Posttraumatic Stress Disorder: Clinical Features, Pathophysiology, and Treatment

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The American Journal of Medicine (2006) 119, 383-390

REVIEW

AJM Theme Issue: Men’s Health

Posttraumatic Stress Disorder: Clinical Features, Pathophysiology, and Treatment W. Victor R. Vieweg, MD,a,b,d,e Demetrios A. Julius, MD,a,d Antony Fernandez, MD,a,d Mary Beatty-Brooks, MA,c John M. Hettema, MD, PhD,d Anand K. Pandurangi, MDd a

Psychiatry, and bMedicine Services, cMedical Media, Hunter Holmes McGuire Veterans Affairs Medical Center, and dDepartments of Psychiatry, and eInternal Medicine, Medical College of Virginia Campus, Virginia Commonwealth University, Richmond, Va. ABSTRACT Posttraumatic stress disorder (PSTD), classified as an anxiety disorder, has become increasingly important because of wars overseas, natural disasters, and domestic violence. After trauma exposes the victim to actual or threatened death or serious injury, 3 dimensions of PTSD unfold: (1) reexperiencing the event with distressing recollections, dreams, flashbacks, and/or psychologic and physical distress; (2) persistent avoidance of stimuli that might invite memories or experiences of the trauma; and (3) increased arousal. Traumatic events sufficient to produce PTSD in susceptible subjects may reach a lifetime prevalence of 50% to 90%. The actual lifetime prevalence of PTSD among US citizens is approximately 8%, with the clinical course driven by pathophysiologic changes in the amygdala and hippocampus. Comorbid depression and other anxiety disorders are common. General principles of treatment include the immediate management of PTSD symptoms and signs; management of any trauma-related comorbid conditions; nonpharmacologic interventions including cognitive behavioral treatment; and psychopharmacologic agents including antidepressants (selective serotonin reuptake inhibitors most commonly), antianxiety medications, mood stabilizing drugs, and antipsychotics. This review of PTSD will provide the reader with a clearer understanding of this condition, an increased capacity to recognize and treat this syndrome, and a greater appreciation for the role of the internist in PTSD. © 2006 Elsevier Inc. All rights reserved. KEYWORDS: Anxiety disorder; Depression; Military veterans; Posttraumatic stress disorder (PTSD); Primary care; Rape victims

The internist has long been interested in war-induced extreme and enduring reactions to psychologic trauma. Jacob Mendez DaCosta introduced the term soldier’s heart (DaCosta’s syndrome) in an extensive Civil War study published in 1871.1 Subsequent labels for traumatic events leading to psychologic disturbances include fright neurosis; traumatic, combat, or war neurosis; railway spine; concentration camp syndrome; rape-trauma syndrome; combat fatigue; post-Vietnam syndrome; and shell shock. The current Diagnostic and Statistical Manual of Mental Disorders (1994) uses “posttraumatic stress disorder” to label this stress-induced condition.2 (“Stress” may be defined as the totality of the experience in response to unpleasant external Reprint requests should be addressed to Victor Vieweg, MD, 17 Runswick Drive, Richmond, VA 23238-5414. E-mail address: [email protected].

0002-9343/$ -see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2005.09.027

stimuli that signal danger— often by causing physical or emotional pain.) The most recent Cecil Textbook of Medicine (2004),3 however, lists neither posttraumatic stress disorder (PTSD) nor PTSD in the index. Thus, a review of PTSD is in order for the internist. PTSD is classified as an anxiety disorder.2 Disorders of anxiety are the most common forms of psychiatric illnesses, with 19.3% of Americans experiencing some form of an anxiety disorder in a 12-month period. Anxiety has many of the symptoms and signs of fear. Anxiety, however, lingers long after the stress stimulus has lifted and the threat has passed. Just as chronic pain is a type of pain that no longer serves a useful purpose, chronic anxiety/fear also serves no useful purpose. Anxiety disorders not only contribute to biopsychosocial morbidity but also may constitute a risk factor for sudden

