J. Douglas Bremner, MD

A 30-year-old woman sustained a closed head injury as a result of a motor vehicle accident (MVA). She was in the process of making a left turn when her vehicle was struck twice by a drunk driver, causing her car to hit a brick wall and her head to be struck twice in the left occipital region. According to her husband's report, the patient did not lose consciousness. However, she did report 10 minutes of anterograde amnesia.	

The patient was transported to a major medical center's ED by ambulance 10 to 15 minutes after the MVA for medical evaluation. Her medical records showed cervical strain, head contusion, and anxiety secondary to the accident. CT and MRI scans demonstrated no remarkable findings.

In the weeks after her accident, the patient complained of daily intense headaches localized to her left occipital region that often averaged an 8 on a 0-to-10 pain scale. Her cognitive symptoms included frequent forgetfulness that disrupted her occupational functioning and overall daily activities and memory impairment. She also reported increased fatigue. The patient's husband noted that she had difficulty in remembering her activities.

In addition, the patient experienced depressed mood, anxiety, and confusion. She blamed herself for the accident, no longer enjoyed driving, and refused to drive after dark. She reported reexperiencing the accident while driving, during which she would feel intense psychological distress, would feel increased physiologic arousal, and would repeatedly "see the accident occurring in her head." Therefore, she attempted to avoid thinking about the event and avoided driving. She also had recurrent nightmares about the accident and lost interest in activities that were once important to her. She said she felt like a different person and that she did not have the same caring feelings for people; her husband confirmed this.

Problems with the quality and duration of this patient's sleep emerged after the MVA; she often self-medicated with generic over-the-counter antihistamines. She easily awakened on hearing a noise and generally maintained a heightened awareness of her surroundings. She was easily fatigued and irritable on a daily basis, had headaches, and had trouble concentrating. These symptoms made it difficult for her to work and impaired her social relationships.

Escitalopram was prescribed to help manage her anxiety, but she reported a lack of interest in taking it or any other psychiatric medication. The patient's medical history was significant for hysterectomy and right breast cyst removal.

Neuropsychological evaluation, performed approximately 5 months after the MVA, demonstrated mild impairments in verbal attention and moderate to severe impairments in both verbal and visuospatial memory. The patient particularly maintained deficits in initial encoding of presented materials. She met criteria for PTSD, based on the 

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition,

 and her results on the Minnesota Multiphasic Personality Inventory-2 (MMPI-2) revealed that she was highly phobic at the time of her testing and may have had a predisposition to stress reactions.	

A common complicating factor in patients who present to the ED with stress symptoms is possible brain injury. Although there is consensus that PTSD can occur in the aftermath of brain injury, estimates of the actual prevalence vary widely (0% to 58%).

 This case illustrates the dilemma of diagnosing PTSD in the presence of mild head injury and loss of memory of the accident.

Diagnostic criteria for PTSD indicate that a person must experience the event with "intense fear, horror, or helplessness."

 But is it possible to encode a traumatic memory if there is no conscious memory of the event because of head injury? Previously it was argued that PTSD was not possible with head injury if there was no explicit memory of the event. However, there is growing consensus that this is not the case.

 has argued that trace memories from accidents can exist that form the core of the memory that leads to PTSD, even if no explicit memory of the event exists.

A number of studies of PTSD have been performed in patients presenting to the ED with head injury. One study of 120 persons who presented with mild traumatic brain injury (TBI) and were hospitalized found that PTSD developed in 14% of the patients at 6 months.

 PTSD was more likely to develop in patients who remembered the event primarily because of more reexperiencing of symptoms.

In another study, PTSD was also more common in patients with TBI who remembered the event and affected only 3% of those with no memory of the accident.

 Of 43 children with and without TBI who were in an MVA, there were no differences in PTSD rates.

 In a study of 96 patients with severe TBI, PTSD was seen in 27%, of whom only 19% had intrusive memories of the trauma and 96% had emotional reactivity

; patients with more PTSD symptoms had worse health and lower levels of functioning

; and those with avoidant coping style had higher levels of PTSD.

In a study of 307 consecutive admissions to a level I trauma center because of mild TBI, over half of patients had at least partial recall of the event.

 PTSD developed in 10% of patients by 12 months after injury, and there were no differences between traumatized and nontraumatized patients with and without TBI. There were also no differences in PTSD between those with and without amnesia for the event.

A study of 107 persons with and without TBI involved in MVAs showed that patients who lost consciousness had greater impairment on neuropsychological testing of speed and recall of verbal material.

 PTSD was as common in patients with TBI as in patients without TBI. In another study, of 34 patients with TBI, 59% met criteria for PTSD by self-report measure but only 3% had PTSD based on clinician-administered assessment with the Clinician Administered PTSD Scale.

 The authors concluded that the effects of head injury led to discrepancies in diagnosis.

PTSD symptoms were not associated with severity of brain injury in a study of 66 patients with severe TBI.

 Also, patients with amnesia had lower norepinephrine/cortisol ratios and fewer PTSD symptoms than those without amnesia.

PTSD is possible in patients with head injury even if there is no explicit memory for the actual event.

 It is possible to encode a traumatic memory (at an implicit level) even if there is no conscious (explicit) recall. For example, patients with hippocampal damage may not be able to spontaneously repeat words that they have seen previously (explicit memory), but if provided with the first few letters of a word, they may be able to fill in the gaps (implicit memory).

A similar situation may occur in trauma patients with amnesia. The event could be encoded in some way that is not available to conscious recall. Some have called this a "body memory," which is some memory trace of the event that has been retained in terms of conditioned responses, physiologic memory, or otherwise. Nonetheless, studies show that PTSD rates are lower in patients with amnesia and that these patients have fewer symptoms in the intrusion category and more symptoms in the hyperarousal category.

