Clinical trial NCT01449955: Rapamycin as a Means of Interference With Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory
Official title: mTOR Kinase as a Therapeutic Target in Reconsolidation of Posttraumatic Stress Disorder-related Traumatic Memory
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Posttraumatic Stress Disorder
Keywords: PTSD
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: North Texas Veterans Healthcare System
First posted: 2011-10-10
Enrollment: 54
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Clinician Administered Posttraumatic Stress Disorder Scale (CAPS)
timeFrame: Baseline and 1 month posttreatment
measure: Clinician Administered Posttraumatic Stress Disorder Scale (CAPS)
timeFrame: change in CAPS score from baseline to 3 months posttreatment
Secondary outcomes:
measure: PTSD Checklist (PCL)
timeFrame: change in PCL score from baseline to 1 month posttreatment
measure: PTSD Checklist (PCL)
timeFrame: change in PCL score from baseline to 3 months posttreatment
measure: Quick Inventory of Depressive Symptomatology (QIDS)
timeFrame: change in QIDS score from baseline to 1 month posttreatment
measure: Quick Inventory of Depressive Symptomatology (QIDS)
timeFrame: change in QIDS score from baseline to 3 months posttreatment
Other outcomes:
Locations:
city: Dallas
country: United States
facility: VA North Texas Healthcare System
state: Texas
Study officials:
affiliation: UT Southwestern Medical Center; VA North Texas Healthcare System
name: Alina M Suris, Ph.D.
role: PRINCIPAL_INVESTIGATOR
affiliation: UT Southwestern Medical Center; VA North Texas Healthcare System
name: Carol North, M.D.
role: STUDY_CHAIR
References:
citation: Blundell J, Kouser M, Powell CM. Systemic inhibition of mammalian target of rapamycin inhibits fear memory reconsolidation. Neurobiol Learn Mem. 2008 Jul;90(1):28-35. doi: 10.1016/j.nlm.2007.12.004. Epub 2008 Mar 7.
citation: Suris A, Smith J, Powell C, North CS. Interfering with the reconsolidation of traumatic memory: sirolimus as a novel agent for treating veterans with posttraumatic stress disorder. Ann Clin Psychiatry. 2013 Feb;25(1):33-40.