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cardiac death. Cardiac arrhythmias, rather than induction or simulated trauma recollection. In the fourth edition (1994) exacerbation of coronary atherosclerosis, seem to be the of the Diagnostic and Statistical Manual of Mental Disorculprit in this setting.4 ders PTSD remains an anxiety disorder.2 There was a reThe terrorist attacks on the World Trade Center and the definition of the trauma. The traumatic event had to involve Pentagon on September 11, 2001, coupled with the current actual or threatened death or serious injury or a threat to the wars in Iraq and Afghanistan, physical integrity of self or others. have thrust PTSD further into the Also, the subject with PTSD had limelight. According to data from to respond with intense fear, helpCLINICAL SIGNIFICANCE the bombing of the Oklahoma lessness, or horror. Furthermore, City Murrah Federal Building in there had to be clinically signifi● Post-traumatic stress disorder consists 1995, approximately one-third of cant distress and impairment in of re-experiencing trauma with distressthe more than 100 000 people witsocial, occupational, or other iming recollections, dreams, flashbacks, nessing the terrorists attack on portant areas of functioning for at and/or psychological/physical distress; September 11, 2001, have develleast 1 month. Table 1 lists the persistent avoidance of stimuli that oped or will develop PTSD.5 diagnostic criteria for PTSD (Dimight invite traumatic memories or exThe intense combat operations agnostic and Statistical Manual of periences; and increased arousal. in the current wars in Iraq and Mental Disorders and InternaAfghanistan have created a series tional Classification of Diseases-9 ● The clinical course is driven by pathoof mental health problems for US CM code ⫽ 309.81).2 physiological changes in the amygdala 6 troops. These problems include PTSD symptoms and signs are and hippocampus. major depressive disorder, generreadily identifiable by the general alized anxiety disorder, and internist. There is, however, con● Treatment includes immediate managePTSD. Compared with pre-desiderable overlap between features ment of symptoms and signs and any ployment mental health problems, of PTSD and other anxiety disortrauma-related comorbid conditions; the greatest increase was in PTSD. ders, mood disorders, and subnon-pharmacological interventions inThe US Department of Defense stance abuse. Not uncommonly, cluding cognitive behavioral treatment; has shown an increased awareness patients with PTSD will be found and psychopharmacologic agents includof combat-related mental health to have several other psychiatric ing antidepressants, antianxiety mediproblems compared with previous disorders. Specific questions must cations, mood stabilizing drugs, and wars and military engagements.7 be asked about the occurrence of a antipsychotics. Even though most mental traumatic event and subsequent health issues enter the medical onset of the clinical features of area through primary care, little PTSD. Practitioners may be reluchas been written about PTSD in primary care.8 The undertant to ask about and patients may be reluctant to reveal reporting of domestic violence and other traumas may lead distressing events that might involve shame or secrecy. Essential features of PTSD include: (1) exposure to a to low recognition of PTSD in primary care. Simply intetraumatic event that involved actual or threatened death or grating questions about trauma exposure together with serious injury, (2) reexperiencing that event with distressing screening for depressive and anxiety symptoms into routine medical examinations may enhance the recognition of recollections, dreams, flashbacks, and/or psychologic and PTSD in primary care.8 Alternatively, features of alcohol or physical distress, (3) persistent avoidance of stimuli that might invite memories or experiences of the trauma, and (4) other substance abuse, excessive use of health services, increased arousal. PSTD comprises an original traumatic other signs of psychologic distress, and suicidality coupled event with the later emergence of a triad of symptomwith a history of trauma exposure may also lead the primary behaviors that include reexperiencing, avoidance/numbing, care provider to a diagnosis of PTSD. and hyperarousal/hypervigilance of sufficient severity to interfere with important aspects of the person’s life. InterCLINICAL FEATURES nists in their role as primary care providers are likely to be The term posttraumatic stress disorder was first used in the the first health care professionals to see patients with third edition (1980) of the Diagnostic and Statistical ManPTSD.11 ual of Mental Disorders, in which it was classified as an Reexperiencing anxiety disorder.9 In this third edition, a diagnosis of PTSD required exposure to trauma that would provoke symptoms The most dramatic form of reexperiencing is the flashback. and signs of PTSD in almost everyone. In the 1987 revision Here the patient feels and acts as if the trauma is recurring. of the Diagnostic and Statistical Manual of Mental DisorReexperiencing also includes distressing memories or ders,10 diagnostic criteria were modified to emphasize the dreams (nightmares) when faced with stimuli linked to the avoidance phenomena in which there are deliberate efforts traumatic event. There may be physiologic or psychologic to avoid thoughts, feelings, activities, and situations that stress reactions, including full-blown panic attacks, associ-

