β-blockers in post-traumatic stress disorder: uses and controversies

Anda van Stegeren

Figure 1.  Representation of the subjects’ emotional rating of stimulus picture categories with increasing (negative) emotional intensity.

CAT: Category; CAT1: Neutral; CAT4: Extreme negative emotional intensity. Reprinted from Neuroimage, 24(3), van Stegeren AH et al. Norepinephrine mediates amygdala activation in men and women during encoding of emotional material. 898–909 (2005), with permission from Elsevier [4].

Application of β-blockers as a possible useful therapeutic intervention after emotional events has become the topic of interest, as well as a subject of discussion, among researchers. Some fundamental research findings have preceded this discussion about the role of noradrenergic blocking agents, such as propranolol, in emotional information processing. β-blockers reduce the physiologic arousal reaction in body and brain, and affect the storage of emotional information. They are frequently used and prescribed to reduce both somatic symptoms (e.g., high blood pressure, angina pectoris, irregular heart rhythm or heart failure) and psychologic problems (e.g., social anxiety).

Evidence for the role of norepinephrine in human emotional memory comes from experimental placebo-controlled studies, where the blockade of the β-adrenergic system with the lipophilic β-blocker propranolol selectively impaired long-term (1 week) memory for an emotionally arousing story, but did not affect memory for a closely matched but relatively neutral story [1,2]. In these experiments subjects were randomly assigned to either a β-blocker (propranolol) or a placebo condition, and half of each group was presented with a slide show in an arousal or neutral version. It appeared that the β-blocker selectively reduced memory for emotional information, at least through its effect on norepinephrine levels in the brain. This was confirmed in recent functional magnetic resonance imaging (fMRI) studies where norepinephrine was shown to be the essential neurotransmitter in the human amygdala, a brain structure crucial in all emotional information processing [3,4]. Watching emotional pictures evoked increased amygdala activation, an effect that was significantly reduced by β-blockade. Administration of the β-blocker propranolol disrupted the normal effect of norepinephrine in the amygdala (i.e., the superior storage of affective information). These recent insights may also create new opportunities for the prevention of chronic post-traumatic stress disorder (PTSD), a disorder that is characterized by memory disturbances related to the traumatic event (box 1).

A very promising model to explain the possible mechanisms underlying the development of chronic PTSD after trauma is put forward by Pitman and Delahanty [5]. A traumatic event (unconditioned stimulus) overstimulates endogenous stress hormones (unconditioned response) mediating an overconsolidation of the event’s memory trace. Recall of the event in response to reminders (conditioned stimuli) releases further stress hormones (conditioned response). This conditioning can become generalized to a variety of (formerly neutral) stimuli, leading to further consolidation of the traumatic memories. Noradrenergic hyperactivity in the basolateral amygdala is hypothesized to mediate this cycle. Interfering with this process could be achieved by preventing presynaptic norepinephrine release with α-2-adrenergic agonists or opioids, or by blocking postsynaptic norepinephrine receptors with β-adrenergic antagonists such as propranolol. Herewith, hormonally enhanced memories and fear conditioning would be reduced [5].

In addition, mechanisms of extinction may (also) play a role in developing chronic PTSD, which was demonstrated in a recent study. As with conditioned fear learning, extinction is dependent upon a particular protein (the N-methyl-D-aspartate receptor) in the amygdala. Inhibition of this receptor blocks extinction, and improving the activity of this receptor with a drug called D-cycloserine speeds up extinction in rats. It was also investigated whether D-cycloserine may facilitate the loss of fear in human patients and it was found that patients receiving D-cycloserine benefited more from exposure-based psychotherapy than placebo-treated controls [6].

The effect of norepinephrine (or antagonists) on memory in the postacquisition phase has not been studied extensively in humans. This contrasts with ample evidence from animal studies [7,8], leading to the conclusion that the release and presence of norepinephrine also appears to play a crucial role in retrieval and consolidation. However, the use of β-blockers as a possible therapeutic intervention after emotional events is dependent upon its effect on memory after the stage of encoding. Therefore, the author’s group designed a study in which the same dosage and stimulus material was applied as in earlier studies [1,2], but the time in which the drug (β-blocker vs. placebo) was active was changed to after the stage of encoding. The group hypothesized that, as with animal studies, norepinephrine levels post-training could also affect memory consolidation in humans, but, within the constraints of an experimental setting and the (relatively low) 40 mg dosage, they could not find support for the effect of noradrenergic blockade during consolidation on later memory performance in humans [9]. However, two clinical outpatient studies have been carried out to date using the β-blocker propranolol after a traumatic event to study if the drug application may prevent the development of subsequent PTSD symptoms [11,12]. In the first study, patients were randomized to begin a 10-day course of double-blind propranolol (n = 18) versus placebo (n = 23) and received 40 mg four-times daily. The propranolol-treated patients were significantly lower physiologic responders than the placebo group during script-driven imagery of the traumatic event at 3 months after the trauma. In the second study, 11 patients received 40 mg of propranolol three-times daily for 7 days, followed by a taper period of 8–12 days. PTSD rates post-treatment were higher in the group who refused propranolol (three out of eight) compared with those who received the medication (one out of 11), as were the levels of PTSD symptoms. Both studies suggest that acute, post-trauma propranolol may have a preventive effect on subsequent PTSD symptoms, or is perhaps even preventing the development of chronic PTSD. It should be noted that the dosage in these studies were much higher and applied for a longer period of time than in the protocol used in the author’s laboratory (once 40 mg) [9]. Perhaps a much higher and/or longer application of propranolol post-training should be used to lead to significant effects on memory consolidation in an experimental setting as well.

