Mismatch vs. Standard Intervention During Memory Reconsolidation Blockade With Propranolol: Effect on Psychophysiological Reactivity During Traumatic Imagery

NCT ID: NCT05853627

Last Updated: 2024-04-11

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE4
• Total Enrollment: 80 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2023-06-15
• Study Completion Date: 2025-06-01

Brief Summary

The proposed R21 project will attempt to further develop a novel intervention for posttraumatic stress symptoms inspired by the science of memory reconsolidation. Work in normal humans has shown that when a stable, consolidated memory is reactivated (i.e., retrieved) under appropriate conditions, it reverts to an unstable state, a process referred to herein as deconsolidation. In such a state, the memory is susceptible to the action of various "amnestic" agents that may inhibit its reconsolidation, thereby weakening it. The β-adrenergic blocker propranolol (PPNL) possesses such amnestic properties. More recent research has found that in order to initiate deconsolidation, there must be a prediction error, or mismatch, between what is expected and what occurs when the memory is reactivated.

Prior placebo-controlled, randomized clinical trials (PBO-RCT) from our laboratory have found that when propranolol is administered concomitant with the reactivation of a psychologically traumatic memory, the memory is weakened, as revealed by subsequent lower physiological (heart rate, skin conductance, facial electromyogram) responding during script-driven mental imagery. Clinical applicability was evaluated in a PBO-RCT, in which PTSD participants receiving propranolol underwent six weekly sessions of 10-20 min of "standard" (STD) traumatic memory reactivation stimulated by reading a narrative. At post-treatment, these participants showed a greater reduction of PTSD symptoms compared to participants who had taken PBO. The goal of the proposed study is to test whether intentionally incorporating innovative mismatch (MM) into traumatic memory reactivation can improve upon physiological responding during script-driven mental imagery.

Participants will be randomized to one of 2 treatment arms: STD/PPNL and MM/PPNL. A baseline assessment will measure psychophysiological responsivity to script-driven mental imagery (target measure). PPNL will be administered 90-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions. In the MM condition, a different, unexpected mismatch (e.g., singing the narrative) will be incorporated into the reactivation. In the STD condition, the participant will read the narrative the same way each time. The focus of the R21 proposal will be to assess whether the MM/PPNL group shows lower subsequent physiological responses than the STD/PPNL group

Detailed Description

The proposed project under the R21 Basic Experimental Studies Involving Humans (BESH) mechanism aims to test whether adding 'mismatch' (MM) to traumatic memory reactivation under the influence of the beta-(nor)adrenergic blocker propranolol (PPNL), compared to no mismatch reactivation, further reduces physiological reactivity during script driven imagery of the traumatic event. We propose that the mechanism for the propranolol MM treatment is a) deconsolidation of the traumatic memory instigated by MM, followed by b) blockade of the reconsolidation of the memory by the amnestic agent PPNL. The efficacy of the MM intervention will be contrasted with a standard (STD) reactivation condition that does not include an intentional MM component. We will randomize individuals who have experienced a traumatic event and meet our entry criteria (please see research strategy) to one of the two treatment arms: STD/PPNL and MM/PPNL. Participants' psychophysiological (heart rate, skin conductance, corrugator electromyogram (EMG)) responses during script driven imagery of their traumatic event will constitute the R21 target.

On the initial assessment day, participant candidates will be screened for eligibility based upon the inclusion/exclusion criteria. After the candidate provides written informed consent, a doctoral-level clinician will administer the psychometric instruments. Participant candidates will complete a narrative describing the traumatic event that caused PTSD.

Based on the narrative, the psychologist will then prepare a 100-word script portraying the most salient aspect ("hot spot") of the narrative, which will be recorded for audio playback in the psychophysiology laboratory. Participants not physiologically reactive to the traumatic script will be excluded. If all of the foregoing is completed successfully, participants will be randomized to one of the two arms above.

The participant will return to the clinic one week later for the first of six weekly intervention sessions. Ninety min. prior to its commencement, the participant will ingest the study medication. The participant will then recite the narrative aloud for 10-20 min. In the STD condition, the participant will recite the narrative in an expected manner, i.e., in the same way during each session. In the MM condition, the participant will recite the narrative in an unexpected manner, different for each weekly session. Examples of unexpected conditions will include such things as reciting their narrative while skipping over each word that contains the letter "e", and reciting the narrative in a make-believe accent. A week following the final intervention session, the participant will return for the post-treatment psychophysiological testing. These will be repeated at the one-month follow-up session.

The data will be analyzed by hierarchical linear modeling and regression techniques. The projected sample sizes will provide adequate power to test the proposed study's hypotheses (see Design and Power Analysis section).