A 23-year-old woman was involved in a head-on vehicular collision at about 35 miles per hour, causing her airbag to deploy. A tractor trailer fell on top of her vehicle, trapping her inside. She was extracted from her vehicle after 30 minutes, during which time a family friend died in the seat next to her. She denied any loss of consciousness during the accident but experienced intermittent loss of consciousness while trapped inside her vehicle and on the way to the nearest medical center. The patient was fully alert and oriented when she arrived at the ED, as evidenced by her Glasgow Coma Scale score of 15.

She sustained numerous physical injuries as a result of the accident, including right posterior shoulder pain, right breast numbness, and left shoulder and neck pain. However, CT and MRI scans demonstrated no evidence of brain injury, and she was discharged. Within the next month, she presented to the ED several times with complaints of intractable pain, shortness of breath, and severe headache. A repeated CT scan demonstrated fractured ribs but no changes in the brain, which was supported by an MRI scan. She had at least 3 subsequent ED visits.

Her first subsequent ED visit was for intractable pain, and the second ED visit resulted in a cholecystectomy. An MRI scan obtained 4 months post-MVA revealed an L5-S1 disk protrusion that was treated by laminectomy. She received multiple nerve blocks for lower back and rib pain related to the accident. About 6 months post-MVA, she presented to the ED with severe headache, blurred vision, photophobia, hot flashes, nausea, neck pain, and decreased "short-term memory," all of which began after the accident. Negative findings on a CT scan led to her being discharged without medical treatment. However, she had received a diagnosis of postconcussive syndrome by one physician.	

The patient reported a number of physical, cognitive, and emotional complaints that she attributed directly to the accident. Cognitively, she had trouble concentrating and was easily distracted. She had difficulty in remembering recent events, future appointments and tasks, and the location of objects. She reported word-finding difficulties and comprehension difficulties for both spoken and written information, as well as new problems with spelling. She had subjective difficulty in performing multiple activities concurrently, planning ahead, and managing her time effectively. These problems persisted for 6 months after the accident and significantly reduced her functional status.

The patient's emotional status included severe anxiety and depression. Both the patient and her parents noted a change in her personality since the accident. She reported emotional lability, disrupted sleep, passive suicidal ideations, and compulsive behavior. She was irritable and became very angry when things were not done in a certain way. She also had recurrent thoughts of the accident; had nightmares relevant to her trauma; and felt very anxious and aroused when driving, especially around tractor trailers. The patient had panic attacks, became extremely anxious in automobiles, and felt considerable guilt about surviving the incident, given the death of the family friend in the seat next to her.

She continued to drive after the accident, although only occasionally, and reported considerable anxiety when doing so. She became withdrawn, had disrupted social relations, and avoided things that would remind her of the accident. Before her neuropsychological evaluation, PTSD was diagnosed, at which time sertraline was prescribed. However, she discontinued the medication for unclear reasons.

She was administered the MMPI-2, and the Gass correction factor was used to control for cognitive and physical symptoms commonly associated with brain injuries. Her profile revealed a poor tolerance for frustration and limited coping mechanisms for dealing with stress. A neuropsychological evaluation revealed several areas of impairment, including mildly to moderately impaired attention; moderate impairment on select spatial perceptual tasks; and impaired ability to acquire new information, which contributed to her poor memory performance.

Her health history included polycystic ovarian disease and diabetes. She was a nonsmoker who rarely drank alcohol and denied substance use. Although the patient denied any history of mental illness, her records indicated childhood sexual abuse that continued to affect some aspects of her life. For example, she refused a gynecologic examination during her post-MVA ED visit.

This case illustrates memory impairment in the aftermath of a car accident that may be attributable to a mild head injury or to PTSD. Patients often present to the ED with symptoms of memory disturbance or cognitive dysfunction, which are often attributed to a brain injury, whether or not there is evidence of such. However, these memory problems could be related to early presentation of PTSD.

Patients with PTSD exhibit a broad range of problems with memory, including gaps in memory, problems with declarative memory, attentional biases to trauma-related information, and intrusive memories. Many ED clinicians may not appreciate that memory impairment can be associated with PTSD in the absence of head injury.

Stress in the absence of physical injury can be associated with changes in memory and brain structures that mediate memory. The hippocampus is an area of the brain that plays a critical role in memory and is sensitive to stress. Studies in animals exposed to stress showed deficits in hippocampal-based memory function

 and alterations in hippocampal morphology.

 More specifically, stress can interfere with long-term potentiation.

 Mechanisms in the hippocampus proposed for these findings include elevated levels of glucocorticoids released during stress,

 stress-related inhibition of brain-derived neurotrophic factor,

Neuropsychological testing as a probe of brain function has been used to better understand PTSD. Several review studies have demonstrated verbal declarative memory deficits in patients with PTSD

 using a variety of measures (including the Wechsler Memory Scale, visual and verbal components of the Buschke Selective Reminding Test, Rey Auditory Verbal Learning Test, California Verbal Learning Test, and Rivermead Behavioral Memory Test). These studies looked at PTSD related to combat, rape, early childhood abuse, and childhood trauma. However, other studies found no evidence of memory impairments related to PTSD.

Women with PTSD had verbal declarative memory deficits specifically associated with PTSD that were not a nonspecific effect of trauma exposure.

 Other memory disturbance studies in PTSD in both men and women have shown gaps in memory for everyday events (dissociative amnesia),

 an attentional bias for trauma-related material,

Neuroimaging studies showed alterations in the hippocampus in patients with PTSD. MRI scans showed smaller volume of the hippocampus in patients with PTSD, particularly decreases in right hippocampal volume that were associated with deficits in short-term memory.

 Findings of smaller hippocampal volume and/or a reduction in 

-acetylaspartate (NAA) in the hippocampus (a marker of neuronal integrity) in adults with chronic PTSD have been replicated in the literature.

 and new-onset PTSD (including patients presenting to the ED)

 did not find hippocampal volume reduction, although reduced levels of NAA--indicating loss of neuronal integrity--were found in the medial prefrontal cortex in children with PTSD.

