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A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol

This study has been completed.
Sponsor:
ClinicalTrials.gov Identifier:
NCT00709735
First Posted: July 3, 2008
Last Update Posted: April 10, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborator:
VA Office of Research and Development
Information provided by (Responsible Party):
Roger K. Pitman, MD, Massachusetts General Hospital
  Purpose

The consolidation of learning is enhanced by adrenalin and other stress hormones. This memory enhancing effect is opposed by propranolol. In posttraumatic stress disorder (PTSD), a psychologically traumatic event may overstimulate stress hormones such as adrenalin, which in turn overly strengthen consolidation of the memory of the event, leading to an excessively powerful and persistent memory. Administration of propranolol after a psychologically traumatic event could reduce subsequent PTSD. Unfortunately, there exists a window of opportunity for influencing the consolidation of a traumatic event into long-term memory. In persons who have already developed PTSD, this would have closed months or years earlier. However, recent developments in animal research suggest that reactivation (retrieval) of a consolidated memory can return it to a labile state, from which it must be restabilized in order to persist. This process, which has been termed "reconsolidation," can be reduced in animals by propranolol.

In a preliminary study performed by the PI and colleagues in Canada, civilian participants with PTSD described the traumatic event during a script preparation session, which served to reactivate their traumatic memory. They then received either propranolol or placebo. A week later, during script-driven imagery of their traumatic events, physiologic responses were smaller in the participants who had received post-reactivation propranolol compared to placebo, suggesting that the traumatic memory had been weakened by the propranolol. These results suggest that that post-reactivation propranolol recapitulates its effects on consolidation, this time by blocking reconsolidation of the traumatic memory.

Several important questions remain unanswered. First, does propranolol also weaken traumatic memories in combat-related PTSD? Second, does this weakening effect only occur when the propranolol is given after combat memory reactivation? If not, this would refute the reconsolidation hypothesis and suggest that propranolol affects non-specific mechanisms. Third, how long does the traumatic memory weakening last?

The proposed project will investigate these questions by performing an improved, double-blind, placebo-controlled study in Iraq and Afghanistan veterans with combat-related PTSD. Participants will be randomly assigned to one of two groups: post-reactivation propranolol or non-reactivation propranolol. Participants in the non-reactivation propranolol group will receive propranolol in the absence of traumatic memory reactivation. Participants randomized to the post-reactivation propranolol group will receive matching placebo capsules. Two days later, all participants will return for a script preparation session, at which time they will describe the details of their traumatic event. Participants randomized to the post-reactivation propranolol group will then receive propranolol, whereas participants randomized to the non-reactivation propranolol group will receive placebo. Participants will then return for psychophysiologic script-driven imagery testing one week and six months later. We hypothesize that those who receive propranolol after reactivation of their memories of their traumatic combat event(s) will show significantly smaller psychophysiologic responses during script-driven imagery testing compared to participants who receive propranolol in the absence of combat memory reactivation, supporting the inference that post-reactivation propranolol blocks the reconsolidation of traumatic combat memories.


Condition Intervention Phase
Posttraumatic Stress Disorder Drug: Propranolol Drug: Placebo Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
Official Title: A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol

Resource links provided by NLM:


Further study details as provided by Roger K. Pitman, MD, Massachusetts General Hospital:

Primary Outcome Measures:
  • Physiological Posterior Probability of Posttraumatic Stress Disorder (PTSD) as Determined From Psychophysiologic Responses During Script-Driven Traumatic Memory Recollection [ Time Frame: Day 8 ]
    The posterior probability of developing PTSD was determined for each participant from a composite of psychophysiological responses during script-driven imagery of traumatic combat events that included assessments of heart rate response in beats per minute, skin conductance response in microSiemens, and corrugator and left lateral frontalis facial muscle electromyogram (EMG) responses in microVolts. Responses for the two traumatic scripts were averaged and square-root transformed for analysis. Responses during personal traumatic imagery of previously studied individuals with and without current PTSD was used to calculate each participant's posterior probability of being classified as PTSD.


