Pharmacotherapies for Acute and Chronic Responses to Psychological Trauma

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.

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.

RESPONSES TO PSYCHOLOGICAL TRAUMA

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

Posttraumatic Stress Disorder

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."1 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.1 Although earlier versions of the DSM listed both acute and chronic PTSD, the latest version of the DSM 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.2 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.

Acute Stress Disorder

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 trauma1:

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

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

•Derealization.

•Depersonalization.

•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 Trauma-Related Disorders

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.3

Both peritraumatic dissociation and trauma-related persistent dissociation have been demonstrated to be markers for long-term psychopathology.4-6 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.7 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.8

PHARMACOTHERAPY FOR PTSD

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.9 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.10

Efficacy of Medication

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.11 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;12 nor did a study comparing the norepinephrine reuptake inhibitor desipramine with placebo.13 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.14 TCAs and MAOIs are as effective as or more effective than SSRIs, but 5 weeks of treatment are necessary for efficacy.15

Compared with placebo, fluoxetine is effective in patients with PTSD related to civilian events but not combat events,16 whereas nefazodone, which has both SSRI and postsynaptic serotonin receptor antagonist properties, was effective for managing combat-related PTSD.17 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.18 Other medications shown to be effective in the management of PTSD include valproic acid, carbamazepine, alprazolam, propranolol, clonidine, mirtazapine, fluvoxamine, and bupropion.19

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.20 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.21 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.22 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.23 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.24 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.25

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.26 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 colleagues27 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.28-35 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, N-methyl-d-aspartate facilitators, and antikindling/antisensitization anticonvulsants.36 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.37 In addition, the a1-adrenergic antagonist prazosin was demonstrated to be effective for nightmares in patients with PTSD.38

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.39 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.40

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.41 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.42-44

Benzodiazepines might be of interest to investigate in the treatment of acute trauma. However, the one controlled study does not support this approach.25 Gabapentin, which modulates GABAergic function, may be useful in PTSD and deserves further study.45 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.46,47

Antidepressants promote neurogenesis in the hippocampus and improve memory in preclinical studies.48 The effects of stress on the hippocampus are reversible with treatment with SSRIs,49-51 tianeptine,52 and phenytoin.44 Antidepressant-induced promotion of neurogenesis may influence the behavioral effects of these medications,53 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.48 Treatment with phenytoin resulted in improved PTSD symptoms,54 a 6% increase in right cerebral volume, and a 5% increase in right hippocampal volume.55 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.48

TREATING PTSD IN THE ED

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.

SUMMARY

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. *

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