Comparing the Two Approved Therapies: Dextromethorphan-Bupropion and Brexpiprazole in Alzheimer's Disease Agitation

In this episode, 'Comparing the Two Approved Therapies: Dextromethorphan-Bupropion and Brexpiprazole in Alzheimer's Disease Agitation,' the expert neurologists explored the following question: What were the key safety and efficacy results that led to its approval and how do they compare with brexpiprazole's? Anton Porsteinsson outlined the clinical trial programs supporting both approved agents, noting that the Cohen-Mansfield Agitation Inventory (CMAI) served as the primary outcome measure across all trials, alongside global severity and improvement measures and caregiver burden and quality of life assessments. He described the dextromethorphan-bupropion program, which included one placebo-controlled parallel-group study and two relapse prevention studies, all of which demonstrated statistically significant reductions in CMAI scores with a generally reasonable tolerability profile including some gastrointestinal symptoms, headache, and dizziness. Alireza Atri contextualized these findings against the broader treatment landscape, emphasizing that while the older off-label agents such as risperidone and olanzapine show modest effect sizes in the range of 0.18 to 0.22, they carry significant adverse event burdens including sedation, falls, extrapyramidal symptoms, and increased mortality risk, whereas neither approved agent demonstrated meaningful signals for cognitive suppression or falls in their respective trials, representing a meaningful improvement in the benefit-risk balance. Dr. Atri also highlighted relapse prevention data from the dextromethorphan-bupropion trials, noting that approximately one-third of patients switched to placebo relapsed within 6 months compared with only 6 to 8% of those who remained on active treatment, underscoring the importance of sustained therapy. 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, 'Choosing Between Approved Therapies: Differentiation, Sequencing, and Black Box Warning Navigation in Alzheimer's Disease Agitation,' panelists continue their discussion on Alzheimer's disease agitation and highlight how clinicians are differentiating between antipsychotic therapies and dextromethorphan-bupropion in practice, how treatment sequencing is evolving with two approved options now available, and how black box warnings are being navigated in the context of shared decision-making.