First Antipsychotic Is Approved for Agitation in Patients wi… : Neurology Today
[ad_1]
Article In Brief
The first antipsychotic drug for treating agitation in dementia was approved. Experts in addressing agitated patients discuss the risks and benefits of the drug and non-drug approaches for managing the agitated behaviors.
On May 11, the US Food and Drug Administration (FDA) announced the supplemental approval of brexipiprazole (Rexulti) for the treatment of agitation associated with dementia due to Alzheimer’s disease (AD). It’s the first FDA-approved treatment option for this indication.
But is it superior to other off-label agents and behavioral approaches that neurologists have used for years? Neurology Today asked experts in behavioral neurology to weigh the evidence for the drug against other available interventions.
The drug’s approval was based on the results of two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies involving patients with AD who exhibited the type, frequency, and severity of agitation behaviors that require medication. In both studies, patients who received 2 mg or 3 mg of brexpiprazole showed statistically significant and clinically meaningful improvements on the Cohen-Mansfield Agitation Inventory total (CMAI) compared with patients in the placebo group at week 12.
“It’s an advance as the first drug specifically approved for agitation in Alzheimer’s disease,” said Samuel Gandy, MD, PhD, Mount Sinai Professor of Alzheimer’s Disease Research, professor of neurology and psychiatry, and associate director of the Mount Sinai Alzheimer’s Disease Research Center in New York City. “It’s useful to have another option in the toolbox. The two drugs that have been the mainstay for off-label treatment of patients with agitation, quetiapine and risperidone, also have the same limitations and black box warnings.”
Agitation (sometimes escalating to aggression) is a common and challenging symptom among many patients with cognitive impairment; the incidence is reported to be as high as 60 percent among people with mild cognitive impairment (MCI) and 76 percent among those with AD. It’s the third most common neuropsychiatric symptom in dementia, after apathy and depression, and is even more frequent (80 percent) among residents of nursing homes. Agitation severity ratings also tend to increase over time.
Although many patients with agitation in dementia can be managed with non-pharmacologic treatments including tailored purposeful activity, music therapy, physical exercise, aromatherapy, touch therapy such as massage, and other behavioral interventions, that is not always sufficient, said Morris Freedman, MD, FAAN, professor of neurology at the University of Toronto and head of neurology and medical director of the Austin Centre for Neurology and Behavioural Support at Baycrest Health Sciences.
“There is a group of patients for which non-pharmacologic approaches simply do not work, and even the champions of behavioral and other interventions will say that we need to utilize medication for these patients,” he said.
What About the Boxed Warning?
Antipsychotics tend to be the first line treatment for agitation with dementia, but until the recent approval of brexipiprazole, the available therapies o were used off-label and the benefits seen in clinical trials have been fairly small. A 2015 report from the Government Accountability Office found that 1 in 7 patients with dementia receives antipsychotic medications; that rises to 1 in 3 among patients in nursing homes. In 2005, the FDA issued a boxed warning for all atypical antipsychotics based on a systematic meta-analysis that revealed a 70 percent increased risk of death among elderly patients with dementia receiving antipsychotic treatment, although the mechanism behind the increased risk is unclear.
The boxed warning is a concern for geriatric psychiatrist Helen Kales, MD, chair of the department of psychiatry and behavioral sciences and Joe P. Tupin Professor of Psychiatry at the University of California, Davis, whose research focuses on management of behavioral and psychological symptoms of dementia.
“We don’t know what the mortality rate for brexpiprazole is because the drug trials were just 12 weeks long,” she said. “Most of the work that the black box warnings were based on were 180-day observational studies. We have no reason to think that the mortality risk for this medication wouldn’t be similar to the others, based on my reading of the trials.”
Concern About Side Effects
Dr. Gandy expects to prescribe brexpiprazole as an alternative agent at first in order to become familiar with it. “I usually start with quetiapine, and if that is unsatisfactory for some reason, move to risperidone, but now I might be equally likely to move to brexpiprazole,” he said. “They each have their own side effects: quetiapine tends to cause drowsiness; risperidone is associated with extrapyramidal symptoms such as restlessness, tremor and stiffness; and brexpiprazole is known to cause some headache and weight gain—although in most of my patients, any weight gain would be welcome, as they tend to be thin.”
He noted that brexpiprazole has also been associated with insomnia. “That’s not something we want to encourage in agitated patients generally,” he said. “I might consider using it in patients who are somnolent during the day and need to be woken up. Because quetiapine is sedating, it can be a problem if the antipsychotic activity doesn’t carry over to their waking hours.
