The Shift From Off-Label Use to On-Label Agitation Therapy

In "The Shift From Off-Label Use to On-Label Agitation Therapy," our experts trace how the standard of care for agitation is shifting away from decades of off-label prescribing.

The panel reviews the historical standard of care for Alzheimer's-associated agitation, which for years relied on off-label antipsychotics such as risperidone, quetiapine, and olanzapine, along with SSRIs. A 2021 Cochrane review found these agents produced only modest benefit and minimal improvement in agitation specifically, a finding that helped motivate dedicated clinical development of two agents now approved on-label for this indication. Despite that evidence, the panel describes a persistent disconnect between practice and evidence, with off-label prescribing continuing due to familiarity, cost, and formulary access even where the supporting data are weak.

A meaningful regulatory shift took effect on April 28, 2025, when long-term care regulations began requiring medication use to follow FDA-approved clinical practice guidelines, opening easier access to on-label, branded agents in that setting, where cost and formulary barriers had previously been more common. Patient assistance foundations can help offset copay costs, though the panel notes this regulatory change does not extend to the outpatient setting, where prescribing is not governed the same way.

Off-label agents carry black-box warnings for increased mortality and fall risk in this population, and the panel discusses the real tension clinicians face between urgency and risk when treating a vulnerable group that, for years, had few well-studied options. One panelist shares a personal reflection on caring for a parent with severe Alzheimer's-related agitation, describing the particular pain of recognizing that the parent, had he been aware of his own behavior, would have been mortified by it, a moment that underscores why better, safer treatment options matter so much to families living through this firsthand.

In "Unmet Needs and Mechanisms Behind Newer Agitation Therapies," the panel will weigh the field's remaining unmet needs against the biology behind a newer treatment option.