# data[].attributes.body
Positives
After an average of 4.5 years, people who adhered most closely to the MIND diet had a 53% reduced rate of Alzheimer’s disease compared to those who did not follow the diet closely.
Negatives
-They could choke

-Poor diet is proven to be bad for the brain and could increase the risk of these
dieting

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talking therapy
-Positive
It helps them talk about how they are feeling and you get a chance to see their behavior
-Negative
They may feel unsafe due to not knowing them. It might be hard to talk about their feelings truthfully.
https://www.alzheimers.org.uk/about-dementia/symptoms-and-diagnosis/talking-therapies#:~:text=Talking%20therapies%20can%20be%20effective,affect%20their%20mood%20and%20behaviour.

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How do talking therapies work?

Talking therapy sessions are delivered by a professional, such as a counsellor, a clinical or counselling psychologist, a psychotherapist, or a psychiatrist. People can have some types of talking therapy over the telephone or online. This includes counselling and cognitive behavioural therapy (CBT).

The approach to therapy will be adapted to each person. It will be based on them and the therapist working together to find out what might be causing the person's problems, as well as ways to manage these problems.

Successful therapy depends on developing a trusting relationship between the person and the therapist. It is important that the person is comfortable with the therapist's approach and manner. Their relationship is confidential. This means the therapist won't tell anyone what they discuss during therapy. There are some exceptions to this, which the therapist should explain during the first meeting. For example if the person with dementia gives their consent, they may be accompanied and supported in the sessions by a family member.
Listen to our helpsheet below for a summary of talking therapies and the other main non-drug treatments for dementia:
Benefits of talking therapies for people with dementia

Talking therapies can be effective for people in the early to middle stages of dementia. Talking therapies are unlikely to help if a person is in the later stages. This is because they are likely to have problems with their attention, communication, understanding and memory, which are all key to being able to benefit from talking therapies. However, there are other ways to support people in the later stages of dementia, such as through sensitive listening or sensory stimulation. See our advice on communicating in the later stages of dementia.

Talking therapies can give a person with dementia the chance to speak openly about their feelings, including how they feel about a recent diagnosis. This can help them adjust and live with their condition more successfully. They might find it helpful to discuss problems with a therapist rather than their friends or family members. A therapist can give them a safe space to explore the reasons why they feel how they do. This can be comforting. It can also help them maintain healthy relationships with their friends and family members.

There is evidence that having talking therapy over several weeks may reduce depression and anxiety in people in the early stages of dementia. The therapy needs to be adapted to the person's level of communication, understanding and memory. It's therefore likely to be most effective if the therapist has experience of working with people with dementia as well as a good understanding of the condition.

Suitable talking therapies are not always available in the person's local area. People in care homes may find it particularly difficult to access talking therapy services. See 'How to find a therapist' below for advice on how to do this.

Types of talking therapy

There are many different types of talking therapy. The main ones are explained below. The most suitable type will depend on what the person wants to get out of it, their stage of dementia and the symptoms they are having.

Counselling

Counselling is the general term for a range of talking therapies, including individual, group and couples sessions. It aims to help a person better understand their problems and then explore ways to manage them. A counsellor won't give the person 'answers'. They will give them time and guidance to look at their problems with a professional.

Counselling is often used to help a person cope with events they've found difficult. It can be particularly helpful for people who have recently been diagnosed with dementia. Being assessed for suspected dementia can be confusing, stressful and make the person feel anxious.

Many people with dementia struggle to make sense of their diagnosis and how their life is changing. They may feel lost, confused, vulnerable or anxious. Counselling can help them manage these worries. It can make them feel less depressed and hopeless, and help them accept their diagnosis.

Psychotherapy

Psychotherapy is a term for another range of talking therapies. The type of psychotherapy that a person is offered will depend on what is most appropriate for them.

A psychotherapist will help a person understand how their personality, beliefs and experiences influence their thoughts, feelings, relationships and behaviour. This can change the way they think and behave. It can also help them deal with problems and difficult situations more successfully.

Psychotherapy can help people with dementia feel less depressed and anxious. This can help them maintain a good quality of life and cope with their condition.

Cognitive behavioural therapy (CBT)

This is one specific type of psychotherapy. Cognitive behavioural therapy (CBT) is based on the fact that the way we think about something (our 'cognition') affects how we feel and then how we behave.

CBT for depression or anxiety is most suitable for people in the earlier stages of dementia. They may have fewer difficulties with their memory, communication and reasoning. They are also usually more aware of their condition and their own thoughts and emotions than a person in the later stages of dementia. This will mean they can effectively engage with the therapy.

CBT sessions may need to be adapted to meet the specific needs of the person with dementia. This might include having shorter sessions, using memory aids (such as cue cards or digital devices) and summarising ideas throughout the sessions. If the person with dementia agrees, a family member or close friend may attend sessions with them. This supporter can also help them use CBT strategies outside of the sessions.

How can talking therapies help carers?

Dementia is a complex, unpredictable and progressive condition. As a result, caring for a person with dementia is unlike caring for a person with other conditions.

Caring can be very rewarding and fulfilling. It can also be very stressful, particularly if there are no or few other people who can help. You may suppress your feelings to protect the person you're caring for and become socially isolated and sleep-deprived. This reduces the ability to cope with negative feelings and stress. As a result, it is common for carers to feel anxious and depressed.

