Rapamycin as a Means of Interference With Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric, Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 7/20/2018 |
| Start Date: | August 2008 |
| End Date: | July 2010 |
mTOR Kinase as a Therapeutic Target in Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory
The purpose of the proposed study is to determine if pairing reactivation of a traumatic
memory with a single administration of Rapamycin (e.g., Sirolimus) in men with combat-related
Posttraumatic Stress Disorder leads to a reduction of the emotional strength of that
particular traumatic memory.
The following hypotheses will be tested:
1. Traumatic memory reactivation paired with a single dose of Rapamycin will decrease
objective measures of stress and self-report of stress during replay of the traumatic
memory, relative to, subjects receiving placebo.
2. Pairing administration of Rapamycin with traumatic memory reactivation will decrease
symptoms of Posttraumatic Stress Disorder one month and three months later, relative to
patients receiving placebo.
memory with a single administration of Rapamycin (e.g., Sirolimus) in men with combat-related
Posttraumatic Stress Disorder leads to a reduction of the emotional strength of that
particular traumatic memory.
The following hypotheses will be tested:
1. Traumatic memory reactivation paired with a single dose of Rapamycin will decrease
objective measures of stress and self-report of stress during replay of the traumatic
memory, relative to, subjects receiving placebo.
2. Pairing administration of Rapamycin with traumatic memory reactivation will decrease
symptoms of Posttraumatic Stress Disorder one month and three months later, relative to
patients receiving placebo.
Post-traumatic stress disorder (PTSD) is characterized by intrusive memories in the form of
unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic
event . Current research efforts have begun to explore the underlying neurochemical changes
associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in
persons exposed to trauma. For example, preliminary evidence suggests that interference with
consolidation of trauma-related memories using the beta-antagonist, propranolol, 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 lifetimes, the utility of this
treatment is limited by the logistical problems of treating everyone at risk. To date, there
have been 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
memory5. 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. In preclinical studies, the global protein synthesis
inhibitor anisomycin can block reconsolidation, leading to a reduction in strength of
traumatic memories. Unfortunately, the toxicity of anisomycin is prohibitive for therapeutic
use. Thus, rather than using a global protein synthesis inhibitor, a more effective and
selective means of reducing consolidation of an established traumatic memory is to target
only a subset of protein translation important for synaptic plasticity. The protein kinase
mTOR (mammalian target of rapamycin) is just such a regulator of a subset of protein
synthesis critical for synaptic plasticity.
unwanted images, nightmares, and flashbacks as the result of being exposed to a traumatic
event . Current research efforts have begun to explore the underlying neurochemical changes
associated with PTSD. Recently, these efforts have focused on the prevention of PTSD in
persons exposed to trauma. For example, preliminary evidence suggests that interference with
consolidation of trauma-related memories using the beta-antagonist, propranolol, 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 lifetimes, the utility of this
treatment is limited by the logistical problems of treating everyone at risk. To date, there
have been 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
memory5. 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. In preclinical studies, the global protein synthesis
inhibitor anisomycin can block reconsolidation, leading to a reduction in strength of
traumatic memories. Unfortunately, the toxicity of anisomycin is prohibitive for therapeutic
use. Thus, rather than using a global protein synthesis inhibitor, a more effective and
selective means of reducing consolidation of an established traumatic memory is to target
only a subset of protein translation important for synaptic plasticity. The protein kinase
mTOR (mammalian target of rapamycin) is just such a regulator of a subset of protein
synthesis critical for synaptic plasticity.
Inclusion Criteria:
- Male Veterans
- Diagnosis of Posttraumatic Stress Disorder related to combat
Exclusion Criteria:
- Hypersensitivity to Rapamycin
- Organic brain damage (including unresolved Traumatic Brain Injury sequela)
- Substance dependence in the last three months
- On any immunosuppressant therapy
- Prominent suicidal or homicidal features
- Medical conditions: systemic infections, congestive heart failure, renal failure,
hepatic failure
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