Findings of a meta-analysis revealed smaller hippocampal volume for both the left and the right sides, equally in adult men and women with chronic PTSD, and no change in children.

 Patients with PTSD also had deficits in hippocampal activation while performing a verbal declarative memory task.

A 42-year-old woman was exposed to carbon monoxide while working at a retail store. She recalled headache, dizziness, blurred vision, jitteriness, nausea, and vomiting prior to losing consciousness. She regained consciousness and was transported via ambulance to a nearby hospital, during which time she again lost consciousness. Upon admittance, the patient's carboxyhemoglobin level was elevated to 25.6%. She was transported by helicopter to another hospital where she received 2 courses of hyperbaric oxygen therapy, which resulted in significant symptom reduction. She was discharged 3 days later. Her records indicate that electroencephalography, MRI, and chest radiography demonstrated unremarkable findings and both her initial and follow-up examinations were unremarkable. Thus, she was cleared for return to work.

However, the patient reported numerous physical and cognitive complaints following the event, including photosensitivity, severe headache, daily nausea, myospasm, myalgia, and constant pain in her chest, legs, and joints. Cognitively, she complained of difficulty in concentrating and memory deficits for recent events and information. She underwent neuropsychological evaluation several months after the event, at which time fexofenadine, carisoprodol, guaifenesin/dextromethorphan/phenylephrine, duloxetine, tizanidine, escitalopram, and celecoxib were prescribed. Her medical history was significant for tubal ligation, and she denied any previous loss of consciousness or head injuries and tobacco, alcohol, or illicit drug use.	

The patient reported a number of mood and behavioral changes since the event and had nightmares that related to her trauma. She returned to her job for approximately 1 week after being discharged but could not continue working because of anxiety, fatigue, and psychological distress and increased arousal related to being in the workplace. She avoided returning to work, was less socially active, went to church less often, stopped volunteering for various organizations, and would stay in bed for several days each week.

She felt a restricted range of affect--what she described as being mentally dull. Her startle response was exaggerated, and she was more emotionally labile, irritable, and jumpy. The patient had difficulty in falling asleep and often woke in the middle of the night when having nightmares that related to her trauma and could not return to sleep. She also had panic attacks and increased anxiety. She reported having difficulty in concentrating and was easily distracted. She acknowledged passive suicidal ideations once while driving but denied current thoughts or plans.

During the neuropsychological examination, the patient was tearful. She found the memory tests particularly difficult and commented that she was "smarter" before the event. Her examination revealed a mild decrease in visual processing span and in the mental manipulation of such information. She showed mild reductions in her ability to learn visuospatial material and severe deficits in her retention of this information over time. She also demonstrated mild deficits in immediate verbal recall, but her performance was average when verbal material was presented in a meaningful context. In addition, she tended to confuse the verbal contents of her memory.

The MMPI-2 was administered, and findings revealed an overall highly elevated clinical profile. Her results indicated that she was overwhelmed by her internal distress, and she endorsed items that reflected a high number of atypical sensory experiences, a loss of a sense of control over her own mental and physical operations, and a general sense of alienation from others.

This patient was treated with an antidepressant with little improvement in symptoms of PTSD.

Preclinical studies show that there is a window during which modification of traumatic memories may affect long-term outcome. In animals that have encoded a traumatic memory, lesions of the hippocampus within the first month will cancel the memory. After a month, hippocampal lesions have no effect on the memory. These studies suggest that there is a critical window of memory consolidation during which memories are stored within the hippocampus and are susceptible to memory consolidation; after this period, memories are stored in the cerebral cortex and are indelible and no longer susceptible to modification.

 Thus, early interventions are important to prevent the development of indelible memories that will maintain chronic PTSD. However, there is not enough evidence to support specific acute therapies for PTSD.

The early period after trauma exposure is a window of time that is very different from chronic phases of PTSD. Therefore, it cannot be assumed that the same treatments will be effective. Animal studies suggest that early interventions may prevent the development of indelible traumatic memories that are resistant to treatment.

 However, not all treatments of early trauma responses will necessarily be effective. Given this situation, it is important to determine whether early interventions are working.

Few studies have examined treatment efficacy in the acute aftermath of trauma. One study showed that cognitive behavioral therapy resulted in improvement in 58% of acute trauma victims versus 8% for supportive therapy.

 For years, military psychiatrists have relied on anecdotal evidence and treated acutely traumatized soldiers with benzodiazepines or chlorpromazine on the battlefield and have kept them close to the front lines. They knew from experience that if you removed a soldier from the front lines, it would be almost impossible to get him to go back. These military psychiatrists were, in effect, practicing a form of desensitization therapy. In other words, exposure to the front lines promoted extinction of fear responses to the traumatic stimulus--in this case, reminders of combat.

Studies of pharmacotherapy for chronic PTSD, although limited, are more advanced than research in the area of acute trauma. These studies, as well as preclinical studies of the neurobiology of stress and treatment response, may help guide thinking about pharmacotherapy for acute trauma. These findings should be applied with caution to acute trauma, since one cannot assume that efficacy for chronic PTSD will translate into effectiveness in prevention of the development of psychopathology in acute trauma survivors.

The dynamic between brain injury and PTSD in patients presenting to the ED is complicated. Cognitive problems can arise from either brain injury or PTSD. Mild cognitive deficits are part of PTSD even without known brain injury. In patients with blows to the head in whom brain injury is not seen on MRI scans, it is difficult, if not impossible, to determine whether the cognitive deficits are due to PTSD, the head injury, or both.	*

1. Bryant RA, Moulds M, Guthrie R, Nixon RD. Treating acute stress disorder following mild traumatic brain injury. 

2003;160:585-587.2. Bryant RA. Posttraumatic stress disorder and mild brain injury: controversies, causes and consequences. 

