Developing Memory Reconsolidation Blockers as Novel Post-traumatic Stress Disorder (PTSD) Treatments
| Status: | Completed |
|---|---|
| Conditions: | Psychiatric |
| Therapuetic Areas: | Psychiatry / Psychology |
| Healthy: | No |
| Age Range: | 18 - Any |
| Updated: | 4/21/2016 |
| Start Date: | March 2009 |
| End Date: | September 2015 |
Developing Memory Reconsolidation Blockers as Novel PTSD Treatments
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.
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.
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.
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