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Starting, Stopping, and Discussing Pharmacologic Treatment of Alzheimer Disease and Other Dementias
The medicine cabinet for dementia-specific drugs is quite bare,1 with only 2 shelves containing 4 Food and Drug Administration (FDA)-approved medications. One shelf contains 3 acetylcholinesterase inhibitors (ACHEIs): donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne). (The fourth drug in this class, the first to receive approval, tacrine [Cognex], was removed from the market in 2012 due to liver toxicity.)2 On the second shelf sits the lonely N-methyl-D-aspartate receptor agonist memantine (Namenda). Another available form of these medications is Namzaric, a combination of donepezil and memantine. With only 4 drugs able to be used for treatment, it is not much of an armamentarium, but it is all we currently have. When to use this limited arsenal and for how long is more art than science, often leaving patients and families to sort out varying opinions of providers based on differing interpretations of the data and personal experience.
Billions of dollars spent in drug research for dementia, and this is all we have, so far, to offer patients and families for pharmacologic treatment. There is still no cure for Alzheimer disease (AD), or any of the other dementias. These medications provide symptomatic treatment but do nothing to alter the underlying disease pathology or progression—a concept that is often hard for families to understand. They are approved for mild to moderate AD and often used off-label for other neurodegenerative dementias.3-5 Since their efficacy may be best when started early in the course of the disease, as recognition of subtle cognitive changes increases, many patients with a clinical diagnosis of mild cognitive impairment are also being prescribed these agents.6
Initiating Pharmacologic Treatment
Once a decision is made to initiate treatment with one of these medications, a frank discussion with patients and families about realistic expectations is necessary. Providers should note that these medications have been developed to decrease symptoms temporarily or slow progression in some people. Communicating this type of information can go a long way toward establishing realistic expectations for prescribed medications. Treatment is clinically beneficial when there is evidence of improvement, stabilization, or a slowing of the rate of decline seen prior to the start of treatment without unacceptable side effects. Too often, patients are started on one of these medications without a frank, initial conversation, or patients/families fail to understand medication use and then seek specialty consultation or second opinions when “the medicine isn’t working.” When patients or their families are later asked what was expected, the response is along the lines of “I expected improvement; their memory isn’t getting better, in fact, it’s worse.”
As with any medication, when a new prescription is initiated, follow-up either by return appointment or telephone should be part of the plan. Regular monitoring of medications in individuals with dementia requires an evaluation of both safety and effectiveness, assessment of cognition, and also of function, behavior, and side effects. Patients and families need to be informed about possible gastrointestinal side effects such as nausea, vomiting, and diarrhea that can occur in up to 20% of patients prescribed ACHEIs.7 Mild nausea can lead to decreased appetite and weight loss that can often go undetected for months if weight is not closely monitored.8 Vivid dreams can also occur with the use of donepezil in some patients when dosed in the evening.9 Failure to recognize this may lead to unnecessary additional medications for sleep, but the proper treatment should be to change the dosing to morning administration or to discontinue the donepezil and try another medication in the class.
The ACHEI drugs were developed to treat AD specifically. However, little research has been done on their use or on the use of memantine in the treatment of other dementias. Acetylcholine levels are low in Lewy Body dementia (LBD), therefore these medications are commonly used in patients with LBD and in Parkinson disease. There is no evidence that ACHEI are of any benefit in frontotemporal dementias.10 Clinicians caring for patients with atypical, non-Alzheimer dementias have no FDA-approved medications specifically for these conditions. Any pharamcologic treatment option offered thus can only be a medication as an “off-label” use.
Discontinuing Medications
The use of prescription medications is at the core of modern medicine and medical training. Extensive time in training is devoted to learning the indications for use, side effects, and efficacy of pharmacologic agents, but little attention is given on when to stop medications. For those of us caring for older adults, deprescribing is as essential a skill as prescribing. We recognize that to “do” may at times require that we “undo.” This does not mean that we stop caring—in dementia care this is especially true.
Stopping the use of these medications can be more problematic than starting. Judging when the benefits of continued use are justified is not easy to assess. Clearly when the harms outweigh the benefits then medication should be stopped. When there are obvious adverse side effects such as vomiting or diarrhea from cholinesterase inhibitors or headaches and dizziness from memantine, then the need to discontinue a medication that is making a patient ill is rather easy. When the signs of potential harm are more subtle, such as gradual weight loss over time or resistance to taking medication by the patient, the discussion of discontinuation of medication can be more challenging and be met with resistance from family members who fear results from stopping the medication.
There is little research and no clear guidelines on the long-term use and efficacy of these drugs. Studies of these medications based on when they were in development in clinical trials only lasted for 6 to 12 months.11 The positive effects of the medications are often difficult to gauge and may not be evident until the medication is discontinued. When the medications are withdrawn, the person may be less active, more confused, have decreased verbal ability, and a decreased ability to participate in activities of daily living.12 There is some evidence that a decline that occurs with discontinuing the medication cannot be reversed by resuming the medication.13 In practice, many providers continue patients on these medications for many years until the late stages of the disease.
Conclusion
Because of the limited number of pharmacologic treatments available, caring for dementia patients requires that providers focus on more than medications, but this does not reduce the number of challenges providers face when deciding whether to start or stop one of these drugs or when trying to communicate effectively with patients and families about treatment and outcome expectations.υ
References
1. Alzheimer’s Association (AA). Medications for memory loss. AA website. https://www.alz.org/alzheimers_disease_standard_prescriptions.asp. Accessed March 19, 2018.
2. Watkins PB, Zimmerman HJ, Knapp MJ, Gracon SI, Lewis KW. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA. 1994;271(13):992-998.
3. Ikeda M, Mori E, Matsuo K, Nakagawa M, Kosaka K. Donepezil for dementia with Lewy Bodies: a randomized, plaebo-controlled,confirmatory phase III trial. Alzheimer’s Res Ther. 2015;7(4). doi:10.1186/s13195-014-0083-0
4. Ellis JM. Cholinesterase inhibitors in the treatment of dementia. J Am Osteopath Assoc. 2005;105(3):145-158.
5. Baskys A, Hous AC. Vascular dementia: pharmacological treatment approaches and perspectives. Clin Interv Aging. 2007;2(3):327-335.
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7. Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24 week, double-blind, placebo controlled trial of donepezil in patients with Alzheimers disease. Donepezl Study Group. Neurology. 1998;50(1):136-151.
8. Cummings JL. Use of cholinesterase inhibitors in clinical practice: evidence-based recommendations. Focus. 2004;2(2):232-252.
9. Jackson S, Ham RJ, Wilkinson D. The safety and tolerability of donepezil in patients with Alzheimers disease. Br J Clin Pharmacol. 2004;58(suppl 1):1-8.
10. Tsai RM, Boxer AL. Treatment of frontotemporal dementia. Curr Treat Options Neurol. 2014;16(11):319.
11. Casey DA, Antimisiaris D, O’Brien J. Drugs for Alzheimer’s disease: are they effective? PT. 2010:35(4):208-211.
12. Hogan DB. Long-term efficacy and toxicity of cholinesterase inhibitors in the treatment of Alzheimer’s disease. Can J Psychiatry. 2014;59(12):618-623.
13. Doody RS, Geldmacher DS, Gordon B, Perdomo CA, Pratt RD; Donepezil Study Group. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer’s disease. Arch Neurol. 2001;58(3):427-433.
