Management of Alzheimer's Disease

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ALZHEIMER'S disease (AD) is a devastating and debilitating neurodegenerative condition and the most common cause of dementia in the elderly. AD may not be a single disease but rather a group of diseases with overlapping pathogenetic mechanisms and clinical manifestations. The condition accounts for an estimated 60-70% of all dementing disorders in the elderly (1). Between 5% and 10% of the population aged 65 years and older, and up to 50% of those older than 85 years of age, are estimated to suffer from AD (2). One hundred thousand deaths per year are attributed to AD in the United States. In the last 50 years, AD has grown from relative obscurity to becoming a defining characteristic of industrialized society. In 1950, at the most 200,000 people in the United States suffered from the ailment. The total stands at 4 million today (3). By 2050, barring a cure, the number of U.S. sufferers is expected to reach 16 million, out of a total of 80 million sufferers worldwide (4).


George T. Grossberg and Abhilash K. Desai. Management of Alzheimer's Disease. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 58:M331-M353 (2003)


Despite consensus on both clinical (5) and neuropathologic (6) definitions of AD, only limited information is known about its etiology and pathogenesis. It is probably caused by several mechanisms that include both genetic and environmental influences (7). The disease manifests as a relentless decline in a broad range of intellectual and functional abilities, followed eventually by death. In addition, as many as 90% of people with AD demonstrate clinically significant behavioral and psychological symptoms at some point in the course of the illness, causing severe emotional suffering. Caring for patients with AD imposes an immense burden on caregivers (8).

Although most patients with AD develop the disease after the age of 65, 5-10% develop the disease at a younger age (early-onset AD). Less than 10% of patients with AD, almost all being early-onset AD, have a familial AD with an autosomal dominant pattern of inheritance. Abnormal genes on chromosomes 21, 14, and 1 appear to account for the vast majority of cases of the early-onset familial AD (9-11). All these genes are almost fully penetrant.

There are 3 stages of AD -- mild, moderate, and severe -- with cognitive and functional decline stretching over 5-8 years on an average (range 2-20 years) (Table 1) (12). A recent study indicates that people with AD often die within about 3 years of diagnosis, especially those above the age of 85 -- a far grimmer prognosis than was previously thought to exist (13). Without treatment, the initial, mild stage usually lasts 2-3 years, during which time patients show short-term memory impairment, often accompanied by symptoms of anxiety and depression. During the moderate stage these symptoms appear to abate, as neuropsychiatric manifestations such as visual hallucinations, delusions, and reversal of sleep patterns emerge. The severe and final stage is characterized by motor signs such as motor rigidity and prominent cognitive decline. Cognitive and functional decline tend to be linear throughout the 3 stages of the disease, whereas caregiver burden is high in severe AD, since at this point patients require almost total care; the physical care burden is the greatest, although the neuropsychiatric care burden can also be considerable.


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Table 1. Measures of Global and Cognitive Dysfunction Associated With the 3 Stages of Alzheimer's Disease.

Stage:

Mild
-- Duration 2-3 years
-- GDS 3-4
-- MMSE 26-18
-- GA Independent living

Moderate
-- Duration 2 years
-- GDS 5
-- MMSE 17-10
-- GA Supervision required

Severe
-- Duration 2-3 years
-- GDS 6-7
-- MMSE 9-0
-- GA Total dependence

GDS = Global Deterioration Scale score: Scale measures progressive need for assistance in daily activities (e.g., choosing clothes, dressing); scores range from 1-2 (normal) through 6-7 (severe dysfunction (219).

MMSE = Mini-Mental State Exam: This 22-item scale measures cognitive function; scores range from 30 (excellent function) to 0 (severe dysfunction) (220).

GA = Blobal Autonomy

Note: Reprinted with permission of Dr. S. Gauthier and Can Med Assoc J. 2002;166 (Reference 12).
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MANAGEMENT OF AD

Although the focus of many physicians is the management of AD with cholinesterase inhibitors (ChEI), it is crucial that physicians develop a global management strategy for their patients with AD and their caregivers. Global management includes early accurate diagnosis and providing counseling and pharmacological treatment to the patient and the family/caregiver (Table 2). The patient and family must agree with the physician on the treatment ultimately selected for use; this decision must include duration and cost considerations. Both the patient's premorbid functioning and potential impact on their quality of life must be taken into account when making any treatment decisions for AD patients. A thorough evaluation of comorbid medical and psychiatric disorders and a review of current medications (including discontinuation of unnecessary or harmful medications) are important. As over-the-counter products are popular, physicians are encouraged to ask about their use and to provide appropriate counsel regarding their safety and efficacy. During the evaluation phase, emphasis must be placed on establishing a good rapport with the patients and their families. Regularly scheduled visits, every 1-2 months initially and then every 3 months, for health maintenance and routine patient assessment will assist in maximizing independence and functioning and will minimize behavioral disturbances associated with the progression of the disease. Families with early-onset familial AD may be encouraged to enroll in a research database for potential future curative therapies.


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Table 2. Goals of Management of Alzheimer's Disease (AD).

Patient care goals
Educating the patient regarding the disease
Symptomatic treatment with a cholinesterase inhibitor (ChEI)
Reducing excess disability
Addressing safety concerns (driving, firearms, wandering, poisonous substances, etc.)
Addressing ability to make medical and financial decisions and capacity to live independently
Screening for abuse and neglect
Treating medical comorbidity with intensity appropriate to the stage of the disease and patient/family wishes
Treating psychiatric comorbidity (depression, psychosis, agitation) with nonpharmacological and, if necessary, pharmacological interventions
Addressing end-of-life-issues
Counseling regarding research options
Family care goals
Increasing effectiveness of care and coping strategies
Increasing satisfaction with the family member's preferred level of involvement -- often, no matter how much an individual is doing for his or her family member with AD, he or she harbors feelings that it is not enough
Decreasing negative consequences on the family
Minimizing family conflicts
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Naming the Disease

The management of AD begins with naming the disease and evaluating its severity. The clinical diagnosis of AD can be accurate 90% of the time. Recent data indicates that AD can be accurately diagnosed even in very mildly impaired individuals (14). A definitive diagnosis of AD still can be made only by histopathologic examination of brain tissue after the patient's death (15). Early and accurate diagnosis affords the patient, family, and physician the time to plan the best way to manage the disease. If diagnosis is made in the early stages of AD, the patient can assume a significant role in planning financial, legal, and care issues as well as housing arrangements for the future. At the time of diagnosis, physicians need to reinforce with caregivers that the condition is a brain disorder, and they need to clear up any misconceptions that the family may have.

