Tratamento da Doença de Alzheimer

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Tratamento da Doença de Alzheimer

Mensagem  Renato O em Sab Jan 05, 2013 5:07 pm


CHOLINESTERASE INHIBITORS — Patients with Alzheimer disease (AD) have reduced cerebral production of choline acetyl transferase, which leads to a decrease in acetylcholine synthesis and impaired cortical cholinergic function. Cholinesterase inhibitors increase cholinergic transmission by inhibiting cholinesterase at the synaptic cleft. Four cholinesterase inhibitors, tacrine, donepezil, rivastigmine, and galantamine are currently approved for use in AD by the US Food and Drug Administration (FDA). Tacrine was the first agent approved for use in AD, but it can cause hepatotoxicity and is rarely used [5]. The choice between the other three agents is largely based upon cost, individual patient tolerability, and physician experience, as efficacy appears to be similar.

DonepezilDonepezil has relatively little peripheral anticholinesterase activity and is generally well tolerated. This combined with its once-daily dosing has made it a popular drug in patients with AD. The recommended dose for donepezil is 5 mg per day for 4 weeks, then increasing to 10 mg per day. Donepezil is available in pill form and also as an oral disintegrating tablet. There was no consistent effect noted on patient-related quality of life measures.

In general, prolonged treatment with donepezil appears to be safe and effective.

Donepezil and other cholinesterase inhibitors appear to modestly improve neuropsychiatric symptoms as well.

RivastigmineRivastigmine appears to be beneficial in patients with mild to moderate AD and has been approved for use by the FDA. Its side effect profile is related to cholinergic effects, with significant nausea, vomiting, anorexia, and headaches. It should be given with food to minimize nausea. One case of esophageal rupture due to severe vomiting has been reported; the manufacturer advises slow titration of the drug (eg, initiating therapy at 1.5 mg twice daily with titration every two weeks up to 6 mg twice daily) and, if treatment is interrupted for longer than several days, it should be restarted at the lowest daily dose and then titrated again. While not compared head-to-head with donepezil, its efficacy appears similar, although it may have more gastrointestinal side effects.

One double-blind, placebo-controlled study found that side effects of rivastigmine may be ameliorated and higher daily doses achieved (9.6 versus 8.9 mg), when it is given three times a day, rather than twice daily.

A transdermal patch formulation of rivastigmine has been approved by the FDA. In 1195 patients with AD, a 10 cm2 patch (9.5 mg per 24 hours) appeared to have similar efficacy with significantly less nausea and vomiting compared to the highest oral dose (6 mg twice daily) [25]. The higher dose patch (20 cm2) was associated with greater cognitive improvement compared to the lower dose patch on one of two primary outcome measures (ADAS-cog).

GalantamineGalantamine (Razadyne; previously marketed as Reminyl) appears to be effective in patients with mild to moderate AD. Randomized controlled trials have found that treatment with galantamine (maintenance dose 24 or 32 mg/day) slowed the decline in both cognition and activities of daily living compared with placebo in patients with early AD. Cognitive benefits of galantamine have been sustained for up to 36 months. A secondary analysis of a randomized controlled trial reported that galantamine-treated AD patients had significantly better overall ADL scores than the placebo group at five months regardless of dementia severity.

Gastrointestinal symptoms (nausea, vomiting, diarrhea, anorexia, weight loss) are the most common adverse effects of galantamine. Like rivastigmine, galantamine appears to have similar efficacy to donepezil in patients with AD but may have more gastrointestinal side effects.

The use of galantamine has been associated with increased mortality in patients with MCI. (See "Mild cognitive impairment: Prognosis and treatment", section on 'Acetylcholinesterase inhibitors'.) Increased mortality has not been observed in patients treated for AD, mixed dementia, or vascular dementia.

Advanced disease — Although efficacy of cholinesterase inhibitors for cognitive effects has been established in patients with mild to moderate AD, it has been less certain that patients with advanced AD, including patients in nursing homes, will benefit from therapy.

MEMANTINE — Memantine (Namenda™; Axura™ in Europe) is an N-methyl-D-aspartate (NMDA) receptor antagonist. The mechanism of action of memantine is distinct from that of the cholinergic agents; it appears to be neuroprotective. Glutamate is the principal excitatory amino acid neurotransmitter in cortical and hippocampal neurons. One of the receptors activated by glutamate is the NMDA receptor, which is involved in learning and memory. Excessive NMDA stimulation can be induced by ischemia and lead to excitotoxicity, suggesting that agents that block pathologic stimulation of NMDA receptors may protect against further damage in patients with vascular dementia (VaD). In addition, the physiologic function of the remaining neurons could be restored, resulting in symptomatic improvement.

Memantine has been available internationally and was approved by the US Food and Drug Administration (FDA) in October 2003 for use in patients with moderate to severe AD.

