Practical Management of Agitation and Psychosis in Patients with Dementia

Patients with dementia often experience symptoms of psychosis and agitation. Improved diagnosis of these symptoms could allow for more appropriate treatment for these patients. During the Neuroscience Education Institute Max! Virtual Meeting, Laxman B. Bahroo, DO, assistant professor and co-director of the Neurology Residency Program at MedStar Georgetown University Hospital, discussed the neurobiological basis for psychosis and agitation in these patients, along with evidence-based treatments.

Psychosis occurs in 25% to 40% of patients with Alzheimer’s disease (AD), 75% of patients with dementia with Lewy bodies, 50% to 60% of patients with Parkinson’s disease dementia, 5% to 10% of patients with frontotemporal dementia, and 15% of patients with vascular dementia. Psychotic symptoms include delusions and hallucinations.

Antipsychotics can be used to treat psychosis, however, this drug class includes a Black Box Warning concerning the potential increased mortality for older patients with dementia-related psychosis.

Pimavanserin is a 5HT2A and 5HT2C antagonist and has no dopamine D2 binding affinity. On July 20, 2020, the FDA accepted filing for pimavanserin for the treatment of hallucinations and delusions associated with dementia-related psychosis. The decision was based on findings from the pivotal phase III HARMONY study, which found that pimavanserin reduced relapse of psychosis by 2.8-fold compared with placebo. Adverse events (AEs) associated with pimavanserin include peripheral edema, confusion, nausea, and potential QTc prolongation.

Psychosis is a possible contributor to agitation, but patients with dementia without psychosis can become agitated as well. Hallmark features of agitation include motor restlessness, irritability, inappropriate or purposeless verbal and/or motor activity, and heightened responsivity to stimuli. Agitation affects at least 50% of patients with AD. First-line treatment is often non-pharmacological, such as considering and addressing unmet needs related to pain or hunger. Assessment of agitation should include an interview with the patient and caregiver/family, medical history, psychiatric history, substance use history, social and family histories, mental status examination, and rating scales.

Agitation and aggression are two different syndromes. Not everyone who is agitated becomes aggressive and not every episode of aggression is immediately preceded by agitation, said Dr. Bahroo. Agitation is excessive motor or verbal activity without any focus or intent, while aggression is a provoked or unprovoked behavior intended to cause harm. Reactive aggression is often precipitated by rejection of care and may not be associated with agitation. Psychotic patients sometimes resist care such as bathing or medication treatment, which can be stressful for care providers and is a common reason for institutionalization. De-escalation strategies are important when the patient is in an agitated state. Behavioral approaches are also advised, including empathic acknowledgement, addressing unmet needs, distracting the patient, and engaging other family members.

There is no universally recognized or FDA-designated indication for agitation in dementia. All psychotropic medication use is thus “off label.” Efficacy is limited and variable, with high placebo effects, and there are several important potential side effects. Older individuals may be more sensitive to medications due to polypharmacy, so “the addition of pharmacologics should be done so judiciously” according to Dr. Bahroo. Be aware of comorbid medical conditions and watch for over-sedation, dizziness, and blood pressure changes. “Pharmacologic therapies are not easy in this indication,” he said, noting that non-pharmacologic approaches are recommended as first-line treatment for dementia-related behaviors.

The best treatment for agitation depends on what is comfortable for people to use, associated AEs, and urgency of treatment, he said. Antidepressants can treat the underlying depression and anxiety but take time for efficacy and can sometimes increase agitation. Mood stabilizers are best for bipolar disorder, underlying mania, or recurrent depression, but the efficacy can be poor, and there can be metabolic side effects. Antipsychotics have the best efficacy, per clinical studies, but they have metabolic AEs and can increase mortality. Cholinergic agents may reduce the incidence of agitation, but there is poor efficacy especially in acute situations. Benzodiazepines work quickly and effectively for calming and sedation, but excess sedation increases fall risk and has paradoxical effects. Other agents to consider are dextromethorphan plus quinidine, prazosin, beta blockers, and estrogen.

Other treatments in review for agitation include brexpiprazole, cannabinoids, eltoprazine, and more. “As we have an aging population, this becomes a more important topic to discuss,” Dr. Bahroo said. “More development is necessary to see if we can get better medications with less side effect potential.”

Presentation: Agitation and Psychosis in Dementia: Practical Management. Presented at the Neuroscience Education Institute Max! Virtual Meeting, Nov. 5-8, 2020.