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The cost-effectiveness of treatment for Alzheimer disease has been questioned. But until the next generation of therapeutics arrives, cholinesterase inhibitors and memantine will probably remain essential components of therapy for cognition and function.
Special Report: Neuropsychiatry
Alzheimer disease (AD) is an acquired neurodegenerative disease that causes persistent and progressively worse dementia. The cognitive deficits of AD include disturbances of language (aphasia); calculation (dyscalculia); visuospatial integrity; motor programming (apraxia); recognition (agnosia); and planning, organization, and problem solving (executive dysfunction). The clinical presentation of AD progresses through 3 stages of severity: mild, moderate, and severe (Table 1).
Neuropsychiatric symptoms associated with dementia, and particularly with AD, have been noted in more than 80% of patients.1 Lyketsos and colleagues2 reported findings from a population study of 5092 community residents (representing 90% of the elderly population of Cache County, Utah). A number of neuropsychiatric disturbances (apathy, irritability, anxiety, delusions, elation, and disinhibition) were reported with similar severity at all stages of dementia.
In contrast, agitation, aggression, and aberrant motor behavior were more common in the later stages of AD. Depression and hallucinations were slightly more prevalent in moderately severe dementia than in mildly severe dementia. Results of this and similar analyses suggest that frank psychotic symptoms are more common in advanced stages of dementia. Generally, patients with AD manifest diminished awareness of their disability (anosagnosia).
DISEASE PROGRESSIONMild stage
In mild AD, the earliest stage of illness, the affected patient appears remarkably forgetful; the patient has a tendency to forget conversations and recent events and will repetitively ask the same questions about planned appointments or activities. Patients are noted to misplace items more easily and to search for them, expressing great frustration in the process.
In its earliest clinical stages, AD also leads to a subtle impairment in expressive language. The patient increasingly pauses to find words, and spontaneous discourse has a vague, rambling quality. These are signs of anomia, a loss of the ability to readily access words (especially nouns and verbs) when conversing or writing.
At this initial stage of the clinical presentation, there will be evidence that the patient is not quite as well organized as in the past. The ability to plan and organize work, personal finances, and other instrumental activities becomes increasingly impaired and requires supervision and assistance. For example, it may appear to others that the patient has an unusual degree of difficulty in learning how to use a new appliance in the home. Often, afflicted patients will begin to show some difficulty in navigational ability. There is an increasing risk of getting lost while driving or finding one’s way in a crowded area, such as a shopping mall.
In mild AD, the neuropsychiatric alterations noted in affected patients are generally subtle and variable in impact. Most commonly, patients seem apathetic: they have less drive and motivation to engage in recreational and other activities. Families will often note that the patient seems content to sit quietly for uncharacteristically long periods. In some patients, emotional display becomes coarser, more intense, and more labile. Some patients are prone to depressive symptoms, anxiety, and irritability. Generally, these symptoms are intermittent and mild.
When AD progresses into the moderate stage of illness, usually about 3 to 5 years after onset of the earliest symptoms, the patient has significantly impaired memory ability and cannot recall much of what has recently occurred. He or she fails to recognize familiar environments or people. Visuospatial confusion is demonstrated by the patient’s substantial misjudging of directionality and distances; driving is no longer safe.
Language disability is marked by increasing difficulty in finding words and in ability to express ideas; inappropriate words (paraphasic errors) are substituted for those that would better convey meaning. In addition, the patient’s ability to comprehend conversation and to read and write is increasingly impaired.
The patient has great difficulty in organizing tasks, and evidence of apraxia and agnosia emerges. As a result, it becomes more difficult for patients to independently attend to grooming, hygiene, and toileting, and to recognize and use eating and writing utensils and household appliances effectively. In moderate AD, the patient becomes substantially dependent on caregivers. This stage of illness also tends to progress more rapidly than the mild stage.
It is generally in the moderate stage of illness that patients with AD exhibit more severe and frequent neuropsychiatric symptoms. Apathy may persist and worsen, and increasing restlessness, as well as verbal and physical agitation, may emerge. Patients may express delusional beliefs of a persecutory nature (eg, theft, abandonment, infidelity) and harbor concerns that their home is not where they live.
It is not unusual for a patient with AD to insist that he leave his home in order to “go home.” This home often refers to where the patient was raised, the patient having forgotten that his or her parents are long since deceased.
Patients may be verbally and physically abusive to those around them. There may be yelling, screaming, and physical aggression directed toward caregivers who attempt to assist, redirect, or comfort the patient. Many patients display purposeless and repetitive motor behaviors, including fidgeting, rearranging household and personal items, and restless searching and pacing.
