Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD
Status:
Not yet recruiting
Trial end date:
2025-03-01
Target enrollment:
Participant gender:
Summary
About 6.4% of the U.S. population suffers from posttraumatic stress disorder (PTSD).
Responses to evidence-based trauma-focused therapies for PTSD vary. This study tests whether
allopregnanolone (Allo) treatment in individuals with refractory PTSD facilitates learning
and memory processes underlying the efficacy of trauma-focused therapies for PTSD.
Trauma-focused psychotherapies show general efficacy in PTSD. However, symptom improvement in
response to such treatments can vary substantially among individuals with PTSD. Several
factors may contribute to treatment response including neurobiological factors that impact
brain capacities needed to reprocess trauma memories and consolidate reconfigured brain
circuits during recovery. During trauma-focused therapies, activation of a threat-related
memory renders the memory "labile" and engages two competing processes: extinction and
reconsolidation. Extinction involves: a) activation of prefrontal cortical (PFC) inhibition
of amygdala-mediated physiological and behavioral defense responses, and b) acquisition and
consolidation of new learning (e.g., the conditioned threat stimulus or CS+ no longer signals
threat in the new time-space context). At the molecular level, extinction involves both
synaptic long-term potentiation (LTP) and long-term depression (LTD). Extinction thus
improves function, but is not permanent, as amygdala-mediated defense responses may reemerge
in a new context, upon re-exposure to the original threat, or with the passage of time.
PTSD has been associated with deficits in both extinction learning and retention.
Reconsolidation blockade also may contribute to PTSD recovery. Protein synthesis inhibitors
(not safe/feasible in humans), beta-blockers, and protein kinase A (PKA) inhibitors can block
reconsolidation (if given within an hour of brief threat memory reactivation),the the latter
by disrupting phosphorylation of serine 845 residues on Glu-R1 AMPA receptors, thus limiting
their synaptic incorporation-a prerequisite for memory reconsolidation. Thereafter, the
former CS+-US association is "remembered", but amygdala-mediated defense responses are not
co-activated by the CS+. Some, but not all human studies, have demonstrated
propranolol-induced blockade of episodic and aversive memory reconsolidation, as well as PTSD
symptom improvement in paradigms combining reconsolidation blockade and extinction.