Journal of Gerontological Nursing

The Benefits of Cholinesterase Inhibitors: Managing the Behavioral and Neuropsychiatric Symptoms of Alzheimer's Disease

Adrianne Linton, PHD, RN

Abstract

Pharmacological treatment can be helpful to improve cognition, functional ability, and behavior symptoms in older adult with Alzheimer's disease, resulting in reduced caregiver burden, delayed nursing home placement, and reduced health care cost.

Abstract

Pharmacological treatment can be helpful to improve cognition, functional ability, and behavior symptoms in older adult with Alzheimer's disease, resulting in reduced caregiver burden, delayed nursing home placement, and reduced health care cost.

Behavioral symptoms that often occur among individuals with Alzheimer s disease (AD) are a source of increased caregiver burden and may be a factor in moving an individual to a nursing care facility. Pharmacologie and non-pharmacologic approaches to the management of these symptoms are available. Cholinesterase inhibitors (ChEIs), which generally are prescribed to delay the progression of AD symptoms, have the added benefit of improving behavioral symptoms in many individuals with AD. By applying an understanding of drug therapy with AD, the advanced practice nurse (APN) is in an excellent position to stabilize patient function, minimize behavioral symptoms, reduce caregiver burden, and delay placement in a longterm care facility.

* Mr. Schultz walked down the driveway of his home, a wheeled trash container in tow. At the end of the driveway, he hesitated, then proceeded to walk down the street. His wife found him 2 miles away, still pulling the container.

* Mrs. Abrams, who lives with her daughter, no longer attends to her personal hygiene. Her daughter's attempts to shower h er result in screaming and hitting.

* Mr. Garcia lives in an assisted living facility. Other residents have complained that he tries to enter their apartments, insisting that he lives there.

What do these people have in common? They all have AD, manifested by various types of cognitive dysfunction and behavioral symptoms. Such examples are commonly encountered by those who care for individuals affected by AD. This devastating progressive neurologic condition extracts a terrible toll on affected individuals and their caregivers. Another common feature is that each of these individuals might benefit from pharmacologie intervention. This article discusses the incidence and effect of AD, the common cognitive and behavioral symptoms, and pharmacologie management of those symptoms.

Alzheimer's disease is the most common cause of mental deterioration in elderly individuals, accounting for approximately 50% to 60% of all cases of dementia in the population older than 65 (Birks, Grimley-Evans, lakovidou, & Tsolaki, 2002; Francis, Palmer, Snape, & Wilcock, 1999). AD is characterized by memory impairment and cognitive disturbances that significantly impair functioning. Most individuals also are affected by behavioral and neuropsychiatrie symptoms at some point during the course of the disease. These behavioral abnormalities should therefore be regarded as a core feature of AD (Cummings, 2000).

Common behavioral symptoms include changes in personality (e.g., apathy, irritability, disinhibition), mood changes (e.g., depression), psychosis, anxiety, agitation, aberrant motor behavior (e.g., wandering, pacing), and neurovegetative changes (e.g., sleep disturbances, changes in appetite) (Cummings, 2000). Behavioral symptoms have a tendency to become more prominent as AD progresses, and often worsen in the more advanced stages of the disease, correlating with severe cognitive impairment (Cummings, 2000).

The increasing elderly population is predicted to pose a significant burden on both caregivers and the economy during the next 2 to 3 decades (Francis et al., 1999). Currently, approximately 4 million people in the United States have AD (Evans, 1990), and the National Institutes of Health estimates that there will be 8.5 million people with AD in the United States by 2030 (Doody et al., 2001). Dementia rates may be as high as 50% among individuals 85 and older (Hebert et al., 1995). This figure is especially startling when one considers that individuals 85 and older comprise the fasted growing segment of the population in the United States.

The cost of care for individuals with AD increases incrementally with increasing cognitive impairment and with behavioral symptoms. The average annual cost per individual has been reported to be $18,408 (USD) for mild AD, $30,096 for moderate AD, and $36,132 for severe AD (Leon, Cheng, & Neumann, 1998). A comparison of costs between individuals with AD with and without behavioral symptoms revealed that behavioral symptoms increased the formal and informal costs of care as much as $20,172, depending on the severity (Murman et al., 2002). Residential care is responsible for the largest proportion of the direct costs of AD (Cummings, Donohue, & Brooks, 2000).

