Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
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|ClinicalTrials.gov Identifier: NCT01490697|
Recruitment Status : Completed
First Posted : December 13, 2011
Results First Posted : June 29, 2017
Last Update Posted : June 29, 2017
Despite substantial therapeutic advances, Posttraumatic 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.
|Condition or disease||Intervention/treatment||Phase|
|Post-traumatic Stress Disorder||Drug: Mifepristone Drug: d-Cycloserine Drug: Placebo-matching Mifepristone Drug: Placebo-matching d-Cycloserine (DCS)||Phase 4|
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||34 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Double (Participant, Investigator)|
|Official Title:||Developing Memory Reconsolidation Blockers as Novel PTSD Treatments|
|Actual Study Start Date :||March 2009|
|Actual Primary Completion Date :||September 2015|
|Actual Study Completion Date :||September 2015|
Experimental: Mifepristone plus d-Cycloserine (DCS)
DCS 100 mg capsule orally followed by mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7.
1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7.
Other Name: RU-486, Mifeprex
100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7.
Other Name: Seromycin
Placebo Comparator: Placebo plus Placebo
Placebo-matching DCS 100 mg capsule orally followed by placebo-matching mifepristone1800 mg tablet orally 4 hours later and 90 minutes prior to traumatic memory retrieval via the traumatic event script preparation procedure, all on Day 7.
Drug: Placebo-matching Mifepristone
Placebo-matching mifepristone tablets
Drug: Placebo-matching d-Cycloserine (DCS)
Placebo-matching DCS capsules
- Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection [ Time Frame: 1 week following treatment (Day 14) ]The posterior probability of developing PTSD was determined for each participant from a composite of psychophysiological responses to script-driven imagery of traumatic events that included assessments of heart rate response in beats per minute, skin conductance response in microSiemens, and corrugator electromyogram (EMG) responses of the left lateral frontalis facial muscle in microVolts. Responses for the traumatic scripts were averaged and square-root transformed for analysis. Responses during personal traumatic imagery of previously studied individuals with and without current PTSD was used to calculate each participant's posterior probability of being classified as PTSD.
- Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score [ Time Frame: Day 7 (Baseline) and Day 14 ]IES-R is a 22-item patient reported measure of PTSD symptoms. Each question is answered using a 5-point scale where 0=not at all to 4=extremely for a total possible score of 0 to 88. Lower scores represent less severe symptoms and higher scores representing more severe symptoms. IES-R change scores were calculated by subtracting the Day 14 IES-R total score from the Day 7 IES-R total score. A negative change from Baseline indicates improvement of symptoms and a positive change from Baseline indicates a worsening of symptoms.
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Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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|