Editors' ChoicePsychiatry

Memory at the margins: Antipsychotic enhances the binding of fear memory with its context

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Science Translational Medicine  16 Sep 2020:
Vol. 12, Issue 561, eabe1717
DOI: 10.1126/scitranslmed.abe1717

Abstract

A nontraditional antipsychotic medication enhances healthy memory function in a mouse model of fear conditioning.

Posttraumatic stress disorder (PTSD) affects around 6% of individuals in the United States, with impairing symptoms such as hypervigilance, sleep problems, unwanted memories of trauma, and avoidance of reminders. The selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine were the last drugs specifically approved for PTSD almost 20 years ago. However, new pharmacological treatments are urgently needed for those suffering with PTSD since SSRIs have relatively small effects compared to placebo.

Ducourneau et al. hypothesized that drug development could be improved using an animal model that recapitulates some of the distinctive memory deficits seen in PTSD. Individuals with PTSD show difficulty in encoding the context in which fear memories are formed. During a traumatic event, a lack of memory for the context is thought to lead to “overgeneralization” of fear, such that the individual is fearful when trauma reminders are later encountered in safe contexts. Similarly, in the mouse model, animals completed a contextual fear learning task in which a shock was delivered in a particular context, unrelated to a tone cue. PTSD-like memory emerged in mice who received corticosterone injection just after this experience, such that they showed fear behavior to the unrelated tone, whereas control mice correctly showed fear only in the context that was predictive of shock. In the mice with PTSD-like memory, administration of the drug brexpiprazole restored fear behavior only in the context linked with shock.

Brexpiprazole is approved as an antipsychotic and an adjunct to SSRIs in major depressive disorder. The next steps in translation to PTSD are on a short horizon. The developer is now running a phase 3 trial pairing brexpiprazole with sertraline in PTSD (NCT04124614). Although the trial targets PTSD symptom reduction, greater insight could be gained by including memory tasks similar to those implemented by Ducourneau et al., to understand brexpiprazole’s influence on memory binding of threat and the context in which it was experienced. However, brexpiprazole raises safety concerns among pregnant women and older adults with dementia and has common side effects that include agitation and insomnia, which are already difficult to treat in PTSD. The addition of a treatment option to the very limited lexicon of safe and efficacious drugs for PTSD would nevertheless represent a major breakthrough.

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