THE EFFECTS OF BEHAVIORAL SYMPTOMS ON THE CAREGIVER

The stress of providing care, termed caregiver burden, must be considered in the management of an individual with AD (Butcher, Holkup, & Buckwaiter, 2001; Robinson, Adkisson, & Weinrich, 2001; Teel & Carson, 2003). The majority of caregivers outside of nursing facilities are family members who often are untrained, are unpaid, have little prior knowledge of the disease, and therefore, are vulnerable to being overwhelmed by caring for an individual with AD (Burns, 2000).

Symptoms such as personality changes, including antisocial and disinhibited behavior, psychosis, and depression are extremely distressing to family caregivers, and can be extremely challenging to handle in both the home environment and the nursing facility. Behaviors such as wandering and aggression are unpredictable and require continuous monitoring (Burns, 2000). Behavioral symptoms are frequently the ultimate reason for moving an individual to a nursing facility (Cummings, 2000; Liken, 2001; Schur & Whitlatch, 2003; Volicer, Hurley, & Blasi, 2003).

HOW CAN APNS RELIEVE THE BURDENOFAD?

Gerontological APNs are involved in AD management, either independently or as part of a health care team, in various settings, including primary care clinics, long-term care facilities, and private homes. APNs frequently participate in the initial diagnosis of AD, and in planning and implementing appropriate therapies to optimize and stabilize the health and well-being of individuals with AD and their families. Because APNs often have close relationships with individuals with AD and their caregivers, APNs are ideally placed to assess and manage behavioral symptoms in individuals with AD.

In community practice, APNs can help to relieve caregiver burden by providing support and education related to strategies to handle abnormal behavior and generally coping with the burden of AD (see Sidebar on page 6 for factors contributing to caregiver burden). These strategies may not only protect caregiver health, which helps to keep the individual with AD at home longer, but also may improve the individual's quality of life. A meta-analysis of psychosocial interventions for caregivers of individuals with dementia indicated that nursing home admissions were delayed by interventions in four of seven studies (Brodaty, Green, & Koschera, 2003). In nursing facilities, successful management of these symptoms by APNs is likely to improve resident quality of life, minimize disruption and distress to others, and reduce the demand for care on staff.

CURRENTLYAVAILABLE THERAPIESFORTHE TREATMENT OF AD SYMPTOMS

ChEIs are currently the only approved therapies for the treatment of the symptoms of mild to moderate AD. Acetylcholine (ACh) is a neurotransmitter involved in cognition, learning, and memory. The symptoms of AD are caused, in part, by a loss of cholinergic neurons, and a resultant decline in ACh transmission in brain regions, including those that regulate behavioral and emotional responses (Cummings, 2000; Cummings & Back, 1998). ChEIs suppress the enzyme that normally breaks down ACh, causing a rise in ACh levels and an increase in brain activity. Donepezil (Aricept), galantamine (Razadyne), and rivastigmine (Exelon) are all currently approved ChEIs. Tacrine (Cognex) is approved, but its use is limited by unacceptable side effects, notably hepatotoxicity.

In clinical trials of 3 to 6 months, ChEIs have consistently shown significant benefits over placebo in stabilizing cognition and global function in individuals with mild to moderate AD (Doody et al., 2001). Because there is no standardized approach to determining the effect size of ChEIs, various studies report different treatment effects. However, many individuals experience modest improvements on the assessment scales used in clinical trials, which translate to substantial benefits in everyday life.

Because of the progressive nature of AD, decline is inevitable; however, historical and clinical trial data show that individuals who are not treated or receive placebo decline significantly more than those treated with ChEIs. Treatments should therefore be regarded as effective if they are successful in stabilizing or slowing decline in cognition and global function, relative to the natural course of the disease. Following an evidence-based review of dementia management studies, the Quality Standards Subcommittee of the American Academy of Neurology recommended ChEIs for individuals with mild to moderate dementia, concluding that the treatment effects were consistently better than placebo (Doody et al 2001). There currently is growing evidence that ChEIs also have a positive effect on the behavioral symptoms of AD.

