Donepezil (Aricept) Equals Placebo at Calming Agitation of Alzheimer's

LONDON, Oct. 4 -- For treating agitation in Alzheimer's disease, the cholinesterase inhibitor donepezil (Aricept) was no better than placebo, found a multicenter study.

After a 12-week trial, Alzheimer's patients with clinically significant agitation given 10 mg of donepezil daily had no significant difference in agitation symptoms compared with patients taking placebo, reported Robert J. Howard, M.R.C.Psych., of Kings College London, and colleagues.

"Although previous trials have indicated that cholinesterase-inhibitor therapy results in modest but significant improvement in the overall severity of neuropsychiatric symptoms in patients with mild levels of behavioral disturbance, this may be explained by improvements in symptoms other than agitation," the investigators wrote in the Oct. 4 issue of the New England Journal of Medicine.

But the results of the CALM-AD (Cholinesterase Inhibitor and Atypical Neuroleptic in the Management of Agitation in Alzheimer's Disease) trial might have been skewed toward failure by the trial design, because the patients had already failed a four-week course of psychosocial therapy, commented Kristine Yaffe, M.D., of the University of California San Francisco.

"The rationale for providing this treatment was that first-line therapy for neuropsychiatric symptoms should be nonpharmacologic," she wrote in an accompanying editorial. "Although this trial design makes good sense and reflects appropriate clinical practice, it may have led to the selection of patients most resistant to any type of treatment or those with the most severe symptoms."

The trial originally consisted of three arms, with patients randomly assigned to receive placebo, donepezil at 10 mg daily, or the atypical antipsychotic risperidone (Risperdal), but enrollment was suspended after the United Kingdom Committee for Safety of Medicines recommended that neither risperidone nor olanzapine (Zyprexa) should be used for the treatment of behavioral symptoms in dementia.

In the redesigned two-arm trial, the investigators randomly assigned 272 patients with Alzheimer's disease who had clinically significant agitation and no response to a four-week psychosocial treatment program to receive either10 mg of donepezil daily (128 patients) or placebo (131 patients) for 12 weeks.

Clinically significant agitation was defined as a score of 39 or higher on the Cohen-Mansfield Agitation Inventory, a scale that runs from 29 to 203, with higher scores indicating greater degrees of agitation.

The main study endpoint was a change in the Cohen-Mansfield Agitation Inventory score at 12 weeks. Secondary measures included change in scores on the Neuropsychiatric Inventory, Neuropsychiatric Inventory Caregiver Distress Scale, and the Clinician's Global Impression of Change.

The authors found that there was no significant difference between the effects of donepezil or placebo on change from baseline to 12 weeks in the agitation inventory scores, with an estimated mean difference in change -- the value for donepezil minus the value for placebo -- of ?0.06 (95% confidence interval, ?4.35 to 4.22).

Reductions in the agitation inventory scores of 30% or more occurred in 19.5% of patients on donepezil, and 20.4% of patients on placebo (value of donepezil minus placebo equal ?0.9% , 95% CI, - 11.4 to 9.6).

There were also no significant differences between treatment and placebo groups in scores for either the Neuropsychiatric Inventory, the Europsychiatric Inventory Caregiver Distress Scale, or the Clinician's Global Impression of Change.

"We chose agitation measured by the Cohen-Mansfield Agitation Inventory as the primary outcome because we believe this measure captures those behaviors that are most likely to lead to requests for drug treatment," the investigators wrote. "However, agitation may not represent a homogenous clinical phenomenon, and this is a potential limitation of the trial."

They also noted that the high proportion of women in their study (87% of the placebo group and 82% of the donepezil group), and the 35% of participants who were not randomized because they had a response to the psychosocial treatment limited the generalizability of their findings.

"Taking the evidence in aggregate, agitation does not appear to be an appropriate target for cholinesterase inhibitors," Dr. Yaffe wrote in her editorial, "but when the intention is to treat cognitive impairment in patients with Alzheimer's disease who have mild-to-moderate neuropsychiatric symptoms, it makes sense to initiate treatment with the cholinesterase inhibitor and then to assess for resolution of neuropsychiatric symptoms before considering an additional drug."