Drug treatments for Alzheimer's disease

No drug treatments can provide a cure for Alzheimer's disease. However, drug treatments have been developed that can improve symptoms, or temporarily slow down their progression, in some people. This factsheet explains how the main drug treatments for Alzheimer's disease work, clarifies their availability, and sets out the most recent guidance from the National Institute for Health and Clinical Excellence (NICE) on their usage. (For more information about Alzheimer's disease, see Factsheet 401, What is Alzheimer's disease?)

What are the main drugs used?

There are two main types of drugs used to treat Alzheimer's disease. Aricept, Exelon and Reminyl all work in a similar way, and are known as acetylcholinesterase inhibitors. Ebixa works in a different way to the other three.

• Aricept (donepezil hydrochloride), produced by Eisai and co-marketed with Pfizer, was the first drug to be licensed in the UK specifically for Alzheimer's disease.
• Exelon (rivastigmine), produced by Novartis Pharmaceuticals, was the second drug licensed in the UK specifically for Alzheimer's disease.
• Reminyl (galantamine) was co-developed by Shire Pharmaceuticals and the Janssen Research Foundation. Originally derived from the bulbs of snowdrops and narcissi, it was the third drug licensed in the UK specifically for Alzheimer's disease.
• Ebixa (memantine) is produced by Merz and marketed in Europe by Lundbeck. It is the newest of the Alzheimer's drugs.

How do they work?

Aricept, Exelon and Reminyl

Research has shown that the brains of people with Alzheimer's disease show a loss of nerve cells that use a chemical called acetylcholine as a chemical messenger (Pierre et al, 2004). The loss of these nerve cells is related to the severity of impairment that people experience.

Aricept, Exelon and Reminyl prevent an enzyme known as acetylcholinesterase from breaking down acetylcholine in the brain. Increased concentrations of acetylcholine lead to increased communication between the nerve cells that use acetylcholine as a chemical messenger, which may in turn temporarily improve or stabilise the symptoms of Alzheimer's disease.

All three cholinesterase inhibitors work in a similar way, but one might suit an individual better than another, particularly in terms of side-effects experienced.

Ebixa

The action of Ebixa is quite different to, and more complex than, that of Aricept, Exelon and Reminyl. Ebixa blocks a messenger chemical known as glutamate. Glutamate is released in excessive amounts when brain cells are damaged by Alzheimer's disease, and this causes the brain cells to be damaged further. Ebixa can protect brain cells by blocking this release of excess glutamate.

Can Ebixa be taken at the same time as Aricept, Exelon or Reminyl?

Research in the United States has suggested that combining Aricept and Ebixa is more effective than using Aricept alone. Although this research is not conclusive, there is little evidence to support a contrary view. Ebixa works in a completely different way from the acetylcholinesterase inhibitors, and if a person stopped taking Aricept in order to try Ebixa, their symptoms could become worse, which could then make it difficult to assess their suitability for Ebixa. However, whether doctors will prescribe both drugs together − especially on the NHS − is currently unclear.

Are these drugs effective for anyone with Alzheimer's disease?

At present Aricept, Exelon and Reminyl are licensed only for people with mild-to-moderate Alzheimer's disease, and are available only as part of NHS care for people with moderate Alzheimer's disease (see 'NICE guidance', below). There are now several studies − including work supported by the Alzheimer's Society − suggesting that cholinesterase inhibitors may also help people with more severe Alzheimer's disease. However, these treatments are not yet licensed for this purpose.

Between 40 and 60 per cent of people with Alzheimer's disease benefit from cholinesterase inhibitor treatment, but it is not effective for everyone, and may improve symptoms only temporarily. According to an Alzheimer's Society survey of 4,000 people, people using these treatments often experience improvements in motivation, anxiety and confidence, in addition to memory and thinking.

Ebixa can temporarily slow down the progression of symptoms, including everyday function, in people in the middle and later stages of the disease. Ebixa is licensed for the treatment of moderate-to-severe Alzheimer's disease, but is not routinely provided as part of NHS treatment (see 'NICE guidance', below). Recent evidence suggests that Ebixa may also help behavioural symptoms such as aggression and agitation (see Factsheet 408, Drugs used to relieve depression and behavioural symptoms and Factsheet 509, Dealing with aggressive behaviour).

Are there any side-effects?

