Understanding and Managing Behavioral Symptoms in Alzheimer's Disease and Related Dementias: Focus on Rivastigmine

Philippe Robert

Disclosures

Curr Med Res Opin. 2002;18(3) 

In This Article

Summary and Introduction

Behavioural and psychological symptoms of dementia (BPSD) are among the most distressing manifestations of dementia and result in considerable social and economic costs. Practical, non-pharmacological approaches such as environmental and behavioural changes may provide some benefit for patients in managing mild BPSD. In addition, various pharmacological approaches to treatment have been employed, such as neuroleptics and atypical antipsychotics, which differ in neurochemical target and clinical effectiveness. Growing evidence suggests that the neurobiological basis of BPSD in Alzheimer's disease (AD) and related dementias is a loss of cholinergic neurones and a resultant decline in acetylcholine (ACh) in brain regions which regulate behavioural and emotional responses, such as the limbic system. This cholinergic deficit can be partly corrected by inhibiting cholinesterase enzymes (ChEs). Studies of ChE inhibitors have shown positive effects to improve or stabilise existing BPSD and delay the emergence of new behavioural symptoms. In placebo-controlled studies, donepezil has reported efficacy in non-institutionalised moderate to moderately severe patients over a period of 24 weeks, but has failed to demonstrate efficacy in mild to moderate AD and in institutionalised patients with severe disease. Galantamine has been shown to delay the onset of BPSD in mild to moderate AD patients in one placebo-controlled study, and improve BPSD in a similar study of patients with cerebrovascular disease or probable vascular dementia. Studies with rivastigmine have shown efficacy in placebo-controlled studies of mild to moderately severe AD and in patients with Lewy body variant AD. Institutionalised patients with severe disease also show symptomatic benefits in BPSD with rivastigmine, resulting in a reduction in concomitant psychoactive medication use. Symptom complexes responding to ChE inhibitors appear to differ - all agents improve apathy, depression and anxiety, while rivastigmine additionally improves hallucinations and delusions, possibility as a result of dual inhibition of acetylcholinesterase and butyrylcholinesterase. The presence of hallucinations has been shown to predict response to rivastigmine. Accumulating data from studies of ChE inhibitors suggest that early intervention and long-term treatment, in addition to providing cognitive benefits, improves BPSD and offers potential to enhance quality of life. Differences seen between the agents in terms of efficacy in BPSD, tolerability and safety profiles may be the result of differences in neuropharmacological profiles.

Alzheimer's disease (AD) is a neurodegenerative disorder affecting major brain areas including the cortex and limbic system, and is characterised by progressive decline in memory with impairment of at least one other cognitive function. For a correct diagnosis, the disorder must not be limited to a period of delirium, must have been present for at least 6 months, and must not have any other alternative explanation. AD features ongoing deterioration of patients' functioning which results in substantial and long-lasting disability over the approximate 7 to 10 years from diagnosis to eventual death.[1] The clinical symptoms of AD usually appear in patients aged more than 60 years and the incidence of AD increases with advancing age. The incidence of AD is high and, although slightly variable among different ethnic groups and populations, generally affects 3% of people aged 65-74 years, 19% of those aged 75-84 years, and 47% of those aged 85 years and over.[2] AD is the likely cause of approximately two-thirds of all cases of dementia[3,4] and affects at least 15 million people worldwide.[5,6] The economic costs associated with AD are vast. Data from 1991 estimated costs in the United States alone at $75 billion.[7] These costs include productivity loss from the workforce (patients and caregivers) and direct medical costs associated with the treatment and institutionalisation of patients with AD.[8] As life expectancy increases, so the incidence of AD will continue to rise, with economic costs in the United States predicted to triple by the year 2030.[9]

The progressive degeneration of neurones in the cortex and hippocampus leads to multiple cognitive deficits recognised widely as the hallmark symptoms of AD. However, in addition to impaired cognition, AD is also characterised by behavioural symptoms which have received much less attention than cognitive symptoms in studies of dementia to date. Nevertheless, behavioural disturbances are important manifestations of AD and other forms of dementia, because they are associated with caregiver distress, increase the likelihood of institutionalisation, and may be predictive of more rapid cognitive decline.[10] Both cognitive and behavioural disturbances also lead to impairment in patients' activities of daily living (ADL). Several terms, such as behavioural disturbances and non-cognitive symptoms, have been used to describe these behavioural symptoms in AD. Given the need for a better understanding and description of the origin, diagnosis and treatment of these manifestations in dementia, the International Psychogeriatric Association (IPA) held a consensus development conference on this topic. In their consensus statement,[11] the panel recommended that the term behavioural disturbances be replaced by behavioural and psychological symptoms of dementia (BPSD), which was defined as follows: 'signs and symptoms of disturbed perception, thought content, mood, or behaviour that frequently occur in patients with dementia'.

Today it is no longer adequate to diagnose dementia syndromes without evaluating BPSD. Indeed, the ability of medications to improve behavioural symptoms in AD is now recommended as a primary outcome in clinical trials of new agents.[12,13] The aim of this article is to review current knowledge of BPSD seen in AD and related dementias, and to outline within the current treatment options for this symptom domain the results from clinical trials of cholinesterase (ChE) inhibitors demonstrating efficacy in BPSD.

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