Conditions

Stress Disorders, Post-Traumatic

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: OTHER
• Blinding Strategy: DOUBLE

Study Groups

Mismatch reactivation condition

The participant will recite their trauma narrative to the psychologist for 10-20 minutes. However, during each recitation, a "mismatch" condition, different for each session, will be added to the reactivation procedure by having the participant do the following (in order of sessions.

Group Type: EXPERIMENTAL

Memory reactivation procedures

Intervention Type: BEHAVIORAL

In the Mismatch condition, a different, unexpected mismatch will be incorporated into the reactivation. In the Standard condition, the participant will read the narrative the same way each time.

Propranolol

Intervention Type: DRUG

Propranolol will be administered 60-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions.

Standard reactivation condition

The intervention will be the same for each of the six intervention sessions. The participant will recite to the psychologist the narrative they previously composed for 10-20 min. The psychologist will congratulate the participant for having succeeded in this task and advise them they are finished for the day.

Group Type: ACTIVE_COMPARATOR

Memory reactivation procedures

Intervention Type: BEHAVIORAL

In the Mismatch condition, a different, unexpected mismatch will be incorporated into the reactivation. In the Standard condition, the participant will read the narrative the same way each time.

Propranolol

Intervention Type: DRUG

Propranolol will be administered 60-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions.

Interventions

Memory reactivation procedures

In the Mismatch condition, a different, unexpected mismatch will be incorporated into the reactivation. In the Standard condition, the participant will read the narrative the same way each time.

Intervention Type: BEHAVIORAL

Propranolol

Propranolol will be administered 60-min prior to each of six weekly 10-20 min. traumatic memory reactivation sessions.

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Initial participants will be males or females 18-65 years old who have experienced a traumatic event that meets the DSM-5 PTSD A criterion, and whose PCL-5 score is >33 (to maximize the likelihood that they will meet our psychophysiological inclusion criterion). In order to be randomized, participants must further meet this psychophysiological inclusion criterion during baseline script-driven imagery testing Although we do not require a diagnosis of PTSD, because we have set a minimum psychophysiological inclusion criterion and a valid Criterion A traumatic event, our sample will include a substantial number, likely a majority, of PTSD participants.

Exclusion Criteria

1. Basal sitting or standing systolic blood pressure <90/60 mm Hg or basal HR <50 BPM. Those participant-candidates excluded for this reason with such readings will be counseled and referred for further clinical consultation if symptomatic or if they wish to be referred even if asymptomatic.

2. Medical condition that contraindicates PPNL, e.g., congestive heart failure, heart block, insulin- requiring diabetes, chronic bronchitis, emphysema, or asthma. Asthma attacks will only be exclusionary if they: a) occurred within the past ten years, b) occurred at any time in life if induced by a β-blocker, or c) are currently being treated

3. Previous adverse reaction to, or non-compliance with, a β-blocker

4. Current use of medication that may involve potentially dangerous or confounding interactions with PPNL, including anti- hypertensives, antiarrhythmics, and benzodiazepines. (Possible inhibition of CYP2D6 isoenzyme-dependent reactions will not be of concern in this study, because PPNL will only be administered once a week)

5. Presence of drugs of abuse, including opiates, marijuana, cocaine, amphetamines, or alcohol at the initial assessment

6. Pregnancy or breast feeding. Women of childbearing potential will have a pregnancy test at the initial assessment

7. Presence of a contraindicating psychiatric condition, e.g., psychotic, bipolar, melancholic, or active substance use disorder; or suicidality (see below)

8. Initiation of, or change in, psychotropic medication within the previous two months. For participants receiving stable doses of pharmacotherapy, they and their clinicians-prescribers will be asked not to alter the regimen during the proposed two-month study period (excluding the one-month follow-up) except in clinically urgent circumstances. If this becomes necessary, a decision will be made on a case-by-case basis about retaining the participant or terminating participation

9. Current participation in any psychotherapy other than supportive. Participants will be asked not to initiate new psychotherapy during the proposed two-month study period (excluding the one-month follow-up) except in clinically urgent circumstances. If this becomes necessary, a decision will be made on a case-by-case basis about retaining the participant or terminating participation

10. Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation

11. Participant candidate does not understand English. This exclusion criterion is necessary because the procedures require a nuanced dialogue with English-speaking investigators.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Kaloyan Tanev, MD

Senior Director of Research, The Home Base Program

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Massachusetts General Hospital Home Base Program

Charlestown, Massachusetts, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

James Cappellucci

Role: CONTACT

jcappellucci@partners.org

857.282.1724

Facility Contacts

Kaloyan Tanev, MD

Role: primary

ktanev@bwh.harvard.edu

617-764-6476

Oren Bazer, BA

Role: backup

obazer@mgh.harvard.edu

774-279-7599

Other Identifiers

1R21MH131987-01A1

Identifier Type: NIH

Identifier Source: org_study_id

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