2001;23:718-728.3. American Psychiatric Association. 

Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision)

. Washington, DC: American Psychiatric Press; 2000.4. Harvey AG, Brewin CR, Jones C, Kopelman MD. Coexistence of posttraumatic stress disorder and traumatic brain injury: towards a resolution of the paradox. 

2003;9:663-676.5. Gil S, Caspi Y, Ben-Ari IZ, et al. Does memory of a traumatic brain event increase the risk for posttraumatic stress disorder in patients with traumatic brain injury? A prospective study. 

2005;162:963-969.6. Glaesser J, Neuner F, Lutgehetmann R, et al. Posttraumatic stress disorder in patients with traumatic brain injury. 

2004;4:5.7. Mather FJ, Tate RL, Hannan TJ. Post-traumatic stress disorder in children following road traffic accidents: a comparison of those with and without mild traumatic brain injury. 

2003;17:1077-1087.8. Bryant RA, Marosszeky JE, Crooks J, Gurka JA. Posttraumatic stress disorder after severe traumatic brain injury. 

2000;157:629-631.9. Bryant RA, Marosszeky JE, Crooks J, et al. Posttraumatic stress disorder and psychosocial functioning after severe traumatic brain injury. 

2001;189:109-113.10. Bryant RA, Marosszeky JE, Crooks J, et al. Coping style and post-traumatic stress disorder following severe traumatic brain injury. 

2000; 14:175-180.11. Creamer M, O'Donnell ML, Pattison P. Amnesia, traumatic brain injury, and posttraumatic stress disorder: a methodological inquiry. 

2005;43:1383-1389.12. Hickling EJ, Gillen R, Blanchard EB, et al. Traumatic brain injury and posttraumatic stress disorder: a preliminary investigation of neuropsychological test results in PTSD secondary to motor vehicle accidents. 

1998;12:265-274.13. Sumpter RE, McMillan TM. Misdiagnosis of post-traumatic stress disorder following severe traumatic brain injury. 

2005;186:423-426.14. Williams WH, Evans JJ, Needham P, Wilson BA. Neurological, cognitive and attributional predictors of posttraumatic stress symptoms after traumatic brain injury. 

2002;15:397-400.15. Flesher MR, Delahanty DL, Raimonde AJ, Spoonster E. Amnesia, neuroendocrine levels and PTSD in motor vehicle accident victims. 

2001;15:879-889.16. Luine V, Villegas M, Martinez C, McEwen BS. Repeated stress causes reversible impairments of spatial memory performance. 

1994;639: 167-170.17. Uno H, Tarara R, Else JG, et al. Hippocampal damage associated with prolonged and fatal stress in primates. 

1989;9:1705-1711.18. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. 

1990;10:2897-2902.19. Diamond DM, Fleshner M, Ingersoll N, Rose GM. Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. 

1996;110: 661-672.20. Sapolsky RM. Why stress is bad for your brain. 

1996;273:749-750.21. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. 

1995;15: 1768-1777.22. McEwen BS, Angulo J, Cameron H, et al. Paradoxical effects of adrenal steroids on the brain: protection versus degeneration. 

1992;31:177-199.23. Fowler CD, Liu Y, Ouimet C, Wang Z. The effects of social environment on adult neurogenesis in the female prairie vole. 

2002;51:115-128.24. Buckley TC, Blanchard EB, Neill WT. Information processing and PTSD: a review of the empirical literature. 

Articles

The following 3 cases illustrate the diagnostic challenges related to differentiating brain injury and posttraumatic stress disorder (PTSD) in patients presenting to the emergency department (ED) in the acute period following a traumatic injury. Such patients pose a dilemma for ED clinicians because of the interplay between head injury and PTSD in the clinical presentation of cognitive impairments in the aftermath of trauma.

PTSD in the Emergency Setting

Stress reactions can be a normal response to traumatic events. However, sometimes such a response can be complicated by brain injury, the symptoms of which can be difficult to disentangle from symptoms of posttraumatic stress disorder (PTSD). In the acute period, acute stress disorder (ASD), which is characterized by symptoms of hyperarousal and dissociation, can develop. When stress symptoms persist in the aftermath of trauma, they can lead to chronic PTSD. Here we review the presentation of PTSD symptoms and discuss various approaches to treatment.

The consequences of acute psychological trauma have long been recognized. Syndromes of "traumatic neurosis" and "shell shock" were initially described during World War I. Soldiers were noted to forget their name or where they were on the battlefield; they also experienced hyperarousal and extreme fear with reminders of the trauma.

Over the course of the 20th century, diagnostic conceptualizations have changed. In earlier versions of the 

Diagnostic and Statistical Manual of Mental Disorders

), "gross stress reaction" was conceived as a temporary response. In 1980, when PTSD was included in the third edition of the 

 the effects of stress were thought to be long lasting in a subgroup of patients. Since the official recognition of PTSD, there has been increased awareness of the potentially debilitating effects of traumatic stress.

PTSD is characterized by specific symptoms that develop after exposure to a "threat to the life of oneself or others accompanied by intense fear, horror, or helplessness."

 PTSD can have an acute or delayed onset after a traumatic event. Symptoms must be present for at least 1 month to meet the minimum criteria for a diagnosis of PTSD.

Three symptom categories are representative of PTSD:

•Intrusion symptoms (intrusive memories, flashbacks, feeling worse with reminders of the trauma, and nightmares).

•Avoidance symptoms (avoidance of thinking about the event, avoidance of reminders, decreased concentration, amnesia, feeling cut off from others, and a sense of foreshortened future).

•Hyperarousal symptoms (increased startle response, hyperarousal, hypervigilance, and decreased sleep).

To meet the criteria for diagnosis, a patient must have 1 intrusion, 3 avoidance, and 2 hyperarousal symptoms.

 listed both acute and chronic PTSD, the latest version of the 

 only includes a general PTSD category with a symptom-duration requirement of 2 months.

