Unmet Needs and Mechanisms Behind Newer Agitation Therapies

"Unmet Needs and Mechanisms Behind Newer Agitation Therapies" takes up what still remains unmet in agitation care, and the biology behind a newer treatment option.

The panel turns to what remains unmet in treating Alzheimer's-associated agitation, starting with the fact that only two on-label agents exist, which is likely insufficient for the full range of patients affected. One of the two on-label agents has a modest effect size of just 0.3, and comparable effect-size data are not yet published for the other, though it shows strong relapse-prevention results over time. Any antipsychotic, on- or off-label, carries an elevated risk of tardive dyskinesia in this population, compounded by age over 60, postmenopausal status, and neurodegenerative disease, three risk factors that stack in exactly the patients being treated.

The panel reflects candidly on why sedating off-label agents became so entrenched: sedation was often mistaken for genuine treatment effect. Benzodiazepines further disinhibit patients, risking worse sexual or physically aggressive behavior, and raise the risk of falls, fractures, and infections. Low-dose quetiapine, dosed at 25 or 50 milligrams at bedtime and well below the roughly 150-milligram threshold where a true antipsychotic effect appears, is often really being used purely for sedation and fall-risk management, even though it is metabolically neutral at that dose. Calming a patient during the day, rather than sedating them at bedtime, a riskier time to be sedated, may better support a normal circadian rhythm.

Because many patients with significant dementia have anosognosia and lack insight into their own behavior, treatment benefit is often reported by the caregiver rather than the patient. The panel then details the mechanism behind one newer option: uncompetitive NMDA receptor antagonism paired with sigma-1 receptor agonism, intended to modulate glutamate, the brain's primary excitatory neurotransmitter, and reduce its neurotoxic effects, a mechanism the panel expects to draw far more research attention in the years ahead.

Up next, in "ACCORD Trials: Efficacy and Safety of Dextromethorphan-Bupropion in Agitation," the experts walk through the pivotal trial data behind a newer, non-antipsychotic agitation therapy.