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Cognitive Symptoms
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Introduction

The U.S. Food and Drug Administration (FDA) has approved two classes of drugs to treat cognitive symptoms of Alzheimer’s disease: cholinesterase inhibitors and NMDA receptor antagonists. Vitamin E supplements are frequently prescribed and have become a part of a standard treatment regimen for most people with Alzheimer’s.


Cholinesterase inhibitors

The first FDA-approved Alzheimer's medications were cholinesterase inhibitors. Three cholinesterase inhibitors are commonly prescribed:

  1. donepezil (Aricept), which is approved to treat all stages of Alzheimer’s disease

  2. rivastigmine (Exelon), approved for mild to moderate Alzheimer’s

  3. galantamine (approved in 2001 under the trade name Reminyl and renamed Razadyne in 2005), also approved for mild to moderate stages

Tacrine (Cognex®), the first drug in this class, was approved in 1993 but is rarely prescribed today because of associated side effects, including possible liver damage.

Cholinesterase inhibitors are designed to increase levels of acetylcholine, a chemical messenger involved in memory, judgment and other thought processes. Acetylcholine is released by certain brain cells to carry messages to other cells. After a message reaches the receiving cell, various other chemicals, including one called acetylcholinesterase, break acetylcholine down so it can be recycled.

Alzheimer’s disease damages or destroys cells that produce and use acetylcholine, reducing amounts available to carry messages. A cholinesterase inhibitor slows the breakdown of acetylcholine by blocking the activity of acetylcholinesterase. By maintaining acetylcholine levels, the drug may help compensate for the loss of functioning brain cells.

Cholinesterase inhibitors may also have other mechanisms that contribute to their effects. Galantamine appears to stimulate the release of acetylcholine and to strengthen the way certain receptors on message-receiving nerve cells respond to it. Rivastigmine may block activity of an additional chemical involved in breaking down acetylcholine.

Cholinesterase inhibitors do not stop the underlying destruction of nerve cells. Their ability to improve symptoms eventually declines as brain cell damage progresses.

What are the benefits of cholinesterase inhibitors?

In clinical trials of all three cholinesterase inhibitors, individuals taking the medications performed better on tests of memory and thinking than those taking a placebo (inactive substance). The degree of benefit was small, and more than half of the recipients showed no improvement at all. In terms of overall effect, most experts believe cholinesterase inhibitors may delay or slow worsening of symptoms in some individuals for about six months to a year, although some may benefit longer.

There is no evidence that combining these drugs would be any more helpful than taking any one of them, and it is likely combining them would result in greater frequency of side effects (discussed below).

There is some evidence that individuals with moderate to severe Alzheimer’s who are taking a cholinesterase inhibitor might benefit slightly more by also taking memantine (Namenda). Memantine is a drug with a different mechanism of action, approved by the FDA in 2003 for symptoms of moderate to severe Alzheimer’s. In clinical trials, memantine showed greater benefit than a placebo, but its effect was modest. Memantine is discussed in more detail below.

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How are cholinesterase inhibitors used?

  • Donepezil (Aricept®) is a tablet and can be administered once daily. Generally, the initial dose is 5 mg a day(usually given at night). After four to six weeks, if it is well tolerated, the dose is often increased to the therapeutic goal of 10 mg a day.

  • Rivastigmine (Exelon®) is available as a capsule or as a liquid. The dosage is gradually increased to minimize side effects. Usually the medication is started at 1.5 mg daily. After two weeks the dosage is increased to 1.5 mg twice a day. The therapeutic goal is to increase the dosage gradually every two weeks to reach 6 to 12 mg a day given in two doses, each equal to half the total. There is a greater frequency of side effects at these higher doses; however, taking drugs with meals may be helpful in reducing the occurrence of side effects.

  • Galantamine (Razadyne) is supplied as tablets in strengths of 4, 8 and 12 mg. The recommended starting dose is 4 mg twice a day. If well tolerated after four weeks or more of treatment, the dose is increased to 8 mg twice a day. There was no statistical benefit in clinical trials for 12 mg twice a day over the dose of 8 mg twice a day, but if 8 mg twice a day is well tolerated after four weeks, the dose can be increased to 12 mg twice a day by the physician. Galantamine is also available in an “extended release” form as Razadyne ER that is designed to be taken once a day.

