Original Author: Bruce Alexander, Pharm.D, BCPP
Latest Reviser: Mary Brabson, Pharm.D. and Paul Perry, Ph.D.
Creation Date: 1996
Last Revision Date: July 2005
Peer Review Status: Internally Peer Reviewed
This monograph reviews treatments currently approved by the FDA as well as available over-the-counter treatments of DAT. Treatment goals for DAT are to improve or slow the progression of loss of memory and cognition and to maintain independent function.
The DSM-IV defines dementia as: "multiple cognitive deficits, which include memory impairment and at least one of the following: aphasia, apraxia, agnosia or disturbance in executive functioning. Social or occupational function is also impaired." (American Psychiatric Association 2000). Dementia of the Alzheimer's Type (DAT) is the most common form of dementia in older individuals (Burns et al 1999, Mayeux and Sano 1999). The incidence increases steadily from 0.5 percent per year at age 65 to almost 8 percent per year after the age of 85 years. The prevalence increases from 3 percent at age of 65 to 47 percent after the age of 85. By the year 2050, the number of patients diagnosed with DAT is projected to rise to 11.3 million to 16 million (Herbert et al, 2003). The direct and indirect costs for caring for an individual with DAT are approximately $100 billion. The average lifetime cost for caring for an individual is approximately $174,000 (Ernst, 2003). Medicare costs for beneficiaries are expected to increase by 75 percent from $91 billion in 2005 to $160 billion in 2010 (Lewin Group, 2004). The clinical presentation of Alzheimer's dementia is cognitive impairment, behavioral disturbance such as wandering and agitation, psychiatric signs/symptoms including psychosis, depression, and anxiety, and impairment of activities of daily living (ADLs) (Burns et al 1999a). The average rate of major depression, psychosis, and agitation in DAT is approximately 8%, 20%, and 20%, respectively (Mayeux and Sano 1999). These conditions may coexist. Treatment of these associated diagnoses or conditions is discussed in other chapters
OBJECTIVE ASSESSMENT
The FDA recommends that all clinical trials submitted for FDA consideration use the Alzheimer's Disease Assessment Scale, Cognitive Subscale (ADAS-Cog) (Mayeux and Sano 1999). This is an 11-item scale that assesses memory, orientation, attention, reasoning, language, and motor performance. Scores range from 0 (no impairment) to 70 (severe impairment). In placebo-treated DAT patients the scores will decrease by 8-10% annually. Significant differences between drug and placebo scores on the ADAS-Cog may be statistically significant, but not clinically significant depending on the number of patients enrolled in the trials. An improvement of 7 points is regarded as being of clinical significance (Burns et al 1999a). Several other tests may be employed in the diagnosis of DAT. These include the Behavioral Pathology in Alzheimer's Disease Rating Scale (BEHAVE-AD) which provides a global rating of non-cognitive symptoms, the Blessed Test assessing ADLs and memory/concentration/orientation, the Cambridge Neuropsychological Test Automated Battery (CANTAB) that consists of thirteen tests of function, attention and memory, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) tests which are used to monitor cognitive decline, the Clock Draw Test which assesses cognitive or visuospatial impairment, the Mini Mental State Exam (MMSE) which is an abbreviated exam for mental status and cognitive function, the Neuropsychiatric Inventory (NPI) which assesses the 12 most common neuropsychiatric disturbances found in dementia and finally the 7 Minute Screen which assesses memory, visuospatial skills and expressive language. It can distinguish between cognitive changes due to the normal aging process and cognitive deficits due to dementia.
STAGING OF DEMENTIA
Progressive dementias are generally staged according to the level of impairment (APA Practice Guidelines 1987). Table 1 describes this classification.
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Table 1. Dementia impairment by stage. |
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Stage |
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Mild |
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Moderate |
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Severe |
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Profound |
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Terminal |
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TREATMENT STRATEGIES Several classes of agents have been investigated for the purposes of restoring cognitive abilities, preventing further decline, and increasing functional status of DAT. Different strategies include the use of anti-inflammatory agents (NSAIDS, glucocorticoids), free radical reduction with antioxidants (Vitamin E, selegiline, gingko biloba), the cholinesterase inhibitors (tacrine, donepezil, galantamine, rivastigmine), and the NMDA receptor antagonist memantine.
Anti-inflammatory Agents
NSAIDs and aspirin inhibit prostaglandin synthesis by decreasing the activity of the enzyme cyclo-oxygenase (COX), that results in decreased formation of prostaglandin precursors. Results of studies in human brain indicate that neuronal up-regulation of COX-2 may contribute to neurodegeneration in DAT. Because of epidemiological data, aspirin and other NSAIDs have been proposed to protect against the development of DAT (APA Practice Guidelines 1997). There has been observed a low rate of DAT in patients with rheumatoid arthritis and several reports with NSAID use suggest a lower rate of DAT in patients on these medications. However, a controlled study has shown that rofecoxib or low-dose naproxen does not slow cognitive decline in patients with mild to moderated DAT (Aisen et al, 2003). The 1-year mean change in ADAS-Cog scores in subjects treated with naproxen 440 mg/d was 5.8 and 5.7 for patients treated with rofecoxib 25 mg/d. These change scores did not differ from the placebo score of 5.7. Adverse events in the treatment group included fatigue, dizziness and hypertension (Aisen et al, 2003). A second study replicated these findings (Thal et al, 2005). In this 4-year study, 725 subjects were treated with rofecoxib 25 mg/d versus 732 placebo-treated patients. There was no difference in ADAS-Cog between groups.