When patients enter the more severe stages of illness, usually about 7 to 9 years after symptom onset, communication with those afflicted becomes very difficult for caregivers. Aphasia reaches a level so severe that the patient can no longer express ideas clearly and has great impairment in understanding the conversation or directives of other people. The patient’s language output is restricted to barely intelligible repetitive utterances. Ultimately, mutism results and meaningful verbal interaction with the patient is extremely difficult.
The patient wholly depends on others for self-care and all other activities to tests. For donepezil and rivastigmine, larger doses were associated with larger symptomatic cognitive effects as assessed by the Alzheimer’s Disease Assessment Scale Cognitive Subscale, a commonly used outcome measure. Clinical global improvement was shown to be superior for each drug over placebo.
The optimal duration of treatment with cholinesterase inhibitors is uncertain. Most blinded trials have been conducted for 6 months; however, trials lasting 1 year have shown sustained effi-cacy.5,6 In addition, longer-term studies with donepezil suggest that patients continue to derive modest benefit from treatment for 2 to 3 years.7
TREATMENT OF COGNITIVE SYMPTOMS
Cholinesterase inhibitors are standard, modestly effective therapy for mild to moderate AD based on accumulated evidence from several pivotal large-scale trials involving all agents presently available within the class (donepezil [Aricept], rivastigmine [Exelon], and galantamine [Reminyl, Razadyne]).3 Despite the postulated differences in mechanisms of action of the cholinesterase inhibitors, Ritchie and colleagues4 demonstrated similar degrees of efficacy for the 3 agents. They conducted a meta-analysis of randomized trials assessing efficacy and safety and conducted regression analyses to compare the effect of dosage on clinical outcomes and completion rates.
Compared with placebo, all 3 drugs showed beneficial effects on cognitive tests. For donepezil and rivastigmine, larger doses were associated with larger symptomatic cognitive effects as assessed by the Alzheimer's Disease Assessment Scale Cognitive Subscale, a commonly used outcome measure. Clinical global improvement was shown to be superior for each drug over placebo.
The optimal duration of treatment with cholinesterase inhibitors is uncertain. Most blinded trials have been conducted for 6 months; however, trials lasting 1 year have shown sustained efficacy.5,6 In addition, longer-term studies with donepezil suggest that patients continue to derive modest benefit from treatment for 2 to 3 years.7
As a class, cholinesterase inhibitors are generally well tolerated. The most common adverse effects include nausea, vomiting, diarrhea, loss of appetite, weight loss, muscle cramps, and insomnia. Administering these medications with a meal helps reduce the risk of side effects. Cholinesterase inhibitors are contraindicated in patients with cardiac conduction abnormalities, such as left bundle-branch block and sick sinus syndrome, as well as gastric ulcer disease, in which bleeding has occurred.
Memantine (Namenda), an N-methyl D-aspartate receptor noncompetitive antagonist, was approved by the FDA for the treatment of moderate to severe AD. Reisberg and colleagues8 reported a beneficial effect of memantine treatment on cognitive and functional measures. As measured by the Severe Impairment Battery, cognition was stable for the first 12 weeks of therapy in the memantine-treated patients, who, at end point, had significantly less impairment than did the placebo-treated patients. Memantine also delayed decline in functional ability compared with placebo.
In a double-blind combination study, moderately to severely impaired patients with AD were randomized to receive donepezil plus placebo (monotherapy) or donepezil plus memantine.9 Compared with donepezil monotherapy, combination therapy with donepezil and memantine resulted in modest cognitive improvement, reduced decline in activities of daily living, and a reduced frequency of neuropsychiatric symptoms.
Winblad and Poritis10 reported on a 12-week trial of memantine monotherapy in institutionalized patients with severe AD or vascular dementia (Mini- Mental State Examination score, less than 10). Memantine led to improvement in global outcomes as well as in functioning and behavior.
Adverse effects with memantine are infrequent but can include headache, sedation, fatigue, constipation, increased confusion, irritability, and agitation.
The cost-effectiveness of AD treatments has been questioned. In the United Kingdom, the National Institute for Clinical Excellence has proposed the withdrawal of cholinesterase inhibitors and memantine from their National Health Service.11 They suggested that there is insufficient evidence that the agents have measurable effects on quality of life and extension of time to admission to nursing home care. Until the next generation of therapeutics arrives, however, cholinesterase inhibitors and memantine will probably remain essential components of AD therapy for cognition and function (Table 2).
Dr Reichman is professor of psychiatry and neurology at the University of Medicine and Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School, Piscataway, NJ. He reports that he is a consultant with the speaker's bureaus at AstraZeneca, Forest Laboratories, Janssen, Novartis, Ortho- McNeil, and Pfizer.Dr Shah is clinical assistant professor of psychiatry at UMDNJ-Robert Wood Johnson Medical School. She reports that she has no conflicts to report concerning the subject matter of this article.
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