Developing Memory Reconsolidation Blockers as Novel Post-traumatic Stress Disorder (PTSD) Treatments
Despite substantial therapeutic advances, Post-traumatic Stress Disorder (PTSD) remains difficult to treat. One promising new area of research is in post-reactivation pharmacologic intervention, which is based upon the concept of blockade of memory reconsolidation. Recent animal research suggests that reactivation (retrieval) of a stored memory can return it to a labile (alterable) state from which it must be restabilized in order to persist. This process is called "reconsolidation," and various drugs have been found to block it in animals. This blockade may lead to a weakening of the original memory trace.
The aim of this study is to pilot the effect of mifepristone on physiologic responding during traumatic imagery. Although mifepristone is widely and safely used to cause a medical abortion, it is also a powerful stress hormone receptor blocker. These stress hormones, called glucocorticoids, may enhance memory (re)consolidation. Indeed, a recent study in animals reported that mifepristone blocked reconsolidation of context-conditioned fear in rats.
Reconsolidation blockade is a two-stage process. First, the memory must be destabilized by recalling it. Second, reconsolidation of the memory must be blocked by a drug. Memory traces formed under stressful conditions may resist destabilization and thus are inaccessible to reconsolidation blockers. However, when a reconsolidation blocker was paired with d-cycloserine (DCS) in animals that had been trained under stressful conditions, reconsolidation blockade became successful. These results suggest that DCS promotes the destabilization of resistant memory traces. The traumatic memories of individuals with PTSD may be particularly resistant to destabilization. Therefore, this study will compare mifepristone paired with DCS to placebo controls.
The same script-driven traumatic imagery method validated in previous studies of propranolol in this lab will be used. Briefly, subjects with PTSD will describe their traumatic event during a script preparation session, which will reactivate the memory. They will then receive a) mifepristone and DCS or b) placebo. A week later, they will engage in script-driven mental imagery of their traumatic event while physiologic responses (heart rate, sweating, etc) are measured. This is a pilot study so there are no formal hypotheses. The aim is to estimate effect sizes for mifepristone and to compare them with effect sizes for propranolol from this lab's previous work.
Post-traumatic Stress Disorder
Drug: sugar pill
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Developing Memory Reconsolidation Blockers as Novel PTSD Treatments|
- Psychophysiologic Responses during script-driven imagery of traumatic events [ Time Frame: 1 week ] [ Designated as safety issue: No ]heart rate, skin conductance, left corrugator electromyogram
|Study Start Date:||March 2009|
|Study Completion Date:||September 2015|
|Primary Completion Date:||September 2015 (Final data collection date for primary outcome measure)|
Experimental: Mifepristone plus d-cycloserine
1800 mg mifepristone post-reactivation and 100 mg DCS pre-reactivation, orally
1800 mg tablet, single dose on script preparation day
Other Name: RU-486, MifeprexDrug: Cycloserine
100 mg capsule, single dose, taken 4 hours prior to script preparation on day 2
Other Name: Seromycin
|Placebo Comparator: Sugar pill||
Drug: sugar pill
sugar pill in the same shape and size as the mifepristone and DCS tablets and capsules
Please refer to this study by its ClinicalTrials.gov identifier: NCT01490697
|United States, Massachusetts|
|Massachusetts General Hospital|
|Boston, Massachusetts, United States, 02114|
|United States, Texas|
|Dallas, Texas, United States, 75216|
|Principal Investigator:||Roger K Pitman, MD||Massachusetts General Hospital|