Pharmacologic Strategies For The Treatment Of Alzheimer's Disease
W. Nathan Rawls, PharmD*
It has been nearly a decade since the first drug to treat Alzheimer's disease (AD) became available. Since then, we have had 4 other treatments approved by the US Food and Drug Administration (FDA), although 1 of these treatments is essentially never used because of its potential hepatotoxicity. The drugs have shown benefit and acceptable tolerability in several large randomized, controlled trials and they are indicated for mild-to-moderate (cholinesterase inhibitors) and moderate-to-severe (memantine) AD. These drugs are increasingly being used. Donepezil is listed in the top 100 brand-name drugs prescribed in 2004, with a 15% increase from 2003.1 However, many questions remain about the appropriate treatment approaches for AD.
Clinicians who prescribe these drugs are faced with questions and concerns from patients, such as "Why isn't my wife/mother/husband/father getting better? These drugs don't seem to work." These issues arise because of poor understanding of the disease process and the expected outcomes. Patients are taking control of their own healthcare and trying more alternative therapies in the hopes of delaying or even reversing the disease—alternative therapies that are not subject to the same rigorous control and oversight as FDA-approved drugs.
The first monograph in our 3-part series on AD focused on setting the scene for pharmacists—the burden of disease, the pathophysiologic processes, and the diagnosis of AD. In Part 2, we focus on treatment of AD from several different vantage points: evidence-based medicine to support the use of cholinesterase inhibitors and the N-methyl-D-aspartate antagonist and new studies on their combination, alternative therapies including nutraceuticals and herbal treatments, and the pharmacologic treatment of neuropsychiatric and behavioral symptoms.
Gary M. Levin, PharmD, BCPP, FCCP, reviews the evidence to support the 4 drugs currently in use (donepezil, galantamine, memantine, and rivastigmine), in addition to more recent data on the long-term effects of these drugs. He also reviews the clinical practice guidelines on treating AD from several medical professional organizations. He relates the drugs' mechanisms of action to the pathophysiologic processes of AD, and provides useful information on dosing and titration. He also discusses the current findings on some of the more controversial treatments, such as vitamin E, statins, and non-steroidal anti-inflammatory drugs.
Complicating the treatment issues in AD are the neuropsychiatric and behavioral manifestations, which are some of the most difficult aspects of the disease to treat and are often the most upsetting to caregivers and families. Frequently, these symptoms are the impetus for hospitalization or permanent placement in a nursing home. Jeanne Jackson-Siegal, MD, reviews the evidence regarding pharmacologic treatment approaches to the neuropsychiatric and behavioral symptoms of AD, including the controversies surrounding the use of antipsychotic drugs. Depression is a common comorbidity of AD; it can be masked by or can mask other neuropsychiatric symptoms because they share some common features. Dr Jackson-Siegal also reviews the current treatment approaches to depression in patients with AD. In Part 3 of this series, she will discuss the use of nonpharmacologic approaches to these symptoms and how they can be used optimally.
Manju Beier, PharmD, FASCP, continues this discussion of drug treatment for AD symptoms by reviewing the limited but very recent studies on combination treatments for AD. She also discusses the other more experimental approaches, including nutraceuticals (dietary supplements) and herbal treatments, with information on current clinical trials. Patients will likely be taking one of these treatments or have questions about them. Ford et al recently showed that 11.3% of US adults are estimated to consume at least 400 IU of vitamin E per day.2 Given the recent meta-analysis suggesting the increase in all-cause mortality with vitamin E and the flurry of responses to this study questioning the conclusions, even seemingly benign treatments can have important consequences.3
The healthcare community is facing important decisions about pharmacologic treatments for AD. In the United Kingdom, the National Institute for Health and Clinical Excellence (the prescribing watchdog for the United Kingdom's National Health Service) retracted its previous guidelines from 2001, which originally supported the use of galantamine, rivastigmine, donepezil, and memantine for AD.4 In the United States, the American Academy of Neurology guidelines for dementia were last updated in 2001. What will the next version include? The prescription drug benefit for Medicare is due to begin next year. How will the insurance companies who cover drugs for seniors address these issues? All clinicians need to have a thorough understanding of the limitations and benefits of these drugs. AD is not just cognitive decline. It affects the entire patient, and its devastating repercussions extend beyond the patient to the entire family.
1. Drug Topics. Top 200 Brand-Name Drugs by Units, 2004. Available at: http://www.drugtopics.com/drugtopics/article/articleDetail.jsp?id=150068. Accessed August 3, 2005.
2. Ford ES, Ajani UA, Mokdad AH. Brief communication: the prevalence of high intake of vitamin E from the use of supplements among US adults. Ann Intern Med. 2005; 143:116-120.
3. Letters to the editor. High dosage vitamin E supplementation and all-cause mortality. Ann Intern Med. 2005;143:150-158.
4. NICE proposes to withdraw AlzheimerÕs drugs from NHS. BMJ. 2005;330:495.
*Clinical Pharmacy Specialist, Veterans Affairs Medical Center, Professor, Department of Pharmacy, University of Tennessee College of Pharmacy, Memphis, Tennessee.
Address correspondence to: W. Nathan Rawls, PharmD, Clinical Pharmacy Specialist, Veterans Affairs Medical Center, Professor, Department of Pharmacy, University of Tennessee College of Pharmacy, 847 Monroe Avenue, Suite 208, Memphis, TN 38163. E-mail: firstname.lastname@example.org.