The application of β-blockers has now been mentioned as an attractive alternative and possible treatment for people who have gone through trauma. It should then be applied in the period immediately after the trauma in order to prevent the development of (chronic) PTSD. The attractiveness of these drugs is related to the relatively low incidence and amount of side effects, as well as few contraindications. It may be a welcome addition to the current evidence-based pharmacotherapy of PTSD, which is mainly directed at the treatment of patients who already developed chronic PTSD [5,13] and cannot be regarded as an unqualified success.

Recently, a group of American psychiatrists announced the publication of a study where they intend to treat people after a trauma with propranolol [14]. The psychiatrist Altemus and her colleagues (from Cornell University) are asking their subjects to take a dose of propranolol whenever they feel the characteristic symptoms of PTSD, such as rapid heart rate or troubled breathing. If the theory is right, the trauma memory should be pliable at that point and propranolol should break the link between recall and fear [14]. This announcement has created some commotion, leading to questions regarding the pros and cons of β-blocker application in the prevention of PTSD.

It has been argued that the disturbed memory aspects of PTSD are a natural response to traumatic events and should not be treated with drugs. People have the ‘right’ to have their traumatic memories or ‘thou shalt not interfere’. It is true, some human interference did not prove to be beneficial for handling traumatic experiences. Forced debriefing, such as critical incident stress debriefing (CISD) and other non-CISD interventions, do not improve natural recovery from psychologic trauma [15]. In this case, no treatment appears to be better than treatment. However, PTSD is a relatively frequent disorder that seriously affects and disturbs a person’s life and well being. It seems strange not to offer victims the choice for possible opportunities in the prevention of developing PTSD.

It is very important to realise that different types of gene–environment interactions can lead to very different manifestations of psychopathology. In a recent review, Olff and colleagues indicate that there is evidence that the particular outcome may result from individual differences in defense and coping strategies, representing important targets for psychotherapy [16]. They conclude that combinations of psychologic and pharmacologic interventions may help an individual to turn maladaptive responses into more adaptive ones.

An additional objection against the preventive use of β-blockers is that it has not been indisputably established experimentally that β-blockade is effective in the consolidation phase. In total, two studies have been carried out that did show an effect of postlearning stress hormone levels on memory performance [17,18]. The post-training stress levels appeared to interact with the amount of arousal at the time of encoding. Cahill and colleagues tested whether postlearning stress hormone levels affected memory for a series of slides 1 week later [17]. Stress levels were raised by administering cold pressor stress (CPS) to subjects after they viewed slides of varying emotional content. CPS, which significantly elevated salivary cortisol levels, enhanced memory for emotionally arousing slides compared with the controls, but did not affect memory for relatively neutral slides. In a second study, healthy subjects viewed a series of slides and immediately after received an intravenous infusion of either saline or epinephrine (40 or 80 ng/kg/min). Epinephrine dose-dependently increased memory for the first three slides when arousal was high (primacy effect), but did not affect memory of the last three slides [18]. Both findings support the view that endogenous stress hormones modulate memory consolidation for experiences that interact with arousal during encoding.

In light of the effective field studies of Pitman and Vaiva already mentioned [11,12], it seems tenable to assume that a (re)consolidation effect of stress hormones and neurotransmitters, such as norepinephrine on memory, can also be found in humans. The time- and dose-dependency of this effect on memory asks for a very clever design and a series of studies to show how this relationship in humans can be portrayed.

One of the critical voices heard in response to the announced publication [14] is that of a member of the US President’s Council on Bioethics, who fears that prescribing β-blockers may impair a person’s ability to judge what is morally acceptable and herewith alter the conscience of the person concerned. It relates to ethical considerations and is fed by the fear of taking out the feeling or emotionality of people. The author would like to make a plea against this fear. Most studies using β-blockers and emotional versus neutral stimulus material incorporated a personal evaluation or judgments of the stimuli the subjects were presented with [1,2,4,9]. So, after subjects saw a picture or film they were asked to rate the emotionality of the stimulus on a certain scale. A strikingly consistent finding in all these studies has been that β-blockers do not affect this cognitive rating, hence do not negatively influence the judgment of how emotional a certain situation or stimulus is (figure 1). Although the physiologic arousal, measured by heart rate, was reduced and – in the case of fMRI studies – even amygdala activation was shown to be lower under β-blocker conditions [3,4], this did not affect the cognitive evaluation of how emotional they found the pictures to be. Even more remarkable was the outcome, that 1 week after confrontation with the stimuli, the author’s group asked their participants for a retrospective cognitive rating of their emotional reaction to the pictures. The results were similar to the week before: the emotional pictures were scored significantly higher than the neutral ones with no effect of drug condition [9]. This outcome appears to support that memory performance, but not the cognitive judgment of the emotionality of the material, is influenced by the β-blocker propranolol [4].

This lends support for the view that β-blockers affect the noradrenergic system and decrease arousal. They are thus intervening with the reconsolidation of unwanted memories without a general sedative effect, but a seemingly specific effect in the storage of emotional information. Summarizing, the author would like to argue that developing new experimental studies to systematically explore postencoding timing protocols with different dosages of β-blockers should provide a better insight for the use and therapeutic application of these drugs in the prevention of PTSD.

Acknowledgements

The author would like to thank Merel Kindt and Walter Everaerd.

Box 1. Post-traumatic stress disorder.

Post-traumatic stress disorder is characterized by specific symptoms that develop following exposure to a “threat to the life of oneself or others”. The symptoms of post-traumatic stress disorder consist of re-experiencing an extreme stressor or traumatic event, by thoughts, images or nightmares; secondly of avoidance of reminders of the traumatic event and the disorder is finally characterized by increased tension, hypervigilance and symptoms of hyperarousal.

From: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [10].