Facilitation of Extinction Retention and Reconsolidation Blockade in PTSD

• Status: Not yet recruiting
• Trial end date: 2025-03-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Boston University
• Collaborator: National Institute of Mental Health (NIMH)
• Treatments: Brexanolone; Pregnanolone

Criteria

Inclusion Criteria:

• Meet criteria for chronic PTSD (i.e., have PTSD for more than 3 months) as determined by the Clinician Administered PTSD Scale (CAPS-5)

• Medically healthy

• Free from any medications that could influence levels of the neurohormones of interest or confound interpretation of study results

• Willing to abstain from alcohol for 2 weeks and from nicotine, marijuana or illicit drugs for 4 weeks before experimental testing (supported by negative urine toxicology testing at screening and throughout study)

• For participants assigned female at birth:

• Must have a natural and regular menstrual cycle

• If of childbearing potential, female and partner must use 2 types of effective birth control (except for hormonal contraceptives, unless intrauterine device [IUD]) for a week before the intravenous (IV) Allopregnanolone (Allo) or placebo infusion, and for one month after

Exclusion Criteria:

• Present an imminent risk to self or others or require clinical intervention to maintain safety

• Diagnosis of substance use disorders within three months of screening

• Bipolar I disorder, or schizophreniform disorders apart from psychosis not otherwise specified (NOS) due to the presence of trauma-related sensory hallucinations

• History of a suicide attempt within 1 year of entering the study

• Moderate or severe traumatic brain injury (TBI)

• Diagnosis of sleep apnea

• Awake resting O2 saturation <96%

• Severe renal failure with creatinine clearance <30 ml/min

• Using any medications or substances (by report or toxicology testing) that may increase the risk of the side effects of IV Allo or adversely affect the experimental results

• Systemic hormone therapy or contraception (Exception: hormonal IUDs such as the Mirena, Kyleena, Liletta, and Skyla will be allowed if the participant still has a normal menstrual periods and is found to ovulate using commercial urine test kit provided by study)

• Pregnancy (urine pregnancy tests given at each in-person session)

• Breast-feeding

• Unable to tolerate IV placement or blood drawing by needle stick