Gus Alva, MD, on Agitation, Psychosis, and Cognition in Alzheimer Disease

Gus Alva, MD, discussed the clinical management of agitation and psychosis in Alzheimer disease, emphasizing the importance of distinguishing between these neuropsychiatric syndromes, the limited but growing approved treatment landscape, and the conceptual value of reframing treatment-resistant depression as difficult-to-treat depression.

Alva conceptualized Alzheimer disease as encompassing at least 3 distinct clinical dimensions requiring separate assessment and management: cognitive decline, agitation, and psychosis. He noted that agitation and psychosis may emerge at any stage along the Alzheimer continuum—from mild cognitive impairment through severe dementia—and that their appearance may herald a worse clinical trajectory, making timely identification and intervention essential.

On agitation, Alva noted that 2 FDA-approved medications are now available: brexpiprazole, an atypical antipsychotic approved in May 2023 as the first drug specifically indicated for agitation associated with Alzheimer dementia, and a second agent targeting depression with a relatively rapid onset of action.¹ He acknowledged the black box warning applicable to all atypical antipsychotics in patients with dementia—reflecting increased risks of cardiovascular, respiratory, and infectious mortality—while framing brexpiprazole's approval as a meaningful regulatory precedent.

On psychosis in dementia, Alva described his own investigational work with pimavanserin—a selective 5-HT2A inverse agonist that is FDA-approved for Parkinson disease psychosis—in the context of the HARMONY phase 3 trial, which evaluated pimavanserin across multiple dementia subtypes including Alzheimer dementia, Parkinson disease dementia, Lewy body dementia, frontotemporal dementia, and vascular dementia.² The trial met its primary endpoint of relapse prevention and was stopped early for efficacy; however, the FDA ultimately did not approve the dementia-related psychosis indication, in part because the trial population was considered to include a disproportionate number of patients with Parkinson disease dementia relative to Alzheimer disease. Alva argued that the accumulated data nonetheless represent a meaningful clinical resource that should inform off-label prescribing decisions in the absence of approved alternatives.

Alva concluded by advocating for the conceptual shift from treatment-resistant depression to difficult-to-treat depression, arguing that the former term carries a pejorative connotation that implicitly frames patients as obstacles rather than individuals with complex, multifactorial conditions affecting quality of life and functionality.

Dr Alva is a board-certified psychiatrist and the Mood Disorders Section Editor for Psychiatric Times.

References

1. Lee D, Slomkowski M, Hefting N, et al. Brexpiprazole for the treatment of agitation in Alzheimer dementia: a randomized clinical trial. JAMA Neurol. 2023;80(12):1272–1281.

2. Ballard C, Banister C, Khan Z, et al. Evaluation of the safety, tolerability, and efficacy of pimavanserin versus placebo in patients with dementia-related psychosis: a phase 3, randomised, placebo-controlled trial. Lancet Neurol. 2018;17(3):213–222.