About 30% of persons who survived a trauma will meet criteria for PTSD early after the trauma; chronic PTSD will develop in about half of these patients.

 There is some evidence that early interventions can prevent the development of chronic PTSD, but not all interventions are necessarily helpful in all patients. On a biologic level, early modifications while memories are being consolidated--to prevent memories from becoming strongly engraved and indelible--are thought to be most useful.

ASD can be diagnosed in the immediate aftermath of a trauma. For an ASD diagnosis, a patient must meet criterion A as in PTSD and also have 3 or more of the following dissociative symptoms during or immediately after the trauma

•A subjective sense of numbing, detachment, or absence of emotional responsiveness.

•A reduction in awareness of surroundings (eg, "being in a daze").

•Dissociative amnesia (ie, inability to recall an important aspect of the trauma).

In addition, persons with ASD will persistently reexperience the traumatic event through recurrent images, thoughts, dreams, illusions, flashback episodes, or a sense of reliving the experience; or experience distress on exposure to reminders of the traumatic event. They will also avoid stimuli that arouse recollections of the trauma (eg, thoughts, feelings, conversations, activities, places, people); have marked anxiety or increased arousal (eg, difficulty in sleeping, irritability, poor concentration, hypervigilance, exaggerated startle response, motor restlessness); and have clinically significant distress or impairment in social, occupational, or other important areas of functioning, or have impairments in ability to pursue some necessary task, such as obtaining necessary assistance or mobilizing personal resources by telling family members about the traumatic experience.

ASD must last at least 2 days and at most 4 weeks, occur within 4 weeks of the traumatic event, not be caused by the direct physiologic effects of a substance (a drug of abuse or a medication) or a general medical condition, not be better accounted for by brief psychotic disorder, and not be merely an exacerbation of a preexisting axis I or axis II disorder.

Other psychiatric disorders associated with trauma exposure include depression, anxiety, dissociative disorders, eating disorders, alcohol abuse, and substance use disorders. There is considerable overlap or comorbidity in trauma patients with these diagnoses. It has been argued that these disorders should be considered part of a "trauma spectrum" of psychiat- ric disorders, all sharing a stress- induced alteration in brain circuits and systems.

Both peritraumatic dissociation and trauma-related persistent dissociation have been demonstrated to be markers for long-term psychopathology.

 In addition, extreme feelings of panic in the aftermath of a psychological trauma, which may underlie the dissociative reaction, have been associated with poor long-term outcome.

 Persistent elevations of heart rate (at 1 week but not at 1 month) in the aftermath of trauma also have been associated with long-term psychopathology.

Psychotherapy and medication, alone or in combination, are the current treatments of PTSD. Medication is often required if symptoms are severe and long lasting; psychiatric comorbidities are present; or the patient is suicidal, continues to experience significant amounts of stress, has great difficulties with functioning, or has not responded to psychotherapy alone. Two selective serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, have received FDA approval for PTSD. However, many other medications are also used to manage the disorder.

Side effects associated with tricyclic antidepressants (TCAs) and dietary restrictions with monoamine oxidase inhibitors (MAOIs) have led most clinicians to treat patients who have a stress disorder with more recently developed medications, such as SSRIs. Thus, SSRIs are the most widely used first-line therapy for PTSD.

 Expert consensus guidelines support this use of SSRIs, suggesting treatment of 12 months or more, and also recommend the use of exposure-type behavioral therapies.

Myriad studies have tested the effectiveness of various medications for managing PTSD. The first controlled trial of medication for chronic PTSD compared the MAOI phenelzine and the TCA imipramine with placebo in persons with chronic combat-related PTSD and found that both medications were more effective than placebo.

 Phenelzine was effective primarily in PTSD for intrusion symptoms but not avoidance symptoms.

A study of patients with mixed causes of PTSD (civilian and combat) found no efficacy for phenelzine compared with placebo;

 nor did a study comparing the norepinephrine reuptake inhibitor desipramine with placebo.

 However, these results are probably influenced by the short (4-week) treatment duration. Patients taking amitriptyline showed significant improvement in combat-related PTSD symptoms, compared with patients taking placebo.

 TCAs and MAOIs are as effective as or more effective than SSRIs, but 5 weeks of treatment are necessary for efficacy.

Compared with placebo, fluoxetine is effective in patients with PTSD related to civilian events but not combat events,

 whereas nefazodone, which has both SSRI and postsynaptic serotonin receptor antagonist properties, was effective for managing combat-related PTSD.

 The mean dosage of nefazodone was 424 mg/d, and improvement was noted in intrusion, avoidance, arousal, depression, anxiety, and sleep symptoms. In a placebo-controlled trial, brofaromine effectively managed PTSD, but the drug manufacturer did not pursue FDA approval for this indication.

 Other medications shown to be effective in the management of PTSD include valproic acid, carbamazepine, alprazolam, propranolol, clonidine, mirtazapine, fluvoxamine, and bupropion.

The first medication to receive FDA approval in the United States for the indication of PTSD was sertraline. A multisite comparison of sertraline (50 to 200 mg/d) versus placebo in 187 outpatients with PTSD showed efficacy for PTSD symptoms in the avoidance and hyperarousal categories but not the intrusion category.

 Twelve weeks of treatment resulted in a medication response rate of 53% at study end point, compared with 32% for placebo. Sertraline was well tolerated, with insomnia as the only adverse effect reported significantly more often than with placebo. Sertraline use was associated with greater treatment response in women than in men.

Emerging data from open-label trials demonstrate efficacy in paroxetine comparable with the findings in sertraline studies.

 A recent study of paroxetine in 551 patients showed up to a 40-point drop in PTSD symptoms as measured with the Clinician Administered PTSD Scale, indicating a significant decrease in PTSD symptom severity.

 Symptom improvement was seen in all of the PTSD symptom categories, including intrusion, avoidance, and arousal.