When you are caring for a person with dementia it's important that you look after yourself and take regular breaks. For more information see our booklet 600, Caring for a person with dementia: A practical guide.

Read our advice and tips on looking after yourself.

Find out more

Carers may also find talking therapies useful. Therapy can help to explore your feelings in private. This may be especially important when you're making decisions about how to look after the person with dementia. For example if they move into residential care you may need time to adjust and learn to accept that you now have less responsibility for them. Therapy can also help if you are feeling guilty or embarrassed about how you feel about the person with dementia.

Counselling

Counselling can help carers be more aware of their thoughts and behaviours. It gives them a chance to think about how to manage their reactions and cope more effectively.

Counselling can also help carers think about the impact their thoughts and behaviours may have on the person with dementia. The way a carer approaches a person with dementia will affect how the person feels and behaves, both positively and negatively. If a carer is stressed and becomes short-tempered, the person with dementia will be more likely to feel anxious, depressed or develop challenging behaviours. The carer may then feel guilty as a result.

Rather than face-to-face sessions, telephone counselling may be more convenient for people who have caring responsibilities. Online counselling and therapy through apps that allow video calls may also be available.

Caring for a person with dementia can affect personal relationships. Therefore partners may find relationship counselling or couples therapy helpful. Relate offers relationship counselling - see the section 'Other resources' for details. Some carers also find it very helpful to speak to professionals who specialise in dementia care, such as an Admiral Nurse (available in some parts of the UK but not everywhere).

There is more information on Admiral Nurses on the Dementia UK website.

Psychotherapy

Psychotherapy can make carers feel less distressed. Carers who have depression may find CBT particular helpful, including face-to-face and telephone sessions.

It's very important that the therapy is tailored to the individual and their circumstances. Computerised CBT (cCBT) packages for carers generally aren't specific to each individual. However cCBT may still be helpful and should be considered if it is the only available option, such as when a carer doesn't have much time available for therapy.

Former carers

If the person with dementia has died, talking therapies can help carers to cope and manage upsetting and stressful thoughts. Therapy may also help them to accept the past and plan for the future. For example, it can help someone to come to terms with their new situation and any loss they may feel. Some talking therapies are specifically focused on helping people deal with losing someone close to them, such as bereavement counselling or bereavement CBT.

What to look for in a therapist

It is important for anyone who is having therapy to feel comfortable with their therapist. The relationship will depend on a number of factors, including the personalities of both the person and the therapist.

For both someone with dementia or a carer, it is likely to be most helpful to find a therapist who has experience or an understanding of the condition.

It is important to meet the therapist face to face (for sessions in person) or to speak to them on the telephone to have a chat and see whether they seem suitable. It is also important to check that the therapist:

is accredited by the relevant professional body (see the section 'Other resources')

abides by a professional code of ethics

has regular professional supervision to make sure their practice is safe and ethical

explains their approach, confidentiality, fees (if applicable), length of sessions and responsibilities (theirs and the person who is having the therapy) before committing to sessions.

How to find a therapist

Many GPs can give people details about therapists in the local area. Some GP surgeries also have talking therapy services based in their practices.

Many of the talking therapies for depression and anxiety mentioned in this section are available through an NHS England programme called Improving Access to Psychological Therapies (IAPT) (see the section 'Other resources' for more detais). A person's GP can refer them to a local IAPT service. The service will assess them and offer support. This could include signposting to relevant activities, self-help materials or psychological therapies. Some IAPT services also let people refer themselves to the service without having to go through their GP.

Talking therapies that people access through the NHS are usually free of charge, although there can be a long waiting list.

Some local charities, faith groups and other organisations may also offer counselling or informal support services. A person's GP or local social services department may have more information about this. Or, use our Dementia Directory to find local support services for people with dementia and carers

Another option is to find a private therapist. A person's friends and family members may be able to recommend a therapist they have had sessions with. Someone who has a lower income will generally be charged less than a person who can afford to pay the full rate.

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Talking therapies for people with dementia and carers

# data[].attributes.attachment_link.description
Talking therapies can be effective for people in the early to middle stages of dementia. In psychological therapy or 'talking therapy' sessions, a person will be supported to talk about how their thoughts and feelings affect their mood and behaviour.

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rivastigmine
-Positive
After 26 weeks of treatment rivastigmine compared to placebo was associated with better outcomes for cognitive function
-Negative
nausea, vomiting, diarrhea, stomach pain, loss of appetite, or weight loss.
https://www.mayoclinic.org/drugs-supplements/rivastigmine-oral-route/side-effects/drg-20065860?p=1#:~:text=Rivastigmine%20may%20cause%20nausea%2C%20vomiting,health%20problems%20such%20as%20dehydration.

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Description and Brand Names

Drug information provided by: IBM Micromedex

US Brand Name

Descriptions

Rivastigmine is used to treat mild to moderate dementia (memory loss and mental changes) associated with Alzheimer's disease or Parkinson's disease. Rivastigmine will not cure or stop Alzheimer's disease or Parkinson's disease from getting worse, however, rivastigmine can improve the thinking ability in some patients.

In Alzheimer's disease, many chemical changes take place in the brain. One of the earliest and biggest changes is that there is less of a chemical called acetylcholine (ACh). ACh helps the brain to work properly. Rivastigmine slows the breakdown of ACh, so it can build up and have a greater effect. However, as Alzheimer's disease gets worse, there will be less and less ACh, so rivastigmine may not work as well.

