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New Treatments For Alzheimer's Symptoms

To Curb Aggression, Paranoia In Dementia Patients, Doctors Turn to Schizophrenia Drugs

Andrea Petersen, The Wall Street Journal

August 26, 2004

Geriatric psychiatrists are using a host of new medications to treat the personality changes and aggression that often accompany Alzheimer's disease -- including drugs generally used to treat schizophrenics.

While most people associate Alzheimer's with the slow erosion of memory, about half of all sufferers also develop psychiatric and behavioral symptoms, including violent outbursts, paranoid thoughts and intense anxiety. Doctors have tried treating such symptoms with tranquilizers and early antipsychotic drugs, but these approaches were either overly sedating or produced dangerous side effects, and health-care providers have been pressured to reduce their use.

Now, a number of new studies show that so-called atypical antipsychotics, a class of drugs normally used to treat young schizophrenics, can reduce the psychiatric symptoms of Alzheimer's and other kinds of dementia. Studies also show that some anticonvulsant medications used for epilepsy also may help. The National Institute on Aging is funding a trial looking at whether one anticonvulsant, Depakote, will actually prevent those with mild to moderate Alzheimer's disease from developing psychiatric symptoms at all.

Some of these drugs -- which include the antipsychotics Zyprexa from Eli Lilly & Co. and Risperdal from Janssen Pharmaceutica -- carry serious side effects of their own, including an increased risk of stroke and diabetes. And they aren't approved by the Food and Drug Administration for use in Alzheimer's disease. But doctors have been increasingly prescribing them to Alzheimer's patients "off-label," and they say the risks of side effects are much lower than with older treatment options.

"It is fair to say that between 50% and 90% of patients treated over a long period [with the older drugs] will experience some form of significant side effects," says Pierre Tariot, a researcher at the University of Rochester in New York who has conducted drug trials to treat behavioral symptoms in dementia patients. "We want to use the most efficacious, safest and best-tolerated medication."

Buoyed by the recent studies and the market potential, Janssen, a unit of Johnson & Johnson, and Eli Lilly are now applying for approval to market some form of their drugs for use in dementia patients. About 6% of prescriptions of Zyprexa already go to elderly dementia patients, according to Eli Lilly. Sales of atypical antipsychotics doubled in the U.S. to $8.08 billion between 2000 and 2003, according to IMS Health, a market-research firm.

Doctors and patients are desperate to do something about the devastating psychiatric symptoms of Alzheimer's disease. Psychiatrists say that behavioral issues and violent outbursts -- not memory loss -- are the primary reasons family members send loved ones with Alzheimer's to a nursing home. And the issue is only going to grow. Currently 4.5 million Americans have Alzheimer's disease, and that number is expected to rise significantly as the population ages, according to the Alzheimer's Association.

The symptoms include everything from paranoid beliefs (such as the notion that someone is stealing belongings), aggression, wandering and hallucinations. While the cause is uncertain, some researchers speculate it may involve the death of brain cells in the reasoning and emotional centers of the brain, as well as excess levels of the neurotransmitter dopamine.

Atypical antipsychotics help reduce excess levels of dopamine, as well as act on other neurotransmitters such as seratonin, which is involved in regulating mood. (Hence the term "atypical," in contrast to older antipsychotics that act more specifically on dopamine.) They are also pricey -- a month's supply costs between $100 and $300, while older antipsychotics cost less than a quarter per pill.

In one study presented in May, Zyprexa was somewhat more effective than Risperdal in alleviating symptoms of agitation and aggression, although neither drug was much more effective than a placebo. In another May study, Risperdal eased insomnia, increasing the length of sleep from 5.5 hours to 7.1 hours in dementia patients.

The science in dementia patients is skimpier on newer atypical antipsychotics such as Bristol-Myers Squibb Corp.'s Abilify and Pfizer Inc.'s Geodon, though a study of Abilify released in May showed that it, too, eased psychotic symptoms in dementia patients more than a placebo. The National Institute of Mental Health is in the middle of a 450-person study comparing Risperdal, Zyprexa, Seroquel -- an atypical antipsychotic from AstraZeneca PLC -- and the antidepressant Celexa, in the treatment of hallucinations, delusions and agitation in Alzheimer's patients.

Doctors have also had success with the anticonvulsant Depakote from Abbott Laboratories, which is usually used to treat epilepsy, bipolar disorder and migraine headaches. The drug damps the speed and frequency with which neurons fire. Scientists also think that Depakote may also inhibit the development of the plaques and tangles that form in the brains of Alzheimer's patients. The National Institute on Aging is recruiting patients for a 300-person trial to see if treatment with Depakote will prevent psychiatric symptoms of Alzheimer's. Information on clinical trials recruiting patients can be found on www.clinicaltrials.gov.

There are some concerns about side effects. Earlier this year, the FDA requested that manufacturers of atypical antipsychotics change their labels to add a warning about an increased risk of diabetes. Studies have also shown a slightly increased risk of stroke and death in elderly dementia patients taking atypical antipsychotics. The studies prompted some drug makers to add a warning on those risks to labels. And in March, the British government said Zyprexa and Risperdal shouldn't be used to treat behavioral symptoms in elderly dementia patients, citing the stroke risk.

But the side effects are much more pervasive and troubling with older antipsychotics, which had been routinely used since the 1950s to treat behavioral and psychiatric symptoms in dementia patients. They can induce Parkinson's-like shaking, as well as tardive dyskinesia, a sometimes permanent disorder marked by repetitive movements. They are also sedating. Doctors say that more than half of all patients treated long-term with the conventional antipsychotics develop severe side effects.

The older drugs started to fall out of favor in 1986, when the Institute of Medicine published a study that documented shocking overuse of the medications by nursing homes to control patients. The government passed reforms a year later that now strictly detail when psychotropic drugs can and can't be used in facilities that receive government dollars. These rules also affect how the newer antipsychotics can be prescribed. For example, doctors aren't supposed to use antipsychotics to treat symptoms such as wandering and "uncooperativeness" that can be controlled in other ways.

Now, many psychiatrists and facilities are sensitive to the history of overprescribing drugs. Tranquilizers such as Xanax and Valium can alleviate anxiety, but they can be overly sedating and may make frail seniors susceptible to falls. Antidepressants such as Prozac and Paxil are sometimes successful in patients whose psychiatric and behavioral symptoms arise from depression and anxiety. And there is evidence that some current treatments that can slow the memory deterioration in Alzheimer's patients also ease behavioral symptoms. Recent studies on Pfizer's Aricept and Namenda, made by Merz GmbH and marketed in the U.S. by Forest Laboratories Inc., show that they too may improve behavioral symptoms.

But doctors are also mindful that there may be environmental and physical factors causing the behavior. Urinary-tract infections, constipation and other kinds of pain, hunger and thirst can lead to so-called agitation, especially in patients who can no longer voice their discomfort. Some psychiatric symptoms can be side effects of medications. The memory loss itself can be scary, leading to intense anxiety, insomnia and wandering. And in the later stages of Alzheimer's, patients no longer recognize the function of objects, which can cause confusion and resistance to care.

Beyond Forgetfulness

Here are some of the drugs being used to treat the behavioral and psychological symptoms of Alzheimer's disease and other forms of dementia. For info on clinical trials recruiting patients, search on www.clinicaltrials.gov for "Agitation in Alzheimer's Disease."