal blood flow to areas in prefrontal cortex that partially
control amygdala; combination of increased amygdala activity and decreased control by prefrontal cortex may explain
exaggerated stress response
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| Genetics and development: genetic component involved in PTSD, fearful behavior, anxiety disorders, and neurobiologic
stress response; early exposure to stress also important; studies show that animals exposed to uncontrollable
stress during infancy have increased stress response as adults (including CRF and norepinephrine responses)
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| Definitions: resilience—when exposed to trauma, stress-resistant individuals do not develop trauma-related psychopathology;
stress recovery—some individuals who develop psychopathology later recover; functional
resilience—individuals live with symptoms of PTSD but learn coping mechanisms to reduce impact; moderating
factors—genetic, developmental, neurobiologic, and psychosocial factors affect resilience
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| Genetic and social factors: polymorphism of serotonin transporter gene (5-HTT) affects response to maltreatment;
individuals homozygous for L allele (L/L) less likely to develop depression in response to maltreatment than individuals
homozygous for S allele (S/S); however, study showed presence of strong social support reduces likelihood
of depression among foster children with genetic vulnerability; genetic polymorphisms also affect release
of epinephrine and norepinephrine and speed at which levels return to baseline
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| Neuropeptide Y (NPY): Special Forces soldiers (highly resilient) have robust norepinephrine response under high-
stress conditions; they also have increased NPY, which provides negative feedback and aids return to baseline;
increased levels of NPY correspond to improved performance during training
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| Lessons in resilience: in-depth interviews with prisoners of war, Special Forces instructors, and civilians who have experienced
severe trauma found common themes of resiliency
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| Role models: resilient role models transmit attitudes, values, skills, and patterns associated with resilience; observation
and imitation effective ways of learning, especially when complex behaviors broken down into manageable pieces
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| Optimism: positive beliefs about future associated with psychologic and physical well-being; optimists tend to engage
readily in problem-solving, facilitating early resolution of acute stress and termination of stress response;
however, some optimists may have difficulty disengaging from problem-solving during long-term, complex
stress (thereby delaying termination of stress response); “realistic optimists” pay attention to relevant negative
information, but do not dwell on it, rapidly disengaging when problem unsolvable; optimism associated with genetic
factors and conditioned responses; learning to refute negative thoughts key
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| Humor: mature defense mechanism critical for resilience
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| “Moral compass”: those individuals who have carefully assessed their values before undergoing traumatic events
tend not to waiver in decisions about right and wrong, leading to less guilt than those who have not established
their moral compass
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| Altruism: studies show association with resilience; study of psychiatric outpatients in London during World War II
found those patients who contributed to their community in meaningful ways had decreased psychopathology;
animal studies—animals who give more in good times receive more in bad times; in brain imaging studies, mutual
cooperation increases activation of dopamine-nucleus accumbens reward system
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| Religion and spirituality: almost all interviewees cited importance; practice guards against despair; studies show
association with psychologic and physical well-being; organized religious or spiritual practice also provides social
support and positive role models
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| Social support: poor social support related to higher rates of PTSD among Vietnam veterans and to clinical depression
among medically ill patients (eg, among patients who suffer myocardial infarction, social support affects risk
for subsequent cardiac event); some studies show profound effect on life expectancy; isolation and poor social support
associated with increased stress response
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| Other adaptive behaviors and traits: “signature strengths”—recognizing and using one’s skills and talents to
manage situations; active coping—avoidance common among individuals with anxiety disorders, but perpetuates
conditioned fear response; exposure therapy can help patient face fear, reduce fear response, and increase sense of
control; stress inoculation and training—gradually increasing stress (keeping level challenging but manageable)
allows learning and mastery; neuroplasticity use-dependent; exercise affects brain physiology and seems to help
battle depression and anxiety and help with neurogenesis in hippocampus; cognitive flexibility—ability to reappraise
situation; acceptance—accepting reality of difficult situation and working with it rather than against it improves
ability to function; meaning and purpose—important for therapy; survivor mission helpful
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Suggested Reading
Basoglu M: Rehabilitation of traumatised refugees and survivors of torture. BMJ 333:1230; Bryant RA et al:
Heart rate as a predictor or posttraumatic stress disorder in children. Gen Hosp Psychiatry 29:66, 2007; Cromer
KR, Sachs-Ericsson N: The association between childhood abuse, PTSD, and the occurrence of adult health problems:
moderation via current life stress. J Trauma Stress 19:967, 2006; Dekel R, Solomon Z: Marital relations
among former prisoners of war: contribution of posttraumatic stress disorder, aggression, and sexual satisfaction. J
Fam Psychol 20:709, 2006; Feldner MT et al: A critical analysis of approaches to targeted PTSD prevention: current
status and theoretically derived future directions. Behav Modif 31:80, 2007; Geuze E et al: Altered pain processing
in veterans with posttraumatic stress disorder. Arch Gen Psychiatry 64:76, 2007; Hoge CW et al:
Association of posttraumatic stress disorder with somatic symptoms, health care visits, and absenteeism among Iraq
war veterans. Am J Psychiatry 164:150, 2007; Norman SB et al: Profiling posttraumatic functional impairment. J
Nerv Ment Dis 195:48, 2007; Portnova AA: Typology of post-traumatic stress disorder in children and adolescents.
Neurosci Behav Physiol 37:7, 2007; Schumm JA et al: Cumulative interpersonal traumas and social support as risk
and resiliency factors in predicting PTSD and depression among inner-city women. J Trauma Stress 19:825, 2006;
Sijbradih M, et al: Treatment of acute posttraumatic stress disorder with brief cognitive behavioral therapy: a randomized
controlled trial. Am J Psychiatry 164:82, 2007; Storr CL et al: Childhood antecedents of exposure to traumatic
events and posttraumatic stress disorder. Am J Psychiatry 164:119, 2007; Tiet QQ et al: Coping, symptoms,
and functioning outcomes of patients with posttraumatic stress disorder. J Trauma Stress 19:923, 2006; Vermetten
E et al: PTSD and Vietnam veterans. Science 315:184; Wu KK, Cheung MW: Posttraumatic stress after a motor
vehicle accident: a six-month follow-up study utilizing latent growth modeling. J Trauma Stress 19:923, 2006.
Educational Objectives
| The goal of this activity is to improve the recognition and management of posttraumatic stress disorder (PTSD). After
hearing and assimilating this program, the clinician will be better able to:
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| 1. Identify patients with PTSD and those at risk of developing PTSD.
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| 2. Explain the neurobiologic model of PTSD.
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| 3. Describe the relationship between associative learning, memory, and PTSD.
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| 4. Discuss the role of genetics in the stress response.
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| 5. List several behavioral, emotional, and psychosocial traits associated with resilience.
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Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
the faculty reported nothing to disclose.
Acknowledgements
Dr. Southwick was recorded in Cleveland at Posttraumatic Stress Disorder Symposium, presented by Cleveland
Clinic Center for Continuing Education, and held November 29, 2006. The Audio-Digest Foundation thanks Dr.
Southwick and the Cleveland Clinic for their cooperation in the production of this program.
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