Role of the Primary Care Physician

The primary care physician will manage a growing number of persons with AD and their family members or other caregivers upon whom these patients depend. In addition to the diagnostic and pharmacological treatment components of managing AD, the physician will be called upon to assist with the behavioral, social, economic, legal, and living-environment problems facing the patient and her or his family. A team approach to managing these complex problems of AD is a practical and effective management strategy. In addition to nurses and physician assistants, the team may include those with expertise in neurology, geriatric psychiatry, social work, clinical psychology, and elder law. The neurologist assists in the differential diagnosis of patients with atypical dementia presentation and in the management of later stage neurologic features of AD, such as seizures. The geriatric psychiatrist assists in the differential diagnosis of complex cases and in the recognition and psychopharmacologic management of behavioral problems such as agitation, psychosis, and depression. The social worker assists in maintaining the integrity of the patient's family unit and in identifying and mobilizing community care resources and may provide psychotherapy for patients and caregivers. The clinical psychologist assists in the diagnosis of early-stage or questionable dementia and provides expertise in behavioral approaches to such problems as depression. The elder law attorney assists in addressing issues such as guardianship and health-care financial planning. Experts from other disciplines such as pharmacy, nutrition, physical therapy, and occupational therapy can also make important contributions to management. For patients with early-onset familial AD, referral to a geneticist or a genetic counselor for the whole family and the patient is recommended.

Educating the Patient and Caregiver

During the workup and in disclosing the diagnosis to the patient and the family, the clinician begins to educate about AD. This discussion should include a frank, honest, balanced view of what is known about the disease process and available treatment options. Education regarding the recognition of current symptoms and the symptoms likely to occur with progression of the disease will assist in formulating plans for safety and health maintenance. Additional sources of education should be provided. These may include material written for the lay person, such as The 36-Hour Day (16) and Forget Me Not (17). The 3 "R's" -- repeat, reassure, and redirect -- can help caregivers reduce escalating behaviors and limit the need for pharmacologic management. Caregivers should be counseled to help patients with AD maintain social and intellectual activities as tolerated, especially important family events.

Referrals to local and national groups, such as the Alzheimer's Association, that are dedicated to the education and support of patients with AD is strongly recommended. Information about agencies such as the Administration on Aging (202-619-1006), the Alzheimer's Association (800-272-3900, www.alz.org), the Alzheimer Research Forum (www.alzforum.org), and the Alzheimer's Disease Education and Referral Center (800-438-4380, www.alzheimers.org) should be provided. An additional resource may be the American Bar Association Commission on Legal Problems of the Elderly (202-662-8690). Other community services, such as the local chapters of the Agency on Aging, Meals on Wheels, and organizations providing transportation, may all be important as a means of reducing the burden of caregiving. The physician is the critical conduit for providing this information to the caregiver.

Genetic Testing

Testing for the apolipoprotein E-4 (APOE-4) gene, one form of a gene on chromosome 19 that is more common in individuals with AD than in age-matched individuals without dementia, is not currently recommended for use in diagnosis because it is found in many undemented elderly and is not found in many patients with AD (18,19). Empirical data on the benefits and potential harm of genetic susceptibility testing with APOE-4 are currently being collected and studied in the multicenter REVEAL study (Risk Evaluation and Education for Alzheimer's Disease) (20). Patients with early-onset familial AD should be referred to Alzheimer Disease Research Centers for counseling regarding the potential benefits of genetic testing. An impersonal relationship or an encounter created solely for the purpose of risk assessment would seem more vulnerable to miscommunication than would an encounter discussing risk assessment that is embedded in a long-term clinical relationship (20).

Caring for the Caregiver

Caring for the caregiver is an essential element of managing the patient with AD. The majority of patients with AD are cared for by family members or other caregivers in their own homes. They frequently continue to devote a substantial amount of time to caring for a patient after admission to a nursing home. Caregivers are responsible for administering medication prescribed by the physician. The burden of caregiving exacts a heavy toll: it is estimated that about half of all caregivers of people with dementia suffer severe emotional distress, and dementia caregivers have significantly higher rates of depression, physical illness, and other health-related problems (21,22). Almost 90% of caregivers interviewed in one study reported fatigue, anger, and depression directly linked to caring for a demented family member (23). Fatigue is probably the most underestimated reaction. Caregiving is also associated with a greater use of sedative hypnotics and a higher mortality rate among caregivers. Caregivers must be warned of the dangers of emotionally, physically, and financially depleting themselves, and regular assessments must be made to screen for psychiatric disorders in the caregivers. Spouses of patients with AD should be also screened for a dementing illness if, during the patient's evaluation, the physician learns about cognitive impairment in the spouse. Caregivers often do not recognize that their guilty feelings lead them to make unrealistic demands. It also is not uncommon for spouses or children to feel that they would be betraying their relatives by sending them to a nursing home.

Many caregivers are reluctant to ask for help. It is important that health care providers ask the caregivers if they need assistance and validate their feelings. Clinicians must be prepared to help the caregivers deal with anger, denial, anxiety, guilt, grief, and clinical depression as they adjust to the progression of the disease. The grief and adjustment process for a caregiver is complex and cyclical, potentially reactivated by the additional impairments at each new stage of the illness. Family and caregiver interventions will help not only the caregivers but also the patients with AD by preventing premature institutionalization (24,25). Educational program, training program, support, and respite services directed toward caregivers of dementia patients may improve their coping skills and reduce stress (26-29).

Reducing Excess Disability/Functional Impairment

Many factors contribute to functional impairment in patients with AD. They include social issues, cultural expectations, environmental factors, sensory deficits (hearing and vision), pain, coexisting disease states (e.g., over- or undercorrection of hypothyroidism, vitamin B12 deficiency, etc.), fear of falling, and lack of motivation. Treatment of medical comorbidity can improve function (30) and can be important in delaying the progression of frailty (31). For patients who need them, the value of new eyeglasses or a hearing aid cannot be overemphasized. Such devices facilitate patients' understanding of and participation in the choices surrounding care at the end of their lives. Addressing these issues can greatly improve AD patients' functional and even cognitive abilities. In addition, nursing care and care by caregivers that creates dependency is a significant factor in causing excess functional impairment. Teaching the caregivers (at home as well as in long-term care facilities [LTCFs]) to implement a restorative philosophy of care is recommended. Restorative care focuses on the restoration and/or maintenance of physical function and helps AD patients to compensate for functional impairment so that the highest level of function is obtained.


COUNSELING REGARDING SPECIFIC ISSUES


Should the Patients Be Told of Their Diagnosis?