In one of the few studies of pharmacologic treatment of acute trauma, 4 patients were treated within 1 to 3 weeks of trauma exposure with the benzodiazepine hypnotic temazepam for 5 nights followed by a 2-day taper and discontinuation.

 One week after discontinuation, patients reported improved sleep and reduced PTSD severity. The authors concluded that controlled trials are needed in this area.

Imipramine was compared with chloral hydrate for children who were acute burn victims; imipramine treatment led to a significant improvement in psychiatric symptoms compared with chloral hydrate.

 In the only controlled study comparing active medication with placebo in acute trauma survivors presenting to an ED, the benzodiazepine alprazolam actually increased the risk of long-term development of PTSD.

Although behavioral treatments are outside the scope of this review, it is of interest in this context to note that treatments such as psychological debriefing or critical incident stress debriefing, which are offered to acute trauma survivors, have been found in several studies to actually worsen outcome relative to no treatment at all.

 There is a natural tendency for psychiatrists and other emergency physicians to want to do something for the acute trauma patient. However, these studies should give us pause before we prescribe or recommend untested treatments. Surely, more research needs to be done in this important area.

Preclinical studies, which show that stress-induced stimulation of noradrenergic function may modulate the laying down of traumatic memories, have stimulated interest in the use of agents that may block noradrenergic function for the treatment of acute trauma. Animal studies have shown that pharmacologic blockade of the b receptor in the amygdala prevents the laying down of emotionally aversive memory. With this in mind, Pitman and colleagues

 treated patients in the ED with the noradrenergic b-blocker propranolol within 6 hours of experiencing trauma and continued treatment for 10 days. Propranolol did not lead to a significant reduction in PTSD symptoms compared with placebo, but there was a decrease in conditioned responses to traumatic reminders. This study suggests that propranolol interfered with the acquisition of conditioned responses but not the development of core PTSD symptoms.

Given the absence of empiric information on the treatment of acute trauma, some guidance may be gleaned from preclinical studies of the neurobiology of stress, which have identified specific circuits and systems that should be targeted for potential pharmacologic interventions.

 However, these systems are plastic and their regulation continues to undergo modification in the aftermath of acute trauma extending into the period of chronicity.

Based on these preclinical studies, new classes of compounds have been recently introduced that may be applicable to the treatment of acute trauma. These include more specific serotonergic agents, corticotropin-releasing factor (CRF) antagonists, antiadrenergic compounds, agents normalizing opioid function, neuropeptide Y enhancers, drugs to down-regulate glucocorticoid receptors, substance P antagonists, 

-methyl-d-aspartate facilitators, and antikindling/antisensitization anticonvulsants.

 CRF antagonists show particular promise given their role in preventing the negative behavioral consequences of stress in animal studies.

Some medications that have efficacy for sleep disturbance or other troubling symptoms may be useful for acute trauma victims, even if they are not associated with broad-based improvements in all trauma-related symptoms. Nefazodone, for example, has proved useful in sleep-related problems in PTSD.

-adrenergic antagonist prazosin was demonstrated to be effective for nightmares in patients with PTSD.

Based on the hypothesis that the trauma-related symptom of emotional numbing is an opiate-mediated phenomenon, there has been some interest in opiate antagonist medications for PTSD. A trial of nalmefene, a non-FDA-approved oral opiate antagonist, showed a favorable response, with a marked decrease of emotional numbing and other symptoms of PTSD--including startle response, nightmares, flashbacks, intrusive thoughts, rage, and vulnerability--in half of the patient sample.

 There is some preliminary evidence that increased activity of the opioid system may contribute to dissociative symptoms, including flashbacks and other symptoms commonly seen in trauma victims, and that these symptoms may respond to opiate antagonists such as naltrexone.

Findings of hippocampal damage in stress and PTSD have promoted interest in mood-stabilizing and antiepileptic medications for the treatment of trauma-related disorders. Theories of kindling and sensitization in the hippocampus, which have been invoked as causes of epilepsy, have also been suggested to underlie the development of chronic PTSD. Medications used for epilepsy, such as carbamazepine and valproic acid, also have effects on mood and have been shown to be efficacious in open-label trials in PTSD, while a 12-week placebo-controlled trial of lamotrigine showed improvement on both reexperiencing and avoidance/numbing symptoms.

 Phenytoin is an agent of particular interest, since it is effective in epilepsy and has been shown in animal studies to block the negative effects of stress on hippocampal morphology.

Benzodiazepines might be of interest to investigate in the treatment of acute trauma. However, the one controlled study does not support this approach.

 Gabapentin, which modulates GABAergic function, may be useful in PTSD and deserves further study.

 CRF receptor antagonists may represent a novel class of antidepressants and anxiolytics; their development is still in its infancy, though they have shown promise in animal studies.

Antidepressants promote neurogenesis in the hippocampus and improve memory in preclinical studies.

 The effects of stress on the hippocampus are reversible with treatment with SSRIs,

 Antidepressant-induced promotion of neurogenesis may influence the behavioral effects of these medications,

 although the relationship between the hippocampus and depression and PTSD is still not clear.

Hippocampal volume loss and memory deficits were reversed in patients with PTSD following treatment with the SSRI paroxetine.

 Treatment with phenytoin resulted in improved PTSD symptoms,

 a 6% increase in right cerebral volume, and a 5% increase in right hippocampal volume.

 These findings suggested that long-term treatment with paroxetine or phenytoin is associated with changes in brain structure that may improve symptoms as well as memory problems.

Patients presenting to the ED with PTSD symptoms of intense fear and persistent elevated heart rate may benefit from treatment with propranolol. A single dose of a benzodiazepine may be needed in some situations; however, prolonged use is not known to be effective in PTSD and may interfere with memory consolidation processes that can lead to recovery.