MANAGEMENTOF BEHAVIORAL SYMPTOMS IN AD

Management approaches include nonpharmacologic (i.e., interpersonal strategies, environmental manipulation) and pharmacologie approaches with ChEIs, psychotropic agents, or both. Nonpharmacologic methods of treatment can be effective in reducing behavioral disturbances in AD (Galasko, 1998), but if ineffective alone, may be used in tandem with pharmacologie treatment. The combination may allow a reduction in the number or dosage of medications used. Nonpharmacological interventions have been the topic of extensive research deserving of separate coverage. Some basic guidelines derived from the work of researchers including Beck, Heacock, and Mercer (1997); Hall and Buckwalter (1987); Matteson, Linton, Cleary, Barnes, and Lichtenstein (1997); and Teri et al (2003) for preventing or managing behavioral symptoms are listed in die Sidebar on page 7.

ChEIs

Evidence is mounting that ChEIs are effective in reducing behavioral symptoms of AD, in addition to their well-documented benefits on cognition and global function (Desai & Grossberg, 2001; Gauthier et al., 2002; Giacobini 2002; Hogan & Patterson, 2002; Lilienfeld 2002). Because these symptoms are often the most distressing to caregivers, relief of these symptoms may be a major factor influencing initiation of treatment.

In many studies, the effects of ChEIs on behavioral symptoms are assessed using the Neuropsychiatrie Inventory (NPI) (Cummings et al., 1994). The NPI uses information from a caregiver who is familiar with the behavior of the individual with AD to assess the frequency and severity of each behavioral disturbance.

In a study by Matthews, Korbey, Wilkinson, and Rowden (2000), significant improvements in behavior on the NPI scale were seen after 6 months of donepezìl treatment, and these improvements were sustained for 18 months. Donepezil treatment also has been shown to be effective in reducing agitation, with fewer psychotropic medications required after 8 weeks of treatment compared with baseline (Kauf er, Gatt, Pollock, Lopez, & DeKosky, 1998). Less decline in behavior was seen in donepezìltreated individuals compared with placebo at the end of a 1-year doubleblind study (Wmblad et al., 2001).

In a 5-month placebo-controlled trial, galantamine has demonstrated similar effects on behavioral symptoms in individuals with mild to moderate AD. NPI scores in individuals receiving either 16 or 24 mg/day of galantamine were significantly better than those of individuals receiving placebo. Unlike the placebo group, individuals receiving galantamine did not deteriorate relative to baseline (Tariot et al., 2000). Other studies have used a variety of outcome measures to show benefits of galantamine on behavioral symptoms (Giacobini, 2002; Hogan & Patterson, 2002; Lyseng-Wllliamson & PIosker, 2002; Wilkinson, Hock, Farlow, van Baelen, & Schwalen, 2002).

Benefits on behavioral symptoms also have been observed in individuals with mild to moderate AD beyond 6 months with rivastigmine, based on behavior subscales of a global fonction assessment tool rather than the NPI (Corey-Bloom, Anand, & Veach, 1998; Desai & Grossberg, 2001). Initial studies describing the effect of ChEIs on behavior included individuals with mild to moderate AD; however, these individuals have a relatively low prevalence of behavioral symptoms compared with those in more advanced stages of the disease. A 6-month trial with donepezil included individuals with moderate to severe AD and a high prevalence of behavioral disturbances (95%), demonstrating the full benefit of ChEIs on behavioral symptoms (Gauthier et al., 2002). Behavior improved across all items of the NPI compared with placebo, most significantly for apathy, anxiety, and depression or dysphoria, some of the most common behavioral symptoms at the start of the trial. Individuals who were not taking psychoactive medications at baseline demonstrated greater treatment benefits with donepezil. The subset of participants with moderate AD showed significant benefits for apathy, delusions, and aberrant motor behavior (Gauthier et al., 2002).

Studies with both donepezil and rivastigmine in nursing home residents, and with generally more advanced AD, also have shown benefits for behavior. Donepezil treatment produced a significantly beneficial effect for agitation/aggression, which was the most common behavioral symptom at baseline (occurring in 64% of all participants) compared with placebo (Tariot et al., 2001). Preliminary reports of open-label studies with rivastigmine suggest possible benefits on behavior, as assessed using the NPI nursing home scale, and a reduction in the use of psychoactive medications to treat behavioral symptoms (Rosier, 2002). Improvements in delusions, hallucinations, anxiety, agitation, and irritability were noted. These studies demonstrate that the increased prevalence of behavioral symptoms in individuals with moderate to severe AD can be effectively and safely managed with ChEI treatment.

