PTSD Symptom Reduction by Propranolol Given After Trauma Memory Activation

OBJECTIVE: In the first of two preliminary studies, we demonstrated in individuals with chronic PTSD that a single (combined 40 mg short- and 60 mg long-acting) 24-hour oral dose of propranolol, compared to placebo, given immediately following reactivation of the PTSD-related memory of the traumatic event, significantly reduced physiological responses during script-driven imagery of that event measured one week later. These results support blockade of reconsolidation of the traumatic memory, a process that is entirely distinct from extinction. In addition, we found a trend for post-reactivation propranolol to reduce self-reported PTSD symptoms, measured via the Impact of Event Scale-Revised (IES-R). In the second preliminary study, we performed 6 weekly treatments that consisted of the subject describing their PTSD-related traumatic events for approximately 10 minutes followed by 0.67 mg/kg (minimum 40 mg) short-acting propranolol plus 1 mg/kg (minimum 60 mg) long-acting propranolol. The mean Clinician Administered PTSD Scale (CAPS) Total Score following the six treatment sessions was reduced by 44% (p=.02). The proposed work will examine whether repeated treatments may succeed in producing more substantive symptomatic improvement.

RESEARCH PLAN: The study design will be a randomized, double-blind, placebo-controlled, clinical trial. A crossover design is not being proposed because the effect is expected to be neither short-term nor reversible. Rather, at the conclusion of the formal study period, individuals randomized to the placebo condition will be offered an equal number of treatment sessions with propranolol. A placebo control will be used, rather than an active treatment control, because the proposed study will be a "proof of concept" test of post-reactivation pharmacological reduction of traumatic memories. The control (and active) treatments will be structured so as to minimize the chance of extinction. We recognize that eventually this new treatment will need to be tested against established PTSD treatments, including exposure, if its clinical utility is to be established. We regard this as a matter for subsequent studies should the present study yield promising results. However, we do intend to compare the effect size we find for the proposed intervention with published effect sizes for other PTSD psychotherapies.

METHODOLOGY: Participants will include male and female combat veterans of the Afghanistan and Iraqi wars meeting DSM-IV criteria for chronic PTSD, recruited locally from the Manchester VAMC Mental Hygiene Clinic or through advertising. The presence of PTSD will be assessed using the CAPS. Participants will be randomly assigned to the propranolol or placebo drug condition. During each of six memory reactivation sessions, the participant will meet with a psychiatrist, who will ask the participant to spend ten minutes describing the event that caused their PTSD, and their reactions to it. The interviewer will facilitate this process by asking questions, keeping the participant focused on the traumatic event and encouraging him/her to identify aspects of the traumatic event that continue to provoke emotional distress. The traumatic memory reactivation will be immediately followed by administration of propranolol or placebo. Following the six treatment sessions, script-driven imagery will be used to assess HR, SC, and facial EMG responses to recollections of the traumatic event and PTSD symptoms will be assessed using the CAPS. A previously developed discriminant function will be used to classify each person as a physiologic "responder" or "non-responder." There will also be a 6-month follow-up assessment.

CLINICAL RELEVANCE: The mechanism of memory reconsolidation offers the possibility that cellular plasticity can be capitalized on to reverse the neuroanatomical and neurophysiological underpinnings of traumatic memories. The possibility that a traumatic memory could be significantly weakened by an intervention as simple as the post-reactivation administration of a widely used and safe medication has profound implications for the treatment of PTSD.

• Drug: Propranolol
  Weekly doses of short and long acting propranolol following recollection of traumatic memory
• Drug: Placebo
  Weekly doses of placebo following recollection of traumatic memory

• Experimental: 1
  Propranolol
  Intervention: Drug: Propranolol
• Placebo Comparator: 2
  Placebo
  Intervention: Drug: Placebo

Inclusion Criteria:

OEF/OIF veteran diagnosed with combat related posttraumatic stress disorder

Exclusion Criteria:

1. Not diagnosed with current, chronic PTSD
2. Current PTSD related to a traumatic event other than the event being treated
3. Age>65.
4. Systolic blood pressure <100 mm HG or resting HR less than 60 BPM.
5. Medical condition that contraindicates the administration of propranolol, e.g. history of congestive heart failure, heart block, insulin-requiring diabetes, chronic bronchitis, emphysema, or asthma. With regard to asthma, because many persons who say they have had an asthma attack, especially as a child, may only have had hay fever, another allergy, or another non-asthmatic episode, a blanket exclusion criteria may be overly restrictive. Therefore asthma attacks will only be exclusionary if they a) occurred within the past 10 years, b) occurred at any time in life if induced by a beta-blocker, or c) are currently being treated, regardless of the date of last occurrence. Cardiological consultation will be obtained as necessary;
6. Previous adverse reaction to, or non-compliance with a beta-blocker.
7. Current use of medication that may involve potentially dangerous interactions with propranolol, including, other beta-blockers, antiarrhythmics, calcium channel blockers, and potent P450 2D6 inhibitors, e.g., fluoxetine, paroxetine, micnazole, sulconazole, metaclopramide, quinidine, ticlopidine, and ritnavir.
8. Presence of drugs of abuse, viz., opiates, marijuana, cocaine, or amphetamines, as determined by urine testing.
9. Pregnancy (in women of child- bearing potential, a pregnancy test will be performed) or breast feeding.
10. Contraindicating psychiatric condition, e.g., current psychotic, bipolar, melancholic, or substance dependence or abuse disorder.
11. Initiation of, or change in, psychotropic medication within the previous two months. For subjects receiving stable doses of pharmacotherapy, they and their providers will be asked not to change the regimen except in clinically urgent circumstances. If this becomes necessary, a decision will be made on a case-by-case basis whether to retain the subject in the study or terminate participation.
12. Current participation in any psychotherapy (other than supportive). Subjects will be asked not to initiate psychotherapy during the course of the proposed study except in clinically urgent circumstances; if this becomes necessary, a decision will be made on a case-by-case basis whether to retain the subject in the study or terminate participation.
13. Inability to understand the study's procedures, risks, and side effects, or to otherwise give informed consent for participation.