Long-term cholinesterase inhibitor treatment of Alzheimer's disease

Abstract

The most prevalent cause of dementia--Alzheimer's disease--is characterised by an early cholinergic deficit that is in part responsible for the cognitive deficits, especially memory and attention defects, seen with this condition. Three cholinesterase inhibitors (ChEIs), namely donepezil, rivastigmine and galantamine, are widely used for the symptomatic treatment of patients with Alzheimer's disease. Placebo-controlled, randomised clinical trials have shown significant effects of these drugs on global function, cognition, activities of daily living (ADL) and behavioural symptoms in patients with this disorder. These trials have been conducted for up to 12 months and were followed by open-label extension studies. One placebo-controlled, randomised clinical trial followed patients for up to 4 years. Both retrospective and prospective follow-up studies suggest a treatment effect for ChEIs that lasts for up to 5 years. Studies have shown comparable effects for ChEIs in patients with moderate-to-severe Alzheimer's disease or mild Alzheimer's disease. Clinically relevant responses consist not only of improvement over 3-6 months but also stabilisation and possibly slower than expected decline. Lack of overt clinical improvement in one domain (e.g. global function, cognition, ADL or behaviour) does not preclude clinically relevant benefit(s) in other domains. If it is judged that the patient has experienced a treatment effect from ChEI therapy during the first 6 months, it is recommended that treatment be continued for at least 1 year before discontinuation is considered again. On average, patients will return to their pre-treatment status between 9 and 12 months of initiation of treatment. However, this return to pre-treatment level does not mean that the treatment effect has disappeared. At this point in time, the patient may still function better than he or she would have without treatment. Setting a fixed measurement, e.g. a Mini-Mental State Examination score, as a 'when to stop treatment limit' is not clinically rational. The length of treatment should depend on several individual patient factors. The earlier the diagnosis is made and the slower the rate of disease progression, the longer the treatment period will tend to be. Treatment duration must therefore be evaluated on an individual basis, and the patient's status compared with what would have been expected without treatment. If a clinical evaluation is conducted with a view to stopping or switching treatment, it is crucial that all domains are evaluated and that the patient is evaluated at more than one point in time before the decision is made.