Agitation is a common and particularly distressing neuropsychiatric symptom in Alzheimer’s disease, often leading to early institutionalization, increased caregiver burden and accelerated functional decline. Recent advances in neuroimaging and pharmacology have expanded our understanding of the underlying mechanisms of agitation and informed the development of targeted therapies.
In this expert interview, Prof. George Grossberg (Saint Louis University School of Medicine, St Louis, MO, USA), an authority in geriatric psychiatry, shares his perspective on the pathophysiological underpinnings of agitation in Alzheimer’s disease, current and emerging pharmacological approaches, and the implications of findings presented at the Alzheimer’s Association International Conference (AAIC) 2025.
Certainly. We are now beginning to better understand the neuroanatomical and neurotransmitter alterations that underlie the symptom of agitation in Alzheimer’s disease. At the neurocircuitry level, there is a disruption in the balance between the prefrontal cortex and amygdala, resulting in a loss of top-down executive control over emotional and behavioural responses. This imbalance contributes to the emergence of agitation.
From a neurochemical standpoint, agitation in Alzheimer’s disease is associated with increased noradrenergic activity, reduced serotonergic transmission and dysregulation of striatal dopamine. These changes create a state of heightened emotional reactivity and impaired behavioural inhibition.
Brexpiprazole, currently the only FDA-approved treatment for agitation in Alzheimer’s disease, restores this balance by reducing noradrenergic hyperactivity, enhancing serotonergic tone and modulating dopaminergic activity. In doing so, it strengthens executive control and decreases emotional drive. This is accomplished via decreasing norepinephrine hyperactivity, increasing serotonergic activity and regulating striatal dopamine, all of which are the neurochemical underpinnings of agitation in Alzheimer’s disease.
Among the investigational treatments, combination dextromethorphan-bupropion (AXS-05) is one of the most promising agents nearing regulatory approval. While it is already approved for major depressive disorder, its multimodal mechanism of action is particularly relevant in Alzheimer’s disease agitation.
Dextromethorphan acts as an NMDA receptor antagonist, highlighting the role of glutamatergic excitotoxicity in agitation. It also functions as a sigma-1 receptor agonist, which may have additional benefits for neuropsychiatric symptoms. Moreover, dextromethorphan increases synaptic serotonin and has anti-inflammatory effects via reduction of microglial activation, both of which are relevant in mitigating agitation.
Bupropion, in this combination, serves primarily as a metabolic inhibitor to boost and sustain dextromethorphan plasma levels. While its direct pharmacodynamic contribution to the treatment of agitation is minimal, its role in optimizing the pharmacokinetics of dextromethorphan is essential.
One of the most exciting developments involves the investigational use of xanomeline-trospium, which has shown potential for treating both psychosis and agitation in Alzheimer’s disease. Xanomeline is a selective M1/M4 muscarinic receptor agonist, and when combined with trospium, a peripherally acting anticholinergic, it allows for central action while mitigating peripheral side effects.
This agent, now approved as Cobenfy™ for schizophrenia-related psychosis, is being explored in the Alzheimer’s disease population. Early data suggest that it could offer therapeutic benefit not only for psychosis but also for agitation.
Article Highlights
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- Agitation in Alzheimer’s disease is driven by disrupted prefrontal-amygdala connectivity and neurotransmitter imbalance.
- Brexpiprazole is the first FDA-approved therapy for Alzheimer’s disease agitation, modulating serotonin, norepinephrine and dopamine.
- Dextromethorphan-bupropion demonstrated promising Phase 3 results.
- Xanomeline-trospium is being explored as a novel therapeutic approach in Alzheimer’s disease.
- Early diagnostics and symptom-targeted treatments may enable personalized care in Alzheimer’s disease.
This content has been developed independently by Touch Medical Media for touchNEUROLOGY. Views expressed are the speaker’s own and do not necessarily reflect the views of Touch Medical Media.
Editor: Katey Gabrysch, Editorial Director.
Disclosures: This short article was prepared by touchNEUROLOGY in collaboration with George Grossberg. The content was developed and edited by human editors. No fees or funding were associated with its publication. touchNEUROLOGY utilize AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat).
George Grossberg is a consultant for Acadia, Alpha Cognition, Axsome Therapeutics, Biogen, BioXcel, Bristol Myers Squibb, Eisai, Karuna, Lilly, Lundbeck, Maplight Therapeutics, Otsuka, and Takeda; has received grant/research support from NIA, and is a speaker’s bureau participant with Otsuka.
Cite: George Grossberg. Advances in managing agitation in Alzheimer’s disease: Insights from AAIC 2025. touchNEUROLOGY. 04 September 2025.
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