More than 80 medications are currently being investigated for use in the treatment of Alzheimer's disease. Patients, families, and clinicians are eagerly awaiting the availability of agents that will more effectively control the symptoms of this most common of dementias. Even more exciting, doctors hope for medications that will halt the progress of cognitive decline or even reverse the destructive process that impedes cognitive functions and ultimately kills brain cells.
While clinicians await the arrival of new treatments, they currently have access to two classes of medications approved by the Food and Drug Administration (FDA) for the treatment of Alzheimer's disease. These widely used medications have sparked controversy between those who consider them valuable treatment tools and those who regard them as hazardous and costly. Let’s look at the pros and cons of these medications from an evidence-based, yet practical viewpoint. The FDA approved “cognitive enhancers” fall into two classes.
Donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne) are inhibitors of the enzyme acetylcholinesterase. They work by diminishing the brain’s normal breakdown of the neurotransmitter called acetylcholine, an important player in the transformation of thought and experience into retrievable memories—a miracle so familiar to us that we may take it for granted unless we have seen the chaos that results from its disruption. Each of these medications is available generically. Although this limits their cost, the associated copayments under some insurance plans can pose a significant burden.
Donepezil and rivastigmine have been approved for mild, moderate, and severe Alzheimer’s disease. Galantamine is approved for mild and moderate stages of the disease. Donepezil is also available in a new and relatively higher dose pill, and rivastigmine is the only one yet available in a skin patch delivery system, suitable for use by patients more amenable to a patch than a pill, or unable to tolerate the gastrointestinal side effects of this class of drugs. These medications share several other side effects that can be clinically significant: disruption of sleep, enhanced risk for bleeding, and slowing of the heart rate to the point of potential danger from fainting or disrupted heart rhythm.
The other class of cognitive enhancers approved for Alzheimer's treatment contains one lonely member, memantine (Namenda). Memantine’s unique mechanism of action involves enhancement of the brain’s sensitivity to an important excitatory amino acid neurotransmitter, glutamate. Glutamate plays a key role in uniting the brain cells that must collaborate to form a specific memory. Glutamate also plays a more sinister role in the brain, contributing to the neuron-destroying process called apoptosis (programmed cell death). Memantine is approved for middle and late stages of Alzheimer's disease and is often combined with a cholinesterase inhibitor once a patient passes beyond the early stage. Memantine’s side effects are often minimal, though occasionally it can enhance or initiate confusion, agitation, constipation, or headache.
Pros and Cons
The effectiveness of these medications appears to be modest but significant for a large number of patients who can tolerate their side effects. At their best, the cognitive enhancers slow down for six months or more the encroachment of Alzheimer's disease on multiple areas of functioning. These medications have been shown to facilitate thinking, to improve performance of activities of daily living, to contribute to the management of some non-cognitive behavioral disturbances, and to reduce the burden of caregiving by perhaps an hour a day.
Critics of these medications point out that, on average, their effect differs from that of placebo (inert medication) by only a few points on scales that include many points. They also criticize the potential of the cholinesterase inhibitors to induce distressing side effects such as severe diarrhea or fainting. A practical approach to the use of these medications requires periodic reassessment of their side effects and benefits.
Many clinicians believe that the cognitive enhancers continue to play a useful role late into the course of Alzheimer's disease. They cite studies showing that significant clinical deterioration can occur even after discontinuation during a late stage of the dementia. In some cases, however, it is appropriate to discontinue these medications, particularly when side effects have exceeded tolerability or the patient’s functional decline has progressed to a very severe stage. Side effects will diminish quickly after discontinuation, but clinical benefits will also dissipate as few as six weeks after they are stopped. Except when abrupt discontinuation is medically necessary, it is advisable to taper the cholinesterase inhibitors and memantine rather than stop them suddenly.
The outstanding efforts of many researchers have made clear that medications are only one part of the successful care of patients with Alzheimer's disease. Education of the patient and family, support of caregivers, attentive medical assessment to reduce additional sources of distress, use of resources such as adult day care programs, and behavioral assessments and interventions each contribute to the successful care of individuals suffering from dementia. In time, there is every reason to hope for medications of great effectiveness to enhance our other treatment elements. Until then, the currently available cognitive enhancers continue to play a useful role in optimizing care.
James M. Ellison M.D., M.P.H. Dr. Ellison is a geriatric psychiatrist with clinical and research expertise.
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