This medicine is available only with your doctor's prescription.

This product is available in the following dosage forms:

Portions of this document last updated: Nov. 01, 2022

Copyright © 2022 IBM Watson Health. All rights reserved. Information is for End User's use only and may not be sold, redistributed or otherwise used for commercial purposes.

# data[].attributes.attachment_link.description
Drug information provided by: IBM Micromedex Rivastigmine is used to treat mild to moderate dementia (memory loss and mental changes) associated with Alzheimer's disease or Parkinson's disease. Rivastigmine will not cure or stop Alzheimer's disease or Parkinson's disease from getting worse, however, rivastigmine can improve the thinking ability in some patients.

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donepezil
-Positive
It is working well against the three major domains of alzheimer
-Negative
things like vomiting, nausea, fatigue, muscle cramps ect.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3321665/

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Introduction:

Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is a specific and reversible inhibitor of acetylcholinesterase (AChE); by increasing levels of available acetylcholine, donepezil may compensate for the loss of functioning cholinergic brain cells.

Aims:

This review evaluates the clinical impact of donepezil by assessing randomized controlled and open-label naturalistic trials, as well as observational studies. A broad perspective is gained of its effectiveness on various outcomes.

Evidence review:

There is strong evidence that donepezil has efficacy against the three major domains of Alzheimer's disease symptoms, namely functional ability, behavior, and cognition. The strongest evidence is for improvement or less deterioration in global outcomes and cognition in the short to medium term. There is limited evidence that improved global outcomes are maintained in the long term and clear evidence to support long-term maintenance of cognitive benefits. Also, donepezil appears to maintain function in the long term and there is some level 1 and 2 evidence of improved or limited deterioration in behavior or mood in the short to medium term. Despite donepezil's effects on major symptoms of Alzheimer's disease, its impact on patients' quality of life has not been consistently demonstrated, perhaps reflecting the difficulty of assessing this aspect in this patient population. Donepezil may also lessen caregiver burden. Donepezil has some effect on markers of brain function, but more data are needed to confirm a neuroprotective effect. There is limited and conflicting evidence that long-term donepezil treatment delays time to institutionalization. There is some evidence that donepezil may be cost effective, especially when unpaid caregiver costs are considered. Donepezil is generally safe and well tolerated.

Clinical value:

AChE inhibitors are the only agents recommended for the treatment of cognitive decline in patients with mild to moderate Alzheimer's disease. Donepezil is more effective than placebo and is well tolerated in improving the major symptoms of this disease. Improvements are usually modest, although stabilization of cognitive and functional symptoms with donepezil can also be considered an important clinical outcome. Donepezil may lessen caregiver burden. Donepezil may also be cost effective, especially when unpaid caregiver costs are considered. More data are required from randomized controlled trials with long-term follow-up to confirm its cost effectiveness and impact on quality of life, disease progression, and time to institutionalization.

Keywords: acetylcholinesterase (AChE) inhibitor, Alzheimer's disease, dementia, donepezil, evidence, outcomes

Patient-oriented evidence

Disease-oriented evidence

Delayed disease progression

Some

Donepezil has an effect on indirect markers of disease progression, such as regional cerebral blood flow, ¹²³ I quinuclidinyl benzilate, quantitative electroencephalogram, and the degree of hippocampal atrophy, in comparison with matched control groups

Table 1

Diagnosis

There is no simple test that provides a definitive diagnosis of Alzheimer's disease. Also, the onset of Alzheimer's is often so gradual and the early signs so mild that they can easily be mistaken for normal mental aging. However, it is important to diagnose Alzheimer's disease as early as possible to give those affected by the disease and their caregivers the opportunity to prepare for disease progression, and to increase the likelihood of gaining benefit from existing treatments.

Diagnosis depends largely on the elimination of other systemic, psychiatric, and neurologic causes of dementia by clinical and laboratory investigation. This is accompanied by a careful assessment of the family and personal history of the individual and their symptoms. The classic clinical features of Alzheimer's disease can be categorized into three domains: function (ADL), behavior, and cognition. Loss of higher level function involving complex decision making and activities (e.g. managing finances) is followed in advanced phases by abnormalities of basic ADL, such as eating, grooming, and using the toilet (reviewed by Cummings 2004). Behavioral disturbances also progress, and mood change and apathy are early markers of the disease. Psychosis and agitation are characteristic of the middle or late phases of the disease ( Cummings 2004). Moreover, primary caregivers, who are usually family members, are documented to suffer frequently from stress, insomnia, and fatigue and as a consequence may require medical care themselves ( Leung et al. 2003).

The scales used most frequently in clinical trials to measure the three key symptom domains in Alzheimer's disease include:

function (ADL): Progressive Deterioration Scale (PDS), Instrumental Activities of Daily Living (IADL), Disability Assessment for Dementia (DAD), Katz ADL

behavior: Neuropsychiatric Inventory (NPI), Behavioral Pathology in Alzheimer's Disease (BEHAVE-AD)

cognition: cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-cog), Mini Mental State Examination (MMSE).