What are the side effects of cholinesterase inhibitors?

Cholinesterase inhibitors are generally well tolerated. If side effects occur, they commonly include nausea, vomiting, loss of appetite, and increased frequency of bowel movements. It is strongly recommended that a physician who is comfortable and experienced in using these medications monitor patients who are taking them and that the recommended guidelines be strictly observed.

It is strongly recommended that a physician who is comfortable and experienced in using these medications monitor patients treated with any of these compounds and that the recommended guidelines be strictly observed. There is no evidence or reason to believe that combining the drugs would be any more beneficial than taking either one alone, and it is likely that combining the drugs would result in greater side effects.

 Treatments topic sheet suitable for use as a patient handout.

Memantine

Memantine was approved in October 2003 by the FDA for treatment of moderate to severe Alzheimer’s disease. Forest Laboratories Inc., memantine’s U.S. developer, markets the drug under the trade name Namenda®.

Memantine is classified as an uncompetitive low-to-moderate affinity N-methyl-D-aspartate (NMDA) receptor antagonist, the first Alzheimer's drug of this type approved in the United States. It appears to work by regulating the activity of glutamate, one of the brain’s specialized messenger chemicals involved in information processing, storage, and retrieval. Glutamate plays an essential role in learning and memory by triggering NMDA receptors to allow a controlled amount of calcium to flow into a nerve cell, creating the chemical environment required for information storage.

Excess glutamate, on the other hand, overstimulates NMDA receptors to allow too much calcium into nerve cells, leading to disruption and death of cells. Memantine may protect cells against excess glutamate by partially blocking NMDA receptors.

Memantine’s action differs from the mechanism of the cholinesterase inhibitors that were previously approved in the United States for treatment of Alzheimer's symptoms. Cholinesterase inhibitors temporarily boost levels of acetylcholine, another messenger chemical that becomes deficient in the Alzheimer's brain.

What is the evidence that memantine may help Alzheimer's symptoms?

Forest submitted evidence in support of memantine’s effectiveness in treating moderate to severe Alzheimer’s disease in a new drug application to the FDA in December 2002, amended in January 2003. In September 2003, the FDA’s Peripheral and Central Nervous System Drug Advisory Committee met to respond to specific questions raised by the FDA regarding application data. Briefing documents and summaries of advisory committee critiques are available on the FDA Web site. At the conclusion of its meeting, the advisory committee voted unanimously that the following data submitted in the new drug application support the safety and effectiveness of memantine in treating moderate to severe Alzheimer’s disease:

  1. A 28-week U.S. study enrolling 252 individuals with moderate to severe Alzheimer’s disease and initial scores ranging from 3 – 14 on the Mini-Mental State Examination (MMSE). In this double-blind study, participants were randomly assigned to receive either 10 mg of memantine twice a day or a placebo. Those receiving memantine showed a small but statistically significant benefit in a test of the their ability to perform daily activities and on the Severe Impairment Battery, a test designed to measure cognition in profoundly incapacitated individuals. On the Clinician Interview-Based Impression of Change Plus Caregiver Input, a measure of overall function, memantine recipients also showed a benefit that was significant in one analysis but not in another. In this study, when participants with MMSE scores of less than 10 were considered as a separate group, memantine recipients showed no benefit compared to those who received placebo on either daily activities or overall function.

  2. A 24-week U.S. study enrolling 404 individuals with moderate to severe Alzheimer’s disease and initial MMSE scores from 5 – 14 who had been taking donepezil (Aricept®) for at least six months, with a stable dose for at least three months. In this double-blind study, participants were randomly assigned to receive either 10 mg of memantine twice a day or a placebo in addition to their donepezil. Those receiving memantine showed a statistically significant benefit in performing daily activities and on the Severe Impairment Battery, while participants taking donepezil plus placebo continued to decline.

Some advisory committee members considered memantine’s effect modest, similar in scope to the effect seen with cholinesterase inhibitors.

The advisory committee found problems with the design of a third submitted study, conducted in Latvia, because it enrolled individuals with vascular dementia as well as Alzheimer’s disease. An additional issue was that although the data showed a positive effect for memantine on reducing dependence on care, the study lacked an acceptable measure of effect on cognitive function. According to current FDA standards, drugs approved specifically to treat Alzheimer’s disease must show a benefit on cognitive symptoms as well as on overall function, which confirms that the effect on cognition is clinically meaningful.

