ORLANDO, FLA. — Alzheimer's disease patients who don't obtain clear-cut cognitive benefits with donepezil nonetheless often experience significant improvement in behavioral symptoms of the dementia, Ralf Ihl, M.D., said at Wonca 2004, the conference of the World Organization of Family Doctors.
“Behavioral symptoms should be considered an evaluable treatment response in patients with mild to moderate Alzheimer's disease. It may require the need for more than one visit to find out if the outcome is positive,” added Dr. Ihl, a psychiatrist at the University of Düsseldorf (Germany) and president of the European Association of Geriatric Psychiatry.
The often-divergent cognitive and behavioral responses to donepezil therapy were highlighted in the Aricept Washout and Rechallenge (AWARE) study, a Pfizer-sponsored randomized clinical trial conducted in eight European nations and the United States.
AWARE had a three-phase design. In phase I, 1,812 patients with mild to moderate Alzheimer's disease received 24 weeks of open-label donepezil at 10 mg/day. During this phase, 193 patients withdrew from the study due to side effects and various other reasons.
Of the 619 patients who completed phase I, 68.8% showed clear benefit in cognitive symptoms as defined by improvement on the Mini-Mental State Examination (MMSE) or physician global assessment. At that point their participation in the trial was over. Phases II and III of AWARE were reserved for the 31.2% of patients who didn't show cognitive improvement in phase I.
Phase II was a double-blind study in which patients were randomized to receive either donepezil or placebo for 12 weeks. In phase III, everyone who participated in phase II was placed on donepezil for 12 weeks of single-blind therapy.
Behavioral symptoms were assessed using the Neuropsychiatric Inventory (NPI). At the close of the double-blind phase II of AWARE, patients in the donepezil arm showed a significant 2.4-point mean improvement on the NPI, while those assigned to placebo displayed a 0.76-point worsening. The greatest improvement with the cholinesterase inhibitor was seen on the depression/dysphoria section of the NPI.
The improvement in behavioral symptoms seen with donepezil in phase II occurred in patients who simultaneously experienced cognitive decline as well as in those who remained cognitively stable or showed cognitive improvement.
“This shows those parameters are not really parallel during the course of the disease,” the psychiatrist observed.
In phase III, patients who had been on donepezil throughout the AWARE trial showed continued behavioral improvement. However, patients who had been on placebo in phase II showed an attenuated improvement in behavioral symptoms in phase III.
“This shows something that many general practitioners already feel: If you interrupt treatment with a drug against dementia you lose something—and you can't win it back later even if you bring in the drug once more,” Dr. Ihl said.
He noted that in 1906 when Alois Alzheimer first described the disease that bears his name, the physician stressed that the symptoms of the dementia include not only cognitive but also behavioral and functional problems that worsen with time.
“Relevant outcomes in Alzheimer's disease include all these dimensions: functional abilities, behavioral problems, quality of life, resource utilization. They all relate to an increased burden. It's not sufficient to look only at cognitive decline. You also have to look at other symptoms where there could be significant benefit,” he said.