Scales to measure severity are also used frequently to indicate effects on disease progression, such as the Clinical Dementia Rating (CDR) scale, and Global Deterioration Scale (GDS). These symptom and severity scales are readily available but suffer from variability due to examiner subjectivity. More objective techniques that can be used to confirm diagnosis by excluding dementia due to other causes include computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET) of the brain. The definitive pathologic hallmarks of Alzheimer's disease, the presence of amyloid plaques and neurofibrillary tangles, can only be detected currently by examining the brain at postmortem.

Prevalence

Estimated values for the prevalence of Alzheimer's disease vary from 1 to 5%, partly because of differences in age samples and diagnostic criteria among the studies conducted ( WHO 2001). A World Health Organization (WHO) study estimated a prevalence of 5% for men and 6% for women in those above 60 years ( WHO 2001); it is thought that more women than men are encountered with Alzheimer's disease because of greater female longevity. A separate study estimated that 6.1% of the worldwide population aged 65 years and older had Alzheimer's disease or another form of dementia in 2000 ( Wimo et al. 2003a). The prevalence of Alzheimer's disease increases dramatically with age; of individuals aged between 75 and 84 years, up to 20% may be affected, while a prevalence of nearly 50% has been reported in those aged over 85 years ( Evans et al. 1989).

The prevalence of Alzheimer's disease in the USA is predicted to increase from 4.5 million in 2000 to 13.2 million by 2050 ( Hebert et al. 2003). This trend is likely to be repeated in many other countries where numbers of people aged over 65 years are expected to increase and be accompanied by disproportionate increases in dementia. For example, in 2000, the percentage of population aged 65 and over was 15.5% in Europe and 12.6% in North America ( Kinsella & Velkoff 2001). The projected percentages for 2030 are 24.3 and 20.3%, respectively (). Moreover, significant increases in the numbers of older people are expected in developing countries, many of whose populations are aging at a much faster rate than in the developed world ( Kinsella & Velkoff 2001). Therefore, the contribution of Alzheimer's disease to the global burden of disease is likely to increase in the coming years.

Table 2

The burden of illness

The progression of Alzheimer's disease is accompanied by significant losses in cognitive and functional ability; consequently, many patients require a high level of care. Also, as median survival after diagnosis is 4-6 years ( Larson et al. 2004), care is usually required long term. The shift from institutional to community care in many countries has increased the burden placed on family caregivers, who are often elderly relatives ( Alzheimer's Society 2004). For example, a UK survey ("Right from the start") of over 2000 caregivers of patients with dementia found that 49% were over 70 years old ( Alzheimer's Society 2004). The caregiver burden encompasses physical, psychologic or emotional, social, and financial problems, and these problems appear to be experienced frequently. In the "Right from the start" survey, 60% of caregivers reported that they were suffering ill health or psychologic problems as a direct result of caring ( Alzheimer's Society 2004).

The value of services provided by unpaid caregivers is significant; in the UK, an estimate of the value in 2001-2002 was £57.4 billion ( Alzheimer's Society 2004). In the USA, the average lifetime cost of care for an individual with Alzheimer's disease was estimated at $US170 000, of which an average $US12 500 was paid by caregivers themselves ( Alzheimer's Association 2004). Many caregivers have to use private savings and assets to meet the cost of caring for a relative, and to pay for practical help and support such as home care or respite care ( Alzheimer's Association 2004; Alzheimer's Society 2004). Also, caregivers in paid work may lose out on income and promotion while those who give up work risk losing work skills, pension rights, and opportunities for reemployment ( Alzheimer's Society 2004). An Alzheimer's Association report estimates that Alzheimer's disease costs American businesses more than $US61 billion a year, of which $US24.6 billion covers Alzheimer's disease healthcare and $US36.5 billion covers costs related to caregivers, including lost productivity, absenteeism, and worker replacement ( Koppel 2002).

Alzheimer's disease also incurs a significant burden in terms of medical, institutional, and welfare resources. A report commissioned by the Alzheimer's Association in the USA predicted that by 2010 Medicare costs for beneficiaries with Alzheimer's disease would increase 54.5%, from $US31.9 billion in 2000 to $US49.3 billion ( Alzheimer's Association 2001). Additionally, Medicaid expenditures on residential dementia care would increase 80%, from $US18.2 billion to $US33 billion in 2010 ( Alzheimer's Association 2001).

Pathophysiology

Alzheimer's disease is characterized by shrinkage of the brain due to cell loss, especially in the areas concerned with memory, rational thought, and language development ( St George-Hyslop 2000). Theories for the cause of brain cell loss have suggested a role for factors such as tau-protein abnormalities ( Liou et al. 2003), metals ( Casadesus et al. 2004), vascular factors ( Fernando & Ince 2004), and viral infections ( Ringheim & Conant 2004). One theory in particular has increasing support: the "amyloid cascade hypothesis," which suggests that the production and accumulation of beta-amyloid peptide plays a key role ( Cummings 2004; Zlokovic et al. 2005). The observations that support beta-amyloid as the common initiating factor in Alzheimer's disease include the following:

all Alzheimer's disease patients have many amyloid plaques containing degenerating nerve endings, and their plaque count far exceeds that found in normal aging ( Perry et al. 1978)

the amount of amyloid plaques in "thinking" regions of the brain correlates in some studies with the degree of mental impairment ( Cummings & Cotman 1995)

the genes now known to cause Alzheimer's disease have been shown to increase beta-amyloid production ( APP, encoding amyloid precursor protein; PSEN, encoding presenilin) or deposition ( ApoE4, encoding apolipoprotein E4) ( Gandy 2005).

