Donepezil no better than placebo to treat behavioural symptoms of Alzheimer's

Oct 4 2007

New research has found that donepezil (known commercially as Aricept) is no more effective than a placebo at tackling the agitation which often accompanies Alzheimer's disease.

The findings, published in the New England Journal of Medicine, result from the CALM-AD trial which was set up by the Medical Research Council to look into the potential use of donepezil, to address the behavioural symptoms associated with Alzheimer's disease. Donepezil is part of a family of drugs called cholinesterase inhibitors which are primarily used to help enhance cognitive function.

A significant proportion of Alzheimer's patients suffer from behavioural disturbances which are particularly distressing for both patients and their caregivers. Amongst the most troubling of these are symptoms grouped under the term ‘agitation' which lead patients to pace, wander, shout or become aggressive. These symptoms are particularly hard to manage, both in the home and in residential care settings and have traditionally been addressed by sedation through the use of tranquilisers.

The team of UK researchers, led by Professor Robert Howard of the Institute of Psychiatry, King's College London, are keen to find effective and acceptable alternatives to the use of tranquillising medication in the treatment of these symptoms. The trial began by comparing the efficacy of risperidone (a major tranquilliser commonly used to treat agitated behaviour in Alzheimer's disease) with donepezil and a placebo in a group of almost 300 Alzheimer patients with severely agitated behaviour. During the course of the trial however, the Committee for the Safety of Medicines issued guidance warning that drugs like risperidone should not be given to Alzheimer's patients because of an increased incidence of stroke seen in patients taking them. The participants in the tranquiliser branch of the trial were immediately taken off the drugs and the trial continued as a comparison of donepezil against placebo.

The researchers used the Cohen-Mansfield Agitation Inventory which assesses the level of agitation by asking those closely observing the patients' behaviour a number of standardised questions. Further tests were carried out looking at other behavioural symptoms and caregiver distress. None of these measures found any difference between the effects of donepezil and placebo. Finally, tests measuring cognitive functions such as memory and attention found that donepezil produced a small but significant improvement in patients. All the patients in the study had severe Alzheimer's disease and their agitated behaviour had been unresponsive to non-pharmacological approaches.

Professor Howard said: “It is becoming increasingly clear that tranquilisers are not an adequate treatment for managing behavioural symptoms in Alzheimer's patients and their use is associated with serious potential side-effects. Sadly, but importantly, our results show that while donepezil may improve memory and attention in some patients it is not effective in the management of these distressing behaviours.”

Professor Howard continued: “The drug treatments that we have for Alzheimer's disease produce reliable but modest improvements in some cognitive symptoms but disappointingly this trial has shown they do not address the behavioural symptoms which often accompany the disease. In many cases of behavioural disturbance other non-drug therapeutic approaches, including training for carers on how to avoid and alleviate symptoms and environmental manipulation should be tried before a drug is prescribed. But when these measures are ineffective, as they were for the patients who entered our trial, we desperately need treatments that work. Improving cognition in Alzheimer's patients is important but there are other often neglected features of the disease where research to provide effective and safe treatments is a huge priority.”