In sharing the diagnosis of dementia, one needs to consider each patient individually (32). Generally speaking, patients in their early stages need to know the nature and prognosis of their disease once the diagnosis is clear to the treating physician. Physicians must not allow their own discomfort -- or the misguided requests of family members -- to subvert the honesty with which they relate to patients. It is also important to ensure that the patient's ability to comprehend is at its highest possible level. Disclosure may also assist in persuading the patient to accept help and in managing social needs (33). It also enables the issue of driving safety to be addressed. With the development of new drug treatments, disclosure allows patients to consent to participation in clinical trials when they still have the capacity to consent. Currently most research relies on relatives to give proxy consent, although this has been challenged as legally unacceptable (34). This said, there are circumstances in which it may be ill-advised to tell a patient that he/she has AD during the first few visits. For example, if the patient has no support system, there is a potential that such a disclosure may undermine his will to live. In such situations, it may be prudent to first assist the patient in establishing support networks and relevant services and then sensitively disclose the diagnosis.

In the late stages of disease the truth may neither benefit nor harm the patient (33). Of course, there exists a greater dilemma in the cases in which some patient understanding remains. With sensitivity, flexibility, and discretion, such bad news may still be delivered. Disclosure of diagnosis should not be a one-office-visit event and must be seen as an ongoing, dynamic process and a fundamental part of the care of a patient with dementia.

Discussion of Future Financial, Health Care, and End-of-Life Issues

Physicians should help both the family and patient to establish medical and legal advance directives for patients with AD and should recommend updating the patient's will early in the course of treatment (35). Open discussions regarding role and responsibility changes within the family system should be encouraged. Assignment of health care proxy, durable power of attorney, and discussion of end-of-life issues, including living wills, should be addressed while the patient is competent to make informed decisions regarding these concerns. It is important to introduce the topic of advance directives sooner rather than later. The unpredictability of serious events such as hip fracture, pneumonia, etc., drive home the point that the discussion should take place before the crisis occurs. Discussions about advance planning do not have to be lengthy or conclusive. But the topic should be an agenda item in encounters with patients with dementia, much like nutrition and safety are.

Safety Issues

Clinicians should counsel the caregivers regarding various safety issues in the home. Caregivers need to be told when the patient will start needing 24-hour care and supervision.

Driving.-- Many elderly patients with AD may continue to drive despite having impaired abilities (36-38). Physicians often fail to identify signs of impaired mental performance in their older patients, further compounding this issue. A history of getting lost, misjudging distances, inappropriate speed, missing signs or signals, moving violations, motor vehicular accidents or near misses, passenger panic, etc., should be documented (39,40). A substantial proportion of even mildly demented people are not safe drivers when directly observed. A substantial proportion of mildly demented people can pass performance tests. For patients with very mild AD, formal, serial performance evaluations are recommended. Patients with more advanced AD should be recommended to discontinue driving. All patients with AD should be systematically evaluated regarding their driving abilities.

Presence of firearms.-- Many elderly in the United States have firearms in their households, most of which are stored loaded (41). Each patient and his or her family/caregiver must be specifically asked about access to firearms. The physician must advocate for the safe storage or removal of these firearms. Any firearms in the patient's house should be disabled in order to prevent accidental gunshot wounds or deaths.

Wandering.-- Families should be warned of the hazards of wandering. Supervised walks and using door locks or electronic guards to prevent wandering are recommended. Registration with the Safe Return Program through the Alzheimer's Association should be encouraged. Ethical considerations should be kept in mind when using electronic tagging devices in patients with AD who have a tendency to wander (42). When used, particularly in mild AD patients, these devices are often demoralizing and dehumanizing.

Poisonous or harmful substances.-- Families and caregivers need to be counseled to keep such substances out of the reach of patients with AD.

Other safety concerns.-- Families and caregivers should be counseled to modify the place of living in order to reduce objects and hurdles that might increase the risk of falls. Sharp objects should be kept out of the patient's reach, and appliances and power tools should be kept unplugged and out of sight. Smoke alarms should be kept in working order. A home visit for safety assessment and guidance by a social worker may be helpful.

Counseling Regarding Long-Term Care Placement

As many as 90% of patients with AD reportedly become institutionalized before death (43). However, most patients with AD continue to live in the community until family caregivers are no longer able to care for them. Patient characteristics (e.g., high cognitive impairment, one or more dependencies in ADL, difficult behaviors) and caregiver characteristics (e.g., high caregiver burden) are both important determinants of long-term care placement for patients with dementia (44). Planned admissions to a LTCF may be better than unplanned admissions (45). Numerous local, state, and federal agencies monitor nursing homes, but vigilant, assertive family members may be most helpful in assuring quality care. High-quality LTCFs encourage family participation. Before choosing a LTCF, consumers should examine reports of the deficiencies found in state inspections. These can be accessed at the website www.medicare.gov. Family members should also contact their state Department of Health with concerns about general conditions or care in nursing homes; the ombudsman in their local aging department about problems with finances, property, or other consumer concerns; and local police or their aging department's office of protective services with any concerns about abuse.


OTHER IMPORTANT ISSUES


Abuse and Neglect

Patients with AD are certainly at high risk of abuse and neglect (46). Estimates of the prevalence of abuse of older adults suffering from dementia range from 5.4% to 11.9% (46). They far exceed the 1-4% prevalence rates typically cited for all older adults, cognitively intact as well as demented (47). The physician must acknowledge that not only will some family members have conflicts with AD patients, but a small number will actually neglect or abuse their AD relatives. This also applies to nonfamily members or professional caregivers. Physicians must be able to identify the potential for emotional, physical, sexual, and financial abuse or neglect, detect its occurrence, and deal with situations in which abuse is present. Financial abuse by telemarketers and other people (including those on television) who make patients with AD easy victims of solicitation should also be suspected and reported to the state's attorney general office. A prior history of abuse is associated with a greater likelihood of abusiveness once dementia occurs. Malnutrition, noncompliance with medications, bruises, decubitii, poor personal hygiene, and other evidence of trauma are some of the signs that should alert physicians that abuse or neglect may be an issue. Physicians need to learn their state's law on reporting of suspected elder abuse. Interventions such as supportive counseling, individual or family psychotherapy for caregivers, respite or in-home care services for patients, and alternative living situations for all parties concerned may be helpful.