Beta-amyloid protein is thought to exert neurotoxic effects via secondary mechanisms, including the formation of neurofibrillary tangles, oxidation and lipid peroxidation, glutamatergic excitotoxicity, inflammation, and activation of apoptotic cell death ( Cummings 2004; Zlokovic et al. 2005) (). Among nuclear groups of neurons responsible for maintenance of specific transmitter systems, cell dysfunction and cell death lead to deficits in the neurotransmitters acetylcholine, norepinephrine, and serotonin ( Palmer et al. 1988; Pappas et al. 2000; Cummings 2004).

Observations of damage and deficits in the cholinergic system provided the rationale for the development of AChEIs, which inhibit the hydrolysis of acetylcholine. By increasing levels of available acetylcholine, AChEIs may help to compensate for the loss of functioning cholinergic neurons.

General treatment principles

The first step recommended in guidelines is the development of a treatment plan taking into account the stage of illness and severity of problems ( APA 1997; California Workgroup 2002). At each stage of impairment, certain symptoms should be anticipated (), and the patient and their family should be helped to plan for future symptoms.

Table 3

Mild: patient has difficulties limited to complex tasks such as balancing a checkbook

Depression
Awareness of and frustration with deficits

Moderate: patient has difficulty completing simple household tasks

Depression
Development of psychotic symptoms such as paranoia

Severe: patient requires assistance with basic activities of daily living such as personal hygiene

Psychosis
Agitation

Profound: patient is terminal and totally dependent

Bedbound with significant motor deficits
Feeding difficulties
Incontinence

A number of nonpharmacologic or environmental interventions may help some patients with dementia. Although limited research data are available to support their use, clinical practice suggests that improved symptoms may occur with behavior-, stimulation-, emotion-, and cognition-oriented interventions ( APA 1997). Treatments directed at caregivers, including supportive psychotherapy, support groups, and respite care, are likely to be helpful to the caregiver and consequently may benefit patients as well.

Cognitive decline

Specific symptoms targeted for treatment include cognitive decline, psychosis and agitation, depression, and sleep disturbances. For the treatment of cognitive decline, guidelines recommend the use of AChEIs in patients with mild to moderate Alzheimer's disease ( APA 1997; Doody et al 2001b; California Workgroup 2002). Review of guideline recommendations for the treatment of other specific target symptoms is beyond the scope of this article.

Four AChEIs (tacrine, galantamine, rivastigmine, and donepezil) are available. Tacrine is rarely used now because of hepatotoxicity ( Rabins 2004), so its characteristics are not reviewed in this article. Other standard prescribed agents for the symptomatic treatment of Alzheimer's disease include memantine and vitamin E. Memantine is an uncompetitive low-to-moderate affinity N-methyl-d-aspartate (NMDA) receptor antagonist that regulates glutamate activity. It was approved in 2003 for the treatment of cognition in moderate to severe Alzheimer's disease and, as it is relatively new to the market, memantine is not yet included in existing evidence-based treatment guidelines.

Vitamin E is recommended by guidelines as a treatment to delay time to clinical worsening ( APA 1997; Doody et al 2001b). However, recent data ( Petersen et al. 2005) conflict with evidence in support of this indication ( Tabet et al. 2000).

The treatment effects and disadvantages of rivastigmine, galantamine, memantine, and vitamin E are summarized in .

Unmet needs

Review of the characteristics of treatments included in shows that various unmet needs remain for the symptomatic treatment of mild to moderate Alzheimer's disease. Although the AChEIs rivastigmine and galantamine have demonstrated consistent gains on cognitive and global scales compared with placebo, these gains have been described as small on many of the measures of effect ( NICE 2005). However, in addition to improvements, AChEI treatment can have a stabilizing effect on cognitive and other symptoms ( Giacobini 2000). The clinical significance of this stabilizing effect requires further investigation.

Randomized controlled trial (RCT) evidence on outcomes of importance to patients and caregivers, such as quality of life and time to institutionalization, is limited and largely inconclusive ( NICE 2005). There is no strong evidence that any of the standard prescribed agents in Alzheimer's disease alters the course of the disease. Also, assessment of the adverse event profile of the AChEIs suggests improved tolerability as another area of unmet need.

Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease and can be given once daily ( Anon. 2005a). Generally, the initial dose is 5 mg/day, usually given at night. After 4-6 weeks, if it is well tolerated, the dose is often increased to 10 mg/day (see Dosage, administration, and formulations), although both the 5 mg and 10 mg doses are clinically effective. Donepezil has been available for 8-9 years and a large number of publications from clinical trials and studies conducted in community-based settings provide sources of clinical evidence.

Outcome measures

Alzheimer's disease is characterized by deterioration in functional ability, behavior, and cognition (see Disease overview). While some scales quantify these patient-oriented outcomes by assessing status in one or more of these domains, others attempt to quantify a patient's overall or global health state with respect to Alzheimer's disease ( Wolfson et al. 2000). lists the scales that have been used most frequently in trials of donepezil in mild to moderate Alzheimer's disease. These scales have evidence of reliability and validity, and have been used widely in studies of other Alzheimer's disease treatments ( Wolfson et al. 2000). However, it should be acknowledged that assessment via different domains is somewhat artificial. For example, cognitive function cannot be dissociated easily from ADLs. Also, the relation of statistical significance to clinical significance is a matter of debate in the field as is the clinical benefit of symptom stabilization. For example, there is some opinion that a change in ADAS-cog score of 3-4 points per year or change in MMSE of 2 points per year is of detectable clinical significance (A. Wimo, personal communication). Similarly, treatment may have no apparent clinical benefit in that symptoms are only stabilized but patient deterioration may follow cessation of treatment.

