A Novel Treatment For Chronic Posttraumatic Stress Disorder (PTSD) Using Post-Reactivation Propranolol

Historical background. Recent animal research indicates that retrieval returns a consolidated memory, or some aspect(s) of it, to a labile state from which it must be restabilized in order to persist. This process is called reconsolidation, although it is not identical to consolidation. Support for reconsolidation comes from experiments in a variety of species ranging from snails to humans; in appetitive, aversive and neutral tasks; and using a broad range of approaches, including systemic or localized drug administration, gene manipulation, and interference by new learning. Memory impairments due to blocked reconsolidation can be long-lasting. Reconsolidation impairments are distinct from extinction in that they can be made to occur even when a reinforced trial is used to reactivate the memory, do not show renewal after contextual shift, can be double-dissociated from extinction, and have distinct neurochemical signatures from extinction. To date there has only been a single, published, controlled study supporting reconsolidation, and its blockade, in humans. That study involved weakening the consolidated memory of a simple motor sequence by presenting a conflicting sequence after reactivation of the memory of the original sequence.

According to a translational model of the pathogenesis of post-traumatic stress disorder (PTSD), a psychologically traumatic event overstimulates endogenous stress hormones, which in turn overly strengthen consolidation of the memory of the event, leading to an excessively powerful and persistent memory that is too easily activated, with consequent anxiety and dysfunction. Animal and human data indicate that the memory-modulating effects of stress hormones are mediated by noradrenergic activity in the amygdala and can be opposed by a β-adrenergic blocker such as propranolol. Administration of propranolol in the immediate aftermath of a psychologically traumatic event reduces the strength of its memory, as manifest in lower physiological responding during script-driven mental imagery of the event measured 3 months later, and lower self-reported PTSD symptoms measured 2 months later.

According to the above model, there exists a window of opportunity for influencing the consolidation of the traumatic event into long-term memory. Once this window has closed, the memory trace is no longer labile, and β-blockers would no longer be able to exert their anti-PTSD effect. Attempting to prevent PTSD by blocking consolidation of the traumatic memory (or some aspects of it) is subject to the formidable limitation that most cases are unlikely to receive clinical attention until long after this window of opportunity has shut. In persons who have developed PTSD, this would have happened weeks, months, or years earlier. However, if a traumatic memory undergoes reconsolidation when it is reactivated, this could re-open the window of opportunity to influence the memory pharmacologically. The post-reactivation administration of propranolol could reduce the strength of a traumatic memory by blocking reconsolidation in a manner parallel to reducing its strength immediately following its occurrence by blocking consolidation. In support of this possibility, consolidated memories for aversive tasks in animals have been shown to become sensitive to β-blockade after reactivation. Specifically, administration of propranolol following reactivation has been found to reduce inhibitory avoidance and auditory fear conditioning; the latter impairment was stable for one month. These results demonstrate in rodents that aversively conditioned memories when reactivated become sensitive to the effects of propranolol.

Previous studies supporting the proposed research. In a preliminary study, we employed a validated psychophysiological script-driven imagery technique to study 19 participants with chronic PTSD resulting from various psychologically traumatic events. Physiological responses during traumatic imagery have been shown to reliably discriminate PTSD from non-PTSD psychological trauma victims, leading to the inclusion of the PTSD criterion "physiological reactivity on exposure to internal cues that symbolize or resemble an aspect of the traumatic event" in the current Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Each participant described the traumatic event that caused their PTSD; this served to reactivate the traumatic memory. Immediately thereafter, the participant received either oral 40 mg short-acting propranolol followed 2 hours later by oral 60 mg long-acting propranolol (n = 9), or look-alike placebo capsules (n = 10), randomized and double-blind. Group demographic and psychometric means for the two groups were highly similar. A trained research assistant composed scripts portraying the event in the participant's own words and recorded them for playback in the laboratory.

One week later, the participant listened to an audio recording of their personal traumatic event in the psychophysiology laboratory and imagined the event as if it were happening to them again, while heart rate (HR), skin conductance (SC), and left corrugator (facial frowning muscle) electromyogram (EMG) responses were measured. Overall physiological responding during mental imagery of the traumatic event was significantly smaller in the PTSD participants who had received propranolol a week earlier compared to those who had received placebo (multivariate p = .007). Drug condition accounted for an impressive 49% of the variance in overall physiological responding. The univariate analyses indicated that HR and SC, but not EMG, responses were significantly smaller in the propranolol compared to the placebo participants. The mean HR and SC responses of the placebo participants were above the normative cut-offs for PTSD (dashed lines), whereas the mean HR and SC responses of the propranolol participants were below the normative PTSD cut-offs. The mean EMG responses of both groups fell below the normative PTSD cut-off. The observed effect sizes (in terms of Cohen's d, i.e., the difference in group means divided by the pooled standard deviation) were all in the predicted direction. By conventional standards, these effect sizes were very large for SC, large for HR, but small for EMG. The psychophysiological results of the present study along with those of the previously reported study in which propranolol was administered in the immediate aftermath of the traumatic event indicate that post-reactivation propranolol recapitulates its effects on consolidation.