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Answers to Frequently Asked Questions aboutMedications for Alzheimer's DiseaseAn interview withDavid S. Geldmacher, MD, Neurologist |
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Dr. Geldmacher is an assistant professor of neurology at Case Western Reserve University and clinical director of the Alzheimer Center of University Hospitals of Cleveland/CWRU. He is a member of the Alzheimer's Association Professional Advisory Board and dedicates much time and energy to supporting and educating those touched by Alzheimer's disease and related disorders.
Substances used against Alzheimer's disease can be broken down into two categories: those that may protect against the disease or slow it, and those for the treatment of symptoms. In this first of two installments, Dr. Geldmacher answers questions about medications now in use for treatment of symptoms and new drugs that may be approved soon. The August newsletter will feature Dr. Geldmacher's comments on Vitamin E, estrogen, ginkgo biloba and other substances that may slow or protect against Alzheimer's disease.
Also known as donepezil hydrochloride, Aricept is the second drug to be approved by the U.S. Food and Drug Administration specifically to treat Alzheimer's disease. Aricept increases the concentration of acetylcholine, a chemical found to be reduced in the brains of individuals with Alzheimer's disease. Aricept helps to increase communication between nerve cells, and in turn, temporarily improves the symptoms of the disease. It is not a cure for Alzheimer's disease nor does it appear to stop the progression of the disease. It can, however, help with cognition and symptoms. At this time, the cost is approximately $120 for a month's supply.
Do most people on Aricept experience an improvement in cognition or symptoms? "No, not a majority. If we look at the data from studies, about one out of every four people on l0 milligrams a day of Aricept will show an easily measurable improvement." Can Aricept be helpful for related disorders? "Probably, although the data does not yet exist. It's being looked at in several related disorders, including vascular dementia and some of the Parkinsonian dementias. Our experience in the Foley ElderHealth Clinic has been that some of our best responses to Aricept have been in people who have possible Alzheimer's disease but also have other features like Parkinson's." When is it appropriate to begin taking Aricept? "It's probably never too soon once the diagnosis of Alzheimer's disease has been established. If we define benefits to Aricept not as improvement in cognition, but as a delay in the decline, then the earlier we start, the higher the functional level that is preserved." What about side effects? Are there steps that can be taken to help with the side effects? "As with all medicines, yes, there are side effects. However, most people will tolerate the medicine with no side effects at all. The side effects that do occur most commonly are things like nausea, loss of appetite, loose stools, or diarrhea. They might occur when the medicine is first started, and typically will reduce as time passes, even to the point of disappearing. At the 10-milligram dose, these kinds of side effects occur more frequently. In our first group of prescriptions, as many as a quarter, or maybe a third of people had some side-effect symptoms when they went up to 10 milligrams. However, very few people discontinue the drug because of them. There really aren't a lot of ways to reduce those particular side effects. Tacrine you can take with food to reduce the side effects, but Aricept does not have that same kind of responsiveness to food. Tums or other similar products can help reduce indigestion from taking Aricept. It's important also to recognize that people with pre-existing digestive problems are likely to have side effects at a higher rate than those who do not." Are there any other side effects? "Some people will develop runny nose or hypersalivation. That can respond nicely to over-the-counter antihistamine-type drugs or allergy-type drugs." Will minimizing the dosage cause fewer side-effect symptoms? "Certainly, people will respond to 5 milligrams. We noted earlier that with people on 10 milligrams of Aricept, one out of four will show very discernable cognitive improvements. With five milligrams, that figure is one out of every six. A lower proportion of people will respond to the 5 milligrams, but 5 milligrams is clearly better than no milligrams. If you can't take 10, you should take 5." Can you take it at different times of the day? "It doesn't make much difference with Aricept. As we move toward other medicines in this field, like Exelon, or we look at the past like Cognex, it did make a difference. Aricept lasts for a very, very long time in the body, about 70 hours, and so the time of day that you take it doesn't make a big impact upon the level in the body." Do doctors ever prescribe Aricept before a diagnosis of Alzheimer's disease? "The government's rule says not before diagnosis. However, there are prescribers who will jump the gun on that. Aricept will have very little, if any, benefit at all for people