Table 5

Global

Clinical Global Impression of Change (CGIC), Clinician's Interview-Based Impression of Change (CIBIC)
Clinical Dementia Rating-sum of boxes (CDR-SB)

Measures general physical and mental condition of patients, including functional ability with respect to ADL, cognition, behavior, mood. CIBIC-plus includes caregiver input
Measures cognitive performance in six areas: memory, orientation, judgment/problem solving, community affairs, home/hobbies, personal care

Seven-point scale to measure improvement (1=very much improved, 7=very much worse)
Each category scored on five-point scale of impairment (0=none, 0.5=questionable, 1=mild, 2=moderate, 3=severe). The sum of ratings (0-18) provides the CDR-SB

Cognitive

Mini Mental State Examination (MMSE)
Cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-cog)

Includes 11 questions on orientation, memory, concentration, language, and praxis
Includes 11 items on orientation, memory, language, and praxis

Scale ranges from 0 to 30, a higher score indicating less impairment
Scale ranges from 0 to 70, a higher score indicating greater dysfunction

Functional

Progressive Deterioration Scale (PDS)
Instrumental Activities of Daily Living (IADL)
Katz activities of daily living (ADL) index

Examines ADL and instrumental ADL in 11 areas, e.g. extent to which patient can leave immediate neighborhood, use of familiar household implements, involvement in family finances and budgeting, self-care, and routine tasks
Measures competence in complex ADL, including telephoning, shopping, food preparation, housekeeping, laundering, use of transportation, use of medicine, ability to handle money
Assesses ability to perform ADL independently in six functions of bathing, dressing, toileting, transferring, continence, and feeding

Scale ranges from 0 to 100, a higher score indicating better functioning
Each behavioral area is scored 1 or 0. Higher score indicates better performance
Scored yes/no for independence in each function. Total score of 6 indicates full function, 2 or less indicates severe functional impairment

Behavior/mood

Neuropsychiatric Inventory (NPI)

Evaluates 10 items: delusions, hallucinations, dysphoria, anxiety, agitation, euphoria, apathy, irritability, disinhibition, aberrant motor behavior (pacing and rummaging). Two more items may also be assessed - night-time behavior, and changes in appetite and eating behaviors

Frequency of behavioral disturbances rated on four-point scale, severity rated on three-point scale. Higher total score indicates more behavioral problems

Global outcomes

There is level 1 evidence that donepezil is effective in improving and maintaining global outcomes in the short to medium term (12-24 weeks). There appears to be a clear treatment effect, since these findings are consistent on three scales: the Clinical Global Impression of Change (CGIC), Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC-plus), and the sum of boxes of the Clinical Dementia Rating (CDR-SB) scale (). Also, there was significant benefit with both the 5 mg/day and 10 mg/day doses of donepezil, with no clear dose-dependent differences. Six systematic reviews found statistically significant differences from placebo in groups treated with donepezil 5 or 10 mg/day in up to seven RCTs ( Pryse-Phillips et al. 2001; Clegg et al. 2002; Wolfson et al. 2002; Birks & Harvey 2003; Warner et al. 2004; NICE 2005; ). In a meta analysis of individual patient data from 10 RCTs ( Whitehead et al. 2004), the odds of improvement in CIBIC-plus scores was approximately twice as great with donepezil 5 or 10 mg/day as with placebo at 12 and 24 weeks.

Table 6

SD vs PL in change from BL (7 studies)

Trends towards improved scores vs PL (8 studies)

Meta analysis

DPZ, 5 or 10 mg/day, 12, 24 wk

OR of improvement vs PL on CIBIC-plus: 5 mg/day, 12 wk, 1.8; 10 mg/day, 12 wk, 1.9; 5 mg/day, 24 wk, 1.9; 10 mg/day, 24 wk, 2.1 (all P ≤0.001)

SD vs PL: 5 mg/day, 12 wk, −2.1; 10 mg/day, 12 wk, −2.5; 5 mg/day, 24 wk, −2; 10 mg/day, 24 wk, −3.1 (all P<0.001)
Whitehead et al. 2004

Meta analysis

DPZ 5 or 10 mg/day, 12, 24, 52 wk

CIBIC-plus: SD vs PL: 5 mg/day, 12 wk ( P=0.005); 10 mg/day, 12 wk ( P=0.0001); 5 mg/day, 24 wk ( P≤0.00001); 10 mg/day, 24 wk ( P ≤0.0001)

SD vs PL: 10 mg/day, 12 wk ( P=0.05); 5 mg/day, 24 wk ( P≤0.00001); 10 mg/day, 24 wk ( P ≤0.00001)

SD vs PL: 5 mg/kg, 12 wk ( P≤0.00001); 10 mg/day, 12 wk ( P≤0.00001); 5 mg/day, 24 wk ( P=0.0004); 10 mg/day, 24 wk ( P≤0.00001); 10 mg/day, 52 wk ( P=0.006)