Memantine appears to have modest benefits in patients with moderate to severe AD:

There is little, if any, evidence that patients with milder AD benefit from memantine. A systematic review reported the results of pooled data from three unpublished studies of memantine in mild to moderate AD. Intention to treat analysis indicated a very small but statistically significant beneficial effect for memantine at six months on cognition (<1 point on the 70-point ADAS-Cog) but no effect on behavior or activities of daily living. Another study analyzed data on 431 patients with mild AD (MMSE 20 to 23) from three trials and found no substantial benefit with memantine.

Memantine also has some evidence of efficacy in patients with VaD. (vascular dementia.)

Memantine also appears to have fewer side effects than the cholinergic agents. Dizziness is the most common side effect associated with memantine. Confusion and hallucinations are reported to occur at a low frequency, but we have noticed that memantine use seems to increase agitation and delusional behaviors in some patients with AD. Others have reported that worsening of delusions and hallucinations is particularly problematic in patients who have dementia with Lewy bodies (DLB).

A number of questions about memantine remain to be answered:

Will long-term treatment benefit those with mild to moderate AD?
Is it truly neuroprotective?
Will additional toxicities appear when it is used in larger numbers of people?

In spite of these unanswered questions, the data look promising and alternative treatments, especially for those with advanced disease, are few. A 2008 systemic review concluded that memantine has been shown to improve cognition and global assessment of dementia, but with small effects that are not of clear clinical significance; improvement in quality of life and other domains are suggested but not proven. As a result, treatment decisions should be individualized and include considerations of drug tolerability and cost.

Memantine plus cholinesterase inhibitors — Memantine may also be beneficial when used in combination with cholinesterase inhibitors:


Vitamin E and selegiline — Alpha-tocopherol (vitamin E) and selegiline (a monoamine oxidase inhibitor) have been studied in AD because of their antioxidant properties. The largest and most influential, but controversial, trial examining disease progression in AD was the first Alzheimer's Disease Cooperative Study (ADCS) that compared selegiline, alpha-tocopherol, or both with placebo. The primary outcome in the study was time to a combined endpoint of death, institutionalization, loss of the ability to perform ADLs, or progression to severe dementia on a Clinical Dementia Rating scale.

There was a delayed progression to outcome in the ADCS treatment groups (placebo 440 days, selegiline 655 days, alpha-tocopherol 670 days, combined treatment 585 days), but their analysis required statistical adjustment because the placebo group had higher MMSE scores at baseline. A number of cognitive tests that were measured as secondary endpoints (including the MMSE and the Alzheimer Disease Assessment Scale, cognitive subscale) failed to show any difference between the groups.

A number of other smaller studies have also investigated the use of selegiline with varying results. A meta-analysis of 12 trials, including the one just discussed, found that eight of the studies suggested some beneficial effect of selegiline in the treatment of cognitive benefits and, in three trials, in the treatment of behavior and mood. Three studies that were longer than one year reported significant delays in time to the primary outcome (death, institutionalization, loss of ability to perform ADLs, or severe dementia). However, the magnitude of the benefits in the meta-analysis was small and largely dependent on one study. Thus, the clinical importance for the population at large is unclear.

In spite of these caveats, these are the first studies to demonstrate a delay to a significant clinical endpoint in AD. Since alpha-tocopherol and selegiline did not differ in terms of efficacy in the largest study, and their combination was no better than either agent alone (and in fact was non-significantly worse), we generally suggest that patients with AD take alpha-tocopherol at a dose of 1000 IU twice daily. We see no advantage for the use of selegiline, which has more side effects and is more costly. A practice parameter from the American Academy of Neurology stated that vitamin E likely delays the time to clinical worsening.

There is growing concern regarding the risk of mortality associated with vitamin E supplementation, and such supplementation is appropriate only for patients with AD or at high risk of developing AD (ie, those who have more than one family member with AD) who lack significant heart disease. We do not recommend vitamin E for the routine prevention of AD or other types of dementia.

Estrogen replacementThere is no evidence that initiating estrogen replacement is beneficial in the treatment of dementia.

In summary, we see no current evidence for initiating ERT in patients with established dementia, and, given the data on HRT for primary prevention of dementia, ERT may actually be harmful.

Antiinflammatory drugs — A role for the use of antiinflammatory drugs in the treatment and prevention of AD continues to be investigated. Pathophysiological studies have demonstrated an amyloid-induced inflammatory reaction with microglial activation and cytokine release. In addition, some epidemiologic studies have suggested that use of nonsteroidal antiinflammatory drugs (NSAIDs and other antiinflammatory medications) are associated with a reduced odds-ratio for developing AD. (See "Prevention of dementia", section on 'NSAID therapy'.)

However, clinical trials do not support this treatment: Except for one small clinical trial of indomethacin, randomized trials of antiinflammatory medications including, naproxen, hydroxychloroquine, diclofenac, rofecoxib, and aspirin have not found a benefit for these agents in slowing cognitive decline in patients with AD. In addition, adverse events have been more common in treated patients compared with controls.