End-of-Life Care

Dementia severity and other patient characteristics are important for informed end-of-life decision making and for assessing effectiveness of interventions in severely demented patients in order to prevent an unfavorable outcome of medical comorbidity, such as pneumonia or hip fracture (48). Patients with advanced dementia commonly develop difficulty eating, often when they become bedridden and dependent in all activities of daily living (49-51). They may resist or be indifferent to food or fail to manage the food bolus properly once it is in the mouth (oral phase dysphagia). In moderately demented patients, prevention of aspiration and weight loss, if possible, may improve mid-term outcome (52). Enteral tube feeding is intended to prevent aspiration pneumonia, to forestall malnutrition and its sequelae, including death by starvation, and to provide comfort. There is no evidence to indicate that tube feeding improves any of these clinically important outcomes, and some data seem to indicate that it does not (53,54). Indeed, tube feeding may increase the risk of aspiration. In addition, the risks of this treatment are substantial. Nasogastric tubes may promote sinus and middle ear infections, and gastrostomy tubes may cause cellulitis, abscesses, necrotizing fasciitis, and myositis. Many patients are put in physical restraints to prevent tube removal. For severely demented patients, the practice of tube feeding should be discouraged on clinical grounds, but this decision needs to be made in the context of the patients' and families' moral and religious belief systems. There are no published studies that compare tube feeding to oral feeding.

It is possible to convert tube feeding to hand feeding and, in some cases, patients may be able to feed themselves again (55). Withdrawing sedatives and psychotropic medications should be considered in AD patients with swallowing problems, because these medications may reduce consciousness and thus predispose the patient to aspiration pneumonia. Improving oral care is recommended to reduce oropharyngeal colonization by pathogens. Inadequate staffing and lack of supervision at mealtime may contribute to weight loss in nursing homes. If fed quickly, AD patients may cough or choke or aspirate. Adequate staffing and allowing patients with AD to take their time to eat is thus very important.

In the presence of dementia, successful cardiopulmonary resuscitation (CPR) is 3 times less likely to succeed, as compared to CPR in patients with metastatic cancer (56). In addition, in the demented population, most cardiac arrests occur in long-term care institutions, not acute-care hospitals. The success rate of CPR is only 1% in demented LTCF residents. The benefits of successful CPR are further diminished because of injuries, such as broken ribs, associated with CPR and because of the need for mechanical ventilation. Families should be counseled about these outcomes and whether the patient and family would like "do not resuscitate" directives instituted. These discussions should ideally occur when the patient is in the early stages of AD and thus can be an active participant.

Antibiotic therapy may be withheld in some frail AD patients who are expected to die soon (such as patients in their severe to terminal stages of AD). Most severely demented AD patients are indeed frail and at high risk of dying from pneumonia or sepsis, in spite of antibiotic treatment (54). Palliative management of symptoms such as pain, dyspnea, etc., in patients with severe to end-stage AD should be similar to that used in patients who are dying from cancer. An agreed-upon, documented goal and treatment approach for all health-care team members is an essential component of end-of-life care for AD patients. Management should involve vigilance to ensure good symptom management, support to families of patients with AD in their end-stages of dementia, communication with other health team members, and objective documentation. Palliative care is an appropriate treatment strategy for the management of patients with advanced AD. Palliative care should never mean that the patient with AD receives less care. Rather, palliative care replaces aggressive intervention, with care oriented toward comfort. Hospice care may be appropriate for patients with AD in the terminal stages of the disease (57).


PHARMACOTHERAPY OF AD


ChEI Therapy

This class of drugs is presently regarded as the standard treatment of AD. Four ChEIs have been approved by the U.S. Food and Drug Administration (FDA) for the treatment of mild to moderate AD. They are tacrine, donepezil, rivastigmine, and galantamine. These compounds increase the concentration of acetylcholine and the duration of its action in synapses by inhibiting the degradation of acetylcholine. These compounds provide symptomatic treatments and may also have disease-modifying effects. They have been shown in several large, multicenter, randomized, double-blind, placebo-controlled trials (of 3-6 months' duration) to improve cognitive function, global outcome, and activities of daily living (58-61). There is also accumulating evidence that ChEIs may improve behavioral and psychological symptoms of AD, such as psychosis and apathy (62). Treatment with ChEIs may also help caregivers by reducing the burden of caregiving (63). The mean effect of drug over placebo represents an improvement in cognition roughly equivalent to stemming 6-12 months of natural decline in untreated patients. There is preliminary evidence from a retrospective return drop-out data indicating that the effects of rivastigmine on cognition may be sustained in rivastigmine-treated patients and indicating that rivastigmine may affect disease progression (64). Evidence with the ChEIs also suggests that the effect is extremely variable, with large improvements in some patients and none in others. At the moment we have no reliable way of distinguishing potential responders from nonresponders. When response occurs, it does so relatively quickly (12 weeks). The only certain way of proceeding is therefore to use a ChEI for at least 12 weeks at the proper dose and to observe the results systematically. The physician should seek evidence of changes in all 3 domains (cognition, ability to perform ADL, and behavior) to determine if the patient has benefited from the ChEI. Group means hide a marked heterogeneity of response, as 40-50% of patients show a definite clinical improvement (>=4 points on the AD assessment scale-cognitive subscale [ADAS-cog], equivalent to stemming half a year or more of natural cognitive decline), whereas 20% show a stronger response (>=7 points on the ADAS-cog, equivalent to stemming a year or more of natural cognitive decline). Responders are maintained close to baseline for 12-18 months on both cognitive and noncognitive measures. No reliable predictors of response have emerged, and in each patient, careful assessment of benefit needs to be undertaken after 2-4 months of treatment.

Tacrine.-- Tacrine was the first ChEI to be approved specifically for the symptomatic treatment of patients with mild to moderate AD. The starting dose for tacrine is 10 mg 4 times daily, and this dose is increased by 40 mg/day no more frequently than every 4 weeks (according to tolerance), to a maximum daily dose of 160 mg (40 mg 4 times daily). Tacrine has been associated with hepatotoxicity (65) and thus requires baseline and multiple follow-up liver enzyme determinations. This along with the need for multiple daily dosing makes it unsuitable as a ChEI of first choice. We recommend that its use be restricted to patients who do not tolerate or respond to ChEIs. Tacrine is extensively metabolized by the liver via the cytochrome P450 1A2 isoenzyme system; therefore, it has the potential to interact with other medications metabolized by this isoenzyme, such as theophylline, fluvoxamine, and cimetidine. Tacrine should be avoided in patients with liver disease.

Donepezil.-- Donepezil was the second ChEI approved by the FDA for symptomatic treatment of mild to moderate AD in the United States. Two placebo-controlled clinical trials of donepezil have been reported in which efficacy was demonstrated for 1 year in mild-to-moderate AD based on cognitive (66) and functional (67) measures. Donepezil is largely metabolized by the liver, although some of the dose is recovered in the urine as unchanged drug (11-17%) (68). It is metabolized by the cytochrome P450 isoenzymes 2D6 and 3A4. Clinically relevant drug interactions with other drugs have not been studied. Interaction with paroxetine (patient developing increased confusion and agitation) has been reported (69). Caution should be exercised in using donepezil in patients with severe hepatic or renal disease. The recommended starting dose is 5 mg daily, which is increased to 10 mg daily after 4-6 weeks. Morning dosing of donepezil may be preferable in some patients who experience nightmares or insomnia. It may be taken without regard to meals unless gastrointestinal side effects occur, in which case it should be taken with meals. Although there is 1 case report of fulminant hepatitis with the concomitant use of donepezil and sertraline (70), laboratory monitoring of liver enzymes is not required.

