Mechanism and Trial Data for an Antipsychotic Agitation Therapy

In "Mechanism and Trial Data for an Antipsychotic Agitation Therapy," our experts turn to the second on-label option for agitation and the trials that supported its approval.

The panel turns to the second on-label agent, brexpiprazole, an atypical antipsychotic approved in 2023, and its distinct receptor profile: a potent partial agonist at serotonin 5-HT1A and dopamine D2 receptors, with antagonism at serotonin 5-HT2A, though the exact mechanism behind its effect on agitation remains unknown. Because it is a partial rather than full D2 antagonist, the theoretical risk of tardive dyskinesia is somewhat reduced, but remains elevated in this population regardless. Notably, the drug is only effective at 2 or 3 milligrams, since 1 milligram failed in trials, meaning the usual "start low, go slow" titration takes longer and requires extra caution around activating side effects.

Two pivotal trials, referred to as Study 6 and Study 7, enrolled patients with a clinical Alzheimer's dementia diagnosis and mini-mental scores between 5 and 22, drawing from both institutional and outpatient settings, and including some patients on SSRIs or with psychotic symptoms, a broader population than the other on-label agent's trials. Study 6 did not use IPA agitation criteria, while Study 7 did; both relied on the NPI and NPI-nursing home assessments. Study 6 tested 1 and 2 milligrams against placebo over 12 weeks, and only the 2-milligram dose separated, prompting Study 7 to test 2 and 3 milligrams, both of which separated from placebo, including across all three CMAI behavior subscales: verbally aggressive, physically non-aggressive, and physically aggressive. The most common side effects across both trials were nasopharyngitis and dizziness, with an overall discontinuation rate of about 5.6% of enrolled patients.

In "Long-Term and Real-World Safety Data on Antipsychotic Agitation Therapy," the panel will take up the longer-term and real-world evidence behind that antipsychotic therapy.