Emerging Pharmacological Approaches for Psychosis and Agitation in Alzheimer's Disease.

Abstract

Psychosis and agitation are among the most distressing neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), linked to faster disease progression and earlier admission to nursing homes.

While nonpharmacological treatments may alleviate mild behavioral symptoms, more severe syndromes often require pharmacological intervention. Brexpiprazole is the only medication approved for agitation in AD, although its limited clinical efficacy has raised criticism.

No drugs have been approved for treating psychosis in AD, highlighting the critical need for new, effective, and safe treatments. Recent studies have elucidated part of the neurobiological basis of NPSs in the AD brain, offering insights for testing repurposed and novel drugs.

We conducted a comprehensive nonsystematic literature review, aiming to provide a critical overview of both current treatments and emerging pharmacological interventions under clinical development for treating psychosis and agitation in AD.

Additionally, we present strategies to optimize the clinical development of new drug candidates. We identify three promising compounds that are currently in phase 3 trials: xanomeline-trospium for AD psychosis, and dextromethorphan-bupropion and dexmedetomidine for agitation in AD.

We propose that biomarkers linked to the neuropsychiatric traits of AD patients should be identified in dedicated studies and then included in phase 2 dose-range-finding studies with novel compounds to establish biological engagement.

Furthermore, phase 3 placebo-controlled studies should be carried out in AD biomarker-confirmed subjects with narrower cognitive impairment ranges and precise NPS severity at screening. Alternative study designs, such as sequential phase approaches, may also be adopted.

COI Statement

Declarations. Funding: This research and the open access fee were funded by the Italian Ministry of Health (Ricerca Corrente, 2022-2024). Conflicts of interest: Authors have nothing to declare. Availability of data and material: Not applicable. Ethics approval: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable. Code availability: Not applicable. Author contributions: Conceptualization: Camillo Imbimbo, Matteo Cotta Ramusino, Giulia Perini, Alfredo Costa. Project administration: Camillo Imbimbo, Matteo Cotta Ramusino, Giulia Perini, Alfredo Costa. Writing—original draft: Camillo Imbimbo, Matteo Cotta Ramusino, Giulia Perini, Silvia Leone, Federico Mazzacane, Valentino De Franco, Alberto Gatti. Writing—review and editing: Camillo Imbimbo, Matteo Cotta Ramusino, Giulia Perini, Silvia Leone, Federico Mazzacane, Valentino De Franco, Alberto Gatti, Alfredo Costa. Supervision: Camillo Imbimbo, Matteo Cotta Ramusino, Giulia Perini, Alfredo Costa. All authors read and approved the manuscript and agree to be accountable for the work.

References:

Gustavsson A, Norton N, Fast T, et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement. 2023;19(2):658–70. https://doi.org/10.1002/alz.12694 . (Epub 2022 Jun 2).
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;7(3):73. https://doi.org/10.3389/fneur.2012.00073 .
Creese B, Ismail Z. Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):2. https://doi.org/10.1186/s13195-021-00949-7 .
Aalten P, Verhey FR, Boziki M, et al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007;24(6):457–63. https://doi.org/10.1159/000110738 . (Epub 2007 Nov 7).
van der Linde RM, Dening T, Matthews FE, et al. Grouping of behavioural and psychological symptoms of dementia. Int J Geriatr Psychiatry. 2014;29(6):562–8. https://doi.org/10.1002/gps.4037 . (Epub 2013 Oct 16).

Article info

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Doi:

10.1007/s40263-024-01133-9

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Emerging Pharmacological Approaches for Psychosis and Agitation in Alzheimer's Disease.

Abstract

Psychosis and agitation are among the most distressing neuropsychiatric symptoms (NPSs) of Alzheimer's disease (AD), linked to faster disease progression and earlier admission to nursing homes.

COI Statement

References:

Gustavsson A, Norton N, Fast T, et al. Global estimates on the number of persons across the Alzheimer’s disease continuum. Alzheimers Dement. 2023;19(2):658–70. https://doi.org/10.1002/alz.12694 . (Epub 2022 Jun 2).
Cerejeira J, Lagarto L, Mukaetova-Ladinska EB. Behavioral and psychological symptoms of dementia. Front Neurol. 2012;7(3):73. https://doi.org/10.3389/fneur.2012.00073 .
Creese B, Ismail Z. Mild behavioral impairment: measurement and clinical correlates of a novel marker of preclinical Alzheimer’s disease. Alzheimers Res Ther. 2022;14(1):2. https://doi.org/10.1186/s13195-021-00949-7 .
Aalten P, Verhey FR, Boziki M, et al. Neuropsychiatric syndromes in dementia. Results from the European Alzheimer Disease Consortium: part I. Dement Geriatr Cogn Disord. 2007;24(6):457–63. https://doi.org/10.1159/000110738 . (Epub 2007 Nov 7).
van der Linde RM, Dening T, Matthews FE, et al. Grouping of behavioural and psychological symptoms of dementia. Int J Geriatr Psychiatry. 2014;29(6):562–8. https://doi.org/10.1002/gps.4037 . (Epub 2013 Oct 16).