Developing Memory Reconsolidation Blockers as Novel Post-traumatic Stress Disorder (PTSD) Treatments

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2013 by Massachusetts General Hospital
Sponsor:
Information provided by (Responsible Party):
Roger K. Pitman, MD, Massachusetts General Hospital
ClinicalTrials.gov Identifier:
NCT01490697
First received: December 9, 2011
Last updated: May 7, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Post-traumatic Stress Disorder
Drug: Mifepristone
Drug: Cycloserine
Drug: sugar pill
Phase 4

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by Massachusetts General Hospital:

Primary Outcome Measures:
  • 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


Estimated Enrollment: 135
Study Start Date: March 2009
Estimated Study Completion Date: May 2013
Estimated Primary Completion Date: May 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mifepristone plus d-cycloserine
1800 mg mifepristone post-reactivation and 100 mg DCS pre-reactivation, orally
Drug: Mifepristone
1800 mg tablet, single dose on script preparation day
Other Name: RU-486, Mifeprex
Drug: 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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criterion:

  • Subject has experienced a traumatic event that meets the DSM-IV11 A1. and A.2. PTSD criteria
  • Subject 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 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 subjects, 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 subjects); 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01490697

Contacts
Contact: Roger K Pitman, MD 617-726-5333 roger_pitman@hms.harvard.edu

Locations
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact: Nellie E Wood, BA    617-643-9602    nwood1@partners.org   
United States, Texas
Dallas VA Recruiting
Dallas, Texas, United States, 75216
Contact: Jessica J Link-Malcolm, Ph.D.    214-857-1014    Jessica.Link-Malcolm@va.gov   
Sponsors and Collaborators
Roger K. Pitman, MD
Investigators
Principal Investigator: Roger K Pitman, MD Massachusetts General Hospital
  More Information

No publications provided

Responsible Party: Roger K. Pitman, MD, Principal Investigator, Massachusetts General Hospital
ClinicalTrials.gov Identifier: NCT01490697     History of Changes
Other Study ID Numbers: 2009P000647
Study First Received: December 9, 2011
Last Updated: May 7, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Massachusetts General Hospital:
stress disorders
posttraumatic
memory
mifepristone
d-cycloserine
psychophysiology

Additional relevant MeSH terms:
Disease
Stress Disorders, Traumatic
Stress Disorders, Post-Traumatic
Pathologic Processes
Anxiety Disorders
Mental Disorders
Cycloserine
Mifepristone
Anti-Infective Agents, Urinary
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Renal Agents
Antibiotics, Antitubercular
Anti-Bacterial Agents
Antitubercular Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Abortifacient Agents, Steroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Contraceptives, Oral, Synthetic
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Contraceptives, Postcoital, Synthetic
Contraceptives, Postcoital
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on September 29, 2014