Propranolol for the Treatment of Acute Stress Disorder

Stress Disorders, Traumatic, Acute Clinical Trial

Official title: Propranolol For the Treatment of Acute Stress Disorder

Status Completed

Clinical Trial Summary

This 10-week study will examine whether propranolol, a medication that blocks the activity of the stress hormones adrenaline and noradrenaline, can relieve acute stress disorder (ASD) and symptoms from persisting long-term. ASD is a condition that some people develop soon after exposure to trauma. They may be anxious, depressed, have trouble sleeping, startle easily, have difficulties concentrating, and feel as though the event is happening again. Propranolol has been used for many years to treat high blood pressure and heart disease, and has been found useful in treating anxiety states such as social phobia and migraine.

Men and women between 18 and 65 years of age who were recently exposed to trauma (between 1 and 3 weeks of evaluation in this study) may be eligible for this study. Candidates must be diagnosed with ASD and must have been mentally healthy before the traumatic event. They will be screened for the study with a medical and psychiatric interview, physical examination, electrocardiogram (EKG), and blood and urine tests.

Participants will be evaluated with the following procedures:

• Neuropsychological tests using pen-and-paper and computer tests to evaluate cognitive function, particularly memory, learning, attention and concentration, and vocabulary and naming.

• Emotion-related performance tasks to determine if the study medication can weaken emotionally arousing information by blocking the activity of adrenaline and noradrenaline. Subjects perform emotion-related and neutral tasks, such as looking at pictures with neutral, pleasant, or unpleasant content, both before and after treatment with the study medication (see below).

• Traumatic script exposure: Subjects recount the traumatic event that caused them to develop ASD. The description is summarized, recorded, and played back to the subject. During the playback, physiological responses, such as heart rate and skin conductance (sweating), are recorded using electrodes taped to the hand and chest.

• Fear conditioning to evaluate the response to an unpleasant stimulus: Several mild electrical shocks are delivered to the wrists while the subject looks at colored squares. Heart rate and skin conductance are measured.

• Magnetic resonance imaging (MRI) to examine brain structure. The subject lies on a table that is moved into the MRI scanner (a narrow cylinder containing a strong magnetic field) and must remain still during the actual scanning. Earplugs are worn to muffle loud noises caused by electrical switching of radio frequency circuits used in the scanning process.

After the evaluation, participants are randomly assigned to receive either propranolol or placebo (a look-alike pill with no active ingredient) for 8 weeks During this time they are seen by a doctor once a week for 4 weeks and then once every other week for the rest of the study. At the end of the 8-week treatment period, participants undergo the same evaluation they had before beginning treatment (see above). The decision to continue treatment will then be decided based on the individual's clinical condition and whether he or she received propranolol or placebo.

Clinical Trial Description

The effects of exposure to severe stress differ between individuals. Still, a typical response pattern consisting of increased anxiety and arousal, sleep difficulties, preoccupation with and re-experiencing of the traumatic event is the rule. In most trauma survivors the severity of this condition diminishes within days or weeks. Still, in some cases psychopathology persists, and can lead to severe and chronic PTSD. The diagnosis of "Acute Stress Disorder" (ASD) was introduced in DSM-IV, addressing psychopathology between 2 days and 1 month of exposure to trauma. It has been shown that 60%-80% of patients who meet criteria for ASD will go on and suffer from PTSD. Nevertheless, pharmacological trials in PTSD have only been performed, with few exceptions, in chronic populations. Chronic PTSD has emerged as a treatment resistant condition, with only partial response to treatment with antidepressant and anxiolytic agents. Therefore, the potential benefits of early treatment intervention in this condition could be immeasurable.

A principal model proposed to explain the initiation and perpetuation of PTSD is the fear-conditioning model. It assumes that intrusive, involuntary, repetitive, vivid emotionally laden memories of the trauma are pivotal to the development of the disorder. Although such memories are a part of the early trauma response, in healthy trauma survivors these memories gradually lose their intrusive quality and much of their emotional charge, allowing recovery. In PTSD this process does not occur. The impediment to recovery may result from deeper encoding and consolidation of the traumatic memories inhibiting the normal process of extinction that is part of the healthy processing of the traumatic event.

Animal and human research has conclusively shown that emotionally charged stimulation is remembered better than less emotionally arousing information. Animal and human data show that catecholamines, particularly norepinephrine, augment consolidation of emotional memory. Furthermore, administration of catecholamine receptor blockers cancels the enhanced memory for emotional, compared to non-emotional, information. These data suggest that administration of catecholamine receptor blockers soon after trauma may obstruct consolidation of emotional memories, thereby preventing or alleviating posttraumatic symptomatology. Treatment experience in humans is limited to the administration of propranolol in single case descriptions and a pilot prevention study that was not sufficiently powered to allow a definite inference. However, the overall impression from administration of propranolol in the early time period after trauma is positive. In light of the neurophysiology and preliminary data presented above, we propose a prospective, randomized placebo controlled study of propranolol treatment in ASD. ;

Study Design

Endpoint Classification: Safety/Efficacy Study, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Disease
• Stress Disorders, Traumatic
• Stress Disorders, Traumatic, Acute

• NCT number: NCT00069355
• Study type: Interventional
• Source: National Institutes of Health Clinical Center (CC)
• Status: Completed
• Phase: Phase 2
• Start date: September 2003
• Completion date: October 2004