Vieweg et al Table 1

PTSD Review

385

Diagnostic Criteria for 309.81 Posttraumatic Stress Disorder2

A. The person has been exposed to a traumatic event in which both of the following were present: 1. The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury, or a threat to the physical integrity of self or others. 2. The person’s response involved intense fear, helplessness, or horror. Note: In children, this may be expressed instead by disorganized or agitated behavior. B. The traumatic event is persistently reexperienced in 1 (or more) of the following ways: 1. Recurrent and intrusive distressing recollection of the event, including images, thoughts, or perceptions. Note: In young children, repetitive play may occur in which themes or aspects of the trauma are expressed. 2. Recurrent distressing dreams of the event. Note: In children, there may be frightening dreams without recognizable content. 3. Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes including those that occur on awakening or when intoxicated). Note: In young children, trauma-specific reenactment may occur. 4. Intense psychologic distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event. 5. Physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event. C. Persistent avoidance of stimuli associated with the trauma and numbing of general responsiveness (not present before the trauma), as indicated by 3 (or more) of the following: 1. efforts to avoid thoughts, feelings, or conversations associated with the trauma 2. efforts to avoid activities, places, or people who arouse recollections of the trauma 3. inability to recall an important aspect of the trauma 4. markedly diminished interest or participation in significant activities 5. feeling of detachment or estrangement from others 6. restricted range of affect (eg, unable to have loving feelings) 7. sense of a foreshortened future (eg, does not expect to have a career, marriage, children, or a normal life span) D. Persistent symptoms of increased arousal (not present before the trauma), as indicated by 2 (or more) of the following: 1. difficulty falling or staying asleep 2. irritability or outbursts of anger 3. difficulty concentrating 4. hypervigilance 5. exaggerated startle response E. Duration of the disturbance (symptoms in criteria B, C, and D) is more than 1 month. F. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify if: Acute: if duration of symptoms is less than 3 months Chronic: if duration of symptoms is 3 months or more Specify if: With delayed onset: if onset of symptoms is at least 6 months after the stressor

ated with this reexperiencing. To establish a diagnosis of PTSD, at least 1 aspect of reexperiencing must be present (Table 1).

Avoidance/Numbing Patients with PTSD may attempt to avoid thoughts or activities related to the trauma. There may be a markedly diminished capacity to experience pleasure (anhedonia), difficulty in remembering aspects of the trauma, blunted affect, a feeling of detachment or estrangement from others, and a perception of a foreshortened future. Three or more parameters of avoidance/numbing must be found to establish a diagnosis of PTSD (Table 1). In PTSD there are both similarities and differences with major depressive disorder.2 There is considerable overlap between PTSD and various mood disorders.

Hyperarousal/Hypervigilance Increased arousal may disrupt sleep, contribute to irritability and anger, and impair concentration. Hypervigilance may

coexist with an exaggerated startle response. Two or more parameters of hyperarousal/hypervigilance must be present to establish a diagnosis of PTSD (Table 1). There is considerable overlap between PTSD and other anxiety disorders such as generalized anxiety disorder and panic disorder.

Prevalence When the diagnosis of PTSD was introduced in 1980, traumatic events sufficient to induce this condition were considered rare.12 Since then, epidemiologic surveys have documented such events to be highly prevalent, with 50% to 90% of the population receiving exposure over the course of a lifetime.13,14 Lifetime prevalence of PTSD is approximately 8%.13 Medical reports of recent military experiences in Afghanistan and Iraq described a striking increase in the prevalence of PTSD largely related to the number of firefights engaged in by the veteran.6

