A Psychophysiologic Study of Weakening Traumatic Combat Memories With Post-Reactivation Propranolol

NCT00709735 | Completed Phase 4 Results

• 1 other identifier: W81XWH-07-1-0440
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 3

Brief Summary

The consolidation of learning is enhanced by adrenalin and other stress hormones. This memory enhancing effect is opposed by propranolol. In posttraumatic stress disorder (PTSD), a psychologically traumatic event may overstimulate stress hormones such as adrenalin, which in turn overly strengthen consolidation of the memory of the event, leading to an excessively powerful and persistent memory. Administration of propranolol after a psychologically traumatic event could reduce subsequent PTSD. Unfortunately, there exists a window of opportunity for influencing the consolidation of a traumatic event into long-term memory. In persons who have already developed PTSD, this would have closed months or years earlier. However, recent developments in animal research suggest that reactivation (retrieval) of a consolidated memory can return it to a labile state, from which it must be restabilized in order to persist. This process, which has been termed "reconsolidation," can be reduced in animals by propranolol. In a preliminary study performed by the PI and colleagues in Canada, civilian participants with PTSD described the traumatic event during a script preparation session, which served to reactivate their traumatic memory. They then received either propranolol or placebo. A week later, during script-driven imagery of their traumatic events, physiologic responses were smaller in the participants who had received post-reactivation propranolol compared to placebo, suggesting that the traumatic memory had been weakened by the propranolol. These results suggest that that post-reactivation propranolol recapitulates its effects on consolidation, this time by blocking reconsolidation of the traumatic memory. Several important questions remain unanswered. First, does propranolol also weaken traumatic memories in combat-related PTSD? Second, does this weakening effect only occur when the propranolol is given after combat memory reactivation? If not, this would refute the reconsolidation hypothesis and suggest that propranolol affects non-specific mechanisms. Third, how long does the traumatic memory weakening last? The proposed project will investigate these questions by performing an improved, double-blind, placebo-controlled study in Iraq and Afghanistan veterans with combat-related PTSD. Participants will be randomly assigned to one of two groups: post-reactivation propranolol or non-reactivation propranolol. Participants in the non-reactivation propranolol group will receive propranolol in the absence of traumatic memory reactivation. Participants randomized to the post-reactivation propranolol group will receive matching placebo capsules. Two days later, all participants will return for a script preparation session, at which time they will describe the details of their traumatic event. Participants randomized to the post-reactivation propranolol group will then receive propranolol, whereas participants randomized to the non-reactivation propranolol group will receive placebo. Participants will then return for psychophysiologic script-driven imagery testing one week and six months later. We hypothesize that those who receive propranolol after reactivation of their memories of their traumatic combat event(s) will show significantly smaller psychophysiologic responses during script-driven imagery testing compared to participants who receive propranolol in the absence of combat memory reactivation, supporting the inference that post-reactivation propranolol blocks the reconsolidation of traumatic combat memories.

Conditions

Posttraumatic Stress Disorder

Keywords

stress disorders; post-traumatic; memory; propranolol; psychophysiology

Outcome Measures

Primary Outcomes (1)

• Physiological Posterior Probability of Posttraumatic Stress Disorder (PTSD) as Determined From Psychophysiologic Responses During Script-Driven Traumatic Memory Recollection

  The posterior probability of developing PTSD was determined for each participant from a composite of psychophysiological responses during script-driven imagery of traumatic combat events that included assessments of heart rate response in beats per minute, skin conductance response in microSiemens, and corrugator and left lateral frontalis facial muscle electromyogram (EMG) responses in microVolts. Responses for the two traumatic scripts were averaged and square-root transformed for analysis. Responses during personal traumatic imagery of previously studied individuals with and without current PTSD was used to calculate each participant's posterior probability of being classified as PTSD.

  Day 8

Secondary Outcomes (1)

• Change From Baseline in the Impact of Event Scale-Revised (IES-R) Total Score

  Day 2 (Baseline ) and Day 8

Study Arms (2)

Reactivation Propranolol (RP)

EXPERIMENTAL

0.67 mg/kg short-acting placebo capsules then 1 mg/kg long-acting placebo capsules 90 minutes later on Day 0 (non-reactivation) followed by 0.67 mg/kg short-acting propranolol capsules then 1 mg/kg long-acting propranolol capsules 90 minutes later on Day 2 (reactivation). All participants then underwent a "script preparation" session in which the investigator elicited five discrete personal memories, including two traumatic combat experiences.

Drug: Propranolol; Drug: Placebo

Non-Reactivation Propranolol (NRP)

ACTIVE COMPARATOR

0.67 mg/kg short-acting propranolol capsules then 1 mg/kg long-acting propranolol capsules 90 minutes later on Day 0 (non-reactivation) followed by 0.67 mg/kg short-acting placebo capsules then 1 mg/kg long-acting placebo capsules 90 minutes later on Day 2 (reactivation). All participants then underwent a "script preparation" session in which the investigator elicited five discrete personal memories, including two traumatic combat experiences.

Drug: Propranolol; Drug: Placebo

Interventions

Propranolol DRUG

0.67 mg/kg short-acting propranolol combined with 1 mg/kg long-acting propranolol

Also known as: Inderal

Non-Reactivation Propranolol (NRP); Reactivation Propranolol (RP)

Placebo DRUG

Placebo (matching propranolol) short-acting and long-acting capsules

Non-Reactivation Propranolol (NRP); Reactivation Propranolol (RP)

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• PTSD Checklist (PCL) score (administered at the referring site) ≤ 50;
• Current, co-existing PTSD of non-combat origin
• Resting systolic blood pressure \<100 mm Hg
• Medical condition that contraindicates the administration of propranolol
• Previous adverse reaction to, or non-compliance with, a β-adrenergic blocker
• Presence of drugs of abuse
• Pregnancy
• Contraindicating psychiatric condition
• Initiation of, or change in, psychotropic medication within the two months prior to recruitment
• Current use of medication that may involve potentially dangerous interactions with propranolol
• Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation
• Does not understand English

Sponsors & Collaborators

• Massachusetts General Hospital: lead
• VA Office of Research and Development: collaborator

Study Sites (3)

VA Medical Center

Bedford, Massachusetts, 01730, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02108, United States

Location

VA Medical Center

Manchester, New Hampshire, 03104, United States

Location

Related Publications (1)

• Wood NE, Rosasco ML, Suris AM, Spring JD, Marin MF, Lasko NB, Goetz JM, Fischer AM, Orr SP, Pitman RK. Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: three negative psychophysiological studies. Psychiatry Res. 2015 Jan 30;225(1-2):31-39. doi: 10.1016/j.psychres.2014.09.005. Epub 2014 Sep 16.

  PMID: 25441015 RESULT

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Stress Disorders, Traumatic

Interventions

Propranolol

Condition Hierarchy (Ancestors)

Trauma and Stressor Related Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Phenoxypropanolamines; Propanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Propanols; Amines; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

Small participant sample due to recruitment difficulties.

Results Point of Contact

• Title: Roger K. Pitman, M.D.
• Organization: Massachusetts General Hospital

roger_pitman@hms.harvard.edu

617-726-5333

Study Officials

• Roger K Pitman, M.D.

  Massachusetts General Hospital

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: June 30, 2008
• First Posted: July 3, 2008
• Study Start: May 1, 2007
• Primary Completion: February 1, 2010
• Study Completion: August 1, 2010
• Last Updated: April 10, 2017
• Results First Posted: April 10, 2017

Record last verified: 2017-04

Locations

US (3)