BARCELONA – A single 40-mg dose of oral propranolol, judiciously timed, constitutes an outside-the-box yet highly promising treatment for anxiety disorders, and perhaps for posttraumatic stress disorder as well, Marieke Soeter, PhD, said at the annual congress of the European College of Neuropsychopharmacology.
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Dr. Marieke Soeter
The concept here is that the beta-blocker, when given with a brief therapist-led reactivation of a fear memory, blocks beta-adrenergic receptors in the brain so as to interfere with the specific proteins required for reconsolidation of that memory, thereby disrupting the reconsolidation process and neutralizing subsequent expression of that memory in its toxic form. In effect, timely administration of one dose of propranolol, a drug that readily crosses the blood/brain barrier, achieves pharmacologically induced amnesia regarding the learned fear, explained Dr. Soeter, a clinical psychologist at TNO, the Netherlands Organization for Scientific Research, an independent nonprofit translational research organization.
“It looks like permanent fear erasure. You can never say that something is erased, but we have not been able to get it back,” she said. “Propranolol achieves selective erasure: It targets the emotional component, but knowledge is intact. They know what happened, but they aren’t scared anymore. The fear association is affected, but not the innate fear response to a threat stimulus, so it doesn’t alter reactions to potentially dangerous situations, which is important. If there is a bomb, they still know to run away from it.”
This single-session therapy addressing what psychologists call fear memory reconsolidation is totally outside the box relative to contemporary psychotherapy for anxiety disorders, which typically entails gradual fear extinction learning requiring multiple treatment sessions. But contemporary psychotherapy for anxiety disorders leaves much room for improvement, given that up to 60% of patients experience relapse. That’s probably because the original fear memory remains intact and resurfaces at some point despite initial treatment success, according to Dr. Soeter.
Nearly 2 decades ago, other investigators showed in animal studies that fear memories are not necessarily permanent. Rather, they are modifiable, and even erasable, during the vulnerable period that occurs when the memories are reactivated and become labile.
Later, Dr. Soeter – then at the University of Amsterdam – and her colleagues demonstrated the same phenomenon using Pavlovian fear-conditioning techniques involving pictures and electric shocks in healthy human volunteers. They showed that a dose of propranolol given before memory reactivation blocked the fear response, while nadolol, a beta-blocker that does not cross the blood/brain barrier, did not.
However, since the fear memories they could ethically induce in the psychology laboratory are far less intense than those experienced by patients with anxiety disorders, the researchers next conducted a randomized, double-blind clinical trial in 45 individuals with arachnophobia. Fifteen received 40 mg of propranolol after spending 2 minutes in proximity to a large tarantula, 15 got placebo, and another 15 received propranolol without exposure to a tarantula. One week later, all patients who received propranolol with spider exposure were able to approach and actually pet the tarantula. Pharmacologic disruption of reconsolidation and storage of their fear memory had turned avoidance behavior into approach behavior. This benefit was maintained for at least a year after the brief treatment session (Biol Psychiatry. 2015 Dec 15;78[12]:880-6).
“Interestingly, there was no direct effect of propranolol on spider beliefs. Therefore, do we need treatment that targets the cognitive level? These findings challenge one of the fundamental tenets of cognitive-behavioral therapy that emphasizes changes in cognition as central to behavioral modification,” Dr. Soeter said.
Most recently, she and a coinvestigator have been working to pin down the precise conditions under which memory reconsolidation can be targeted to extinguish fear memories. They have shown in a 30-subject study that the process is both time- and sleep-dependent. The propranolol must be given within roughly an hour before to 1 hour after therapeutic reactivation of the fear memory to be effective. And sleep is an absolute necessity: When subjects were rechallenged 12 hours after memory reactivation and administration of propranolol earlier on the same day, with no opportunity for sleep, there was no therapeutic effect: The disturbing fear memory was elicited. However, when subjects were rechallenged 12 hours after taking propranolol the previous day – that is, after a night’s sleep – the fear memory was gone (Nat Commun. 2018 Apr 3;9[1]:1316. doi: 10.1038/s41467-018-03659-1).
“Postretrieval amnesia requires sleep to happen. ,” Dr. Soeter said. It’s still unclear, however, how much sleep is required. Perhaps a nap will turn out to be sufficient, she said.
Colleagues at the University of Amsterdam are now using single-dose propranolol-based therapy in patients with a wide range of phobias.
“The effects are pretty amazing,” Dr. Soeter said. “Everything is treatable. It’s almost too good to be true, but these are our findings.”
Based upon her favorable anecdotal experience in treating a Dutch military veteran with severe combat-related PTSD of 10 years’ duration which had proved resistant to multiple conventional and unconventional interventions, a pilot study of single-dose propranolol with traumatic memory reactivation is now being planned in patients with war-related PTSD.
“After one pill and a 20-minute session, this veteran with severe chronic PTSD has no more nightmares, insomnia, or alcohol problems, and he now travels the world,” she said.
Her research met with an enthusiastic reception from other speakers at the ECNP session on PTSD. Eric Vermetten, MD, PhD, welcomed the concept that pharmacologic therapy upon reexposure to fearful cues can impede the molecular and cellular cascade required to reestablish fearful memories. This also is the basis for the extremely encouraging, albeit preliminary, clinical data on ketamine, an N-methyl-D-aspartate receptor antagonist, as well as 3,4-Methylenedioxymethamphetamine (MDMA) for therapeutic manipulation of trauma memories.
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Dr. Eric Vermetten
“Targeting reconsolidation of existing fear memories is worthy of looking into further,” declared Dr. Vermetten, professor of psychiatry at Leiden (the Netherlands) University and a military mental health researcher for the Dutch Ministry of Defense.
New thinking regarding pharmacotherapy for PTSD is sorely needed, he added. He endorsed a consensus statement by the PTSD Psychopharmacology Working Group that decried what was termed a crisis in pharmacotherapy of PTSD (Biol Psychiatry. 2017 Oct 1;82[7]:e51-e59. doi: 10.1016/j.biopsych.2017.03.007. Epub 2017 Mar 14).
“We only have two [Food and Drug Administration]-approved medications for PTSD – sertraline and paroxetine – and they were approved back in 2001,” Dr. Vermetten noted. “Research has stalled, and there is a void in new drug development.”
Dr. Soeter’s study of the time- and sleep-dependent nature of propranolol-induced amnesia was supported by the Netherlands Organization for Scientific Research, where she is employed.