Generally, cholinesterase inhibitors and Ebixa are very well tolerated, with good side-effect profiles. Not everyone experiences the same side-effects, or has them for the same length of time, if they have them at all. The most frequent side-effects of Aricept, Exelon and Reminyl include nausea and vomiting, diarrhoea, stomach cramps and headaches, dizziness, fatigue, insomnia and loss of appetite, while side-effects of Ebixa include dizziness, headaches, tiredness, increased blood pressure and, on rare occasions, hallucinations and confusion.

Ebixa is not recommended for people with severe kidney problems because there has been no safety test for this group of people as yet. Caution is recommended for people with epilepsy and heart problems.

Side-effects can be less likely for people who start treatment by taking the lower prescribed dose for at least a month. Sometimes 'splitting' the dose, taking half in the morning and half later in the day, can help, but the correct full daily dose must be maintained overall.

It is important to discuss any side-effects with the doctor.

None of these drugs is addictive.

How and where can these drugs be obtained?

Aricept, Exelon and Reminyl

In the first instance, these drugs can only be prescribed by a consultant. A GP will need to refer the person to a hospital for a specialist assessment. A consultant will carry out a series of tests to assess whether the person is suitable for treatment, and will write the first prescription, if appropriate. Subsequent prescriptions may be written by the GP or the consultant.

Some people may wish to obtain these drugs privately. Private prescriptions can be obtained through a consultant, a GP or a private hospital. Private prescriptions are subject to consultation fees, prescription charges and dispensing fees, which vary. The current cost of these drugs to the NHS ranges from £800 to £1,000 per patient each year.

Whether these drugs are obtained on the NHS or privately, the patient must be willing to take the treatment, and should discuss any possible benefits, risks or side-effects with the doctor.

Ebixa

Ebixa is the newest of the Alzheimer's drugs in the UK, launched in October 2002. It is not routinely available as an NHS treatment.

Are these drugs effective for other types of dementia?

The acetylcholinesterase inhibitors were developed specifically to treat Alzheimer's disease. We do not yet know whether they can be helpful for people with other forms of dementia, although there is evidence that they may be effective in dementia with Lewy bodies and dementia related to Parkinson's disease. One of the cholinesterase inhibitors, Exelon, is licensed for the treatment of dementia associated with Parkinson's disease, but use as an NHS treatment has not yet been considered by NICE. (See Factsheets 403, What is dementia with Lewy bodies?, and 442, Rarer causes of dementia.)

There are several trials examining cholinesterase inhibitors for the treatment of vascular dementia, but the benefits are very modest, except in the individuals with a combination of both Alzheimer's disease and vascular dementia. Cholinesterase inhibitors are not licensed for the treatment of vascular dementia. (See Factsheet 402, What is vascular dementia?) Research is continuing.

Taking the drugs

It may be helpful if the consultant seeks the carer's views of the person's condition before treatment and during follow-up appointments. He or she should also seek the patient's views. The person must take the drugs as prescribed, and the consultant will need to be sure that this is the case.

Dosages vary. Usually a patient will start on a low dose, which will be increased later to maximise effectiveness. It is important to be on the highest tolerable dose to get the maximum effect:

• Aricept is administered once a day, and can be taken with or without food. It is available in 5mg or 10mg tablets.
• Exelon is taken twice a day, normally in the morning and evening. People start with 3mg a day, which will usually increase to a dosage of between 6mg and 12mg. An Exelon patch is also available, and delivers a similar daily dosage to 12mg per day of the capsules.
• Reminyl The recommended starting dose for Reminyl XL capsules is 8mg each day. The 4mg tablets (twice-daily starting dosage) were discontinued at the end of July 2006, and supplies are limited. This was due to reduced demand following the introduction of the once-daily formulation, Reminyl XL. The other, higher-strength, Reminyl tablets for maintenance treatment (twice-daily 8mg and 12mg), and Reminyl XL once-daily capsules, continue to be available. Reminyl will also remain available as a 4mg/ml (twice-daily) oral solution. Reminyl XL is available in 8mg, 16mg and 24mg capsules.
• Ebixa comes in two forms, as 10mg tablets and as 10mg oral drops. The tablets can be broken in half, into 5mg doses, and taken with or without food. The recommended starting dose is 5mg a day, increasing after four weeks to up to 20mg a day.

If the person misses a dose, they should take it as soon as they remember, if it is on the same day. If it is the next day, the person should not take two tablets but should simply continue with their normal dose.

