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Completed

NCT Number: NCT01490697

Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments

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.

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Key information

Conditions

Post-traumatic Stress Disorder Mental Disorders Stress Disorders, Post-Traumatic Stress Disorders, Traumatic Trauma and Stressor Related Disorders

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 4

Primary location

Massachusetts General Hospital, Boston, Massachusetts, United States

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Mifepristone

Drug

1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7.

Other names: RU-486, Mifeprex

D-cycloserine

Drug

100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7.

Other names: Seromycin

Placebo-matching Mifepristone

Drug

Placebo-matching mifepristone tablets

Placebo-matching d-Cycloserine (DCS)

Drug

Placebo-matching DCS capsules

Primary outcomes

  1. 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.

Secondary outcomes

  1. 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.

Sponsors and collaborators

Lead sponsor

Roger K. Pitman, MD

Other

Registry information

Official study title

Developing Memory Reconsolidation Blockers as Novel PTSD Treatments

Important dates

Study start
2009
Primary completion
2015
Study completion
2015
First posted
Dec 13, 2011
Registry last updated
Jun 29, 2017

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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