Treatment Strategies for the Behavioral Symptoms of Alzheimer's Disease
The impact of behavioral symptoms associated with Alzheimer's disease is substantial. These symptoms contribute to diminished quality of life for patients and caregivers and increase the cost of care in nursing homes. Early recognition of behavioral symptoms and appropriate treatment are important for successful management. Nonpharmacologic strategies remain the cornerstone of the management of Alzheimer's disease–related behavioral symptoms. However, nonpharmacologic strategies may not be effective for problem behaviors, and pharmacologic intervention may be necessary. Relevant articles were identified through various MEDLINE searches with no date restrictions, with an emphasis on recent studies that used cholinesterase inhibitors and memantine. Additional reports of interest were identified from the reference lists of these articles. To facilitate cross-study analyses in the review of cholinesterase inhibitors and memantine, the database search was limited to randomized, placebo-controlled trials that used the Neuropsychiatric Inventory to assess behavioral symptoms of Alzheimer's disease. Overall, evidence from trials of cholinesterase inhibitors and memantine suggests that when these agents are optimized for the various stages of Alzheimer's disease, they can also prevent the emergence of neuropsychiatric symptoms. Although results from the literature are not uniformly positive, cholinesterase inhibitors have been shown to produce significant improvements in behavioral symptoms in patients with both mild-to-moderate and moderate-to-severe Alzheimer's disease. Evidence also indicates that memantine might be of benefit as an adjunct to long-term cholinesterase inhibitor treatment in patients with moderate-to-severe Alzheimer's disease and that memantine monotherapy may have some beneficial effects on behavior in patients with mild-to-moderate disease. Of importance, although no direct comparisons have been performed, these agents seem to have an improved safety and tolerability profile compared with the frequently used antipsychotic drugs. When nonpharmacologic strategies are deemed insufficient to ease problem behaviors in patients with Alzheimer's disease, treatment with cholinesterase inhibitors, alone or in combination with memantine as appropriate for the stage of disease, may be considered as a first-line option in the early pharmacologic management of Alzheimer's disease–related behavioral symptoms.

Alzheimer's disease is a degenerative brain disorder that causes cognitive decline, loss of function, and emergence of behavioral or neuropsychiatric symptoms. It is the most common cause of dementia in the United States, affecting about 4.5 million Americans in 2000, and is most prevalent in the elderly, occurring in 3% of the population aged 65–74 years, 19% of the population aged 75–84 years, and in almost 50% of seniors aged 85 years or older. Alzheimer's disease is particularly common among nursing home residents, with more than half of those aged 65 years or older having Alzheimer's disease or related dementias.

Alzheimer's disease follows a predictable course that usually begins with memory loss. As the disease progresses, cognitive impairment becomes profound and daily functioning skills decline. Although typically thought of as indicative of late-stage disease, behavioral symptoms can appear early in the course of the disease, well before clinical diagnosis. These symptoms can include social withdrawal, depression, paranoia, and mood changes. A study of the natural history of Alzheimer's disease showed that 53% of patients demonstrated symptoms of depression an average of 26 months before diagnosis (Figure 1). As the disease advances, symptoms such as anxiety, irritability, and agitation become more pronounced. Nearly 90% of patients with Alzheimer's disease develop behavioral symptoms during their illness; as many as 40% have symptoms of mild depression, and up to 66% experience anxiety.



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The behavioral aspects of Alzheimer's disease are highly distressing for the patient. Symptoms of agitation (including inappropriate motor activity), apathy, and psychosis (e.g., hallucinations) are common and are exacerbated in the presence of the patient's existing disabilities. Behavioral symptoms further erode independence and engender feelings of fear, anger, and frustration. In a survey of patients with Alzheimer's disease in residential care in the United Kingdom, loss of self-esteem and feelings of fear, bewilderment, and frustration contributed to depression and withdrawal. More distressing symptoms, such as agitation, violence, incontinence, and wandering, often prompt nursing home placement.

Behavioral symptoms are also a major source of stress for the caregiver. Behavioral disturbances have been shown to be a strong predictor of caregiver burden and are associated with increased financial hardship for the caregiver (e.g., loss of income, out-of-pocket expenses for formal health care or excess costs related to the caregivers' health problems). Indeed, caregivers of patients with Alzheimer's disease often consider behavioral and psychiatric symptoms to be the most challenging and distressing aspects of the disease.