SD vs PL, all P ≤0.00001: 5 or 10 mg/day, 12 or 24 wk

Systematic review

DPZ 5 or 10 mg/day, NR

SD vs PL: P<0.05 (6 studies)

SD vs PL: 5 mg/day, P≤0.01 (4 studies); 10 mg/day, P<0.001 (2 studies)
Wolfson et al. 2002

DPZ 5 or 10 mg/day, NR

SD vs PL (improvement) at 12, 18, 24 weeks (1 study)

DPZ 10 mg/day, 12 wk

SD vs PL for CIBIC-plus: MD 0.4 ( P<0.008) (1 study)

SD vs PL: MD 1.3 ( P<0.004) (1 study)

SD vs PL: MD 3.1 ( P<0.001) (1 study)

DPZ 5 mg/day, 24 wk

SD from BL (1 study)

This strong evidence is supported by a large open-label trial conducted to investigate the efficacy of donepezil in a routine setting in clinical practice ( Froelich et al. 2004). On the CGIC scale, nearly 80% of 186 patients showed an improvement or remained stable at week 24 relative to baseline; 54% showed little to much improvement, 25% were stable, and 17% were minimally worse.

There is limited evidence to show that the effect of donepezil on global outcomes is maintained beyond 24 weeks. One study of longer duration was identified in a systematic review ( Birks & Harvey 2003). This 52-week, double-blind, parallel-group RCT included 286 patients with mild to moderate Alzheimer's disease treated with donepezil 5 mg/day for 28 days and then 10 mg/day (according to the clinician's judgment) or placebo. Global outcomes were assessed using the Gottfries-Brane-Steen (GBS) scale. At 52 weeks, the mean difference from placebo was −6.01, an improvement with borderline statistical significance ( P=0.05).

Cognition

There is strong evidence that donepezil treatment improves cognition and that these improvements are maintained in the short to medium term (12-24 weeks) (). A meta analysis revealed benefits associated with donepezil 5 and 10 mg/day compared with placebo as shown by improvements in ADAS-cog MMSE scores at 12 and 24 weeks ( Birks & Harvey 2003). Another meta analysis of trials lasting 12-24 weeks showed weighted mean differences in ADAS-cog of −2.51 for 5 mg/day and −3.01 for 10 mg/day donepezil compared with placebo ( NICE 2005). This improvement in ADAS-cog score is broadly in line with results reported in other systematic reviews ( Pryse-Phillips et al. 2001; Wolfson et al. 2002; Birks & Harvey 2003; Warner et al. 2004) and in a meta analysis of individual patient data ( Whitehead et al. 2004).

The evidence in favor of improved cognition in the short to medium term conflicts with the results of a small RCT ( Hegerl et al. 2003). A 12-week study of donepezil 5 or 10 mg/day reported no significant improvement in ADAS-cog score versus placebo, although this trial included only 40 patients ( Hegerl et al. 2003). In another more recent but larger study (n=153), patients received donepezil 5 mg/day for 6 weeks, then 10 mg/day for 18 weeks ( Seltzer et al. 2004). At 24 weeks, there were significant improvements in both MMSE and ADAS-cog versus placebo ( P=0.03 and P=0.008, respectively).

The effect of donepezil on cognition appears to be maintained long term. A meta analysis showed that improvements in MMSE score are maintained at 52 weeks with donepezil 10 mg/day compared with placebo (weighted mean difference 1.84 points, P=0.006) ( Birks & Harvey 2003). In the AD2000 RCT of 565 community-resident patients, improvements in MMSE score were maintained beyond 52 weeks with donepezil 5 or 10 mg/day ( Courtney et al. 2004). There was a significant improvement in average score versus placebo over 2 years, albeit a modest one (0.8 points, P<0.0001), with no significant difference between dose groups. Interpretation of results from this study, however, must take into account concerns regarding its recruitment rate and methodology ( Akintade et al. 2004; Holmes et al. 2004a). Only one fifth of the planned number of patients was recruited and high discontinuation rates during the study are likely to have detrimentally affected the power of the study. Also, the study had repeated wash-out periods, and 16% of patients also had vascular dementia.

Some level 3 and 4 evidence also shows that donepezil treatment reduces the rate of decline in MMSE score. In an open-label, matched control study, 205 AChEI-treated and 218 untreated Alzheimer's disease patients were compared over 1 year ( Doody et al. 2001c). The decline in MMSE score was significantly less in 53 patients treated with donepezil (dose not specified) than in the untreated group (−1.5 vs −3.7 points, P=0.007). In a 3-year retrospective chart review (level 4 evidence) of patients given combination therapy of donepezil (≥5 mg/day) and vitamin E (≥1000 U/day) ( Klatte et al. 2003), average MMSE values decreased at 1, 2, and 3 years (average cumulative change −1.43, −4.05, and −6.27, respectively). The authors report that the decline was significantly slower than in untreated patients included in the 1986-1996 Consortium to Establish a Registry for Alzheimer's Disease (CERAD) database. However, the numbers of patients treated long term in this study were small (40 had 1-year, 38 had 2-year, and 22 had 3-year follow-up). Other level 3 evidence shows decreases in MMSE score from baseline at 1 year or 18 months but, as these studies did not include untreated control groups, it is difficult to put these data into context ( Saine et al. 2002; Blasko et al. 2004; Requena et al. 2004).