Table

KEY CONCEPTS IN THE NONPHARMACOLOGIC MANAGEMENT OF BEHAVIORAL SYMPTOMS

KEY CONCEPTS IN THE NONPHARMACOLOGIC MANAGEMENT OF BEHAVIORAL SYMPTOMS

Psydiotropic Medications

Psychotropic drugs such as neuroleptics and benzodiazepines are currently often considered first-line therapy for disturbing behavioral symptoms. However, only a modest response to diese treatments is seen in individuals with AD (Cummings, 2000). In addition, some of these drugs can lead to worsening of other symptoms, such as cognitive dysfunction.

Typical antipsychotic drugs such as haloperidol can have side effects such as restlessness, sedation (leading to worsening cognition), and postural hypotension (which may lead to falls) (Cummings, 2000). The newer atypical antipsychotics like risperidone, ziprasidone, quetiapine, and olanzapine have a better safety profile, and are widely used in the management of behavioral symptoms. These medications generally are better tolerated than typical antipsychotics with respect to movement disorders; however, the atypical antipsychotics are associated with somnolence and weight gain (Doody et al, 2001; Lehne, 2004; Street et al., 2002; Tariot & Ismael, 2002). Serious side effects of atypical antipsychotics are relatively uncommon; however, cardiac dysrhythmias may occur (Lehne, 2004). Risperidone also has been associated with an increased risk of stroke in elderly individuals with dementia (Risperdai® [Risperidone], 2003).

Given their potentially serious adverse effects, use of psychotropic medications should be monitored carefully and re-evaluated frequently (American Psychiatric Association, 1997). Many families are uncomfortable with the use of these medications and prefer them to be prescribed only if other interventions are not effective (Burns, 2000).

ADDITIONAL BENEFITS OF ChEI THERAPY ON CAREGIVER TIME

As AD progresses, the amount of care required increases, placing greater demands on the caregiver. The maintenance of functional ability (in relation to activities of daily living [ADL]), and management of behavioral symptoms with ChEIs may delay the need for a high level of care and supervision.

Because caregivers play such an important role in the management of AD, it is essential that they are able to perceive clear benefits of treatments on behavioral symptoms and ADLs, because they are likely to be less concerned with results of cognitive tests than with the individual's daily fonction. These benefits may be seen not necessarily as an improvement in memory, but in effects such as increased activity and conversation, better performance of daily activities, and less confusion or abnormal behavior.

In a study of individuals with moderate to severe AD, caregivers of donepezil-treated individuals reported spending, on average, 52 minutes less per day assisting with ADL than caregivers of those treated with placebo. They also recorded lower scores on a Caregiver Stress Scale (Feldman et al., 2003). Similar benefits on caregiver time have been observed with galantamine. At the end of a 6-month pivotal trial, caregivers of individuals who had received the maximum approved dose of galantamine (24 mg/day) reported spending approximately 40 minutes less per day compared with baseline, and 1 hour less per day compared with placebo, assisting the individual with ADL. In an open-label extension of this trial, the reduced levels of caregiver time were maintained for a further 6 months for those remaining on galantamine 24 mg/day (Borson & Papadopoulos, 2001; Lilienfeld & Parys, 2000).

Table

TABLEDOSING AND ADMINISTRATION OF CHOLINESTERASE INHIBITORS

TABLE

DOSING AND ADMINISTRATION OF CHOLINESTERASE INHIBITORS

ChEI USE MAY DELAY NURSING HOME PLACEMENT

Most family caregivers prefer to care for their family member who has AD at home for as long as possible, and generally are reluctant to place relatives in nursing facilities, despite the increasing demand for care as the disease progresses. A delay to the time when specialized care is required is therefore very important to many family caregivers. Optimal management of behavioral symptoms may enable the individual with AD to remain at home (Brodaty, Green, & Koschera, 2003).

