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Dementia is not a part of normal aging, and it is more than just forgetfulness. Dementia is a progressive clinical syndrome whereby intellectual function and other cognitive skills (memory) are lost, leading to a decline in the ability to perform activities of daily living. Often in the later stages, it is complicated by neuropsychiatric disturbances. Alzheimer's disease (AD), a progressive degenerative disorder of the brain, is the most common cause of cognitive impairment in the elderly, accounting for about 60% of all dementias. The prevalence of AD increases rapidly with age, doubling every 5 years after the age of 60.1
Importance of Early Detection
Prevalence rates of AD in the United States are expected to triple over the next 50 years, a consequence of the overall aging of the US population. Because of the profound and far-reaching impact of AD, this projected increase is expected to pose a tremendous challenge.2 Central to the successful management of AD is the prompt and accurate diagnosis of the disease. Current guidelines call for a 2-tiered approach in which patients first undergo screening using a brief cognitive assessment tool, followed by a comprehensive battery of physical, psychological, and neurologic tests if signs of possible cognitive impairment are evident on screening. Once a conclusive diagnosis of AD has been made, keeping in mind that the definitive diagnosis of AD can be made only on autopsy, the development of a disease management approach targeting the needs of the patient and his or her caregiver becomes a primary concern.
Pharmacologic interventions may play an important role in the overall management of AD. Deficits in cholinergic and glutamatergic neurotransmission have been linked to the symptomatology of AD, and current therapies, including acetylcholinesterase inhibitors (AChEIs) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine, have been developed to compensate for these deficits. Monotherapy regimens involving an AChEI or memantine have been shown to slow the progression of cognitive symptoms in patients with moderate-to-severe AD, although memantine is currently the only agent approved for use in this setting.3,4 Furthermore, combination therapy involving memantine and an AChEI has been shown to yield increased cognitive benefits relative to AChEI monotherapy, a result that is believed to be attributable to the distinct therapeutic mechanisms associated with NMDA receptor openchannel antagonists and AChEIs.5
Nonetheless, recent findings indicate that the therapeutic effects of these antidementia agents are not limited to cognition, but also are responsible for improving outcomes related to patient functioning and behavior, 2 domains that may have a great deal of significance for patients and caregivers. Furthermore, recent clinical trial data suggest that antidementia agents may significantly delay nursing home placement, a unique end point that can be tremendously distressing to patients with AD and their caregivers. In addition to the therapeutic benefits of these agents, however, associated side effects and potential drug-drug interactions also must factor into decisions regarding the pharmacologic treatment of AD.
The 4 AChEIs approved by the FDA for the treatment of mild-to-moderate AD are tacrine (Cognex), donepezil (Aricept), galantamine (Razadyne, Razadyne ER), and rivastigmine (Exelon). Although tacrine has proved effective, hepatic effects and multiple daily dosing (qid) have rendered its use in AD impractical. Consequently, the other 3 are the ones predominantly used today, and all have been studied extensively. These agents are initiated at a low dose and are titrated over 2-to 4-week intervals to enhance tolerability. Donepezil and galantamine extended-release are dosed once daily, whereas the others are dosed twice daily. The most clinically important adverse effects include nausea, weight loss, diarrhea, vivid dreams, and muscle cramps. Adverse effects appear to be the greatest with rivastigmine and the least with donepezil. In terms of efficacy, no one agent appears to be better than another.6-8 Given that cost is fairly equivalent for all of them, the choice is usually based on adverse effects, dosing convenience, and clinical experience.
NMDA Receptor Antagonist
Memantine is FDA-approved for the treatment of moderate-to-severe AD. This drug is initiated at a dose of 5 mg daily and is titrated to the target dose of 20 mg daily over a 4-week period. More specifically, the dose is increased each week by 5 mg (using twice-daily dosing), until the maximum therapeutic dose of 10 mg twice daily is attained. The most clinically important adverse effects are rare and include dizziness, headache, confusion, and constipation; however, if experienced, they are usually temporary.9
Caregiver and family education/support is paramount to ensure that everyone involved understands the disease and the limitations of treatment. Patients and caregivers should be educated that they may not see an actual improvement in cognitive functioning, but the agents may help slow the decline of cognitive loss. Often, office-based assessments (such as the Mini Mental State Examination, or MMSE) are not sensitive to these changes, and the caregiver or patient impression may be more valuable. It is also thought that the patient may be benefiting from the medication through the slowing of disease progression, even if benefits cannot be noted by the patient or family.10 Therapy with AChEIs should be continued indefinitely, because stopping therapy has been shown to result in a rapid cognitive decline, and restarting therapy may not restore function to prior levels. Discontinuation of these agents should be considered only if there is rapid deterioration while on the medication and no perceived benefit. If a patient has adverse effects or a perceived lack of benefit with one of the AChEIs, then it is reasonable to try another agent, because a lack of response to one may not predict a lack of response to all of the agents. Patients and families starting memantine should be counseled that they may actually see a worsening of cognitive/behavioral symptoms before an improvement occurs, but this usually lasts only for the first few weeks of therapy.9 Nonpharmacologic interventions are also important in coping with AD and include environmental modifications, psychosocial interventions, and caregiver respite.10
Dr. Ivey is a clinical pharmacist with the Medication Management Program for Older Adults at the University of North Carolina School of Pharmacy.
1. Hebert LE, Scherr PA, Bienias JL, Bennett DA, Evans DA. Alzheimer disease in the US population: prevalence estimates using the 2000 census. Arch Neurol. 2003;60:1119-1122.
2. Brookmeyer R, Gray S, Kawas C. Projections of Alzheimer's disease in the United States and the public health impact of delaying disease onset. Am J Public Health. 1998;88:1337-1342.
3. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333-1341.
4. Rogers SL, Friedhoff LT. The efficacy and safety of donepezil in patients with Alzheimer's disease. Dementia. 1996;7:293-303.
5. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I. Memantine treatment in patients with moderate to severe Alzheimer disease already receiving Donepezil. JAMA. 2004;291:317-324.
6. Aricept Package Insert, Prescribing Information. Available at : www.aricept.com. Accessed October 30, 2006.
7. Razadyne ER Package Insert, Prescribing Information. Available at: www.razadyneer.com. Accessed October 30, 2006.
8. Exelon Package Insert, Prescribing Information. Available at : www.exelon.com. Accessed October 30, 2006.
9. Namenda Package Insert, Prescribing Information. Available at: www.namenda.com. Accessed October 30, 2006.
10. Aupperle PM. Navigating patients and caregivers through the course of Alzheimer's disease. J Clin Psychiatry. 2006;67(suppl 3):8-14.