It is also very challenging to predict which patient will respond to which medication, Dr. Freedman said. “There are algorithms and different recommendations for drugs to use, but for a given patient, there’s no real way of anticipating which drug is going to work. We are considering using an AI [artificial intelligence] approach to help guide us in medication selection, but at present, the way I choose drugs for management of agitation is based on general principles.”
Dr. Freedman said he tries not to prescribe antipsychotics unless he has to because those drugs can affect mobility, and many of these patients have gait and balance problems. “But I will start with an antipsychotic if the patient is actually psychotic,” he added. “You can have agitation and aggression without psychotic features, such as hallucinations, but if there is genuine psychosis, it does make sense to try an antipsychotic. On the other hand, if a patient has agitation with features of depression or anxiety, I’ll go first with an antidepressant or anti-anxiety drug.”
“When I started, I didn’t have any resources or funding. We obtained the resources that we have now because the program demonstrated great success in helping people with dementia. I think that VBM is going to make a major difference in the lives of our patients.”—DR. MORRIS FREEDMAN
Like Dr. Gandy, Dr. Freedman considers side effect profile to be particularly important. “If a patient is too overactive, I might select a drug with sedating effects, while if they are very lethargic, I would choose one that is more stimulating. It’s basically a common-sense approach,” he said
“We need to see how brexpiprazole differs from the other atypical antipsychotics available. Certainly it adds to our options, but I don’t have much experience with it. Will it really be different or have any other advantages over the other drugs we’ve used? That’s unknown.”
Address Underlying Causes
Dr. Kales, for one, is skeptical. “The Cohen-Mansfield criteria come from the non-pharmacologic intervention area and were meant to cast a wide net to ensure that we are meeting unmet needs,” she said. “They were never meant to be used in drug trials, so their use here is interesting and certainly an expanded definition of agitation. The indication for agitation could be applied to almost anything—any patient in a long-term care facility doing something somebody doesn’t like. That’s my concern.”
She also noted that the Centers for Medicare and Medicaid Services has had a decade-long goal, since the launch of the National Partnership in 2012, to reduce the use of antipsychotics in nursing homes. “What will they say now? That it’s OK to use this particular drug because the FDA has approved it? I don’t know how you fix that,” she said.
Other aspects of the trial design concern Dr. Kales, such as the fact that most participants come from sites outside the United States—many in Eastern Europe—and the cohort is comprised of 96 percent White individuals. “That does not reflect the heterogeneity of this country,” she said.
“If you focus on the results within the US population alone, those results were primarily negative,” Dr. Kales continued. “And with the approval of this drug, it’s likely that many African American patients may be getting this medication, which is concerning to me. We know that African American patients tend to be prescribed higher doses of antipsychotics as more of a go-to [and]that similar behavior in African American patients may be seen by staff as more concerning or aggressive than it might be in White patients—studies have shown that. And I worry that we don’t know about the risks of this drug in these patients, because they were not really included in the studies.”
Dr. Kales’ biggest concern is that the approval of brexpiprazole may lead to increased, unnecessary prescribing. In a review of more than two decades of scientific studies, published in The British Medical Journal in 2015, she found that antipsychotics are much less effective than non-drug treatments in controlling the symptoms of dementia, including agitation and aggression.
“We have plenty of medication use among people with dementia already,” she said. “The National Partnership was successful in reducing the use of antipsychotics, but at the same time we saw increased use of gabapentin, benzodiazepines, and opioids. What disheartens me is that I feel like we were on the cusp of looking more at underlying causes, rather than simply sedating people so that they stay quiet and we don’t know what’s going on with them.”
A Behavioral Management Approach
For nearly 10 years, Dr. Kales has worked to advance the use of an algorithmic approach toward the assessment and management of behavioral symptoms of dementia called DICE (Describe, Investigate, Create, Evaluate), which she created in collaboration with colleagues at Johns Hopkins Alzheimer’s Disease Research Center and Center for Innovative Care in Aging. DICE involves the following actionable components:
- Describe: Ask the caregiver, and the patient if possible, to describe the who, what, when, and where of situations where problem behaviors occur, and the physical and social context.
- Investigate: Look into all aspects of the patient’s health—including dementia symptoms, current medications, and sleep habits—that may interact with physical, social, and caregiver-related factors to cause the behavior.
