Elsevier

The Lancet

Volume 356, Issue 9247, 16 December 2000, Pages 2031-2036
The Lancet

Articles
Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study

https://doi.org/10.1016/S0140-6736(00)03399-7Get rights and content

Summary

Background

Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia.

Methods

A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis.

Findings

Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable.

Interpretation

Rivastigmine 6–12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.

Introduction

Dementia with Lewy bodies has been recognised during the past decade as a common form of dementia in the elderly, accounting for 15–25% of dementia presentations.1, 2 Fluctuating cognitive impairment and attention deficits are usually accompanied by recurrent visual hallucinations and parkinsonism.3 Delusions, depressed mood, sleep disturbance, and auditory hallucinations are common neuropsychiatric features of Lewy-body dementia. This large patient group poses a considerable therapeutic challenge since neuroleptic medication, the mainstay of management of psychosis and behavioural problems in most other disorders, can provoke severe, irreversible, and often fatal sensitivity reactions in this type of dementia.4 A two-fold to threefold increased mortality associated with neuroleptic sensitivity reactions in dementia with Lewy bodies has been shown by necropsy studies to be at least in part mediated via acute blockade of postsynaptic dopamine D2 receptors in the striatum.5 Clinicopathological correlative studies in Lewy-body dementia have also shown extensive deficits in cholinergic neurotransmission.6 Neocortical cholinergic activity (assessed by choline acetyltransferase) is more severely depleted in dementia with Lewy bodies than in Alzheimer's disease, a deficit correlated with the presence of visual hallucinations and global severity of cognitive impairment. Postsynaptic muscarinic receptors are better preserved and more functionally intact in Lewy-body-type dementia than in Alzheimer's disease, partly because of the absence of neocortical neurofibrillary tangle deposition. Therefore, drugs enhancing central cholinergic function offer a rationally based therapeutic approach for Lewy-body dementia,7 cognitive and hallucinatory symptoms being the anticipated targets.8 Preliminary findings from open studies with cholinesterase inhibitors lend support to this possibility,9, 10, 11 as do reports of patients diagnosed clinically with Alzheimer's disease, but responding well to cholinesterase inhibitor treatments, only to be diagnosed with Lewy-body dementia at necropsy.12, 13

Our objective was to examine the efficacy, tolerability, and safety of rivastigmine, given twice daily, at doses up to 12 mg per day, over 20 weeks, in patients with probable Lewy-body dementia. Rivastigmine is a cholinesterase inhibitor of the carbamate type and is symptomatically effective and safe in patients with mild to moderately-severe Alzheimer's disease at a dose of 6–12 mg daily.14, 15

Section snippets

Study population

We enrolled male and female patients who: had a clinical diagnosis of probable Lewy-body dementia;3 had mild to moderately-severe dementia as defined by a mini-mental state examination (MMSE)16 score over nine (no upper limit); gave written informed consent; had contact on at least 5 out of 7 days per week with a responsible caregiver; and were proficient in the language in which psychometric tests were provided. Exclusion criteria included: severe extrapyramidal symptoms—ie, a Hoehn and Yahr17

Results

120 patients were randomised to receive either rivastigmine or placebo. Their baseline demographic and background characteristics are described in detail elsewhere21 and summarised in table 1. The two treatment groups (59 patients rivastigmine, 61 placebo) were closely similar in age, sex, and MMSE scores (table 1). Most patients in both treatment groups (90, 75%) had one, or more, coexistent medical condition. The most common medical disorders were musculoskeletal (34, 28%), cardiovascular

Discussion

In our study, rivastigmine at daily doses of 6–12 mg produced significant and clinically relevant behavioural effects in Lewy-body dementia. Patients given rivastigmine were less apathetic and anxious, and had fewer delusions and hallucinations than those on placebo. In some patients improvements were substantial. Objective measures of cognitive functioning, especially attention and memory, also showed striking improvement. Effects were symptomatic and reversed on drug withdrawal. Rivastigmine

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