Alzheimer disease.

Only a few years ago, the diagnosis of Alzheimer disease (AD) was often avoided by busy clinicians and met with despair by patients and their families. Therapeutic nihilism was the norm, and for good reason as there was no proven medication to help treat the symptoms of the illness. Today, however, we have two different classes of accepted treatments for AD and five specific Food and Drug Association (FDA)-approved medications from which physicians may choose. Furthermore, there are multiple trials underway of other novel approaches that may prove even more effective. Yet, if you ask these same busy clinicians if we are better off today, the answer might at best be only moderately positive. What is the problem?

In this issue of the Southern Medical Journal, Potyk reviews much of the available evidence for the current FDA-approved medications in a comprehensive fashion. (1) This review points out that these current drugs, while more effective than placebo comparisons, do not reverse the illness. Despite alleviating symptoms, there is little evidence that the drugs actually slow the overall progression of the illness. (2,3) Although symptomatic benefits are indeed real, clinicians generally perceive the benefits to be small in comparison to the overall devastation of the illness.

Potyk also addresses the issue of prevention in his review. To put this discussion in perspective, if there are currently 4 million Americans with AD, then there are probably some 8 million children of Alzheimer patients who have reason to worry about their increased risk of developing the disease during their lifetime. It is that population of Americans who might be most interested in preventative drugs for AD. Potyk discusses the possible use of hormonal replacement, statins, nonsteroidal anti-inflammatory drugs and anti-oxidants for prevention. Although Potyk's definitively negative conclusion about hormonal therapy may well be debated, (4) his enthusiasm, tempered by caution about the need for further prospective research with the other agents is well warranted. The key point here is that agents used for prevention might not be effective for disease treatment nor vice versa.

So where does this leave the busy clinician? The therapeutic effects of the current medications are marginally positive and the benefits of preventative medications are still quite speculative. In some respects, the mood of therapeutic nihilism continues in the clinic, and practitioners often then turn to the same nonpharmacologic approaches that have been the mainstay of Alzheimer support for decades. In their review of "Complementary and Integrative Approaches to Dementia," Sierpina and colleagues restate the limitations of pharmacologic approaches and emphasize the possible benefits of a wide range of alternatives, including relaxation therapy, biofeedback, psychoeducational approaches, and creative expression. (5) Unfortunately, the authors of this review are unnecessarily negative about the benefits of medication therapy and overly optimistic about the limited data with nonpharmacologic approaches.

The critical issue is not whether one general approach is better than another in the treatment of AD but whether they might be additive therapeutically. Clearly, Sierpina and colleagues are correct when pointing out that there is no single "silver bullet" from the pharmacological arsenal. Until a safe and effective preventative treatment is discovered in prospective clinical trials, combinations of both medical and nonpharmacological therapies should be the standard. The question is when and how each therapy will benefit the overall treatment of an individual patient. This kind of scholarly proof is only achieved through clinical trials building upon the standard of the day. For instance, if cholinesterase inhibitors are the current standard of treatment, then trials of a nonpharmacologic intervention should be done with the steady background of optimal cholinesterase treatment. Ideally, there would also be an active placebo comparator in the study of a complementary treatment. All too often this is not the case, and more controlled, randomized clinical trials are desperately needed in this area of research.

In summary, the question is not whether traditional pharmacologic approaches are better or more important than complementary and integrative approaches but how they should be used together. To do this properly, we must be careful in choosing our research questions, outcome variables, and clinical study designs to optimize the information obtained in any clinical trial. Despite the amazingly fast progress in understanding the pathophysiology of AD and early progress with some symptomatic treatments, there is still much work to be done. Cooperation between pharmacological and nonpharmacological research efforts will help speed that process; the two aforementioned articles highlight some of the interesting directions which may be pursued.

"Every gun that is made, every warship launched, every rocket fired,
signifies in the final sense a theft from those who hunger and are not
fed, those who are cold and are not clothed."
--President Dwight D. Eisenhower

References

1. Potyk D. Treatments for Alzheimer disease. South Med J 2005;98:628-635.

2. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med 1997;24;336:1216-1222.

3. Feldman H, Gauthier S, Hecker J, Vellas B, et al. Efficacy of donepezil on maintenance of activities of daily living in patients with moderate to severe Alzheimer's disease and the effect on caregiver burden. J Am Geriatr Soc 2003;51:737-744.

4. Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 2003;289:2651-2662.

5. Sierpina VS, Sierpina M, Loera JA, et al. Complementary and integrative approaches to dementia. South Med J 2005;98:636-645.

Trey Sunderland, MD

Reprint requests to Trey Sunderland, MD, Chief, Geriatric Psychiatry Branch, National Institute of Mental Health, Clinical Research Center 2-5360, 9000 Rockville Pike, Bethesda, MD 20892. E-mail: [e-mail]