386 Overall the most common traumatic events are witnessing a severe injury or death, involvement in a fire or other natural disaster, and involvement in a life-threatening accident (all 3 are more common in men than women).12 Physical attack, combat-related trauma, being threatened with a weapon, captured, or kidnapped are also more common among men than women. Rape, sexual molestation, and parental neglect and physical abuse during childhood are more common among women than men. Note that trauma exposure meeting criteria for increased PTSD risk may be acute, such as assault or accidental injury, or chronic and recurrent, such as childhood abuse or domestic violence. Sexual differences in the type of trauma experienced also may drive aspects of PTSD. Women are more than 4 times more likely to develop PTSD than men after normalizing for the traumatic event. Rape is the trauma most likely to lead to PTSD and occurs more commonly among women (9%) than men (⬍1%).12 Other risk factors for PTSD include youth, lower socioeconomic status, preexisting psychiatric condition, childhood conduct problems, parental neglect, family history of a psychiatric condition, severity of reaction to initial trauma including dissociation, and poor social support system.12

Comorbidity Other anxiety disorders and depression in varying degrees of severity commonly accompany PTSD and may make the diagnosis of each condition more difficult.12 Substance abuse is a common condition developing after the onset of PTSD. Temporal discordance is the clearest evidence of

The American Journal of Medicine, Vol 119, No 5, May 2006 comorbidity. That is, depression and/or an anxiety disorder preceding the traumatic event leading to PTSD and substance abuse after the traumatic event offer the most compelling evidence for multiple psychiatric conditions. Not uncommonly, especially among older patients, medical conditions may be comorbid with PTSD. Exposure to trauma increases the risk of poor physical health.15,16 Boscarino17 reported a direct link between trauma and a broad spectrum of medical conditions in a 20-year follow-up of men initially exposed to severe stress. David et al18 compared male veterans admitted to a rehabilitation unit for PTSD or alcohol dependence and reported that PTSD subjects were more likely to have diabetes mellitus, heart disease, obesity, and osteoarthritis than their substance abuse counterparts.

Clinical Course The initial clinical response to a traumatic event is driven by the amygdala and is often in the form of the “fight or flight response.” Subsequently, the clinical course is modified by memories managed in the hippocampus and a cognitive understanding of stimulus, experience, and expectations governed by the prefrontal cortex. That is, both the external event phenomena and the (internal) biopsychosocial dimensions of the person involved determine the short-term, midrange, and long-term biologic and psychologic responses to the traumatic event.19 In a well-studiedgroup of rape victims, Foa et al20 reported that 94% of study subjects had all the clinical symptoms and signs of PTSD 1 week after the rape. This would

Figure 1 Body’s response to a threat or perceived threat. See text below for detailed analysis of central nervous system structures and their role in the fear response. After the diagram in the June 10, 2002, issue of Time Magazine.31 Event A: Immediate (subcortical) response to threat ● Visual and auditory stimuli reach the thalamus on sighting or hearing the menacing animal. ● This information immediately leaves the thalamus and goes to the fear center in the amygdala. ● The amygdala alerts other brain structures including the hypothalamus and locus ceruleus producing sweaty palms, tachycardia, increased blood pressure, and a surge in norepinephrine. ● The subject is then prepared for a “fight or flight response.” Event B: Cognitive processing of immediate response to threat ● After fear activation, information is sent from the thalamus to the cortex for cognitive processing. ● The neocortex (executive portion of the cortex) analyzes the raw data from the sensory organs and decides whether to continue or discontinue the fear response. ● If the neocortex decides to maintain the fear response, the amygdala remains on the alert. General comments ● Olfactory and tactile stimuli are sent directly to the amygdala bypassing the thalamus, evoking stronger memories and feelings than do sights and sounds. ● The thalamus is the hub for sights and sounds with visual cues separated according to size, shape, and color, and auditory cues separated by volume and dissonance. ● The cortex gives meaning to the sights and sounds and determines whether to turn off or continue anxiety and fear responses. ● The amygdala is the emotion center of the brain and gives emotional valence to memories processed in the hippocampus. ● Stimulating the bed nucleus of stria terminalis causes longer-term unease characteristic of anxiety. ● The hippocampus is the memory center of the brain, an important regulator of the stress response, and a major feedback site for glucocorticoids.

