Brexpiprazole and Dextromethorphan-Bupropion: Mechanisms of Action and Key Clinical Trial Data for Approved Alzheimer's Disease Agitation Therapies

In 'Brexpiprazole and Dextromethorphan-Buproprion: Mechanisms of Action and Key Clinical Trial Data for Approved Alzheimer's Disease Agitation Therapies,' the expert neurologists examined the following critical questions: Brexpiprazole was approved by the Food and Drug Administration (FDA) in 2023 and dextromethorphan/buproprion in 2026 for the treatment of Alzheimer's disease agitation. What are the mechanisms of action of these therapies?What were the key safety and efficacy results seen in the clinical trials? Alireza Atri provided an overview of the neurobiological rationale underlying Alzheimer's disease agitation, explaining that neurodegeneration disrupts the balance between top-down executive control and bottom-up emotional drive, leading to dysregulation across noradrenergic, serotonergic, dopaminergic, and glutamatergic systems. He described brexpiprazole's mechanism of action as a partial agonist at dopamine D2 receptors and serotonin 5-HT1A receptors, an antagonist at serotonin 5-HT2A receptors, and a blocker at alpha-adrenergic receptors, distinguishing it from conventional antipsychotics through its partial agonism rather than full receptor blockade. Anton Porsteinsson outlined the clinical trial evidence, noting that across three studies, brexpiprazole at doses of 2 and 3 milligrams demonstrated statistically significant reductions in the Cohen-Mansfield Agitation Inventory (CMAI) compared with placebo, with benefits also observed on global severity and improvement measures as well as caregiver burden and quality of life outcomes. Dr. Atri also introduced the dextromethorphan-bupropion combination, explaining that dextromethorphan functions as a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, while bupropion serves primarily to inhibit the rapid metabolism of dextromethorphan, allowing for more sustained therapeutic drug levels. Throughout the conversation, the experts provided a comprehensive reflection on the field and the factors that may shape how clinicians approach care moving forward. In the next episode, 'Comparing the Two Approved Therapies: Dextromethorphan-Bupropion and Brexpiprazole in Alzheimer's Disease Agitation,' panelists continue their discussion on Alzheimer's disease agitation and highlight the mechanism of action of dextromethorphan-bupropion, the key safety and efficacy results that led to its Food and Drug Administration (FDA) approval, and how its clinical trial data compare with those of brexpiprazole.