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Single-dose propranolol tied to ‘selective erasure’ of anxiety disorders
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.
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.”
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. Sleep may be the final and necessary link to prevent the process of reconsolidation,” Dr. Soeter said. It’s still unclear, however, how much sleep is required. Perhaps a nap will turn out to be sufficient, she said.
www.mdedge.com
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.
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.”
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. Sleep may be the final and necessary link to prevent the process of reconsolidation,” Dr. Soeter said. It’s still unclear, however, how much sleep is required. Perhaps a nap will turn out to be sufficient, she said.
Single-dose propranolol tied to ‘selective erasure’ of anxiety disorders
BARCELONA – The evolutionary treatment targets reconsolidation of fear memories.
www.mdedge.com
