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New advisory on antipsychotics may limit care options

If the drugs' risks now outweigh their benefits, where do physicians and patients go for help?

From the July-August ACP Observer, copyright 2005 by the American College of Physicians.

By Janet Colwell

When it comes to treating behavioral disturbances in elderly patients with dementia, physicians have very few pharmaceutical options. Those meager numbers may have shrunk even further in the wake of a recent request from the Food and Drug Administration (FDA) that all atypical antipsychotics carry label warnings, saying the drugs may increase patients' likelihood of dying from heart attack or stroke.

The FDA's April 2005 public health advisory comes on the heels of other studies that highlight the drugs' cardiovascular risks—findings that pose a dilemma for physicians who work in nursing homes or care for elderly patients. While atypical antipsychotics have only a modest effect on behavioral disorders associated with dementia, they are sometimes the best pharmaceutical weapons available. If the drugs' risks now outweigh their benefits, where do physicians and patients turn to for help?

"If you look at the evidence base for treatment of agitated behavior in dementia, the truth is that very, very little data exist for any treatment to work," said Jay S. Luxenberg, ACP Member, director of medical services at the Jewish Home in San Francisco and associate clinical professor at the University of California, San Francisco School of Medicine. "The new risks push you away from using atypical antipsychotics—but the problem is, you don't have an alternative that is any more effective." (See "The top 10 most frequent drug events in long-term care by drug type.")

That's particularly bad news for patients and their families for two reasons, Dr. Luxenberg continued. For one, behavioral problems are often the most difficult dementia symptoms for family caregivers to handle. And because behavioral problems are so intractable, they are often the trigger for moving patients into a nursing home—where many start taking atypical antipsychotics.

The new risk-benefit equation

According to the FDA's April announcement, an analysis of 17 studies of four atypical antipsychotic drugs found the death rate to be 1.6 to 1.7 times higher in elderly patients taking the drugs vs. those on placebo. The FDA did not release details of the specific studies, saying only that most deaths were caused by "heart related events" or infections, particularly pneumonia.

Some analysts have expressed frustration with the announcement and its use of vaguely-worded cause-of-death categories, which gives physicians very little information to share with families trying to weigh the medications' pros and cons. Still, the FDA advisory and recent study findings put physicians on notice.

"If the benefit was huge—if I could tell a family member that there is a 50% chance I'm going to make your grandmother better on this medicine—then it might be worth the 1% to 2% risk of a stroke," said Kaycee M. Sink, MD, medical director of the Roeana B. Kulynych Memory Assessment Clinic at Wake Forest University's Sticht Center on Aging in Winston-Salem, N.C.

"But," she added, "if I say, 'Your grandmother might get a little better and there's now a risk of stroke three times greater than placebo and between one-and-a half and two times the risk of death,' suddenly the small chance for benefit doesn't look so good." Dr. Sink was the lead author of a Feb. 2, 2005, Journal of the American Medical Association article that reviewed and summarized the evidence for medications used to treat behavioral symptoms of dementia. The review concluded that while atypical antipsychotics showed modest benefits, those benefits were complicated by an increased risk of stroke.

Prescribing atypical antipsychotics for patients with dementia is considered off label in the United States, where the drugs are FDA-approved only for treating schizophrenia and mania.

Even without specific approval for dementia symptoms, the atypical antipsychotics covered by the FDA advisory represent the No. 1 drug expenditure for Medicaid in nursing homes, according to 1999 figures released by the Centers for Medicare and Medicaid Services (CMS) last year. Those same figures showed that antipsychotics were also the second most expensive drug prescribed to Medicaid patients, at $120 per month.

A June 2003 article published by the American Medical Directors Association (AMDA), a national professional association of long-term care physicians and medical directors, found that antipsychotic drugs—mostly atypicals—are prescribed to 21% of nursing home residents. (The article is online.) And in Arkansas, almost one-third of the state's 3,300 Medicaid patients with dementia are taking antipsychotics, said College Regent William E. Golden, FACP, professor of medicine at the University of Arkansas for Medical Sciences in Little Rock, Ark.

"The newer drugs have fewer risks of extrapyramidal side effects, and consequently are used much more than in the past," Dr. Golden said. Given the drugs' costs and increased mortality risk, however, "the patient's disruptiveness or behaviors really need to justify the use of a drug."

Growing evidence

Approved by the FDA in 1990, clozapine (Clozaril) was the first novel or atypical antipsychotic to be introduced in this country. The atypicals—which include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel) and ziprasidone (Geodon)—were embraced by the medical community. Unlike the older generation of conventional neuroleptic medications, the newer drugs were not generally associated with extrapyramidal side effects, such as drooling and rigidity, nor with postural hypotension or anticholinergic effects including dry mouth, constipation, blurred vision and increased confusion.

During the 1990s, several studies provided evidence of atypicals' effectiveness. However, signs of potentially serious side effects began to emerge.