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Table 2 Interval Baseline 4 wk 8 wk 12 wk Quarterly Annually Every 5 y

Recommended Monitoring of Patients Receiving Second-Generation Antipsychotic Drugs26 Personal/Family History

Weight (BMI)

Waist Circumference

Blood Pressure

Fasting Plasma Glucose

Fasting Lipids

4

4 4 4 4 4

4

4

4

4

4

4

4

4

4

4

4

4

BMI ⫽ body mass index.

suggest that PTSD features constitute an expected reaction to such trauma. Three and 9 months after the rape, only 15% to 25% of subjects, respectively, met criteria for PTSD. Thereafter, this percentage remained stable consistent with unremitting and chronic PTSD that may last for any length of time.

Disability Associated with Posttraumatic Stress Disorder Chronic PTSD is often debilitating with work impairment or even unemployment, altered life trajectories, compromised social relations, marital discord and divorce, and onset of impulse dyscontrol and even violence. Among US military veterans, chronic PTSD commonly leads to disability compensation.21

PATHOPHYSIOLOGY The centerpiece of the central nervous system involved in the fear response is the amygdala. This brain structure governs our ability to experience fear and learn to avoid pain by interceding between emotion and attention in 2 related ways.22 Amygdala signals enhance processing of fear-inducing information by higher cortical structures. That is, they increase the emotional valence assigned to information and memory in the cortex thereby making this information easier to access in future settings. Also, the amygdala is able to recognize danger signals quickly by primitive visual pathways that bypass the cortex and neocortex. In so doing, the amygdala evaluates objects and organisms in the environment before interacting with them. This brain structure can quickly activate just about every system in the body to fight ferociously or retreat rapidly. In addition to placing the body on alert, the amygdala stimulates the nearby hippocampus to help the brain to learn and form new memories specific to danger. The magnitude and experience of the threat followed later by reexperiencing, avoidance/numbing, and hyperarousal/hypervigilance constitute important determinants of the clinical course leading to PTSD. Figure 1 outlines the body’s initial response to a threat.

TREATMENT The American Psychiatric Association has recently published guidelines for the treatment of patients with PTSD.23 Included in these guidelines is treatment of patients with acute stress disorder. Acute stress disorder is a common precursor to PTSD. For an in-depth review of treatments for PTSD, the reader is referred to the practice guidelines developed by the International Society for Traumatic Stress Studies edited by Foa et al.24

General Principles The first task is to reduce or eliminate the symptoms and signs of PTSD and any trauma-related comorbid conditions. Next, the clinician seeks to improve adaptive functioning and return the patient to a psychologic state of safety and trust. Finally, general treatment focuses on limiting any generalization of the initial trauma and protecting the patient with PTSD against subsequent relapse.

Nonpharmacologic Treatment In randomized clinical trials, most patients with PTSD treated with psychotherapy improve or recover. Bradley et al25 conducted a multidimensional meta-analysis of psychotherapy for PTSD including studies published between 1980 and 2003. More than one-half of patients with PTSD completing treatment with “various forms of cognitive behavior therapy or eye movement desensitization and reprocessing improve.”25 The authors cautioned, however, that most patients continued to have significant symptoms and signs of PTSD posttreatment. Follow-up data beyond brief intervals were also largely absent. The principal role for the primary care physician in PTSD is psychoeducation and referral as necessary. These clinicians should have a practice that allows weekly follow-up for several weeks after initiation of treatment. Follow-up can move to biweekly and then monthly visits. Referral to support groups may be appropriate. Nonpharmacologic models of treatment for PTSD are built on a biopsychologic understanding of this condition.26 Disturbances in PTSD are associated with a broad range of psychologic processes including attention, beliefs, cognitive-affective responses, coping styles, memory, and social-

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PTSD Review

support systems.26 For a review of the 3 major theories of PTSD— emotional processing theory, dual representation theory, and cognitive theory—the reader is referred to a recent review by Brewin and Holmes.26