Rivastigmine.-- This was the third ChEI approved by the FDA for symptomatic treatment of mild to moderate AD in the United States. Rivastigmine should be titrated every 4 weeks, as opposed to every 2 weeks, as recommended when the drug was first made available. Slower titration and taking rivastigmine with a full meal significantly improves tolerability, especially with regard to gastrointestinal side effects. One unique feature of rivastigmine that distinguishes it from other ChEIs is the very low risk of drug interactions in AD patients receiving multiple medications for "real-world" comorbidities (71). This is because the metabolism of rivastigmine occurs primarily via enzymatic cleavage (hydrolysis) by cholinesterases at the site of action and does not require the cytochrome P450 enzyme system. The starting dose is 1.5 mg twice a day with meals (breakfast and supper), and this dose is increased by 3 mg/day, not faster than every 4 weeks (as tolerated), to a therapeutic dose of 6-12 mg/day. The highest tolerated dose is recommended, as there is some evidence that higher doses may provide greater benefits. A more rapid progression of AD while receiving placebo treatment was predictive of a significantly stronger patient response to rivastigmine therapy on various measures (72). Laboratory monitoring is not required.

Galantamine.-- This was the fourth ChEI approved by the FDA for symptomatic treatment of mild to moderate AD in the United States. Metabolism is hepatic via glucuronidation and the cytochrome P450 isoenzymes 2D6 and 3A4; interactions with other drugs that are metabolized through this pathway are therefore possible. Caution should be used in patients with liver disease. The starting dose is 4 mg twice a day, and this dose is increased every 4 weeks. The therapeutic dose is 16-24 mg/day. A 6-month study showed no additional benefit and a higher rate of side effects with a dose of 32 mg/day (73). Laboratory monitoring is not required.

Role of Butyrylcholinesterase and Nicotinic Modulation

Humans have 2 types of cholinesterase: acetyl and butyryl. The physiological role of butyrylcholinesterase is being investigated, but levels of this enzyme have been shown to increase as AD progresses, whereas levels of acetylcholinesterase decrease (74). Both enzymes are found in neuritic plaques, and their inhibition with ChEIs may modify the deposition of beta-amyloid, a key component of the pathophysiology of AD as we currently understand it. The clinical significance of this action, if any, in terms of slowing progression of the disease or better symptomatic efficacy in later stages has yet to be fully established. Of the currently available ChEIs, only tacrine and rivastigmine have the ability to inhibit butyrylcholinesterase. Of the currently available ChEIs, only galantamine has the property of allosteric modulation of the presynaptic nicotinic receptors. The potential significance of this effect is additional increase in cholinergic neurotransmission. Whether this provides any additional clinical benefit over other ChEI has not been proved at the present time.

Which ChEI Should Be the First Choice?

Only direct comparisons between various currently available ChEIs will provide definitive data that can be used to maximize patient outcome. In general, these agents all have similar degrees of efficacy. However, there are some important differences (refer to Table 3). Certain patients may benefit more from one particular agent over the others. For AD patients living alone who do not have close daily supervision over their medications, donepezil may be preferable because of its once-a-day dosing. For patients with AD who also have hepatic disease or who are on numerous other medications metabolized by cytochrome P450 2D6 and 3A4 enzymes, rivastigmine may be preferable because of its lack of cytochrome P450 metabolism. Patients with AD who experience impaired sleep or excessive dreaming with donepezil may benefit more from rivastigmine or galantamine.


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Table 3. Characteristics of Commonly Used Cholinesterase Inhibitors (ChEIs).

1. Elimination half-life (hr)
- Donepezil: 70-80
- Rivastigmine: 0.6-2*
- Galantamine: 7-8
- Clinical Relevance: Easier to switch from drug with shorter half-life

2. Metabolism
- Donepezil: Liver
- Rivastigmine: By AchE
- Galantamine: Liver
- Clinical Relevance: Liver metabolism involves P450 system: potential for drug interaction

3. Protein binding
- Donepezil: 96%
- Rivastigmine: 40%
- Galantamine: 8%
- Clinical Relevance: Potential for interaction with drugs having high protein binding

4. Food interaction
- Donepezil: No
- Rivastigmine: Yes
- Galantamine: No
- Clinical Relevance: Need to take the drug with meals if food interaction

5. Dosing
- Donepezil: Once daily
- Rivastigmine: Twice daily
- Galantamine: Twice daily
- Clinical Relevance: Compliance issues

6. Pricing
- Donepezil: 2 Level
- Rivastigmine: Flat rate
- Galantamine: 3 Level [note: generic became available in 2008]
- Clinical Relevance: Cost implications

7. BuChE inhibition
- Donepezil: No
- Rivastigmine: Yes
- Galantamine: No
- Clinical Relevance: Unknown

8. Nicotinic modulation
- Donepezil: No
- Rivastigmine: No
- Galantamine: Yes
- Clinical Relevance: Unknown

9. Specific AchE subtype inhibition
- Donepezil: No
- Rivastigmine: Yes
- Galantamine: No
- Clinical Relevance: Unknown

10. Titration
- Donepezil: 1 Step
- Rivastigmine: 2-4 Steps
- Galantamine: 2-3 Steps
- Clinical Relevance: Complex titration may influence decisions in busy practices

* Enzyme inhibition significantly outlasts elimination half-life.

Note: BuChE = butyrylcholinesterase; AchE = acetylcholinesterase. Reprinted (with modification) by permission of Dr. R. Bullock and Br J Psychiatr. 2002;180:135-139.
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Switching From One ChEI to Another

There is some preliminary evidence that if a patient does not respond to one ChEI, switching to another may be beneficial (75,76). Switches can also be performed to cope with side effects (75,77). In general it is not difficult to switch from one drug to another among the 3 ChEIs (donepezil, rivastigmine, and galantamine). Combination of ChEI is not recommended. Standard dose escalation using monthly titration is recommended. Preliminary data indicate that for patients experiencing no safety/tolerability problems on a ChEI, another ChEI can be administered the following day with no washout period (78,79). If the patient is experiencing safety/tolerability problems with a ChEI, a washout period of 7 days, or until symptoms resolve, is recommended before switching to another ChEI (78,79). As yet, no guidelines for switching from one ChEI to another have been published.

