A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - 65 |
| Updated: | 4/2/2016 |
| Start Date: | May 2007 |
| End Date: | April 2011 |
| Contact: | Roger K Pitman, M.D. |
| Email: | roger_pitman@hms.harvard.edu |
| Phone: | 617-726-5333 |
The consolidation of learning is enhanced by adrenalin and other stress hormones. This
memory enhancing effect is opposed by propranolol. In post-traumatic 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 subjects 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 subjects 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. Subjects will be randomly assigned to one of two groups: post-reactivation propranolol
or non-reactivation propranolol. Subjects in the non-reactivation propranolol group will
receive propranolol in the absence of traumatic memory reactivation. Subjects randomized to
the post-reactivation propranolol group will receive matching placebo capsules. Two days
later, all subjects will return for a script preparation session, at which time they will
describe the details of their traumatic event. Subjects randomized to the post-reactivation
propranolol group will then receive propranolol, whereas subjects randomized to the
non-reactivation propranolol group will receive placebo. Subjects 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 subjects who receive propranolol in the absence of
combat memory reactivation, supporting the inference that post-reactivation propranolol
blocks the reconsolidation of traumatic combat memories.
memory enhancing effect is opposed by propranolol. In post-traumatic 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 subjects 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 subjects 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. Subjects will be randomly assigned to one of two groups: post-reactivation propranolol
or non-reactivation propranolol. Subjects in the non-reactivation propranolol group will
receive propranolol in the absence of traumatic memory reactivation. Subjects randomized to
the post-reactivation propranolol group will receive matching placebo capsules. Two days
later, all subjects will return for a script preparation session, at which time they will
describe the details of their traumatic event. Subjects randomized to the post-reactivation
propranolol group will then receive propranolol, whereas subjects randomized to the
non-reactivation propranolol group will receive placebo. Subjects 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 subjects who receive propranolol in the absence of
combat memory reactivation, supporting the inference that post-reactivation propranolol
blocks the reconsolidation of traumatic combat memories.
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 subjects 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 subjects 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 subjects 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 subjects 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: Subjects will be randomly assigned to one of two groups: post-reactivation
propranolol or non-reactivation propranolol. After written informed consent is obtained,
subjects 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. Subjects
randomized to the post-reactivation propranolol group will receive matching placebo
capsules. Two days later, all subjects 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. Subjects randomized to the post-reactivation
propranolol group will then receive the combined propranolol dose, whereas subjects
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 subject's combat
events in their own words. Subjects 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
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
(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 subjects 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 subjects 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 subjects 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 subjects 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: Subjects will be randomly assigned to one of two groups: post-reactivation
propranolol or non-reactivation propranolol. After written informed consent is obtained,
subjects 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. Subjects
randomized to the post-reactivation propranolol group will receive matching placebo
capsules. Two days later, all subjects 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. Subjects randomized to the post-reactivation
propranolol group will then receive the combined propranolol dose, whereas subjects
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 subject's combat
events in their own words. Subjects 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
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
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
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