Back to resultsDeveloping Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
Primary Purpose
Post-traumatic Stress Disorder
Status
Completed
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
Mifepristone
d-Cycloserine
Placebo-matching Mifepristone
Placebo-matching d-Cycloserine (DCS)
Sponsored by
About this trial
This is an interventional treatment trial for Post-traumatic Stress Disorder focused on measuring stress disorders, posttraumatic, memory, mifepristone, d-cycloserine, psychophysiology
Eligibility Criteria
Inclusion Criterion:
- Participant has experienced a traumatic event that meets the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)11 A1. and A.2. PTSD criteria
- Participant currently meets DSM-IV criterion B.5, viz., "physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event."
Exclusion Criteria:
- Medical condition that contraindicates the administration of mifepristone, e.g., history of adrenal failure; concurrent corticosteroid therapy; hemorrhagic disorders; cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin dependent diabetes mellitus; severe anemia; heavy smoking; porphyria; allergy to mifepristone; concurrent anticoagulant therapy; or medical condition that contraindicates the administration of DCS e.g., hypersensitivity to cycloserine, epilepsy, severe renal insufficiency.
- Pregnant (as determined by mandatory blood pregnancy testing, or currently breast feeding. (Note: Women who have had a hysterectomy or are post-menopausal (defined as over the age of 50 with no menstrual period for at least 12 months) will be exempted from pregnancy testing. Furthermore, women of childbearing potential will only be included if: a) they are using contraception in the form of barrier methods with spermicide, hormonal methods (e.g. birth control pill), or intrauterine devices (IUDs), or b) they have not been sexually active for the preceding 60 days.)
- Contraindicating psychiatric condition, e.g., current psychotic, bipolar, melancholic, or substance dependence or abuse disorder; or currently suicidal.
- Cognitive Impairment or dementia
- Initiation of, or change in, psychotropic medication within one month prior to recruitment
- Current use of medication that may involve potentially dangerous interactions with mifepristone, including certain CYP 3A4 substrates such as calcium channel blockers, azole antifungals, macrolide antibiotics, and tricyclic antidepressants. (Note - we have not included in this list benzodiazepines or selective serotonin reuptake inhibitors, because these drugs are frequently used by PTSD participants, and they have sufficiently wide therapeutic ranges such that any transient increases in blood levels induced by a single dose of mifepristone will not endanger participants); or current use of medication that may involve potentially dangerous interactions with DCS, including ethionamide, isoniazid, and pyridoxine.
- Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation;
- Age less than 18.
Sites / Locations
- Massachusetts General Hospital
- Dallas VA
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Mifepristone plus d-Cycloserine (DCS)
Placebo plus Placebo
Arm Description
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.
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.
Outcomes
Primary Outcome Measures
Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection
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.
Secondary Outcome Measures
Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score
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.
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01490697
Brief Title
Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
Official Title
Developing Memory Reconsolidation Blockers as Novel PTSD Treatments
Study Type
Interventional
2. Study Status
Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
March 2009 (Actual)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
September 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Roger K. Pitman, MD
4. Oversight
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Post-traumatic Stress Disorder
Keywords
stress disorders, posttraumatic, memory, mifepristone, d-cycloserine, psychophysiology
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
34 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Mifepristone plus d-Cycloserine (DCS)
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo plus Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Mifepristone
Other Intervention Name(s)
RU-486, Mifeprex
Intervention Description
1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7.
Intervention Type
Drug
Intervention Name(s)
d-Cycloserine
Other Intervention Name(s)
Seromycin
Intervention Description
100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7.
Intervention Type
Drug
Intervention Name(s)
Placebo-matching Mifepristone
Intervention Description
Placebo-matching mifepristone tablets
Intervention Type
Drug
Intervention Name(s)
Placebo-matching d-Cycloserine (DCS)
Intervention Description
Placebo-matching DCS capsules
Primary Outcome Measure Information:
Title
Physiological Posttraumatic Stress Disorder (PTSD) Probability as Determined From Psychophysiologic Responses to Traumatic Recollection
Description
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.
Time Frame
1 week following treatment (Day 14)
Secondary Outcome Measure Information:
Title
Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score
Description
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.
Time Frame
Day 7 (Baseline) and Day 14
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criterion:
Participant has experienced a traumatic event that meets the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)11 A1. and A.2. PTSD criteria
Participant currently meets DSM-IV criterion B.5, viz., "physiological reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event."
Exclusion Criteria:
Medical condition that contraindicates the administration of mifepristone, e.g., history of adrenal failure; concurrent corticosteroid therapy; hemorrhagic disorders; cardiovascular, hypertensive, hepatic, respiratory or renal disease; insulin dependent diabetes mellitus; severe anemia; heavy smoking; porphyria; allergy to mifepristone; concurrent anticoagulant therapy; or medical condition that contraindicates the administration of DCS e.g., hypersensitivity to cycloserine, epilepsy, severe renal insufficiency.
Pregnant (as determined by mandatory blood pregnancy testing, or currently breast feeding. (Note: Women who have had a hysterectomy or are post-menopausal (defined as over the age of 50 with no menstrual period for at least 12 months) will be exempted from pregnancy testing. Furthermore, women of childbearing potential will only be included if: a) they are using contraception in the form of barrier methods with spermicide, hormonal methods (e.g. birth control pill), or intrauterine devices (IUDs), or b) they have not been sexually active for the preceding 60 days.)
Contraindicating psychiatric condition, e.g., current psychotic, bipolar, melancholic, or substance dependence or abuse disorder; or currently suicidal.
Cognitive Impairment or dementia
Initiation of, or change in, psychotropic medication within one month prior to recruitment
Current use of medication that may involve potentially dangerous interactions with mifepristone, including certain CYP 3A4 substrates such as calcium channel blockers, azole antifungals, macrolide antibiotics, and tricyclic antidepressants. (Note - we have not included in this list benzodiazepines or selective serotonin reuptake inhibitors, because these drugs are frequently used by PTSD participants, and they have sufficiently wide therapeutic ranges such that any transient increases in blood levels induced by a single dose of mifepristone will not endanger participants); or current use of medication that may involve potentially dangerous interactions with DCS, including ethionamide, isoniazid, and pyridoxine.
Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation;
Age less than 18.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roger K Pitman, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dallas VA
City
Dallas
State/Province
Texas
ZIP/Postal Code
75216
Country
United States
12. IPD Sharing Statement
Citations:
PubMed Identifier
25441015
Citation
Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015 Jan 30;225(1-2):31-39. doi: 10.1016/j.psychres.2014.09.005. Epub 2014 Sep 16.
Results Reference
result
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Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
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