Anti-Oxidants
Vitamin E. Vitamin E limits free-radical formation, oxidative stress, and lipid peroxidation (Mayeux and Sano 1999). In addition, it promotes survival of cultured neurons exposed to beta-amyloid. A two-year trial involving 341 patients treated for 2 years used endpoints of time until institutional placement, loss of the ability to perform basic ADLs, severe dementia, or death (Sano et al 1997). The time until 50% of patients reached at least one of these 4 endpoints for placebo, vitamin E 2000 IU/d, selegiline 10 mg/d, or both drugs was 440 days, 670 days, 655 days, and 581 days, respectively. Vitamin E, selegiline, and the combination were more effective than placebo. There were no significant differences in any of the cognitive assessment scales for any of the treatments. Side effects (e.g., syncope, falls) were more frequent with the combination treatment. The authors concluded that vitamin E or selegiline slow the progression of the disease. The value of vitamin E is questionable. A group of 769 subjects with mild cognitive impairment were treated with vitamin E 2000 IU/d, donepezil 10 mg/d or placebo for 36 months (Petersen et al, 2005). The proportion of patients who eventually developed possible or probable DAT was the same regardless of the treatment. The authors concluded that Vitamin E had no benefit in patients with mild cognitive impairment although donepezil was effective in the first 12 months.
Selegiline. Selegiline is an inhibitor of monoamine oxidase (MAO-B). Its action in DAT is thought to be neuronal protection by decreasing the production of free radicals and by neuronal rescue from cell death. In addition to the Mayeux and Sano study (1999) mentioned above, one additional study suggests that selegiline is a beneficial treatment. (Alafuzoff et al, 2000) A 6-year double-blind follow-up study contrasted selegeline 10 mg/d to placebo in the treatment of 80 patients diagnosed with DAT. Selegiline treated patients had higher endpoint MMSE scores than those patients treated with placebo. However, when the brain tissue was autopsied in the 17 subjects who died during the follow-up period it was found that selegiline had no influence on the brain lesions (plaques, tangles and beta-A4 load) attributed to DAT.
Ginkgo Biloba. Derived from the leaves of trees in the southern and eastern US, southern France, China and Korea, ginkgo biloba has been marketed to enhance mental focus and improve memory and concentration. Two randomized controlled trials are available to evaluate its' ability to improve memory. A 52-week, randomized controlled trial of 309 patients diagnosed with mild to severe DAT or vascular dementia contrasted the effectiveness of ginkgo 120 mg/d to placebo (Le Bars et al 1997). The ginkgo treated group had an ADAS-Cog score 1.4 points better than the placebo group. No differences were observed in the number of patients reporting adverse events or in the incidence and severity of these events. The ginkgo stabilized a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. A 6-week trial among 230 healthy patients with MMSE greater than 26 found that ginkgo 120 mg/d like placebo provided no measurable benefit in memory or related cognitive function to adults with healthy cognitive function. (Solomon et al 2002).
Cholinergic Agents.
Early trials with the acetylcholine precursors (ie. choline, lecithin) failed because they did not increase central cholinergic activity (Mayeux and Sano 1999, APA Practice Guidelines 1997). Also, postsynaptic agonists were unacceptable because of adverse effects. Anticholinesterases (ie. cholinesterase inhibitors) increase cholinergic synaptic transmission by inhibiting acetylcholinesterase in the synaptic cleft. These agents are classified as reversible or pseudo-irreversible and by their selectivity for different cholinesterase enzymes. Only four agents are currently available in the US. These include physostigmine (reversible, nonselective), tacrine (reversible, nonselective), donepezil (reversible, selective), and galantamine (reversible, selective).
Physostigmine and Tacrine. Physostigmine is not widely used because of short half-life requiring q 2 hr dosing, plus a 57 to 70% rate of nausea and vomiting (Mayeux and Sano 1999). Tacrine was marketed in 1993. The drug requires qid dosing and 55% of patients with mild to moderated DAT dropped out of the studies because of adverse effects (primarily, elevation in hepatic enzymes). Both of these drugs produced on the average a 4 to 6 % advantage on the ADAS-Cog score compared to placebo in greater than 6 month duration studies.