In June 2003, Forest reported preliminary results from another add-on therapy trial enrolling participants with mild to moderate Alzheimer’s who were also taking any of three commonly prescribed cholinesterase inhibitors — donepezil (Aricept®), galantamine (Razadyne®, formerly Reminyl®) or rivastigmine (Exelon®). Data from this trial were not included in the new drug application seeking approval of memantine for moderate to severe disease. According to the company, the data showed that participants receiving memantine in combination with a cholinesterase inhibitor did not experience significantly greater benefit in cognition or overall function than those who received a cholinesterase inhibitor and a placebo. These preliminary results suggest that memantine may not be as effective in individuals with mild to moderate Alzheimer’s who are taking a cholinesterase inhibitor as it may in more severely ill individuals. This data has not yet been peer reviewed or presented in a professional forum.

How is memantine supplied and prescribed?

Memantine is supplied as an oral medication in 10 mg tablets. Forest is providing prescribing information at www.namenda.com or by calling 1.877.2-NAMENDA (1.877.262.6363). Adverse effects occurring more commonly with memantine than with placebo included headache, constipation, confusion and dizziness.

 Treatments topic sheet suitable for use as a patient handout.

Vitamin E

How might vitamin E supplements benefit a person with Alzheimer’s disease?

The normal cell function termed “oxidative metabolism” results in byproducts known as free radicals. Free radicals are highly reactive compounds that quickly “attack” other cell substances, causing damage to the cell wall, metabolic machinery and genetic material (DNA). The cells have natural defenses against this damage, which include the antioxidants vitamins C and E, but with age some of these protective mechanisms decline. Brain cell damage caused by free radicals may play a role in Alzheimer’s disease.

What was the result of the multicenter national study of vitamin E and Alzheimer’s disease?

Research reported in the April 24, 1997, issue of the New England Journal of Medicine investigated the effectiveness of vitamin E and selegiline, a drug with antioxidant properties that is prescribed for treating Parkinson’s disease. The research was part of the Alzheimer’s Disease Cooperative Study, a consortium of academic Alzheimer's research centers sponsored by the U.S. National Institute on Aging.

This study suggests that either selegiline or vitamin E delays the occurrence in patients with Alzheimer’s disease to one or more of the following “endpoints”: death, institutionalization, progression from moderate to severe dementia or loss of ability to perform two of three basic activities of daily living (eating, grooming or toileting). When both agents were given together, there was also a delay in progression of Alzheimer’s disease as measured by these endpoints. However, both agents together did not help more than either drug alone. These agents did not improve memory and thinking test scores.

These results are encouraging but as yet have not been confirmed by other studies. We also do not know if these agents would be helpful in milder or severe stages of Alzheimer’s disease. There was no evidence that intellectual deterioration was slowed. Finally, any medication may have side effects or potential interactions with other drugs. For example, it is known that certain doses of selegiline (higher than those used in the study) can lead to serious interactions with some types of foods and certain medications.

Should vitamin E be prescribed?

Vitamin E worked at least as well as selegiline on Alzheimer’s progression in this study and had fewer side effects. vitamin E also costs less. For these reasons it is preferred over selegiline in Alzheimer’s disease treatment. Vitamin E is considered to be a “benign” medication and most people can take it without side effects. However, any change in medications should first be discussed with your primary care physician because all medication can cause side effects or interactions with other medications. People taking “blood-thinners” like warfarin (Coumadin®), ticlopidine (Ticlid®), and others may not be able to take vitamin E or will need to be monitored closely by their physician if they are taking vitamin E.

What dose of vitamin E is best?

Exactly what dose of vitamin E is the “best” is not known. The doses of vitamin E in the study were 1,200 IU twice daily. Other doses need to be studied to answer this question confidently. Many doctors recommend 400 IU twice daily because they believe this dosage to be safe for most individuals and it should have the antioxidant effect desired in the brain.

Prepared by John C. Morris, M.D., professor of neurology at Washington University at St. Louis


 

Alzheimer's Association

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