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Posttraumatic Stress Disorder | A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol

Posttraumatic Stress Disorder research study

What is the primary objective of this study?

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.

Who is eligible to participate?

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

Which medical condition, disease, disorder, syndrome, illness, or injury is researched?

Posttraumatic Stress Disorder

Study Interventions

Interventions can include giving participants drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available or noninvasive approaches such as surveys, education, and interviews.

Drug:Propranolol0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol

Drug:PlaceboPlacebo (matching propranolol) short-acting and long-acting capsules

Study Arms

Research studies and clinical trials typically have two or more research arms. An arm is a group of people who receive the same treatment in the study.

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.

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.

Study Status

Completed

Start Date: May 2007

Completed Date: August 2010

Phase: Phase 4

Type: Interventional

Design:

Primary Outcome: Physiological Posterior Probability of Posttraumatic Stress Disorder (PTSD) as Determined From Psychophysiologic Responses During Script-Driven Traumatic Memory Recollection

Secondary Outcome: Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score

Study sponsors, principal investigator, and references

Principal Investigator: Roger K Pitman, M.D.

Lead Sponsor: Massachusetts General Hospital

Collaborator: VA Office of Research and Development

More information:https://clinicaltrials.gov/show/NCT00709735

Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015 Jan 30;225(1-2):31-9. doi: 10.1016/j.psychres.2014.09.005. Epub 2014 Sep 16.

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