Risks and benefits of current and novel drugs to treat agitation in Alzheimer’s disease

ABSTRACT

Introduction

At present, no pharmacological interventions have been approved for the treatment of agitation in Alzheimer’s disease (AD), an important neuropsychiatric symptom that has been linked to increased mortality and greater caregiver burden. Antipsychotics offer some benefit, but increase the risk of adverse events such as falls, extrapyramidal symptoms, stroke, and mortality. Over the past 10 years, several new and repurposed medications have shown promise for treating AD-associated agitation.

Areas covered

We review the risks and benefits of emerging therapies for agitation in AD, which include newer atypical antipsychotics, selective serotonin reuptake inhibitors, cannabinoids, and dextromethorphan combination products. Other drugs such as mirtazapine, prazosin, and lithium are also discussed. Clinicaltrials.gov, PubMed/MEDLINE, EMBASE and Cochrane Central databases were searched for relevant studies from 1 January 2012 to 1 May 2022.

Expert opinion

At the present time, there are no pharmacological interventions for the treatment of agitation in AD whose benefits clearly outweigh their potential safety concerns. Therefore, management of agitation in AD should primarily be based on non-pharmacological approaches. When medications are considered necessary, they should only be initiated with the caregiver’s appreciation of their risks and benefits and with careful and ongoing assessment of their safety.

KEYWORDS:

• Agitation
• Alzheimer’s disease
• clinical trial
• dementia
• drug
• neuropsychiatric symptoms
• pharmacological
• pharmacotherapy

Article highlights

• Finding novel pharmacotherapies for treating agitation in AD is an important area of research and many promising candidates have been identified.

• Results of completed (e.g. brexpiprazole, nabilone, dextromethorphan-quinidine) and ongoing (e.g. pimavanserin, escitalopram, dronabinol) clinical trials evaluating new treatments for AD-related agitation are reviewed.

• While some of the newer pharmacological interventions hold promise, further studies are required to document efficacy and/or safety, and demonstrate that they are clearly better than currently used atypical antipsychotics.

This box summarizes key points contained in the article.

Declaration of interests

K Lanctôt reports grants from Alzheimer’s Association (PTC-18-543,823, PTCG-20- 700,751), Alzheimer Society of Canada, Alzheimer’s Drug Discovery Foundation (Grant No: 2,016,354), Canadian Institutes Health Research (FRNs PJ2 179,753, PJT183584), National Institute on Aging (R01AG046543), and Weston Brain Institute; consulting fees from BioXcel Therapeutics, Bright Minds, Cerevel Therapeutics, Eisai Co. Ltd, Exciva, ICG Pharma, Jazz Pharmaceuticals, Kondor Pharma, H Lundbeck A/S, Merck, Novo Nordisk, Praxis Therapeutics, Sumimoto Pharma Co. Ltd; stock options from Highmark Interactive outside the submitted work. 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.

Authors’ contributions

NH and KL outlined the overarching goals of the review and NH wrote the Expert Opinion section. HW conducted the literature search; HW, ES, KB reviewed the literature. Aside from the Expert Opinion section, HW wrote most of the manuscript with contributions from ES and KB. KL and NH provided feedback on the scientific content of the review. All authors edited and approved the final version of the manuscript.

Additional information

Funding

This paper was supported by funding from the Alzheimer’s Drug Discovery Foundation (ADDF), Weston Brain Institute (WBI), Canadian Consortium on Neurodegeneration in Aging, which is supported by a grant from the Canadian Institutes of Health Research with funding from several partners, Toronto Cannabis and Cannabinoid Research Consortium (TC3) Fellowship, Glaxo Wellcome-Sunnybrook Drug Safety Clinic Graduate Student Fellowship, and MITO2i and the Thomas Zachos Scholars.