who have normal age-associated memory changes. But, in that gray zone between healthy aging associated memory change and clear-cut diagnosis, there's a whole spectrum of illness called mild cognitive impairment, and those people often are affected. There will be clinical trials in that specific group in the next couple of years. So there's a range of unregulated physician judgment between no dementia and dementia, and everyone makes personalized decisions there. I would prescribe it for someone who had clear-cut impairment and decline from previous levels of cognitive ability that don't quite meet criteria for dementia." What should a person expect if he/she stops taking Aricept? "If the medicine was still doing something, they should expect a fairly rapid decline; that is, a decline over the course of a couple of weeks to the point where their disease would have been had they never taken Aricept. Because of the way the disease runs and the way the drug works, there is a theoretical point where most people will fail to benefit from Aricept. Somewhere in the severe range of the illness, where the brain doesn't make enough acetylcholine for the Aricept to work on anymore, when those people stop their medicine, nothing happens! So, the more severe the person, the less likely you are to see worsening on stopping Aricept; that is, a sudden worsening, since the disease will continue along its own course." If I am presently taking Cognex, should I switch to Aricept? "If someone is taking Cognex at a total dose of 80 or more milligrams a day, and they're having no side effects, there is no reason to switch. The effectiveness of Aricept and Cognex, and the expected to-be-released Exelon, are probably all very close. The main differences among them are how often you take them and what the side effects look like. If someone's able to take Cognex with no side effects, there is no urgency to change to any other drug. I'll say the same about Aricept when Exelon comes out — if the drug is working, don't mess with success! What is estrogen? "Estrogen is a hormone dominant in the female reproductive system. Men also produce this hormone by converting testosterone into estrogen. In the brain, this hormone increases the amount of acetylcholine, enhances antioxidant properties, and increases nerve cell growth. In some studies, estrogen has been shown to improve cognition in those with Alzheimer's and may have a protective effect in asymptomatic individuals." Does research indicate how many people might benefit from estrogen? "We cannot make a statement about how many people will benefit from estrogen because there have been no clinical trials of estrogen versus something else in altering the progression of the disease. As a national research site, the University Alzheimer Center has an estrogen trial under way, but so far there are no answers. All of the information that we have on estrogen comes from studies comparing people who took estrogen in the past with those who did not or clinical trials that are too small to generalize. Overall, we find that those who took estrogen after menopause have less Alzheimer's disease. It appears that estrogen does one of two things: either it delays the onset of Alzheimer's or it slows its progression." Does it also improve cognition in people with related disorders? "Estrogen has shown a clear benefit on cardiovascular morbidity or reduced risk of heart attacks in related situations. Since heart disease is one of the biggest risks for stroke, and stroke is the cause of vascular dementia, we would expect that women who have gotten a cardiovascular benefit from estrogen should develop vascular dementia at a lower rate. However, the time window between development of heart disease and development of vascular dementia is highly variable and completely unpredictable." Do the benefits of taking estrogen outweigh the risks? "If we look at Alzheimer's disease or dementia alone, the data is not strong enough to support the use of estrogen. However, if we put it in the real world, the reduced risk of fractures from osteoporosis and the reduced risk of cardiovascular death versus the increase in risk of breast cancer for women who do not have a maternal history of breast cancer clearly weighs in favor of estrogen." When is it appropriate to begin taking estrogen? "It's appropriate to begin when, in consultation with the family doctor or gynecologist, the net benefits of taking estrogen are believed to outweigh the net risks of doing so. What are the benefits of vitamin E? Where is it found? "Vitamin E can be taken as a vitamin supplement or obtained naturally through diet (green leafy vegetables, nuts, vegetable oil or seed oil, whole grains, wheat germ, rice, sweet potatoes, and avocados). Because vitamin E is an antioxidant, researchers believe that it may aid in the breakdown of free radicals that may be damaging brain cells in individuals with Alzheimer's disease." Does research indicate how many people might benefit from vitamin E? "I can't give a percentage of people because most studies by the Food and Drug Administration do not allow what we call 'responder analysis,' where they count the number of people who respond positively