Current recommendations for the treatment of PTSD include SSRI therapy and cognitive behavioral therapy. Patients who have sustained symptoms should be considered candidates for these treatments. Other medications mentioned in this article may be helpful, but their usefulness is dependent on the particular symptom being targeted.

Unfortunately, little is known about effective pharmacologic interventions for acute psychological trauma, with the only published controlled trial showing that benzodiazepine treatment (which has been commonly used in clinical practice in combat situations) actually makes patients worse in the long run. The use of SSRIs for chronic PTSD is well established. However, there is no evidence that SSRIs prevent the development of chronic PTSD.

Given findings that certain treatments for patients in the acute stages may make things worse, psychiatrists and other physicians need to proceed with caution when managing acute stress reactions.

Some studies show that propranolol has efficacy in PTSD prevention by blocking the encoding of negative memories, possibly through blockage of noradrenergic b receptors in the amygdala. Studies of the neurobiology of stress will continue to guide our drug development and will suggest future clinical trials that should be undertaken. New agents, such as CRF antagonists, offer particular interest for studies of the pharmacotherapy of acute trauma with applications to prevention. *

1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (Text Revision). Washington, DC: American Psychiatric Press; 2000.
2. Kulka RA, Schlenger WE, Fairbank JA, et al. Trauma and the Vietnam War Generation: Report of findings From the National Vietnam Veterans Readjustment Study. New York: Brunner/Mazel; 1990.
3. Bremner JD. Does Stress Damage the Brain? Understanding Trauma-Related Disorders From a Mind-Body Perspective. New York: WW Norton; 2002.
4. Marmar CR, Weiss DS, Schlenger WE, et al. Peritraumatic dissociation and posttraumatic stress in male Vietnam theater veterans. Am J Psychiatry. 1994;151:902-907.
5. Bremner JD, Marmar C, eds. Trauma, Memory, and Dissociation. Washington, DC: American Psychiatric Press; 1998.
6. Cardena E, Spiegel D. Dissociative reactions to the San Francisco Bay Area earthquake of 1989. Am J Psychiatry. 1993;150:474-478.
7. Bryant RA, Panasetis P. The role of panic in acute dissociative reactions following trauma. Br J Clin Psychol. 2005;44:489-494.
8. Bryant RA, Marosszeky JE, Crooks J, Gurka JA. Elevated resting heart rate as a predictor of posttraumatic stress disorder after severe traumatic brain injury. Psychosom Med. 2004;66:760-761.
9. Alarcon RD, Glover S, Boyer W, Balon R. Proposing an algorithm for the pharmacological management of posttraumatic stress disorder. Ann Clin Psychiatry. 2000;12:239-246.
10. Ballenger JC, Davidson JR, Lecrubier Y, et al. Consensus statement on posttraumatic stress disorder from the International Consensus Group on Depression and Anxiety. J Clin Psychiatry. 2000; 61(suppl 5):60-66.
11. Frank JB, Kosten TR, Giller EL Jr, Dan E. A randomized clinical trial of phenelzine and imipramine for posttraumatic stress disorder. Am J Psychiatry. 1988;145:1289-1291.
12. Shestatzky M, Greenberg D, Lerer B. A controlled trial of phenelzine in posttraumatic stress disorder. Psychiatry Res. 1988;24:149-155.
13. Reist C, Kauffmann CD, Haier RJ, et al. A controlled trial of desipramine in 18 men with posttraumatic stress disorder. Am J Psychiatry. 1989;146: 513-516.
14. Davidson J, Kudler H, Smith R, et al. Treatment of posttraumatic stress disorder with amitriptyline and placebo. Arch Gen Psychiatry. 1990;47:259-266.
15. Cyr M, Farrar MK. Treatment for posttraumatic stress disorder. Ann Pharmacother. 2000;34:366-376.
16. van der Kolk BA, Dreyfuss D, Michaels M, et al. Fluoxetine in posttraumatic stress disorder. J Clin Psychiatry. 1994;55:517-522.
17. Zisook S, Chentsova-Dutton YE, Smith-Vaniz A, et al. Nefazodone in patients with treatment-refractory posttraumatic stress disorder. J Clin Psychiatry. 2000;61:203-208.
18. Baker DG, Diamond BI, Gillette G, et al. A double-blind, randomized, placebo-controlled, multi-center study of brofaromine in the treatment of post-traumatic stress disorder. Psychopharmacology (Berl). 1995;122:386-389.
19. Sutherland SM, Davidson JR. Pharmacotherapy for post-traumatic stress disorder. Psychiatr Clin North Am. 1994;17:409-423.
20. Brady K, Pearlstein T, Asnis GM, et al. Efficacy and safety of sertraline treatment of posttraumatic stress disorder: a randomized controlled trial. JAMA. 2000;283:1837-1844.
21. Marshall RD, Schneier FR, Fallon BA, et al. An open trial of paroxetine in patients with noncombat-related, chronic posttraumatic stress disorder. J Clin Psychopharmacol. 1998;18:10-18.
22. Marshall RD, Beebe KL, Oldham M, Zaninelli R. Efficacy and safety of paroxetine treatment for chronic PTSD: a fixed-dose, placebo-controlled study. Am J Psychiatry. 2001;158:1982-1988.
23. Mellman TA, Byers PM, Augenstein JS. Pilot evaluation of hypnotic medication during acute traumatic stress response. J Trauma Stress. 1998;11: 563-569.
24. Robert R, Blakeney PE, Villarreal C, et al. Imipramine treatment in pediatric burn patients with symptoms of acute stress disorder: a pilot study. J Am Acad Child Adolesc Psychiatry. 1999;38:873-882.
25. Gelpin E, Bonne O, Peri T, et al. Treatment of recent trauma survivors with benzodiazepines: a prospective study. J Clin Psychiatry. 1996;57:390-394.
26. Rose S, Bisson J, Churchill R, Wessely S. Psychological debriefing for preventing post traumatic stress disorder (PTSD). Cochrane Database Syst Rev. 2002;2:CD000560.
