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.

Fig. 1

Emerging drugs for agitation and psychosis in Alzheimer’s disease. A Schematic representation of potential neurotransmitter pathways involved in agitation and psychosis in AD. B Main pharmacological binding profiles of emergent drugs for agitation in AD. C Main pharmacological binding profiles of emergent drugs for psychosis in AD. 5-HT 5-hydroxytryptamine, 5-HT1A 5-hydroxytryptamine receptor 1A, 5-HT2A 5-hydroxytryptamine receptor 2A, 5-HT6 5-hydroxytryptamine receptor 6, α alpha adrenergic, α1 alpha-1 adrenergic receptor, α2 alpha-2 adrenergic receptor, CB cannabinoid receptor, D dopamine, D2 dopamine receptor D2, D3 dopamine receptor D3, M muscarinic, M1 muscarinic receptor M1, M4 muscarinic receptor M4, NET norepinephrine transporter, NMDA N-methyl-d-aspartate receptor, PDE10A phosphodiesterase 10A, SERT serotonin transporter, σ1 sigma 1 receptor. Figure created with BioRender.com