One study published in the February 2003 issue of Journal of Clinical Psychiatry found that treatment with low-dose risperidone led to significant improvement in aggression, agitation and psychosis associated with dementia. However, five trial participants taking risiperidone suffered strokes, while one had a transient ischemic attack. (The authors noted that these events were not necessarily connected to taking the drugs, as affected patients were between age 79 and 89 and had significant risk factors.) Later studies established a stronger association between atypical antipsychotics and cardiovascular risks.

This year's FDA review was the first to link the drugs with a significant increased risk of death. In a later development, the FDA on May 27 issued a "not approvable" letter to Johnson & Johnson, rejecting its bid to market risperidone for treatment of psychosis in patients with Alzheimer's disease.

Other options?

The FDA's April advisory shouldn't surprise physicians who have paid attention to the clinical evidence, noted Steven Levenson, MD, medical director of seven long-term care facilities owned by the Baltimore-based Genesis Health Care, and AMDA's president-elect.

"Almost everything that one has to be aware of is either in the manufacturers' warnings or somewhere in the literature," Dr. Levenson said.

However, "what's already out there is not being followed, noticed or put into practice," he added. "I've seen a lot of physicians get a call saying, 'The patient's agitated, the patient's hard to handle,' and there's hardly anything that happens between that oversimplified problem statement and the prescribing of a drug."

The AMDA recently revised its dementia guideline to highlight atypicals' cardiovascular risks. The guideline now states that atypical antipsychotics should be used only after other strategies have failed—and that patients taking them should be closely monitored, especially when they have other cardiovascular risk factors.

High on the list of alternative treatment strategies is to do some digging into why a patient is agitated. Often, removing the source of the problem stops the disturbing behaviors.

Dr. Luxenberg recalled one elderly female patient who was visibly upset, shaking her hands and yelling—prompting staff to request medication. But an audiologist figured out that the woman's hearing-aid batteries were dead, and that the hearing aids were acting like plugs. As soon as they were removed, the woman calmed down.

"What I've learned to do over the years is say, 'Tell me what you mean by that' or 'Describe the symptoms,'" said Dr. Levenson. "Behavior is a symptom, not a disease, and it is often an expression of something the person needs or wants to express."

Also consider whether a patient's behavior is being caused by an existing drug regimen. "I assume that symptoms of almost any kind may be due to a drug until proven otherwise," said Dr. Levenson, "as opposed to assuming it's a new disease or treatable condition."

And, Dr. Sink pointed out that caregiver education is another key piece of the treatment puzzle. "Educating caregivers about what the behaviors mean and that the patient isn't trying to be difficult on purpose can go a long way," she said. If, for instance, "there's agitation around taking a bath, and the caregiver wants them to take one every day—maybe that's not necessary."

Different drugs

According to Dr. Sink, the list of pharmaceutical options is very short, but there are some medications you can try. Cholinesterase inhibitors, for example, may help delay cognitive and functional decline. While the benefits of these drugs on behavioral symptoms are slight, she said, they have less serious side effects than antipsychotics.

And physicians should consider treating specific symptoms, such as anxiety or depression, she added. There is no compelling evidence that antidepressants will have a positive effect on behavioral symptoms, she said, but they may be beneficial if symptoms are related to underlying depression. Selective serotonin reuptake inhibitors, for example, have been shown to be safe in treating depression in patients with dementia. (See "How can you soothe an agitated patient?")

The new findings on atypical antipsychotics may lead some physicians to try other drugs off label that have shown promise in clinical trials and appear to be safer than antipsychotics. But Dr. Luxenberg noted that "in medicine, we've made a lot of blunders by relying on that type of information." While randomized controlled trials are the best tools available to test drugs' effectiveness, he added, behavioral symptoms are hard to measure in a study.

According to Dr. Levenson, the FDA advisory is a strong reminder that not all agitated or combative behaviors are symptoms of psychoses.

"Consider alternative approaches before taking the path of least resistance, which is to treat the symptom with a drug," he advised. "Recognize the risks—and if the drug is not making a material difference, don't continue it."

The information included herein should never be used as a substitute for clinical judgment and does not represent an official position of ACP.

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How can you soothe an agitated patient?

According to the Alzheimer's Association, 56% of patients who have dementia suffer from Alzheimer's disease. With these patients, the association recommends trying nonpharmaceutical interventions first to control behaviors:

  • Create a calm environment. Remove stressors, triggers or danger. Move patients to a safer or quieter place; offer security objects, rest or privacy; limit their caffeine use; give them an opportunity to exercise; develop soothing rituals; and use gentle reminders.

  • Avoid environmental triggers. Reduce or eliminate noise, glare and too much background distraction, including television.

  • Monitor personal comfort. Check for pain, hunger, thirst, constipation, full bladder, fatigue, infections and skin irritation. Ensure a comfortable temperature, and be sensitive to fears, misperceived threats and frustration over an inability to communicate.

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