Older adults in long-term care facilities are being prescribed newer psychiatric medications that were approved with little direct evidence of safety in patients aged 65 and older. The FDA’s own labeling guidance allows drugmakers to state that there is “insufficient information to detect differences in safety and/or effectiveness between geriatric and younger adult patients,” and geriatricians say that disclaimer has done little to slow prescribing. The gap between regulatory clearance and real-world safety monitoring is widening as new psychotropic agents reach a population already known to face elevated mortality risk from this drug class.
Geriatric data gaps and the speed of off-label prescribing
When the FDA approved brexpiprazole (marketed as Rexulti) for agitation associated with dementia due to Alzheimer’s disease, it became the first drug cleared for that specific indication. The approval rested on randomized trials that evaluated brexpiprazole against placebo over just 12 weeks, according to a JAMA-published trial. That short window leaves open questions about what happens to frail, elderly patients who take the drug for months or years in nursing homes.
The FDA’s advisory committee briefing materials for brexpiprazole cited a class-wide mortality signal: roughly 4.5% of elderly dementia patients on antipsychotics died during trials, compared with 2.6% on placebo, according to the agency’s own meta-analysis of older antipsychotic data. That nearly two-to-one ratio has been known since the mid-2000s, when a study published in the New England Journal of Medicine quantified higher death rates among elderly antipsychotic initiators. Yet the approval of brexpiprazole for a geriatric indication shows the FDA is willing to grant new uses in this population even while the class-level risk signal persists.
The practical result is a familiar pattern. A drug receives a narrow indication, and prescribing expands quickly in long-term care settings where behavioral symptoms are common and staffing is thin. Because post-marketing surveillance for mortality or hospitalization among patients 65 and older typically lags by years, clinicians and families are left relying on trial data that were never designed to capture long-term outcomes in the oldest, sickest patients.
FDA labeling rules, the Beers Criteria, and international reviews
The FDA’s geriatric labeling guidance sets out what drugmakers must disclose in the “Geriatric Use” subsection of a product’s label. When clinical trials enroll too few patients aged 65 and older to draw reliable conclusions, sponsors are expected to say so explicitly. The agency’s sample language, published in a separate document, includes the verbatim disclaimer about insufficient information to detect age-related differences. That transparency requirement, however, does not block approval or restrict prescribing. It functions as a disclosure, not a guardrail.
The American Geriatrics Society has tried to fill the gap through its Beers Criteria, a consensus list of medications considered potentially inappropriate for adults 65 and older. The 2023 update to the AGS Beers Criteria identifies multiple psychotropic medication classes as carrying elevated risk in older adults, citing evidence quality and strength of harm signals. The list is widely used in pharmacy reviews and quality metrics for nursing homes, but it is advisory. Prescribers can override it when they judge the benefit outweighs the risk, and in dementia care, behavioral crises often push clinicians toward pharmacologic options regardless of guideline warnings.
The concern is not limited to the United States. Canada’s drug review body, CADTH, flagged limited data for patients 65 and older when it evaluated esketamine (Spravato), a newer treatment for depression. The CADTH Canadian Drug Expert Committee recommendation noted the sparse evidence base for older adults as a constraint on its assessment. That finding mirrors the FDA’s own labeling disclaimers and reinforces the geriatricians’ central argument: regulatory bodies in multiple countries are clearing psychiatric drugs while openly acknowledging they lack the data to confirm safety in the age group most likely to receive them.
Unanswered questions about post-approval monitoring
Several critical gaps remain. No publicly available post-marketing surveillance dataset specific to brexpiprazole in patients 65 and older has emerged since the drug’s approval for Alzheimer’s-related agitation. Without that data, clinicians cannot compare real-world mortality or hospitalization rates against the short-term trial results. The 12-week trial design that supported approval tells prescribers almost nothing about what to expect at six months or a year of continuous use in a nursing home population.
Researchers who studied the effects of the FDA’s earlier black-box warning on antipsychotics found that the warning did reduce antipsychotic prescribing in elderly dementia patients, but it also shifted some use toward other sedating or psychoactive drugs that carry their own risks. That dynamic raises a question the current evidence cannot answer: if geriatricians succeed in discouraging newer antipsychotics, will prescribers substitute other medications with equally sparse geriatric safety data, such as certain anticonvulsants or antidepressants used off-label for behavior?
Regulators have tools to detect emerging safety problems, but those systems are not tailored to frail elders in long-term care. The FDA’s adverse event reporting database aggregates signals across all adults, and nursing home residents are rarely the focus of targeted analyses. Even when safety reviews are conducted, they may not distinguish between community-dwelling seniors and those in skilled nursing facilities, where polypharmacy, cognitive impairment, and multiple comorbidities amplify risk.
Geriatricians argue that more granular monitoring is essential. They point to the need for registries or large observational cohorts that track psychotropic use in residents with dementia, including dose changes, concomitant medications, falls, strokes, and deaths. Such data could help determine whether newer agents like brexpiprazole meaningfully improve agitation or quality of life, or whether they simply reproduce the risk profile already seen with older antipsychotics under a different brand name.
Regulatory trade-offs and the pressure to treat
Regulators face a genuine dilemma. Families and clinicians caring for people with advanced dementia often describe severe agitation, aggression, or psychosis that is distressing and sometimes dangerous. Nonpharmacologic interventions-such as environmental modifications, caregiver training, and structured activities-require time and staffing that many facilities lack. In that context, the availability of a medication with even modest short-term efficacy can feel like a lifeline.
The FDA’s framework for balancing benefit and risk in serious conditions is laid out in documents such as its patient-focused benefit-risk guidance, which emphasizes incorporating patient and caregiver perspectives when judging whether a drug’s risks are acceptable. For dementia-related agitation, caregivers may be willing to tolerate substantial side effects if a medication reduces episodes of violence or allows a loved one to remain in a less restrictive setting. That perspective helps explain why the agency may accept limited geriatric data when unmet need is high.
Yet this same flexibility can widen the gap between regulatory approval and geriatric best practice. Nursing home residents are systematically underrepresented in clinical trials, and those who are enrolled tend to be healthier than the average long-term care patient. As a result, the patients most likely to receive new psychotropics are the least likely to resemble the trial populations used to justify approval.
Some experts have called for conditional approvals that would require manufacturers to conduct robust post-marketing studies specifically in adults 75 and older, or in residents of skilled nursing facilities, as a condition of maintaining geriatric indications. Others suggest tying Medicare and Medicaid quality measures more directly to documented use of nonpharmacologic approaches before initiating antipsychotics or related drugs.
What residents and families can do now
While structural reforms move slowly, individual residents and families still have options. Advocates recommend asking prescribers to explain what is known-and not known-about a proposed drug’s safety in people over 65, including any black-box warnings or Beers Criteria recommendations. Families can request trial periods with clear goals, such as fewer aggressive episodes or improved sleep, and regular attempts to taper or discontinue the medication if those goals are not met.
They can also push facilities to invest in nonpharmacologic strategies, from music therapy and personalized activity plans to staff training in de-escalation techniques. These approaches may not eliminate the need for medications, but they can reduce reliance on drugs whose long-term effects in frail elders remain uncertain.
For now, the evidence base for many newer psychiatric medications in older adults is thin, and the regulatory system largely accepts that uncertainty. As more psychotropic agents reach the market with limited geriatric data, the burden falls on clinicians, residents, and families to navigate an uneasy trade-off: treating distressing symptoms today while knowing that the full risks for tomorrow have yet to be measured.
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*This article was researched with the help of AI, with human editors creating the final content.