- Create: Working with the caregiver, develop a plan to prevent and respond to behavioral issues, including changing activities and environment as well as education and support for the caregiver.
- Evaluate: Assess how well the plan is being followed, how it’s working, and what might need to be changed.
She cited the example of a patient whose daughter brought him in complaining of difficulties getting him in the car for medical appointments. “She said, ‘He’s agitated. He’s impossible. Can’t you just give him something?’ I examined him and sent him for an X-ray, and it turned out he had a rotator cuff tear. People with dementia can’t always express pain verbally,” she said.
Dr. Kales worries that the approval of brexpiprazole will lead to more reflexive use of antipsychotics in people with dementia. “I would hope that before covering this drug, a policy body like CMS would require documentation that underlying causes have been explored and remedied and medications used when the patient is still behaving in a way that puts them, the people they’re living with, or their caregivers at risk,” she said. “It’s not that we should never use medications—I do use them regularly—but we also want to make sure that if there are modifiable causes of agitation, we’re attending to those.”
The Benefits of Virtual Behavior Management
Dr. Freedman and his colleagues at Baycrest Health Sciences in Toronto have developed a novel Virtual Behavioral Medicine (VBM) model for the management of patients with dementia and agitation, which combines non-pharmacological and pharmaceutical interventions, and recently received funding from the Ontario Government to deliver the program.
In a study published in 2022 in the Journal of Alzheimer’s Disease, he and his team found that the VBM program led to a 60 percent reduction in the need for admission to a specialized inpatient behavioral neurology unit.
“Prior to the development of VBM, essentially all patients with an application for admission to the inpatient behavioral neurology unit were admitted when a bed became available,” Dr. Freedman said.
Patients with agitation and aggression in dementia often cannot be cared for at home or in general long-term care settings, and in most areas, there are not enough acute care beds to meet the demand for specialized treatment.
“Our hospital has a 20-bed acute care unit for these patients, and people often had to wait up to a year to be admitted. That’s useless when people are agitated and aggressive,” said Dr. Freedman.
“So, about three years ago, we decided to try our care model virtually. The program is a game-changer. Although virtual care is not new, what is novel is using it to manage patients with dementia and behaviors such as marked physical aggression using a virtual inpatient model. It’s a ‘virtual hospital’ specifically for people with agitation and aggression in dementia.”
The VBM program serves patients in long-term care and living at home in the community, as well as those who have been admitted to acute care facilities. “When you take a person with dementia who has agitation and aggression and move them to an acute care hospital or a specialized behavioral unit, the move itself can make people temporarily worse,” Dr. Freedman said. “Our team works to keep people out of the hospital, and if they have been hospitalized, to get them better to the point that they can go to long-term care or back to a home setting.”
The VBM core team is comprised of physicians (behavioral neurologists and clinical behavioral neurology fellows), a registered nurse, pharmacist, clinical navigators, social worker, and neuropsychologist with expertise in nonpharmacological behavioral management. The team works in close collaboration with health care teams in long-term care, acute care, and the community, including primary care physicians, psychiatrists, geriatricians, internists, physiatrists, behavioral support staff, nurses, occupational therapists, care coordinators, social workers, recreational therapists, and family members.
“Since this unit is virtual, there are no limitations due to physical space or bed availability,” Dr. Freedman said. “We do rounds as often as every week to two, going from facility to facility or home to home, by videoconferencing. During those rounds, we review patient progress, monitor therapy, manage medication, and review non-pharmacological strategies. While we have a core VBM team, the extended team varies with each patient and includes health care professionals in the [long-term care] homes, acute care hospitals, and the community.”
There is significant interest in replicating the program locally and internationally, Dr. Freedman said. “We received funding from the Ontario government to deliver additional cases of VBM at another hospital in Toronto, and the funding increases the more patients we see. We are working to double the number of patients we are serving. VBM is very scalable; you just need a behavioral neurologist or psychiatrist with experience, who is comfortable with virtual care of patients with dementia and agitation, and who can lead the team.
“When I started, I didn’t have any resources or funding. We obtained the resources that we have now because the program demonstrated great success in helping people with dementia. I think that VBM is going to make a major difference in the lives of our patients.”
Disclosures
Dr. Gandy is a scientific advisory board member for Cognito Therapeutics and has served as a n expert witness for the Bell Law firm. Drs. Freedman and Kales had no disclosures.
[ad_2]
Source link
