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PSYCHOPHARMACOLOGY
Highlights from 2022 NEI Congress: Management of Agitation Associated With Alzheimer’s Dementia
November 6, 2022   

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2022 NEI Congress Session Highlight

When a patient presents with agitation it represents a substantial challenge to mental health professionals, especially if the agitation is accompanied by psychotic symptoms or progresses to violence or aggression. Too often, the management of agitation includes the use of restraints and/or seclusion, which can be traumatic for the patient, instill distrust in the medical team, and create risk of physical injury to both the patient and the staff. At the 2022 NEI Congress, Dr. Stephen M. Stahl delivered a presentation on best practices for the management of agitation in patients with Alzheimer’s dementia.

Neuropsychiatric Symptoms in Alzheimer's Disease: Focus on Agitation
Presented by Stephen M. Stahl, MD, PhD, DSc (Hon.)

Agitation is quite common in Alzheimer’s dementia, affecting 45–53% of patients. In his presentation, Dr. Stahl differentiated agitation from aggression, explaining that aggression tends to refer to behavior with intentional harm, whereas agitation is a state of heightened motor or verbal activity without any focus or intent. Dr. Stahl emphasized that "not everyone who is agitated becomes aggressive, and not every episode of aggression is preceded by agitation."

First-line treatment for agitation involves addressing unmet needs that may be contributory, such as hunger, thirst, or pain; applying de-escalation strategies; and ensuring environmental safety. Current pharmacological treatment for agitation associated with Alzheimer's dementia is off-label, with limited and variable efficacy. However, research into the neuronal networks hypothesized to underlie agitation associated with Alzheimer's dementia has led to investigational treatments that may soon be clinical options, and this was the focus of Dr. Stahl’s presentation.

There are three main treatable symptom domains in Alzheimer’s dementia: memory problems, psychosis, and agitation (Figure). Dr. Stahl explained that "whereas psychosis and agitation can be rather readily distinguished from memory decline in Alzheimer’s dementia, agitation and psychosis can easily be confused with each other... However, it is important to [distinguish them] whenever possible, as the neuronal pathways for these different behaviors are also different, and so are their evolving treatments."

Dr. Stahl

Figure. Circuits of treatable symptoms in dementia. (Left) Acetylcholine and glutamate can be targeted by acetylcholinesterase (AChE) inhibitors and the N-methyl-D-aspartate (NMDA) antagonist memantine, respectively, to improve cognition in the memory network. (Middle) Psychosis can be targeted at the serotonin node as well as the dopamine node of the psychosis network. In particular, the 5HT2A antagonist pimavanserin is approved to treat psychosis in Parkinson’s disease. (Right) Multimodal neurotransmitters (norepinephrine, serotonin, dopamine, and glutamate) can be targeted in the agitation network to improve the symptom of agitation in dementia. The NMDA antagonist dextromethorphan (in various forms) and the multimodal agent brexpiprazole are being studied for their use in agitation associated with dementia.

Put simply, agitation in dementia may occur because there is an imbalance in "top-down" cortical inhibition and "bottom-up" limbic and emotional drives. More precisely, it is hypothesized that the loss of top-down inhibition due to the destruction of cortical glutamatergic neurons leads to a deficiency in thalamic filtering of sensory and emotional input, resulting in the motor and emotional outputs of agitation. Several treatment strategies that have the potential to target this neurocircuitry are under investigation (Table). Most notably, the multimodal agent brexpiprazole and the N-methyl-d-aspartate (NMDA) antagonist dextromethorphan (in various forms) are in Phase III trials for their use in agitation associated with Alzheimer’s dementia. Agents with other potential mechanisms are in earlier development.


Table. Emerging and investigational treatments for agitation associated with Alzheimer’s dementia.
Mechanism Agent Phase
Multimodal monoamine actions brexpiprazole Multiple Phase III trials completed
NMDA antagonism dextromethorphan + bupropion Phase II/III trial completed; two ongoing Phase III trials (recruiting)
deudextromethorphan Two Phase III trials completed (one failed); several trials ongoing
dextromethorphan + quinidine Phase II
Cannabinoid receptor agonist nabilone Phase III (recruiting)
dronabinol Phase II (recruiting)
Alpha 2 adrenergic agonist dexmedetomidine Phase II (recruiting)
Alpha 2C adrenergic antagonist ORM-12741 Phase II
Serotonin 6 antagonist masupirdine Phase III (recruiting)
Alpha 1 antagonist prazosin Phase II

Source:  Stephen M. Stahl, MD, PhD, DSc (Hon.). Neuropsychiatric Symptoms in Alzheimer's Disease: Focus on Agitation. Presented November 6 at 2022 NEI Congress, Colorado Springs, CO.

To Learn More: The recording of this presentation by Dr. Stahl, as well as all of the other presentations from the 2022 NEI Congress, will be available as Encore Presentations for NEI Members.

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