Tips: questions to ask the doctor

• What are the potential benefits of taking these drugs?
• How long will it be before I see a result?
• How often do these drugs need to be taken?
• If I get side-effects, should I stop taking the drug immediately?
• What will happen if I stop the drug suddenly?
• What other treatments (prescription and over-the-counter) might interact with these drugs?
• Can I drink alcohol while taking the drug?
• How might these drugs affect other medical conditions?
• What changes in health should I report immediately?
• How often will I need to visit the clinic or surgery?
• Can someone with Alzheimer's disease living in a residential or nursing home take these drugs?
• Are there any costs associated with taking these drugs?
• Why have I been prescribed one drug rather than another?
• If one drug proves ineffective can I try another drug?

Stopping treatment

If the person with dementia decides to stop taking a drug, they should speak to the doctor first, if possible, or as soon as they can after stopping treatment.

If someone stops taking their prescribed drug, their condition will deteriorate over a period of about four to six weeks, until their symptoms are no better than in someone who has never taken the drug.

NICE guidance

The National Institute of Health and Clinical Excellence (NICE) reviews drugs and decides whether they represent good enough value for money to be available as part of NHS treatment. The most recent NICE guidance on anti-Alzheimer's drugs recommends that people in the moderate stages of Alzheimer's disease should be given treatment with donepezil (Aricept), galantamine (Reminyl) or anrivastigmine (Exelon), including individuals with dementia and learning disabilities.

This differs from the previous NICE guidance, which indicated these drugs could be prescribed to people in the early-to-moderate stages of Alzheimer's disease.

The new guidance also states that memantine (Ebixa) should not be prescribed as part of NHS care, but emphasises further studies with Ebixa as an important research priority.

The clinical care guideline on the care and treatment of people with dementia, which NICE publishes alongside its guidance, stresses that there must be a degree of flexibility around what constitutes the 'moderate stages' of Alzheimer's disease.

NICE has not yet formally appraised the use of Aricept, Exelon or Reminyl for the treatment of dementia with Lewy bodies or dementia associated with Parkinson's disease. The decision as to whether these treatments are appropriate for particular individuals lies with the specialist doctor.

A more detailed summary of the NICE guidance is provided below:

Donepezil, galantamine and rivastigmine are recommended as options for moderate Alzheimer's disease only, and if:

• treatment is started by a doctor who specialises in the care of people with dementia
• patients who are started on one of the drugs are checked every six months, usually by a specialist team
• the check-up includes a test called the Mini Mental State Examination (MMSE) and assessment of the patient's behaviour and ability to cope with daily life
• the views of carers on the patient's condition are discussed at the start of drug treatment and at check-ups
• the drug is no longer supplied if the patient's MMSE score falls below ten points, or if the drug isn't working (see Factsheet 436, Mini Mental State Examination)
• the least expensive of the three drugs is prescribed first. However, if it is not suitable for the patient another drug could be chosen.

Memantine is not recommended as an option for people with moderately severe to severe Alzheimer's disease, unless it is being used as part of a clinical trial (research).

Patients prescribed donepezil, galantamine or rivastigmine before the implementation of the NICE guidelines for mild Alzheimer's disease, or memantine for moderately severe to severe Alzheimer's disease, will continue to receive their prescription. Treatment should continue until the patient, carer and/or specialist decides it is the right time to stop.

From July 2006 Reminyl 4mg tablets (twice-daily starting dosage) are discontinued and supplies are limited. The other higher-strength Reminyl tablets for maintenance treatment (twice-daily 8mg and 12mg) and Reminyl XL once-daily capsules continue to be available. Reminyl will also remain available as a 4mg/ml (twice-daily) oral solution. Reminyl XL is available in 8mg, 16mg and 24mg capsules. The recommended starting dose for Reminyl XL capsules is 8mg/day.

Printed copies of CG42 Dementia: Understanding NICE guidance can be ordered from NICE by calling 020 7067 5800, or downloaded from http://www.nice.org.uk/

Alzheimer's Society continues to campaign for drugs to be made freely available to anyone who may benefit from them.

Your local Alzheimer's Society branch will always be willing to talk to you and offer advice and information to support your needs.

For more information, Dementia Catalogue, our specialist dementia information resource, is available on the website at alzheimers.org.uk/dementiacatalogue

Reference

Tariot MD, PN et al for the Memantine Study Group (2004) Memantine Treatment in Patients With Moderate to Severe Alzheimer Disease Already Receiving Donepezil; A Randomized Controlled Trial, Journal of the American Medical Association 291:317-324.

Factsheet 407

Last updated: September 2008
Last reviewed: September 2008

Reviewed by: Clive Ballard, Director of Research, Alzheimer's Society