Dementia: Update for the Practitioner

Treatment of dementia is a rapidly changing field. We are doing a fairly good job identifying symptomatic treatments, and now our strategies are focused on secondary prevention, treating mild cognitive impairment, and primary prevention.

The mainstay of Alzheimer's disease treatment is a cholinergic approach. We have good evidence that memory and cognitive disturbances result from reduced cholinergic transmission. There is a wide range of evidence showing degeneration of the cholinergic projections in patients with Alzheimer's disease, as well as loss of cholinergic cell bodies and a reduction of the enzymes involved. We also know that anticholinergic drugs often create memory deficits.

Today we can treat Alzheimer's patients with an array of cholinesterase inhibitors. Among these there are some differences in dosing frequency, but very few differences in side effects. Those differences that do exist may have to do with the kinds of studies that were done to assess these agents.

The two domains of efficacy required for approval of these agents are cognitive benefit and the global clinical impression that individuals are improving. In cholinesterase trials, cognitive benefit has been measured primarily through the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-cog), and clinical benefit through the Clinical Global Impression of Change (CGI-C) or the Clinicians Interview-Based Impression of Change (CIBIC).

Tacrine was the first cholinesterase inhibitor to be approved, but it is no longer frequently used because its short half-life required multiple daily dosing, up to four times a day, and systematic checking of liver enzymes at periodic intervals.

The next agent to come along was donepezil, and it has been very popular since its approval in 1996. It has been readily accepted because it can be administered once daily. Two dosage forms have been assessed and shown to be efficacious. Clinical trials have not shown a systematic difference between 5 and 10 milligrams; however, as we come to know more about cholinesterase inhibitors, we believe there may be a benefit to higher doses.

With donepezil, the titration period is relatively short and can be accomplished in four to six weeks. It is significantly longer for other agents. Side effects, including nausea, diarrhea, abdominal discomfort, and some sleep disturbances have been reported, and many of these occur with other agents as well.

There are several studies demonstrating persistent effects of cholinesterase inhibitors over long periods of time. Similar data exist for each of the approved cholinergic agents as well, and we find that efficacy over placebo continues out to at least a year and may even have a benefit for individuals in residential settings.


	Donepezil: One-Year Double-Blind Trial


	The least-squares mean change from baseline in Mini Mental State Examination score for patients treated with Donepezil or with placebo. B. Winblad et al., "A One-Year, Randomized, Placebo-Controlled Study of Donepezil in Patients with Mild to Moderate AD," Neurology 57, no. 3 (August 14, 2001): 48–95.

The next agent to approach the market was rivastigmine. This agent is a nonselective pseudo-irreversible cholinesterase inhibitor that targets both acetylcholinesterase and butyrlcholinesterase, though the clinical relevance for butylcholinesterase is unclear. This drug requires more than once-daily dosing. Efficacy has been shown for several doses from 1 to 12 milligrams, but there is better efficacy at higher doses.


	Effect of Rivastigmine on Cognition


	The ADAS-cog mean change from baseline with rivastigmine therapy or with placebo, showing the effect of rivastigmine on cognition. Courtesy of Dr. Mary Sano. Source of data: J. Corey-Bloom et al. for the ENA 713 B352 Study Group. International Journal of Geriatric Psychopharmacology 1 (1998), 55–65. J. Messina et al., Journal of the College of Psychiatric and Neurologic Pharmacists 2000.

The next agent to approach the market was galantamine, a selective competitive cholinesterase inhibitor that also modulates nicotinic receptors. Again, it is unclear whether this particular action has a clinical effect, but there is some suggestion that it might have an effect on attention.

The target dose for this agent is 16 to 24 milligrams per day, and multiple BID dosing is required. Titration periods are slower than with donepezil. The recommendation is to titrate from 4 milligrams BID to 8 milligrams BID over four weeks, but often a slower titration is more helpful. Side effects of galantamine are comparable to other cholinesterase inhibitors, including nausea, vomiting, anorexia, weight loss, and diarrhea, but there are no hepatotoxic effects or drug interactions.


	Reminyl^® Cognitive Function Over Five Months vs. Placebo


	The mean change from baseline in Mini Mental State Examination score for patients treated with Reminyl (Galantamine hydrobromide) or with placebo over a five-month period. Courtesy of Dr. Mary Sano. Source of data: P. Tariot, W. Parys, P. Kershaw. Poster presented at the 52nd Annual Meeting of the American Academy of Neurology, San Diego, C.A. April 29–May 6, 2000

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