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

ABSTRACT

Introduction

Neuropsychiatric symptoms (NPS) in Alzheimer’s Disease (AD) are associated with negative outcomes for patients and their care partners. Agitation is a common and distressing NPS, without safe and effective treatments. Nonpharmacological interventions are first line treatment, but not effective or appropriate for every patient. Current pharmacological treatments of agitation in AD include off-label use of antipsychotics, sedative/hypnotics, anxiolytics, mood-stabilizing anticonvulsants, acetylcholinesterase inhibitors, NMDA receptor antagonists, and antidepressants. Despite prevalent use, efficacy and safety concerns remain.

Areas covered

Better understanding of neurobiological mechanisms of agitation have fueled recent clinical trials. This article is an update to our 2017 review. Comprehensive search of ClinicalTrials.gov was completed from January 2017 to February 2023 using the search terms “Alzheimer’s Disease” and “Agitation”. Subsequent scoping review was completed in PubMed and Google Scholar. Several agents were identified, including: brexpiprazole, cannabinoids, dexmedetomidine, dextromethorphan, escitalopram, masupirdine, and prazosin.

Expert opinion

Clinical trials utilize both novel and repurposed agents for agitation in AD. With increasing understanding of the neurobiological mechanisms that fuel development of agitation in AD, use of enahanced trial design and conduct, advanced statistical approaches, and accelerated pathways for regulatory approval, we advance closer to safe and efficacious treatment options for agitation in AD.

KEYWORDS:

• Agitation
• Alzheimer’s disease
• Brexpiprazole
• Cannabinoids
• Dexmedetomidine
• Dextromethorphan
• Escitalopram
• Masupirdine
• Neuropsychiatric symptoms
• Prazosin

Article highlights

• Despite a high prevalence of agitation in AD, there are still no approved treatments or guidelines

• New insights and knowledge related to mechanistic underpinnings in agitation have fueled a surge of research on novel and repositioned therapeutic agents

• Recent press releases and conference presentations related to brexpiprazole and dextromethorphan/bupropion show successful primary and secondary endpoints related to treating and preventing relapse of agitation in AD

Declaration of interest

A Porsteinsson reports personal fees from Acadia Pharmaceuticals, Athira, Biogen, Cognitive Research Corp, Eisai, Functional Neuromodulation, IQVIA, Maplight Therapeutics, Merck, MJH Life Sciences, Novartis; grants to his institution from Alector, Athira, Biogen, Biohaven, Cassava, Eisai, Eli Lilly, Genentech/Roche, Vaccinex, NIA, NIMH, and DOD. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.