Importance of Starting ChEI Early

Patients with AD who begin treatment with a ChEI later do not do as well as those who began treatment early (73,80,81). In a 1-year study, in which the double-blind, placebo-controlled phase lasted for 26 weeks, all subjects -- whether started on rivastigmine or placebo -- were switched to open-label rivastigmine and followed for an additional 26 weeks (81). Patients who were initially placed on placebo and later started on rivastigmine seemed to respond to the ChEI and had a significant increase in cognitive function, but then they started to decline. They never caught up to the group that started on rivastigmine initially. Similar findings were seen with galantamine and donepezil (73,80). An open-label extension study found that the group that was started on donepezil (10 mg/day) and continued on this dosage functioned better for 18 to possibly 24 months longer than persons who were initially on placebo and then started on donepezil (10 mg) (80). These findings indicate the importance of starting ChEI as early as possible in AD. Early institution of ChEI may also delay the emergence of neuropsychiatric symptoms in patients with mild to moderate AD, as shown in a 5-month placebo-controlled study with galantamine (82).

More Advanced AD and ChEI Therapy

There is preliminary evidence that the beneficial effects of ChEIs may extend to more advanced (moderate to severe AD) stages and that effects may even be more robust than seen in mild to moderate AD (83). In this 24-week, randomized, double-blind placebo-controlled study, the donepezil group showed significant improvement in the neuropsychiatric inventory (NPI) scores, whereas the placebo group worsened slightly. The donepezil group was better than the placebo group for all individual items in the NPI, with statistically significant differences seen for depression, anxiety, and apathy (83).

Treatment of AD With ChEIs in the Nursing Home Setting

Very little controlled data is available for the potential benefits of ChEIs in patients with AD in the LTCF setting. Donepezil was found to be beneficial in the domain of cognition and overall dementia severity compared to placebo in a 6-month treatment period of AD patients in the nursing home setting (84). Unfortunately, no significant differences were obtained in the noncognitive domains of behavioral disturbances and ADL in this study. An open-label, 52-week study of rivastigmine in nursing home patients with AD demonstrated improvement in many of the behavioral and psychiatric symptoms, such as irritability, anxiety, delusions, hallucinations, disinhibition, aberrant motor activity, nighttime behavior, and appetite (85). In addition, about 40% of patients who were on neuroleptic medications for these symptoms were able to reduce or discontinue these medications over the course of the study. Patients with AD in the nursing home are generally older, exhibit greater severity of dementia, and have more comorbid illness than do AD patients in the community.

Use of ChEIs in Non-Alzheimer's Dementias

ChEIs are approved for use in mild to moderate AD only, and use of these agents to treat other dementing disorders is an off-label use. There is initial evidence from randomized, double-blind, placebo-controlled studies that ChEIs may also benefit cognition, daily functioning and behavioral symptoms in vascular dementia (VaD) and Lewy body disease/dementia (LBD) (86-88). Both of these dementing disorders have been found to have an associated cholinergic deficit. Preliminary data indicates that early and widespread cholinergic losses may help differentiate LBD from AD (89), suggesting that cholinergic replacement therapy may be even more effective in LBD than in AD, especially in mild-stage disease. We recommend a trial of ChEIs for patients with VaD and LBD. Other disorders associated with cholinergic deficit include but are not limited to Parkinson's disease with dementia and Down's syndrome with progressive cognitive decline. These disorders may also benefit from a trial with ChEI, although large controlled studies are lacking. The only double-blind, placebo-controlled 24-week pilot study in patients with Down's syndrome and AD showed that improvement in the donepezil group was not significantly better than improvement with placebo. Surprisingly, noncognitive symptoms showed less improvement than they did in the placebo group (90). The biological basis of these findings is not yet certain. No therapeutic benefit is anticipated in dementia syndromes without a cholinergic deficit, such as frontotemporal dementia or Huntington's dementia. Nonprogressive dementias, such as those secondary to traumatic brain injury or anoxic encephalopathy, may also not respond to ChEIs.

Patient Selection, Management of Adverse Effects, and Therapeutic Outcome

All pivotal studies have investigated patients with mild to moderate AD. How early in the course of AD ChEIs should be initiated and for how long they are of use have not been elucidated fully. Although most studies have been done in patients with mild to moderate AD (Mini-Mental State Exam [MMSE] scores between 10 and 26), clinicians are recommended to consider ChEI even in patients with AD and scores of more than 26 or less than 10. We recommend that patients should continue on these medications until they no longer have meaningful interactions with other individuals, because ChEIs may still help alleviate behavior problems even when cognition is severely impaired. Several factors influence medication prescribing for most older patients with AD, resulting in considerable variability and the need to individualize treatments. Elderly patients often take multiple medications, so the clinician must be aware of potential drug interactions. Patients with symptomatic bradyarrhythmia, active peptic ulcer disease, and acute exacerbation of chronic obstructive pulmonary disease and asthma may experience worsening of their problems because of the mild peripheral cholinergic effects of ChEIs. Generally, ChEIs can be safely instituted once these conditions are stabilized. Adverse effects are similar for all ChEIs and typically are gastrointestinal (nausea, vomiting, diarrhea, anorexia, and weight loss) in nature. They are usually seen during dose escalation. Other adverse effects such as abdominal pain, dizziness, syncope, and headache have been also described but are less common. Adverse effects are usually mild to moderate in severity and resolve spontaneously or after dosage reduction. The frequency of adverse effects dramatically increases when the dose of a ChEI is increased too rapidly (in 1-2 weeks). Their frequency is very low during the maintenance phase. Potential for prolonging the effects of the muscle relaxant succinylcholine, used during anesthesia, exists with all ChEIs but does not seem to be clinically significant, although the anesthetist should be informed of the possibility. We do not recommend discontinuing these drugs a few days prior to surgery because of the risk of cognitive deterioration. If for any reason a ChEI is discontinued for a significant period and need to be reinstituted, it should be done by again starting at the lowest dose and gradually titrating upward to the highest tolerated therapeutic dose. These drugs have not been well studied in patients with severe hepatic or renal impairment. Hence, caution should be exercised when using a ChEI in this patient population.