Donepezil. Donepezil (Ariceptª) was approved in 1996 and has the advantage of once daily dosing (Mayeux and Sano 1999). Of the available treatments for DAT, donepezil has been the most frequently studied. In two studies with patients rated as having mild to moderate DAT, donepezil produced on average a 4-6% decrease versus placebo on cognitive and global change scales (Rogers et al 1998, Burns et al 1999b). The most frequent side effects were GI-related and insomnia occurred in 14% of patients. Another study reported similar results (Filip and Kolibas 1999). This study reported that a normal Clock Drawing Test of the MMSE predicted a better response to selegiline than donepezil. Another study using a retrospective method with double blind controlled data reported that donepezil produced significant behavioral improvement in 41% of patients (Mega et al 1999). Significant improvement compared to placebo was seen in disinhibition, irritability, anxiety, agitation, and delusions. A long-term follow-up study was assessed the safety and efficacy of donepezil among patients diagnosed with mild to moderately severe DAT. They concluded that donepezil was effective and safe for up to 144 weeks (Doody et al 2001). A 24-week trial of donepezil 10 mg/d was contrasted to placebo in the treatment of 290 patients diagnosed with moderate to severe DAT (Feldman et al 2003). Donepezil was shown to decrease caregiver time and lower the level of caregiver stress by slowing the decline of ADLs in patients with moderate to severe AD. Finally, donepezil 10 mg/d for 24 weeks was shown to improve global, cognitive function and behavioral measures in 209 patients diagnosed with moderate to severe DAT (MMSE scores of 5-12) (Feldman et al, 2005).
Rivastigmine. Rivastigmine (Exelonª) was approved for marketing in 2000 for the treatment of AD (Jann 2000). In two randomized trials involving 1424 patients rivastigmine improved scores on neuropsychological tests and measures of behavior in about 25% to 30% of patients (Rosler et al 1999, Corey-Bloom et al 1998). Although the improvements were greater than placebo, the clinical gains were judged as modest. The MMSE did not change significantly with treatment. About 20% of patients were unable to tolerate 6 to 12 mg/d because of cholinergic adverse effects (ie, nausea, vomiting, diarrhea). The drug does not appear to be involved in drug interactions and can be dosed once daily. There have been no direct comparison studies to tacrine or donepezil.
Galantamine. In a randomized controlled trial, 285 patients diagnosed with mild to moderate probable DAT were treated with galantamine 18, 24 or 36 mg/day versus placebo for 3 months (Wilkinson and Murray 2001). Patients treated with the 24 mg/d dose had better outcomes on ADAS-cog than compared with placebo. The treatment difference at this dose was 3 points on the intent-to-treat analysis. Side effects similar to other cholinomimetic agents were well tolerated at 18 and 24 mg per day. Galantamine (Razadyne) was recently renamed Reminyl by the manufacturer. The change occurred voluntarily following results from two studies involving a total of 2,000 people in which 13 people died while taking Reminyl compared to 1 death in the placebo group.
Memantine. Memantine (Namenda) is a NMDA glutamine receptor antagonist that is reserved for moderate to severe DAT and blocks the effect of high levels of glutamate that can lead to neuronal dysfunction (Danysz et al, 2000). In a study of 252 patients randomized to memantine 20 mg/d or placebo for 28 weeks, the memantine group was three times more likely to remain ADL function independent than the placebo group. The authors concluded from this result that memantine delays transition to dependent ADL status (Rive et al 2004). A second 28-week study, compared memantine to placebo to determine the effects of memantine on resource utilization and costs in DAT patients (Anders et al, 2003). In this randomized controlled trial, 252 patients received memantine, and 166 patients received placebo. Caregiver time was less in the memantine group as well as a later institutionalization and decreased direct non-medical costs. Due to the cost of the medication, the memantine group showed higher direct medical costs. In patients being treated for moderate to severe DAT with donepezil, cognition, ADLs, global outcome, and behavior were improved with the addition of memantine. While generally well tolerated, side effects reported in the study include confusion (7.9%) and headache (6.4%) (Tariot, 2004).
CONCLUSIONS
The utility of NSAIDs in the prevention of DAT has not been shown. Of the anti-oxidants, only selegeline has been shown to delay the development of DAT, but it is difficult to determine if a delay of 20 to 30 weeks is significant for a disease that lasts 10 years. Gingko biloba has been shown to be efficacious in one study but a replication study found it no more effective than placebo. Donepezil is the preferred cholinergic agent because of its balance of efficacy and side effects. However, it is only a palliative treatment as it slows but does not reverse the progression of the disease compared to placebo. Treatment of DAT can begin at any time after the diagnosis (Mayeux and Sano, 1999, Burns et al 1999a). Only memantine and donepezil have been shown to be effective in moderate to severe DAT. There is no data to suggest their utility in nursing home patients. Only donepezil has been shown to be effective for long-term use. All treatments for DAT should be continued for 6 months and the treatment re-assessed based on pre-treatment agreed outcome measures.
The family and/or caregiver should be involved in decisions to use medication and be given a realistic picture of expected treatment outcomes (Burns et al 1999a). It is possible that partial drug response may lead to problems with the patients, such as their desire to drive again due to improved memory and concentration. The family should also be told that the patient may worsen with drug discontinuation.
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