27. Pitman RK, Sanders KM, Zusman RM, et al. Pilot study of secondary prevention of posttraumatic stress disorder with propranolol. Curr Psychiatry Rep. 2004;51:241-242.
28. Luine V, Villegas M, Martinez C, McEwen BS. Repeated stress causes reversible impairments of spatial memory performance. Brain Res. 1994;639: 167-170.
29. Uno H, Tarara R, Else JG, et al. Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci. 1989;9:1705-1711.
30. Sapolsky RM, Uno H, Rebert CS, Finch CE. Hippocampal damage associated with prolonged glucocorticoid exposure in primates. J Neurosci. 1990;10:2897-2902.
31. Diamond DM, Fleshner M, Ingersoll N, Rose GM. Psychological stress impairs spatial working memory: relevance to electrophysiological studies of hippocampal function. Behav Neurosci. 1996;110: 661-672.
32. Sapolsky RM. Why stress is bad for your brain. Science. 1996;273:749-750.
33. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995;15: 1768-1777.
34. McEwen BS, Angulo J, Cameron H, et al. Paradoxical effects of adrenal steroids on the brain: protection versus degeneration. Biol Psychiatry. 1992; 31:177-199.
35. Fowler CD, Liu Y, Ouimet C, Wang Z. The effects of social environment on adult neurogenesis in the female prairie vole. J Neurobiol. 2002;51:115-128.
36. Friedman MJ. What might the psychobiology of posttraumatic stress disorder teach us about future approaches to pharmacotherapy? J Clin Psychiatry. 2000;61(suppl 7):44-51.
37. Mellman TA, David D, Barza L. Nefazodone treatment and dream reports in chronic PTSD. Depress Anxiety. 1999;9:146-148.
38. Raskind MA, Dobie DJ, Kanter ED, et al. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000;61:129-133.
39. Glover H. A preliminary trial of nalmefene for the treatment of emotional numbing in combat veterans with post-traumatic stress disorder. Isr J Psychiatry Relat Sci. 1993;30:255-263.
40. Bills LF, Kreisler K. Treatment of flashbacks with naltrexone. Am J Psychiatry. 1993;150:1430.
41. Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary study of lamotrigine for the treatment of posttraumatic stress disorder. Biol Psychiatry. 1999;45:1226-1229.
42. Hui Z, Guang-Yu M, Chong-Tao X, et al. Phenytoin reverses the chronic stress-induced impairment of memory consolidation for water maze training and depression of LTP in rat hippocampal CA1 region, but does not affect motor activity. Brain Res Cogn Brain Res. 2005;24:380-385.
43. Reagan LP, McKittrick CR, McEwen BS. Corticosterone and phenytoin reduce neuronal nitric oxide synthase messenger RNA expression in rat hippocampus. Neuroscience. 1999;91:211-219.
44. Watanabe Y, Gould E, Cameron HA, et al. Phenytoin prevents stress- and corticosterone- induced atrophy of CA3 pyramidal neurons. Hippocampus. 1992;2:431-435.
45. Brannon N, Labbate L, Huber M. Gabapentin treatment for posttraumatic stress disorder. Can J Psychiatry. 2000;45:84.
46. Arborelius L, Skelton KH, Thrivikraman KV, et al. Chronic administration of the selective corticotropin-releasing factor 1 receptor antagonist CP-154,526: behavioral, endocrine and neurochemical effects in the rat. J Pharmacol Exp Ther. 2000;294: 588-597.
47. Habib KE, Weld KP, Rice C, et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc Natl Acad Sci U S A. 2000;97: 6079-6084.
48. Vermetten E, Vythilingam M, Southwick SM, et al. Long-term treatment with paroxetine increases verbal declarative memory and hippocampal volume in posttraumatic stress disorder. Biol Psychiatry. 2003;54:693-702.
49. Malberg JE, Eisch AJ, Nestler EJ, Duman RS. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J Neurosci. 2000; 20:9104-9110.
50. Duman RS, Malberg J, Nakagawa S. Regulation of adult neurogenesis by psychotropic drugs and stress. J Pharmacol Exp Ther. 2001;299:401-407.
51. Lee HJ, Kim JW, Yim SV, et al. Fluoxetine enhances cell proliferation and prevents apoptosis in dentate gyrus of maternally separated rats. Mol Psychiatry. 2001;6:610, 725-728.
52. Czeh B, Michaelis T, Watanabe T, et al. Stress-induced changes in cerebral metabolites, hippocampal volume, and cell proliferation are prevented by antidepressant treatment with tianeptine. Proc Natl Acad Sci U S A. 2001;98:12796-12801.
53. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809.
54. Bremner JD, Mletzko T, Welter S, et al. Treatment of posttraumatic stress disorder with phenytoin: an open-label pilot study. J Clin Psychiatry. 2004;65:1559-1564.
55. Bremner JD, Mletzko T, Welter S, et al. Effects of phenytoin on memory, cognition and brain structure in post-traumatic stress disorder: a pilot study. J Psychopharmacol. 2005;19:159-165.
56. Foa EB, Davidson JRT, Frances A, Ross R. Expert consensus treatment guidelines for posttraumatic stress disorder: a guide for patients and families. J Clin Psychiatry. 1999;60(suppl 16):4-76.
57. Staab JP. Posttraumatic stress disorder: drug therapy. American College of Physicians, Physicians' Information and Education Resource. Available at: http://pier.acponline.org/physicians/public/d251/ drug.tx/d251-s7.html. Accessed July 5, 2006.

The presentation of patients to the emergency department following trauma is often complicated by the behavioral reaction to the accident that brought them there. In some cases, the mental reaction to psychological trauma is the primary presenting phenomenon. ED physicians and staff often use medication to treat the acute effects of psychological trauma. However, there is little empiric evidence to support this practice.

Author | J. Douglas Bremner, MD

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