PTSD Symptom Reduction by Propranolol Given After Trauma Memory Activation

OBJECTIVE: In the first of two preliminary studies, the investigators 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, the investigators 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, the investigators 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. The investigators 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. The investigators regard this as a matter for subsequent studies should the present study yield promising results. However, the investigators do intend to compare the effect size the investigators 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.