Psychopharmacology After a traumatic event, no specific drug or combination of drugs prevents the emergence of acute stress disorder or later of PTSD. However, selective serotonin reuptake inhibitors are considered the first-line drug treatment for PTSD and the only ones to have received Food and Drug Administration indication.23 Selective serotonin reuptake inhibitors include fluoxetine, sertraline, paroxetine, fluvoxamine, citalopram, and escitalopram. Selective serotonin reuptake inhibitors may reduce or eliminate the clinical features of the 3 symptoms clusters of PTSD (reexperiencing, avoidance/numbness, and hyperarousal). Other antidepressants including tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors (venlafaxine and duloxetine), and monoamine oxidase inhibitors may be of benefit in treating the patient with PTSD. Benzodiazepines may reduce anxiety and improve sleep in PTSD. They may not control or eliminate the core triad of PTSD, however. A significant limitation of this class of drugs is that subjects with PTSD who are prone to addiction may abuse or become dependent on benzodiazepines. Also, these drugs may interfere with the cognitive processing of the trauma necessary for psychotherapeutic interventions to be successful. Psychotropic drugs other than antidepressants and antianxiety agents may be necessary to target residual PTSD symptoms and signs. Second-generation (newer, atypical) antipsychotic drugs may be needed to treat comorbid psychotic-like features or anxiety refractory to other agents. These second-generation agents include clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Because of the side effects of leukopenia, seizures, and myocarditis/cardiomyopathy, clozapine would be the least attractive choice among the second-generation antipsychotic drugs. First-generation (older, typical) antipsychotic drugs are more likely than second-generation drugs to produce significant motor side effects (tardive dyskinesia and the extrapyramidal syndromes of dystonic reactions, druginduced Parkinsonism, and akathisia) at clinically effective doses and are a second-line choice to treat psychotic-like features in PTSD.23 Second-generation antipsychotic drugs are more likely to be associated with drug-induced weight gain than firstgeneration agents. Clozapine and olanzapine are most likely implicated in drug-induced weight gain and features associated with the metabolic syndrome. Ziprasidone and aripiprazole are least likely to induce weight gain. Risperidone and quetiapine have a moderate capacity to induce weight gain. Table 2 outlines recommended cardiovascular and endocrine follow-up of patients taking second-generation antipsychotic drugs.27

389 Various symptom clusters and mood instability may be treated with so-called mood stabilizer anticonvulsants (divalproex, carbamazepine, topiramate, and lamotrigine). Central nervous system adrenergic hyperarousal may drive PTSD symptoms, including nightmares and flashbacks, prompting trials of ␣2-adrenergic agonists and ␤-adrenergic blockers. There is an emerging interest in treating PTSDassociated nightmares with the postsynaptic alpha-adrenoceptor blocker prazosin.28-30 Almost certainly, the patient with PTSD who is referred to the psychopharmacologist will require multiple psychotropic drugs from different classes of drugs.

CONCLUSIONS Interest in PTSD extends beyond the field of mental health to engage the speciality of internal medicine and its various subspecialities. Combat-related trauma is a common cause of PTSD among men, and rape is a common cause of PTSD among women. The initial response to the traumatic stress is largely biologic and driven by the amygdala. Memories managed by the hippocampus and executive decisions managed in the neocortex drive the short-term, mid-range, and long-term outcomes of subjects exposed to severe stress. That is, the later response to the traumatic event will determine whether acute and chronic PTSD will persist. (PTSD is probably a recovery failure from a universal set of emotions and reactions to severe stress.) One-quarter or fewer of the subjects exposed to the traumatic event will have chronic PTSD. The primary care physician will usually be the first health-care professional to engage the potential subject with PTSD. Including PTSD in the differential diagnosis of persons presenting with multiple psychologic and somatic complaints and asking about possible exposure to severe stress are essential steps in better managing PTSD. Education and supportive psychotherapy can be within the purview of the primary care provider of the potential subject with PTSD. Selective serotonin reuptake inhibitors can also be started by the primary care physician. Referral to specialists should be a ready choice. Continued engagement with the patient and specialist by the primary care physician offers the best course for potential subjects with PTSD. Systematic studies of PTSD engaging primary care, psychiatrists, psychologists, neurophysiologists, and neuroradiologists will lead to earlier recognition of PTSD, better management, and improved outcome of this condition. Internal medicine has a vital role to play in such efforts.

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