Dose titration should be as slow as necessary to prevent the development of gastrointestinal or other side effects. The risk of nausea can be reduced by administering the medication on a full stomach, and intermittent antiemetics can be used if necessary. Patients should be titrated up to the highest therapeutic dose they can tolerate (for donepezil it is 10 mg/day, for rivastigmine it is 12 mg/day, and for galantamine it is 24 mg/day). Once therapy with ChEI is begun and the therapeutic dosage reached, patients should be evaluated every 3 months to monitor response to treatment in 3 domains, cognitive, functional, and behavioral. If unacceptable side effects occur at higher doses, the dose should be decreased as long as it is in the therapeutic range. If side effects develop with dose escalation, we recommend going back to the tolerated dose and then increasing the interval of dosage escalation. ChEI should be discontinued if side effects persist at the lowest therapeutic dose, if the patient shows accelerated decline after a 6-month trial, or if a medical condition develops that significantly increases the risk benefit ratio. The lowest therapeutic dose is 5 mg/day for donepezil, 6 mg/day for rivastigmine, and 16 mg/day for galantamine. If patients with AD are not able to tolerate more than donepezil 5 mg/day, rivastigmine 3 mg/day, or galantamine 8 mg/day, another agent should be considered. Patients who have been on one ChEI and failed to benefit (due to intolerable side effects or accelerated decline) should be considered for a trial with another ChEI. Incontinence and increased behavioral disturbances (irritability) have been described with donepezil use and may be seen with other ChEIs as well.

The course of AD tends to be slowly progressive, with a loss of 3-5 points per year on a standard assessment instrument such as the MMSE. Caregivers and patients must have realistic expectations (Table 4); these drugs' effects are modest, and sometimes no symptomatic improvement is noted. In fact, a report of ‘no change’ means that these drugs are helping, because without ChEI treatment, one would have seen a decline in functioning.


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Table 4. Clinical Expectations From Cholinesterase Inhibitor Therapy.

Primary benefits
- Maintain current level of daily functioning or slow the decline in current level of functioning
- Maintain current level of cognition or slow the cognitive decline associated with Alzheimer's disease (AD)
- Decrease emergence of behavioral and psychological disturbances associated with AD

Secondary benefits
- Decrease caregiver burden and distress
- Decrease overall health-care cost
- Delay institutionalization
- Caregiver and physician expectations
- "No change" means cholinesterase therapy is helping
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If a ChEI is stopped, rapid deterioration can occur in some patients. Also, reintroducing the drug after the AD patient has been taken completely off a ChEI may not yield the same benefit. By tapering the dosage slowly, we can detect early those patients who are going to lose function or show cognitive deterioration. If they do, then there exists a good reason not to take them off the drug. Only very early in the disease will the patient be able to self-report improvement or benefit. Many of the patients, by the time they are diagnosed, have already lost insight and are unable to appreciate the benefits of ChEIs.

Other Agents for Treatment of AD

Metrifonate.-- Metrifonate is another ChEI that has been investigated for the treatment of mild to moderate AD. Metrifonate was found to be beneficial in areas of cognition, global functioning, and ADLs, compared to placebo in patients with mild to moderate AD, in a meta-analysis of 4 randomized, double-blind, placebo-controlled trials (91). Unfortunately, development of this agent was halted recently secondary to problems with muscle weakness and respiratory paralysis.

Memantine.-- Memantine, a noncompetitive, highly voltage-dependent NMDA antagonist, has been approved for use in the treatment of dementia in Germany for over 10 years and recently was approved for use in the treatment of AD in the European Union. It has been found to be useful in more advanced (moderate to severe) cases of AD (92). Patients with AD in the United States may import the drug or consider participating in double-blind, placebo-controlled studies currently underway at numerous sites all over the country. The FDA is currently reviewing the data for approval of its use in the United States.

Ginkgo biloba extract.-- Oken and colleagues reviewed the published literature on efficacy of Ginkgo biloba for AD (93). They identified 4 well-designed, randomized, placebo-controlled studies that met their inclusion criteria. They concluded that treatment with Ginkgo biloba extract (120 to 240 mg/day for 3-6 months) had a small but significant effect on objective measures of cognitive function in AD. We need further research to determine whether there is improvement in noncognitive behavioral or ADL functions with Ginkgo biloba extract, since this is critical in evaluating the use of treatment in AD. Also, there is no data regarding the safety of the use of Ginkgo biloba extract along with ChEIs.

Antioxidants (vitamin E and selegiline).-- In a double-blind, randomized, placebo-controlled study (94), fewer participants (58%) in group taking vitamin E (2000 IU/day) and selegiline (5 mg bid) reached 1 of the 4 endpoints (death, institutionalization, loss of 2 out of 3 basic ADL, or severe dementia), compared to 74% with a placebo. However, more participants taking vitamin E suffered a fall compared to patients receiving a placebo. It was not possible to interpret the reported results for specific endpoints (95). There was no difference between the vitamin E group and the selegiline group. There appeared to be no additive benefit to treatment with both agents. The principal concerns with high-dose (2000 IU) vitamin E are gastrointestinal upset and prolonged clotting time, with easy bruisability or bleeding. A lower dose (400 iu bid) of vitamin E is recommended by many experts for patients with AD and may be associated with lowered risk of adverse effects without compromising the beneficial effects. In patients with AD, selegiline leads to small short-term improvement in cognition and activities of daily living. Selegiline does not improve emotional state or global response (96). For patients with AD who can tolerate vitamin E, there is no reason to take selegiline.

Estrogen.-- Clinical trials indicate that oral conjugated equine estrogen is not an effective treatment for AD in postmenopausal women (97,98). Hence, estrogen is not recommended for the treatment of cognitive or functional deficits attributable to AD. Preliminary data indicate that short-term estrogen therapy may safely decrease the frequency and severity of behavioral disturbances of dementia in elderly patients (99,100). Larger randomized, controlled studies are needed to further explore the potential benefits of estrogen in the treatment of behavioral disturbances (aggression, sexual disinhibition) in patients with AD. There is increasing evidence that estrogen may decrease the risk for or delay the onset of AD in postmenopausal women (101,102). However, this has not been universal (103,104), and a number of methodological shortcomings in these studies have been identified (105). These potential benefits have to be weighed against the known risks of estrogen, such as increased risk of thromboembolism and gynecological cancers.



TREATMENT OF BEHAVIORAL AND PSYCHOLOGICAL SYMPTOMS OF AD


The most challenging aspect of AD care is management of behavioral and psychological signs and symptoms of dementia (BPSD) (106,107). BPSD are common, serious problems that affect the quality of life of both patient and caregiver and that frequently result in premature institutionalization. The majority of BPSD in AD are of clinical significance based on their severity and because of co-occurrence of multiple symptoms (108). BPSD are associated with more rapid rates of cognitive and functional decline. BPSD include agitation, aggression, delusions, hallucinations, depression, apathy, sleep disturbances, and sexually inappropriate behaviors (Table 5). These difficulties occur in 90% of patients at some point in the course of the disease and have been described in all dementing illnesses. Many clinical practice guidelines (109,110) have addressed the treatment of these disturbances, noting that even modest improvement in these behaviors can markedly improve quality of life for both patient and caregiver. Practice guidelines frequently recommend starting with behavioral and environmental approaches, followed by a wide variety of pharmacologic interventions, including antipsychotics, antidepressants, and anticonvulsants. For a comprehensive review of management of BPSD in patients with AD, the reader is referred to the review article on recognition and management of behavioral disturbances in dementia by the authors (107).