and the number of people who respond negatively. With disease-slowing agents, there isn't a particular symptom to track, such as a memory test score. We seem to have a mismatch between what the public desires and the kind of evidence our government wants. Not only the government but our medical scientific community delivers studies that are based on average response. The public wants to know, "What's my individual response going to be?" But we can't tell someone what their individual response is going to be until they take the drug." Can vitamin E be helpful for people with related disorders? "Probably. Parkinson's disease seems to be affected by antioxidants, perhaps to a somewhat lesser extent than Alzheimer's disease. Probably the third most common forms of dementia in the country are the Parkinsonian dementias." Does vitamin E help with vascular dementia? "It is possible. Vitamin E is an antioxidant. While antioxidants are good for heart disease whatever is good for heart disease reduces your risk of stroke, which is good for vascular dementia. In the same way that we talk about the net benefit of estrogen in multiple systems, vitamin E has a net benefit in multiple systems. It's known to reduce cardiovascular problems and colon cancer, and it's probably associated with a reduced risk of prostate cancer. Taking vitamin E does lots of good things and has almost no negative side effects." Is there a recommended dosage for vitamin E as a supplement? "We need to start with two ends of the spectrum. One end is normal health, and the other is Alzheimer's disease. For dietary purposes, the recommended daily allowance for vitamin E is 32 units a day. That's what a healthy nourishing diet would contain, and that's what most multivitamins contain. Alzheimer's disease studies have been done with 2000 units a day. That dose was chosen to give the maximum antioxidant capacity to every single person in the study. In the middle of that spectrum are those people who might have pre-symptomatic illness, those people whose genes could give them the risk for developing the illness. We don't know in a group of people who will and who will not get Alzheimer's disease so what dose of vitamin E should be used? No one knows. The cardiovascular doses, the ones that have been shown to benefit heart disease, colon cancer, and prostate cancer are on the order of 400 to 800 units a day -- many times more than the dietary dose, but probably less than the symptomatic dose. That's usually what I recommend -- 400 to 800 (IU) units a day." Are there any risks to trying this? Does a person need to talk to their doctor? "Blood thinners like Coumadin are a potential risk combined with vitamin E. People on blood thinners should definitely tell their physician that they're beginning to take vitamin E. Since high doses can interfere with the blood-clotting system, the physician may need to adjust the dose." What is ginkgo biloba? "Ginkgo biloba is a plant extract containing several compounds that may have positive side effects on cells within the brain and body. Ginkgo is thought to have both antioxidant and anti-inflammatory properties, to protect cell membranes, and to regulate neurotransmitter function. Ginkgo has been used for centuries in traditional Chinese medicine, and currently it is being used in Europe to alleviate cognitive symptoms associated with a number of neurological conditions." Does research indicate how many people might benefit from taking ginkgo biloba? "The research that's been done is too preliminary or too questionable to have a definitive answer. Ginkgo is now being looked at in some legitimate studies. The one big study that's been published was in the Journal of the American Medical Association in October 1997. The study compared ginkgo to a placebo over one year in people with dementia of all sorts, not just Alzheimer's disease. There were some serious flaws in the study, which limit our ability to generalize it. There was a very, very small, improvement in cognitive performance on tests. Caregiver ratings showed no change in performance of the people taking ginkgo. We could detect a small, measurable improvement, but not something that you would notice." Are there any risks to trying this? Does a person need to talk to their doctor? "Although it's always advisable to review any medication with your family doctor, it's an over-the-counter preparation so you don't need to get a doctor's permission to try it. The dosage in the study was 40 milligrams of ginkgo biloba extract three times a day. There were no major side effect problems in the study with that dose. There are two sides to every drug, efficacy, or how well it works, and safety. Efficacy here is questionable, but safety looks pretty good at that dose. In other words, 40 milligrams, three times a day, won't hurt you. Since the failure to respond was an average failure to respond, that may mean that half the people get better and half the people get worse. My response to using gingko is, give it a try. If you discern a difference after three months of treatment, keep going. If you don't, don't waste your money." Are there possible interactions with other medications? "That's unknown. Since