Extinction of Fear Memories With Glucocorticoids in Veterans With PTSD
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 1/1/2014 |
| Start Date: | April 2010 |
| End Date: | September 2013 |
| Contact: | Jessica Link-Malcolm, PhD |
| Phone: | (214) 857-1014 |
The purpose of this study is to examine the effects of glucocorticoid administration
following traumatic memory reactivation on psychiatric symptoms in veterans with
combat-related PTSD, in addition to examining the effects of glucocorticoid administration
following traumatic memory reactivation on physiological responses to veteran's personal
combat memories. The following hypotheses will be tested:
1. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation
will demonstrate fewer PTSD and depression symptoms one week later, compared to those
who receive a placebo after traumatic memory reactivation.
2. The glucocorticoid reduction effects will be cumulative; that is, reduction will
persist, and further post-reactivation glucocorticoid administration will further
reduce symptoms
3. Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for
subjects receiving an exogenous glucocorticoid compared to those subjects receiving
placebo
4. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation
will demonstrate decreased physiological responses one week later, compared to those
who receive a placebo after traumatic memory reactivation.
5. As with the psychological measures, suppression of the physiological measures will
demonstrate both persistence over time and accumulation with subsequent
post-reactivation glucocorticoid administration.
following traumatic memory reactivation on psychiatric symptoms in veterans with
combat-related PTSD, in addition to examining the effects of glucocorticoid administration
following traumatic memory reactivation on physiological responses to veteran's personal
combat memories. The following hypotheses will be tested:
1. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation
will demonstrate fewer PTSD and depression symptoms one week later, compared to those
who receive a placebo after traumatic memory reactivation.
2. The glucocorticoid reduction effects will be cumulative; that is, reduction will
persist, and further post-reactivation glucocorticoid administration will further
reduce symptoms
3. Decreases in PTSD and depression symptoms will persist at 1, 3, and 6 months for
subjects receiving an exogenous glucocorticoid compared to those subjects receiving
placebo
4. Subjects who receive an exogenous glucocorticoid after traumatic memory reactivation
will demonstrate decreased physiological responses one week later, compared to those
who receive a placebo after traumatic memory reactivation.
5. As with the psychological measures, suppression of the physiological measures will
demonstrate both persistence over time and accumulation with subsequent
post-reactivation glucocorticoid administration.
Background information and related research:
Post-traumatic stress disorder (PTSD) is characterized, among other things, by intrusive
memories in the form of unwanted images, nightmares, and flashbacks. These memories are
associated with intense distress and involve excessive physiological and psychological
responses to fear associated stimuli. Prevalence rates of combat-related PTSD are
increasing due to Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments,
with the estimated risk for PTSD from service in the Iraq War at 18%, and 11% for
Afghanistan.
According to the Pentagon's own mental health taskforce, 38% of soldiers, 31% of marines,
49% of National Guard members, and 43% of marine reservists have shown symptoms of
post-traumatic stress disorder or other psychological problems within three months of
returning from active duty. Estimates from the National Center on PTSD suggest that 40% of
OEF/OIF troops may have or will acquire PTSD. The Department of Defense (DoD) reports that
22% of OEF/OIF troops have been flagged for PTSD and referred for follow-up care, and
records indicate that over 39,000 OEF/OIF vets had been treated for PTSD as of December,
2006.
Current research efforts are exploring the underlying neurochemical changes associated with
PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to
trauma by administration of medication to affect the underlying neurochemical processes. For
example, preliminary evidence suggests that interference with consolidation of
trauma-related memories using the beta-antagonist, propranalol, may prevent PTSD in humans
with recent traumas. , However, given that as much as 90% of the US population is exposed
to at least one traumatic event during their lifetime, the utility of this treatment is
limited by the logistical problems of treating everyone at risk for developing PTSD after a
trauma. To date, there are very few systematic studies on humans that focus on changing the
underlying traumatic memory once PTSD has been established.
The trauma experience is initially stored in short-term memory, then consolidated into
long-term memory. However, the long-term stability conferred by the consolidation process
undergoes a period of labiality as follows. Each time a consolidated memory is activated,
the memory trace becomes newly labile and must be consolidated again to remain in long-term
memory. This process is called reconsolidation. Reconsolidation therefore offers a
biologic window during which long-term memories can be disrupted. Preclinical studies have
begun to unravel the biological changes that underlie these processes. Both pharmacological
agents, including glucocorticoids, and protein synthesis inhibitors can interfere with
memory consolidation and reconsolidation. Endogenously produced stress-hormones, or
glucocorticoids, enhance consolidation for emotionally-arousing experiences, but these
effects are dependent on dose, aversiveness of task, and timing of hormone administration.
Conversely, glucocorticoids appear to impair the retrieval of memories of aversive
experiences.10 Recent data also suggest that glucocorticoids enhance extinction of traumatic
memories.
