A 2023 update on the advancements in the treatment of agitation in Alzheimer's disease

Introduction: Neuropsychiatric symptoms (NPS) in Alzheimer's Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is one of the most common and distressing NPS, yet we lack safe and effective treatment options. While nonpharmacologic interventions are considered first line treatment, these may not be effective or appropriate for every patient. Our current approaches to the pharmacologic treatment of agitation in AD consist of the off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite their prevalent use, they have questionable efficacy and significant safety concerns.

Areas covered: Advances in the understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. A comprehensive search of ClinicalTrials.gov was completed from January 2017 to June 2022 using the search terms "Alzheimer's Disease" and "Agitation". A subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified for promise in treating agitation, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin.

Expert opinion: Clinical trials remain underway utilizing both novel and repurposed agents to address symptoms of agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel the development of agitation in AD, the use of enhanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we are advancing closer to having safe and efficacious treatment options for agitation in AD.

Comments：

Agitation is a common and distressing neuropsychiatric symptom in AD, and the lack of safe and effective treatment options is a significant challenge for patients, caregivers, and healthcare professionals. Nonpharmacologic interventions are generally considered the first-line treatment for agitation in AD, but they may not be effective or appropriate for every patient.

Pharmacologic treatment options for agitation in AD include off-label use of various drugs, such as antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. However, these drugs have questionable efficacy and significant safety concerns, including increased risk of stroke, falls, and mortality.

Recent advances in the understanding of neurobiological mechanisms of agitation have led to the identification of several agents with promise for treating agitation in AD, such as brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin. Clinical trials are underway utilizing both novel and repurposed agents to address symptoms of agitation in AD.

Advanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval can help accelerate the development of safe and efficacious treatment options for agitation in AD. However, it is essential to balance the potential benefits of pharmacologic treatment with the potential risks and side effects, especially in the elderly population with multiple comorbidities. Therefore, a personalized approach to treatment, considering individual patient characteristics and preferences, is crucial for effective management of agitation in AD.