Defining and Treating Agitation in Alzheimer Disease, With Jason Kellogg, MD

Jason Kellogg, MD, discussed the clinical definition, prevalence, pharmacologic management, and tolerability considerations of agitation in Alzheimer disease, as well as the significant and underaddressed burden that agitation places on family caregivers.

Kellogg opened by noting that the International Psychogeriatric Association published a validated consensus clinical and research definition of agitation in cognitive disorders in 2024, distinguishing it from related but distinct clinical entities including akathisia, aggravation, anger, aggression, and assault—each of which may require different treatment approaches.¹ He expressed enthusiasm for this standardization, noting that definitional ambiguity has historically hampered both clinical communication and research in this area. He cited a prevalence of over 50% for agitation in Alzheimer disease, attributing its emergence in part to the disease's progressive involvement of the frontal lobes, which govern executive function and consequence-based decision-making. As frontal lobe function deteriorates, patients become more emotionally reactive and impulsive. He noted that approximately 8 million Americans are currently living with Alzheimer disease, with projections suggesting that number will double by 2038 absent disease-modifying breakthroughs.

On pharmacologic management, Kellogg described the 2 currently FDA-approved treatments for agitation associated with Alzheimer disease: brexpiprazole, a partial dopamine agonist and atypical antipsychotic, and dextromethorphan-bupropion, which acts via glutamate receptor antagonism and sigma-1 receptor agonism. He emphasized that tolerability is a paramount consideration in this population given patients' age, frailty, and medical comorbidities. Specific concerns he highlighted include sedation—which can precipitate falls, deep vein thrombosis, and cognitive worsening—QTc prolongation, extrapyramidal symptoms including tardive dyskinesia, and the potential for dopamine blockade to worsen cognition in a population already compromised in this domain.

Kellogg concluded by drawing attention to the profound and often invisible burden carried by family caregivers of patients with Alzheimer disease, noting that agitation is most often directed at the caregiver—the person most invested in the patient's wellbeing—who typically receives little acknowledgment in return. Research consistently shows that agitation and other disruptive neuropsychiatric behaviors are the strongest predictors of caregiver burden and depression, more so than the cognitive symptoms of dementia itself.² Kellogg described his practice of acknowledging caregiver strengths explicitly and referring caregivers to separate mental health support when needed, rather than treating both patient and caregiver himself.

Dr Kellogg is founder and chief executive officer of Progyny Psychiatric Group.

References

1. Sano M, Cummings J, Auer S, et al. Agitation in cognitive disorders: progress in the International Psychogeriatric Association consensus clinical and research definition. Int Psychogeriatr. 2024;36(4):238–250

2. Ornstein K, Gaugler JE. The problem with "problem behaviors": a systematic review of the association between individual patient behavioral and psychological symptoms and caregiver depression and burden within the dementia patient–caregiver dyad. Int Psychogeriatr. 2012;24(10):1536–1552.