Neuropsychiatric Adverse-Event Reporting With Brexpiprazole Across Approved Indications: A Disproportionality Analysis Using the FDA Adverse Event Reporting System (FAERS)
This disproportionality analysis of FAERS data reveals that brexpiprazole use in patients with Alzheimer's disease-associated agitation is associated with a distinct neuropsychiatric adverse event profile, characterized by significantly higher reporting of delirium, falls, and agitation compared to its use in major depressive disorder and schizophrenia, while showing lower rates of akathisia and tardive dyskinesia.
Original paper licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). This is an AI-generated explanation of the paper below. It is not written or endorsed by the authors. For technical accuracy, refer to the original paper. Read full disclaimer
In the world of medicine, some treatments are designed to calm the mind, while others aim to steady the body. When a drug is approved to help people with severe mental health conditions, doctors and regulators watch closely to see how it behaves in the real world, outside the controlled environment of clinical trials. This is especially true for medications that affect the brain, where the line between a helpful effect and a harmful side effect can sometimes blur. One such medication is brexpiprazole, a drug used to treat schizophrenia and major depression. Recently, it received a new, historic approval to help manage agitation in people with Alzheimer's disease. This new use meant the drug would be given to a much older group of patients, many of whom have fragile health and take many other medicines. The big question for safety experts was whether this drug would cause different problems in these elderly patients compared to the younger people it had been helping for years.
To answer this, researchers turned to a massive digital library of safety reports known as the FDA Adverse Event Reporting System. Think of this system as a global mailbox where doctors, pharmacists, and patients send notes whenever something unexpected happens after taking a medicine. The researchers sifted through millions of these notes, focusing specifically on reports involving brexpiprazole. They separated the reports into three distinct groups based on why the patient was taking the drug: those with Alzheimer's disease, those with major depression, and those with schizophrenia. By comparing the notes from the Alzheimer's group against the other two, they looked for patterns that stood out—events that happened much more often in the elderly patients than in the others, suggesting a specific risk for that population.
The study uncovered a clear and distinct pattern of safety concerns for the Alzheimer's patients. While the drug worked for its intended purpose, the reports showed that elderly patients were far more likely to experience certain troubling side effects than the younger patients. The most striking finding was a sharp increase in reports of delirium, a state of sudden confusion and disorientation. The data showed that delirium was reported in the Alzheimer's group at a rate more than thirty times higher than in the depression group. Alongside this, there was a significant rise in reports of falls, hallucinations, and a condition called neuroleptic malignant syndrome, which is a rare but serious reaction involving fever and muscle stiffness. The researchers also noted a high number of reports regarding agitation itself, though they were careful to note that this was tricky to interpret because agitation was the very symptom the drug was supposed to treat.
Not every side effect was more common in the elderly group. In fact, the study found that older patients reported fewer instances of certain movement problems, such as restlessness or involuntary muscle movements, compared to the younger patients. This difference might be because the elderly patients were given lower doses of the medication, or perhaps because their cognitive impairment made it harder for them to describe these specific sensations. The researchers also compared the Alzheimer's patients to those taking a different, similar drug called quetiapine. They found that the risk of falling was about the same for both drugs, suggesting that the danger of falling might be a general risk for this type of medication in older people, rather than something unique to brexpiprazole.
The study also highlighted how the landscape of drug use has shifted. Before the drug was approved for Alzheimer's in 2023, very few reports came from that group. By 2025, the number of reports from Alzheimer's patients had surged, surpassing the number of reports from patients with depression. This rapid increase reflects the growing use of the drug in this new population. The researchers emphasized that their work does not prove that the drug causes these problems, but rather that these problems are being reported much more frequently in this specific group. The high rate of serious outcomes, including death, in the Alzheimer's group was largely attributed to the advanced age and severe illness of these patients, rather than the drug itself.
Ultimately, this analysis serves as an early warning system. It suggests that when doctors prescribe this medication to elderly patients with Alzheimer's, they need to be extra vigilant. They should watch closely for signs of sudden confusion, falls, and hallucinations, and be mindful of the other medicines these patients are taking, which can sometimes make these risks worse. The findings provide a clear picture of where the risks lie, helping doctors make safer choices for a vulnerable population while continuing to offer relief for a condition that causes immense distress. The study confirms that while the drug is a valuable tool, its safety profile changes significantly when used in the very old, requiring a different kind of care and attention.
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