Developing Memory Reconsolidation Blockers as Novel Posttraumatic Stress Disorder (PTSD) Treatments
Condition: Post-traumatic Stress Disorder
MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic
Intervention: Mifepristone; d-Cycloserine; Placebo-matching Mifepristone; Placebo-matching d-Cycloserine (DCS)
Intervention description: 1800 mg tablet, single dose 90 minutes prior to script preparation on Day 7.; 100 mg capsule, single dose, taken 4 hours prior to to mifepristone on Day 7.; Placebo-matching mifepristone tablets; Placebo-matching DCS capsules
Intervention MeSH terms: Cycloserine; Mifepristone
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: stress disorders; posttraumatic; memory; mifepristone; d-cycloserine; psychophysiology

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.
    

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.