In particular, long-term use of the COX-2 inhibitor rofecoxib has been associated with an increased risk of cardiovascular events, and this problem may be a drug class effect of COX-2 inhibitors. In addition, a placebo-controlled AD prevention trial comparing celecoxib to naproxen was suspended in December 2004; the suspension was due to the finding of an increased rate of cardiovascular events in patients receiving celecoxib in an unrelated colonic polyp prevention trial; however, it was announced that subjects receiving naproxen sodium had an increased rate of cardiovascular events. These issues are discussed in detail elsewhere.

Ginkgo biloba — A systematic review of ginkgo for cognitive impairment and dementia concluded that ginkgo biloba, while safe, has inconsistent and unconvincing evidence of benefit. We do not advocate use of ginkgo because of questionable efficacy and lack of regulation, including variability in the dosing and contents of herbal extracts. The studies evaluating ginkgo biloba for the prevention and treatment of dementia are presented elsewhere.

Statins — While there have been investigations in a potential role of statin therapy in the prevention and treatment of Alzheimer disease, there is as yet, no established role for statins for these indications.

Dietary supplements

Vitamin B — Supplementation with B vitamins, in particular those that are involved in homocysteine metabolism, have been studied in patients with AD in hopes that they may demonstrate efficacy in preventing or slowing the progression of AD. An 18-month randomized trial of high dose vitamin B-complex supplementation (folate, B6, B12) in 340 patients with mild to moderate AD found no beneficial effect on cognitive measures.

Omega-3 fatty acids — Observational studies have suggested a possible association between dietary intake of fish and omega-3 fatty acids and a lower risk of dementia.

However, clinical trials have not supported a therapeutic role for omega-3 fatty acid supplementation in the treatment of AD.


Behavioral disturbance — Behavioral disturbance can profoundly affect patients with dementia as well as their families and caregivers. Recognition and treatment of delusions, hallucinations, depression, agitation, and aggression are important aspects of the care of patients with dementia. This topic is discussed separately. (See "Treatment of behavioral symptoms related to dementia".)

Nutrition — Inadequate nutrition is common in patients with AD and is associated with increased morbidity and mortality. Interventions such as oral nutritional supplements may improve weight and fat-free mass. A systematic review found that provision of high calorie supplements can help with weight gain in patients with dementia; however, the limited available data did not support a benefit in regard to functional and survival outcomes. Other interventions (appetite stimulants, assisted feeding) were less clearly associated with weight gain.


Cognitive rehabilitation — Cognitive rehabilitation aims to help patients in the early stages of dementia to maintain memory and higher cognitive function and to devise strategies to compensate for declining function. Studies regarding the efficacy of this approach are limited by the lack of standardized techniques. A 2012 systematic review concluded that the studies to date provide evidence that cognitive stimulation programs benefit cognition, but that studies were of variable quality and further research is indicated. This provides hope that cognitive remediation approaches are both feasible and of potential benefit in patients with dementia. However, it will be critical to show that improvements extend to other “real life” tasks before these interventions can be endorsed.

Exercise programs — A randomized trial in 153 community-dwelling patients with AD found that, compared with routine medical care, patients who were assigned to exercise (goal minimum of 30 minutes per day) and whose caregivers received training in managing behavioral problems had improved physical functioning and less depression. In another study of 134 nursing home residents with dementia, those randomized to an individualized-exercise program demonstrated less severe decline in ADL performance over 12 months of follow-up, but had similar rates of falls, fracture, and death.

Occupational therapy — In a randomized trial, 68 of 135 community-dwelling patients with mild to moderate dementia were assigned to receive 10 sessions of occupational therapy over five weeks. Individualized therapy sessions focused on training patients and caregivers in the use of aids, coping behaviors, and other strategies to compensate for those functional deficits that were specifically problematic for the patient. Assessments of motor and process skills and activities of daily living were significantly improved compared with controls, both at six weeks and at three months, implying that the treatment has some durability. The intervention also appeared to be cost-effective, specifically reducing costs of informal care giving.

These multidisciplinary, nonpharmacologic approaches to management of dementia have significant advantages in having none of the side effects that significantly complicate drug treatment in this patient population. More research is needed to confirm benefits seen in these trials and to provide a standardized approach that can be applied in the general community.

Patient referral — Timing of referral to a specialist depends upon the comfort and knowledge base of the primary care provider in managing dementia and on the availability of specialty clinics where additional resources are available, such as social workers and neuropsychologists. Factors that would be important in considering patient referral are: uncertainty about the diagnosis of an early dementia (eg, when difficulty arises distinguishing dementia from normal aging, depression, or encephalopathy); when a non-Alzheimer dementia is likely (early and severe behavioral changes, languages problems, hallucinations or parkinsonism); when there is a young onset (<65-years-old); and when there is a strong family history.

Risk factor control — Aggressive identification and treatment of risk factors for stroke, cardiovascular disease, and dementia may represent an important strategy for decreasing the incidence of dementia and for slowing the progression of cognitive decline.

Renato O

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