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Pharmacotherapies for Acute and Chronic Responses to Psychological Trauma

Pharmacotherapies for Acute and Chronic Responses to Psychological Trauma

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 (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").



•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


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


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