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Table 5. Common Behavioral Disturbances in Dementia.

Aggression

Verbal
- Screaming
- Cursing
Physical
- Hitting
- Biting
- Kicking
- Scratching
- Grubbing

Nonaggressive behavioral

Verbal
- Repetitive questioning
- Complaining
Physical
- Wandering
- Pacing
- Hoarding
- Rummaging
- Hiding
- Taking other people's belongings
- Voiding in inappropriates places
- Shadowing
- Resistance to care
- Intrusiveness
- Fatigability
- Mannerisms

Affect mood
- Anxiety
- Depressive symptoms
- Apathy
- Irritability
- Anger outbursts

Thought and perception
- Delusions
- Hallucinations
- Illusions
- Misperceptions

Vegetative symptoms
- Sleep disturbances
- Insomnia
- Increased daytime napping
- Sundowning

Sexual
- Hyposexuality
- Hypersexuality
- Sexual disinhibition

Appetite
- Poor food intake
- Hyperphagia
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Figure 1 provides an algorithm for the management of behavioral disturbances in patients with dementia. Before any behavioral symptoms are ascribed to AD, the possibility that the symptom is produced by environmental influences or by intercurrent medical problems needs to be eliminated. Environmental influences that may affect behavior include temperature extremes, excessive noise, and physical restraints. In addition, many medical conditions, including cardiovascular disease, chronic obstructive pulmonary disease, infection, anemia, and metabolic disorders, may produce behavioral symptoms. One of the more common conditions that may elicit behavioral disturbances in patients with AD is unrecognized pain. Because AD individuals frequently are unable to express pain verbally, any patient exhibiting new or increased behavioral symptomatology should be carefully evaluated for the presence of pain.


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Figure 1. An algorithm for the management of behavioral disturbances in patients with Alzheimer's disease (AD)

Behavioral Disturbances:

1) Ensure that patient is not in immediate danger to self or others: may need to use chemical or physical restraints

2) Look for delirium, pain, comorbid medical conditions, medications, environmental factors, and personal needs as potential causes of behavioral disturbances and treat accordingly

3a) Mild-to-moderate behavioral disturbances: Nondrug approaches are primary intervention

3b) Severe behavioral disturbances: Psychotropic drugs may be needed
-- Psychotic symptoms, Sever agitation/aggression: Atypical antipsychotics
-- Depressive symptoms, anxiety: Antidepressants/anxiolytics
-- Manialike symptoms, agitation/aggression: Mood stabilizers or atypical antipsychotics
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After environmental or physical reasons for behavioral symptoms are eliminated, it is essential to determine which psychiatric syndrome of dementia is producing agitation. Treatment of depression, psychotic symptoms, and anxiety symptoms is more effective than treating several individual peripheral symptoms such as insomnia, aggression, weight loss, etc. Psychotropic medications play a critical role in the management of behavioral disturbances of patients with AD. Table 8 lists the principles of using pharmacotherapy to manage behavioral disturbances in patients with dementia. Although improved quality of life for AD patients and caregivers can be achieved in many cases with appropriate pharmacotherapy, there is currently no FDA-approved medication for the treatment of behavioral symptoms of AD. For the treatment of mild behavioral problems, ChEIs are an effective treatment option, although in some patients they may exacerbate BPSD (111).


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Table 8. Principles of Pharmacotherapeutic Management of Behavioral Disturbances in Dementia Patients.

1. Use drugs only when secondary causes (environmental, medical) of behavioral disturbances have been ruled out and nonpharmacologic interventions have failed.

2. Review current medications and consider tapering or discontinuing unnecessary, ineffective, or harmful medications.

3. Consider adverse drug reactions or drug-drug interactions as a potential cause of behavioral disturbances.

4. Target symptoms and their impact on functioning should be documented prior to initiation of drug therapy.

5. If pharmacotherapy is used, start low and go slow and use it in conjunction with nonpharmacologic interventions.

6. Select agents based on target symptoms, side-effect profile, and individual patient characteristics.

7. Give the medication for an adequate time at an adequate dose.

8. Closely monitor for and document side effects and beneficial effects.

9. If found beneficial, continue the medication for a few months. If the patient has been stable for that period, consider decreasing or discontinuing the medication.

10. Educate patient and family regarding the benefits and side effects of medications.
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NONPHARMACOLOGICAL INTERVENTIONS


Nonpharmacological interventions are the key to management of BPSD. The majority of AD patients are calmer and better adjusted when treated with low-tech, nondrug approaches that help to decrease problem behaviors and promote independence (Table 6). The foundation of nonpharmacologic management is recognizing that the person with dementia is no longer able to adapt and that instead the environment must be adapted to the patient's specific needs. Caregivers should be counseled to learn to change what can be changed through information gathering and direct action. They must also train themselves to cope with their reactions to what cannot be changed (and "intrapsychic" tricks or reframing perspectives -- "tomorrow will be better," "my husband is difficult but he could be worse"). Positive outcomes derived from support groups include not only increased knowledge of the illness and services available as well as decreased feelings of isolation but also creative and practical suggestions for dealing with BPSD using nonpharmacological interventions. Adult day services are often an effective method for managing demented patients and postponing the need for institutionalization. Caring for loved ones with AD is psychologically and physically challenging but also provides the family with opportunities for personal growth and deepening of relationships with the patient and other family members. Behavioral disturbances are often provoked through interaction with caregivers. The manner in which caregivers approach the patient with AD is critical, because most episodes of aggressive behavior occur during contact with caregivers. Effective strategies include leaving the patient and returning later or having one caregiver distract the patient while another is providing care. As ADL dependence on others increases, patients are at risk of invalidism, social isolation, lower self-esteem, depression, and a loss of control over their destiny, which may in turn generate a sense of helplessness and hopelessness. Inactivity also increases the risk of pressure sores, falls, loss of range of motion, and muscle wasting. Structured and unstructured activities improve subjective well-being, help maintain function, and decrease BPSD. People with AD are still people, with the same emotional needs as all people. They need to know they are loved and they need to feel good about themselves, to be respected, to have the approval of others who are important to them, to be stimulated in body, mind, and spirit, to feel secure, to be included (not alienated and marginalized), and to be needed. Every effort must be made