Continuous treatment with donepezil (9 to 12 months) has been shown to be associated with a delay of nearly 2 years in dementia-related nursing facility placement compared with those on limited treatment (Geldmacher, Provenzano, McRae, Mastey, & leni, 2003), keeping individuals with AD in the community for a median time of more than 5 years following treatment initiation. A long-term observational study also indicated that during a 3year follow-up period, 40% of untreated individuals entered nursing facilities compared with only 6% of those taking donepezil (Lopez et al., 2002). Because nursing facility placement is the largest direct cost associated with AD, delaying nursing home placement is likely to greatly reduce the annual cost of care (Clegg et al., 2002; Fillit, Hill, & Futterman, 2002; Getsios, Caro, Caro, & Ishak, 2001; LysengWilliamson & Plosker, 2002; Murman et al., 2002; Wolfson et al., 2002), and should be regarded as an important benefit of treatment with ChEIs.

Financial considerations have been the subject of several studies with differing conclusions (Courtney et al., 2004; Marin et al., 2003; Wimo, 2004). The financial effect of ChEIs was the subject of a review by Khang, Weintraub, and Espinoza (2004). The authors examined evidence of cost savings, which is based only on financial costs, and cost effectiveness, which is based on both direct and indirect costs. Analysis of both perspectives yielded mixed results, in part attributed to variations in quality and generalizability. They particularly cautioned against applying results from studies of community residing individuals to nursing home populations. The authors recommended additional studies of cost effectiveness that include outcomes appropriate to the nursing home setting and a prospective approach to cost considerations (Khang et al., 2004).

TOLERABILITY AND EASE OF USE OF ChEIS

In addition to efficacy, it is important that treatments are well tolerated and easy to use in both the nursing facility and the home environment, particularly because family caregivers are unlikely to have had any formal caregiving training (Burns, 2000). Dosing and administration guidelines for donepezil, galantamine, and rivastigmine are shown in the Table.

Because elderly individuals with AD may be frail and are likely to have significant comorbid illness requiring drug therapy, adverse events and interactions of any drug selected must be considered. The most frequent side effects with ChEIs are gastrointestinal in nature, such as nausea, vomiting, and diarrhea, with nausea occurring most oftea The majority of adverse effects are regarded as mild to moderate in severity. Gastrointestinal disturbances can usually be minimized by starting with low doses and increasing them gradually. A review of donepezil, rivastigmine, and galantamine studies reported adverse effects in up to 17% of participants taking donepezil, up to 50% of those taking rivastigmine, and up to 17% taking galantamine (Doody et al., 2001). Headache, dizziness, fatigue, and insomnia also have been reported. However, several studies have reported discontinuation in up to 25% of participants taking rivastigmine because of side effects including weight loss (Doody et al., 2001) (see Sidebar for cautions when prescribing ChEIs).

CONCLUSIONS

Behavioral symptoms are a core feature of AD, and a significant source of caregiver stress. These symptoms often can be effectively managed. When nonpharmacologic interventions fail, ChEIs, psychotropic medications, or a combination of these may be helpful. These approaches offer benefits for both individuals with AD and their caregivers.

As well as benefits on cognition and functional ability, treatment with ChEIs has led to benefits for a range of behavioral symptoms in individuals with mild, moderate, and more severe AD (including those in nursing facilities). Significant improvements in behavioral symptoms have been reported following donepezil treatment. The benefits on functional ability translate to a reduction in the time spent by caregivers assisting with ADL, and are therefore likely to contribute to a reduction in caregiver burden.

Treatment with donepezil also has been associated with a delay to nursing home placement and reduced health care costs. Keeping individuals with AD in the community for longer should be considered an important benefit of ChEI treatment. ChEIs generally are well tolerated, and have a favorable tolerability profile compared with traditional psychotropic drugs. ChEIs, therefore, are a useful addition to the range of treatments available for improving behavior in individuals with AD.

APNs can help to stabilize the health of individuals with AD and ease caregiver burden by combining their experiences in managing behavioral disturbances with knowledge of currently available effective therapies. APNs should be aware of the value of combining ChEIs with other therapies to optimally manage behavioral symptoms in individuals with AD.

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KEY CONCEPTS IN THE NONPHARMACOLOGIC MANAGEMENT OF BEHAVIORAL SYMPTOMS

TABLE

DOSING AND ADMINISTRATION OF CHOLINESTERASE INHIBITORS

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