Preclinical work in our laboratory at the UT Southwestern Medical Center has established
that corticosterone can dose-dependently reduce an established fear memory in rodents. In
this study, mice were trained to associate foot-shock with a specific training context to
induce fear memory. When this fear memory was reactivated by the contextual stimulus and
then followed by glucocorticoid administration, subsequent reactivation of the fear memory
produced significantly less fear responses relative to mice administered saline after memory
reactivation. After only one pairing of reactivation and glucocorticoid, this effect was
reversible with a subthreshold reminder shock and was transient, indicating that the effect
of glucocorticoids was on the extinction process. These results strongly suggested
glucocorticoid treatment paired with therapeutic traumatic memory reactivation as a specific
therapy for PTSD in humans and directly informed our pilot studies in PTSD patients.
Post-traumatic stress disorder (PTSD) is characterized, among other things, by intrusive
memories in the form of unwanted images, nightmares, and flashbacks. These memories are
associated with intense distress and involve excessive physiological and psychological
responses to fear associated stimuli. Prevalence rates of combat-related PTSD are
increasing due to Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) deployments,
with the estimated risk for PTSD from service in the Iraq War at 18%, and 11% for
Afghanistan.
According to the Pentagon's own mental health taskforce, 38% of soldiers, 31% of marines,
49% of National Guard members, and 43% of marine reservists have shown symptoms of
post-traumatic stress disorder or other psychological problems within three months of
returning from active duty. Estimates from the National Center on PTSD suggest that 40% of
OEF/OIF troops may have or will acquire PTSD. The Department of Defense (DoD) reports that
22% of OEF/OIF troops have been flagged for PTSD and referred for follow-up care, and
records indicate that over 39,000 OEF/OIF vets had been treated for PTSD as of December,
2006.
Current research efforts are exploring the underlying neurochemical changes associated with
PTSD. Recently, these efforts have focused on the prevention of PTSD in persons exposed to
trauma by administration of medication to affect the underlying neurochemical processes. For
example, preliminary evidence suggests that interference with consolidation of
trauma-related memories using the beta-antagonist, propranalol, may prevent PTSD in humans
with recent traumas. , However, given that as much as 90% of the US population is exposed
to at least one traumatic event during their lifetime, the utility of this treatment is
limited by the logistical problems of treating everyone at risk for developing PTSD after a
trauma. To date, there are very few systematic studies on humans that focus on changing the
underlying traumatic memory once PTSD has been established.
The trauma experience is initially stored in short-term memory, then consolidated into
long-term memory. However, the long-term stability conferred by the consolidation process
undergoes a period of labiality as follows. Each time a consolidated memory is activated,
the memory trace becomes newly labile and must be consolidated again to remain in long-term
memory. This process is called reconsolidation. Reconsolidation therefore offers a
biologic window during which long-term memories can be disrupted. Preclinical studies have
begun to unravel the biological changes that underlie these processes. Both pharmacological
agents, including glucocorticoids, and protein synthesis inhibitors can interfere with
memory consolidation and reconsolidation. Endogenously produced stress-hormones, or
glucocorticoids, enhance consolidation for emotionally-arousing experiences, but these
effects are dependent on dose, aversiveness of task, and timing of hormone administration.
Conversely, glucocorticoids appear to impair the retrieval of memories of aversive
experiences.10 Recent data also suggest that glucocorticoids enhance extinction of traumatic
memories.
Preclinical work in our laboratory at the UT Southwestern Medical Center has established
that corticosterone can dose-dependently reduce an established fear memory in rodents. In
this study, mice were trained to associate foot-shock with a specific training context to
induce fear memory. When this fear memory was reactivated by the contextual stimulus and
then followed by glucocorticoid administration, subsequent reactivation of the fear memory
produced significantly less fear responses relative to mice administered saline after memory
reactivation. After only one pairing of reactivation and glucocorticoid, this effect was
reversible with a subthreshold reminder shock and was transient, indicating that the effect
of glucocorticoids was on the extinction process. These results strongly suggested
glucocorticoid treatment paired with therapeutic traumatic memory reactivation as a specific
therapy for PTSD in humans and directly informed our pilot studies in PTSD patients.
Inclusion Criteria:
1. male veterans enrolled to receive care through the VA North Texas Healthcare System
2. diagnosis of combat-related PTSD
Exclusion Criteria:
1. Hypersensitivity to dexamethasone
2. Current use of steroids
3. Current psychosis
4. Organic Brain Damage
5. Current major depressive disorder with melancholic features
6. Substance dependence in the last 3 months
7. Prominent suicidal or homicidal features
8. Medical conditions: diabetes, uncontrolled hypertension, severe congestive heart
failure, hepatic failure, or any other contraindicated medical condition (such as HPA
Axis disease, Addison's Disease or Cushing's Disease).
9. Veterans taking medication with established drug interactions with dexamethasone
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