Researchers Question Front-line Alzheimer's Drugs

It's a dark day when the few drugs available to treat Alzheimer's disease start looking like they don't do much good. Aricept, Reminyl and Exelon are collectively known as cholinesterase inhibitors.

Researchers Question Front-line Alzheimer's Drugs

It's a dark day when the few drugs available to treat Alzheimer's disease start looking like they don't do much good. Aricept, Reminyl and Exelon are collectively known as cholinesterase inhibitors. They are the standard treatment options in Canada for patients who suffer from mild to moderate symptoms of Alzheimer's. Last year, Canadian physicians wrote more than one million prescriptions for these drugs, worth $129 million, according to market watcher IMS Health. But a growing body of evidence suggests the three medications may not work. In fact, they may cause serious harm.

In a recent paper published in the British Medical Journal, a German research team challenged the validity of 22 so-called "gold standard" clinical trials that purported to show the therapeutic benefits of Aricept, Reminyl and Exelon. The scientists concluded that "because of flawed methods and small clinical benefits, the scientific basis for recommendations of cholinesterase inhibitors for the treatment of Alzheimer's disease is questionable."

Individual nerve cells communicate with one another through the release of a chemical called acetylcholine. Once acetylcholine, a neurotransmitter, has done its job, it is eliminated by an enzyme called acetylcholinesterase. Aricept, Reminyl and Exelon suppress acetylcholinesterase and help maintain acetylcholine levels that, in Alzheimer's patients, steadily drop as brain cells die. The trouble is, the results of clinical drug trials are often over-interpreted, says Dr. Hanna Kaduszkiewicz, the German paper's lead author and a physician at the University Medical Centre Hamburg-Eppendorf, Hamburg's largest hospital. "There are a lot of reasons for this tendency," she says. "One of them certainly is that doctors always want to be able to give something to their patients, and therefore tend to be more positive about innovations than they should be."

The new doubts about the three drugs created a storm of controversy, with scientists from around the world challenging the German findings. However, it is indisputable that only a small fraction of patients respond positively to any of the three drugs, although more exact percentages are not known. As well, the response rate is so low, and the side effects so potentially serious, that some clinicians are asking whether these drugs ought to be prescribed at all. But Dr. Jack Diamond, scientific director of the Alzheimer Society of Canada, says such factors aren't reason enough to get rid of the drugs. "What we want now is not to say, 'Right, cholinesterase inhibitors don't work, we don't want to use them,' " Diamond says. "What should be done is more research to identify the responders."

It seems unlikely that drug companies would line up to do that kind of study, according to Dr. Thomas Perry, a scientist at the Therapeutics Initiative, an independent organization at the University of British Columbia that assesses drug data. "Imagine, if you're the drug company, if only one out of 10 patients benefits," Perry says. "You'd cut your market to 10 per cent of what it would otherwise have been." Perry acknowledges it is possible the drugs may work "for a few people," but in general, he says, "I wouldn't expect much," other than the common side effects, such as nausea, vomiting, diarrhea, and weight loss. And, Perry adds, "our analysis of all the experiments leads us to think that about one in 50 people started on the drugs will have something fairly nasty happen to them."

By nasty, Perry means a "serious adverse event," defined as either death, hospitalization, prolonged hospitalization or permanent disability. For example, the three drugs can cause loss of bowel control. "If that led to an older person lying in a pool of their own feces for a few days," says Perry, "their skin may break down, they may get an infection, they may get hospitalized - and some of them die." So questionable is the value of these drugs that British Columbia no longer pays for them. But Diamond says anecdotal evidence suggests caregivers coping with difficult patients find the drugs invaluable. "Those small clinical changes are enormously important to them," says Diamond. "It makes a huge difference to their whole quality of life." In the wake of the controversy, Perry has some drug advice. "If you're going to try it, try it very cautiously, and you and your family should be aware of the adverse effects," he says. "Don't just take it because the doctor said, 'I want you to try this.' "

Maclean's November 21, 2005