Secondary Outcome Measures:
  • Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score [ Time Frame: Day 2 (Baseline ) and Day 8 ]
    IES-R is a 22-item patient reported measure of PTSD symptoms. Each question is answered using a 5-point scale where 0=not at all to 4=extremely for a total possible score of 0 to 88. Lower scores represent less severe symptoms and higher scores representing more severe symptoms. IES-R change scores were calculated by subtracting the Day 2 IES-R total score from the Day 8 IES-R total score. A negative change from Baseline indicates improvement of symptoms and a positive change from Baseline indicates a worsening of symptoms.


Enrollment: 23
Actual Study Start Date: May 2007
Study Completion Date: August 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Reactivation Propranolol (RP)
0.67 mg/kg short-acting placebo capsules then 1 mg/kg long-acting placebo capsules 90 minutes later on Day 0 (non-reactivation) followed by 0.67 mg/kg short-acting propranolol capsules then 1 mg/kg long-acting propranolol capsules 90 minutes later on Day 2 (reactivation). All participants then underwent a "script preparation" session in which the investigator elicited five discrete personal memories, including two traumatic combat experiences.
Drug: Propranolol
0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol
Other Name: Inderal
Drug: Placebo
Placebo (matching propranolol) short-acting and long-acting capsules
Active Comparator: Non-Reactivation Propranolol (NRP)
0.67 mg/kg short-acting propranolol capsules then 1 mg/kg long-acting propranolol capsules 90 minutes later on Day 0 (non-reactivation) followed by 0.67 mg/kg short-acting placebo capsules then 1 mg/kg long-acting placebo capsules 90 minutes later on Day 2 (reactivation). All participants then underwent a "script preparation" session in which the investigator elicited five discrete personal memories, including two traumatic combat experiences.
Drug: Propranolol
0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol
Other Name: Inderal
Drug: Placebo
Placebo (matching propranolol) short-acting and long-acting capsules

  Show Detailed Description

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years to 65 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria: Afghanistan and Iraq War veterans who have been diagnosed as having combat-related PTSD

Exclusion Criteria:

  1. PTSD Checklist (PCL) score (administered at the referring site) ≤ 50;
  2. Current, co-existing PTSD of non-combat origin
  3. Resting systolic blood pressure <100 mm Hg
  4. Medical condition that contraindicates the administration of propranolol
  5. Previous adverse reaction to, or non-compliance with, a β-adrenergic blocker
  6. Presence of drugs of abuse
  7. Pregnancy
  8. Contraindicating psychiatric condition
  9. Initiation of, or change in, psychotropic medication within the two months prior to recruitment
  10. Current use of medication that may involve potentially dangerous interactions with propranolol
  11. Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation
  12. Does not understand English
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00709735


Locations
United States, Massachusetts
VA Medical Center
Bedford, Massachusetts, United States, 01730
Massachusetts General Hospital
Boston, Massachusetts, United States, 02108
United States, New Hampshire
VA Medical Center
Manchester, New Hampshire, United States, 03104
Sponsors and Collaborators
Massachusetts General Hospital
VA Office of Research and Development
Investigators
Principal Investigator: Roger K Pitman, M.D. Massachusetts General Hospital
  More Information

Publications:
Responsible Party: Roger K. Pitman, MD, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT00709735     History of Changes
Other Study ID Numbers: W81XWH-07-1-0440
First Submitted: June 30, 2008
First Posted: July 3, 2008
Results First Submitted: May 1, 2012
Results First Posted: April 10, 2017
Last Update Posted: April 10, 2017
Last Verified: April 2017

Keywords provided by Roger K. Pitman, MD, Massachusetts General Hospital:
stress disorders
post-traumatic
memory
propranolol
psychophysiology

Additional relevant MeSH terms:
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Trauma and Stressor Related Disorders
Mental Disorders
Propranolol
Adrenergic beta-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Antihypertensive Agents
Vasodilator Agents