A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol
Condition: Posttraumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

Detailed description: 
      Background: Animal evidence indicates that some consolidated memories when reactivated
      (retrieved) need to be reconsolidated. During this process, memories can be enhanced or
      weakened. In a preliminary, randomized, double-blind, placebo-controlled study, we tested
      whether post-reactivation administration of the beta-adrenergic blocker propranolol, which
      reduces reconsolidation of aversive memories in rodents, would reduce the emotional strength
      of traumatic memories, or conditioned fear responses, in patients with non-combat-related
      PTSD. Civilian participants described their traumatic event during a "script preparation"
      session and thereafter received either a combined dose of short- and long-acting propranolol
      (n=9), or placebo (n=10). A week later, they engaged in script-driven mental imagery of their
      personal traumatic events, while peripheral physiologic responses were recorded as measures
      of the emotional strength of the traumatic memory. We found that physiologic responses were
      significantly smaller in the participants who had received post-reactivation propranolol
      compared to placebo a week earlier: F(3,15)=5.1, p=.007, η2=.49. The results of this
      preliminary study are consistent with pharmacologic blockade of reconsolidation of traumatic
      memories in PTSD. However, 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 when combined with traumatic 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, i.e., does recovery of the conditioned fear response occur?

      Objective/Hypothesis: The first objective is to replicate and extend the finding from the
      preliminary study to Iraq and Afghanistan combat veterans with PTSD by showing that
      propranolol following combat memory reactivation results in a significantly greater weakening
      of traumatic combat memories than propranolol alone, supporting the proposition that this
      weakening is due to pharmacological blockade of memory reconsolidation, rather than
      non-specific actions of propranolol. We hypothesize that participants who undergo script
      preparation for the combat event(s) that caused their PTSD, followed by (post-reactivation)
      propranolol, will show significantly smaller psychophysiologic responses during script-driven
      imagery testing a week later compared to those who receive (non-reactivation) propranolol two
      days prior to combat script preparation. The second objective to show that this effect is
      long-lasting, which would be expected if the underlying mechanism is reduction of the
      traumatic memory trace by blockade of reconsolidation. We hypothesize that the effect will
      remain significant when participants undergo follow-up psychophysiologic script-driven
      imagery testing six months later.

      Specific Aim: To perform a controlled, randomized, double-blind study in Iraq and Afghanistan
      veterans with combat-related PTSD that addresses the above hypotheses.

      Study Design: Participants will be randomly assigned to one of two groups: post-reactivation
      propranolol or non-reactivation propranolol. After written informed consent is obtained,
      participants randomized to the non-reactivation propranolol group will receive a "test" dose
      of 0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol.
      Participants randomized to the post-reactivation propranolol group will receive matching
      placebo capsules. Two days later, all participants will return for an approximate 15-30
      minute "script preparation" session, at which time they will describe the details of their
      traumatic combat event(s) to the Principal Investigator. Participants randomized to the
      post-reactivation propranolol group will then receive the combined propranolol dose, whereas
      participants randomized to the non-reactivation propranolol group will receive placebo. Based
      upon the history obtained during the script preparation session, the Principal Investigator
      will compose "scripts" approximately 30 seconds in duration portraying each participant's
      combat events in their own words. Participants will then return for script-driven imagery
      testing sessions in the psychophysiology laboratory one week and six months later. During
      each of these sessions, they will undergo recording of heart rate, skin conductance, and
      corrugator and frontalis electromyogram during a baseline period. They will then listen to a
      recording of their traumatic scripts and be instructed to imagine the events portrayed as if
      they were happening again, while physiologic measures are recorded. Responses (change) scores
      for each physiologic variable for each session will be calculated by subtracting the
      preceding baseline period mean from the imagery period mean. The physiologic data will be
      analyzed by multivariate analysis of variance (MANOVA) followed by univariate ANOVAs. The
      hypothesis predicts that at each time period, the physiologic responses of the
      post-reactivation propranolol group will be significantly smaller than those of the
      non-reactivation propranolol group.

      Relevance: If a traumatic memory undergoes reconsolidation when reactivated, this could
      re-open the window of opportunity to influence the memory pharmacologically. This could have
      important implications for the treatment of PTSD. Should the proposed psychophysiologic study
      confirm that post-reactivation propranolol weakens traumatic combat memories, it would be a
      relatively short leap to clinical studies of the therapeutic efficacy of this novel modality.
    

Intervention name(s): Propranolol; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol; Placebo (matching propranolol) short-acting and long-acting capsules
Other intervention name(s): Inderal
Intervention MeSH terms: Propranolol
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: stress disorders; post-traumatic; memory; propranolol; psychophysiology