it's an over-the-counter drug, it's considered a nutritional supplement. It has not been put through all the rigorous FDA tests of drug interactions." How does ginkgo work? "It probably acts as an antioxidant. If we compare the studies of vitamin E and ginkgo, the vitamin E studies are much better, stronger studies. If we look at the dose of vitamin E used in the Alzheimer's study, it's a more potent antioxidant dose than the one used in the gingko study. If you were going to ask me about taking gingko and vitamin E together, I would probably tell you they do the same thing. If one of them is (and I'll make up the number), 10 times stronger than the other, then there's probably not much reason to take both. If someone comes out with a ginkgo study and proves me wrong, I'm glad to listen. I think antioxidants are a very reasonable and probably quite effective treatment for slowing progression, and I would go with the best, safest one. So far, vitamin E has the lead in that category. It's been shown to have benefits besides slowing Alzheimer's disease, and it's known to be safe and effective." What are non-steroidal anti-inflammatories (NSAIDS)? "NSAIDS are drugs such as ibuprofen, Advil or Motrin, for example, commonly used for the temporary relief of aches, pains, and fevers. These are available over the counter or by prescription. NSAIDS may aid in preventing or delaying the onset of Alzheimer's by reducing inflammation that may contribute to nerve cell damage." Does research indicate how many people might benefit from taking NSAIDS? "Again, I can't give percentages. No large study has compared NSAIDS to placebo. However, in studies comparing people who had been taking NSAIDS and people who had not, those on NSAIDS developed less Alzheimer's disease or were older when they got it. On average, that suggests a protective effect of NSAIDS on Alzheimer's disease. Do they work for every single person? There's no way of saying." Can NSAIDS be helpful for related disorders? "So far, Alzheimer's disease appears to be the major form of dementia that has a large inflammatory component. For many years, the research said there was no inflammation in the brain. Only modern techniques are finding these inflammatory markers. Our current state of knowledge suggests NSAIDS should be much better for Alzheimer's than other related forms of dementia. However, our state of knowledge five years ago would have told us that they wouldn't have worked in Alzheimer's disease. Right now, the answer is no. In the future, the answer may change." Is there a recommended dosage? "No, they should not be used with dementia as the sole indication because we don't have that safety versus efficacy comparison. We don't know the efficacy, but in this case, we do know there are adverse safety effects such as intestinal bleeding." Are there any risks to trying this? Does a person need to talk to their doctor? "Absolutely! These can be very dangerous drugs. Besides intestinal bleeding at high doses, they can interact with other medicines. They also can interact with other illness states such as kidney disease." What new drugs may be approved this year? How well do they work? "There will be probably two or three new drugs that may improve the symptoms of Alzheimer's disease over the course of the next 12-18 months. The first of these is called Exelon, and we expect it to be approved sometime within the next couple of months. Exelon, like Tacrine or Cognex, and like Aricept, is a cholineserase inhibitor. They all work by identical mechanisms in the brain, and we therefore expect their efficacies will all be quite similar. Side effects will distinguish between them, so, when someone hears there's a new drug coming out, that does not now mean that there's a better drug coming out. They should not run to their doctors to change from Aricept onto something else. Our main concern is that these other drugs will probably have more side effects in more people than Aricept does. We need to change the perception that any drug is better than nothing, and that any new drug must be better than any old drug. That is no longer going to be the case. The new drugs are going to have roughly equal potencies, and there's no new mechanisms, no new class of drug that's expected to come out within the next two or three years. These are all what we call 'me-too' drugs. Two other drugs have been submitted for FDA approval. One still has the chemical name metrifonate, and Physostigmine, and that will have the brand name of Synaptom. While these and Exelon have been submitted, there's no guarantee that any or all will be approved. We think that at least two of the three will be approved. We'll be doing a phase two study on a muscarinic agonist, which is one of those drugs that fool the brain into thinking that it's getting acetylcholine. That type has failed so far in trials because of side effects. This one has a slightly different spin on it, so we'll give it another try! For information on participating in drug trials or one of the many other research opportunities at the University Memory and Aging Center, please call Kathleen Shaw at (216) 844-6326 or 1-800-252-5048. |
University Hospitals of Cleveland