Donepezil appears to be at least as effective as other treatments of cognitive function, such as rivastigmine, galantamine, tacrine, and vitamin E (). One systematic review reported no significant differences in cognitive function (MMSE or ADAS-cog) between donepezil and rivastigmine (12-week open-label study) or galantamine (52 week RCT) ( Warner et al. 2004). In an open-label trial of donepezil and rivastigmine, there was no significant between-group difference in change from baseline MMSE score ( Mossello et al. 2004). Similarly, there were no significant differences in MMSE or ADAS-cog scores in an open-label study of patients treated with donepezil, rivastigmine, or galantamine ( Aguglia et al. 2004). A difference was observed between tacrine-and donepezil-treated groups in another open-label study ( Doody et al. 2001c); the difference from the untreated group was significant in donepezil-treated patients ( P=0.007) but not in the tacrine group ( P=0.33). One RCT showed significant differences between donepezil- and vitamin E-treated patients in favor of donepezil in MMSE and ADAS-cog scores, the greatest differences seen in patients with fluctuating cognition ( Onofrj et al. 2003). However, only 23 patients were included in this trial and the randomized part of the study was of short duration (30 days).

Function

There is level 1 evidence that donepezil treatment produces significantly improved or less deterioration in functional ability than placebo ( Clegg et al. 2002; Wolfson et al. 2002; Birks & Harvey 2003; Warner et al. 2004; ). Although this finding was not statistically significant in all short-term trials ( NICE 2005), there is evidence of significant benefit with long-term donepezil treatment. In a 1-year trial of donepezil 10 mg/day, there was significant benefit versus placebo in the primary endpoint, time to clinically evident decline in function ( Wolfson et al. 2002; Birks & Harvey 2003; Warner et al. 2004). One systematic review reports that, in this study, donepezil delayed median time to primary endpoint by 5 months compared with placebo ( Warner et al. 2004).

Two RCTs also found significant differences in favor of donepezil over placebo in maintaining or improving function in the long term (; Wimo et al. 2003b; Courtney et al. 2004). In one trial, subdomain analysis of the PDS at week 52 showed benefits with donepezil 5 or 10 mg/day treatment in 9 of 10 domains ( Wimo et al. 2003b). The difference from placebo reached statistical significance for the telephone ( P=0.009), memory ( P=0.003), and self-care ( P=0.042) items. In the same study, significantly fewer patients in the donepezil group deteriorated in individual IADL items at week 52 compared with placebo-treated patients. In the AD2000 study, the donepezil group had better Bristol Activities of Daily Living Scale (BADLS) scores at all timepoints after 12 weeks ( Courtney et al. 2004); the average difference was 1 point better with donepezil than with placebo ( P=0.0004), and efficacy was maintained over 2 years. There was no significant difference between the 5 and 10 mg/day dose groups ( P=0.24).

This evidence is supported by level 3 evidence showing that patients' function remained relatively stable after up to 12 months of donepezil 5 or 10 mg/day treatment ( Saine et al. 2002; Santens & Ventura 2003; Aguglia et al. 2004; Mossello et al. 2004; ). Also, donepezil appears to be at least as effective in maintaining function as other treatments, such as rivastigmine and galantamine. In a comparative study of donepezil, rivastigmine, and galantamine, there were no significant differences between groups in IADL and ADL at 6 months ( Aguglia et al. 2004). Another trial found no significant difference between donepezil and rivastigmine groups in IADL score changes over time but a significantly lower decline in ADL with donepezil at 9 months ( P=0.02) ( Mossello et al. 2004).

Behavior/mood

There is some level 1 evidence showing that donepezil has an effect in improving or limiting deterioration in behavior or mood in the short to medium term ( Birks & Harvey 2003; NICE 2005; ). This is supported by level 2 evidence of significant benefit compared with placebo ( Holmes et al. 2004b; ). This trial began with an open-label phase of treatment with donepezil 5 mg/day for 6 weeks followed by 10 mg/day for a further 6 weeks. At 12 weeks, total NPI and NPI distress scores were significantly lower compared with baseline. Further improvements in NPI and NPI distress scores were observed in the medium term during the subsequent 12-week randomized part of the study, and these improvements were significant in comparison with placebo.

Table 9

1

Systematic review

DPZ may have some effect in improving or limiting further deterioration on the NPI scale vs PL, at least in the short term (4 studies)

1

Systematic review

DPZ 10 mg/day, 12 and 24 wk

SD vs PL at 24 wk (MD −4.42, P=0.01) but not at 12 wk (1 study)

2

RCT

DPZ 10 mg/day (n=41) or PL (n=55), 12 wk

SD vs PL for improvement in NPI (−2.9 vs 3.3, P=0.02) and NPI distress scores (−2 vs 1, P=0.01)
Holmes et al. 2004b

3

OL

DPZ 5 then 10 mg/day (n=134), 12 wk

SD vs BL for improvement in NPI (13 vs 22; P<0.0001) and NPI distress scores (7.9 vs 13.5, P<0.0001). All domains of NPI improved (except elation) ( P<0.005)
Holmes et al. 2004b

3

OL

DPZ 5 mg/day (n=70), 12 wk

30% responded (≥4-point reduction in NPI), 60% showed no change, 10% worsened (≥4-point increase in NPI)
Tanaka et al. 2004

3

MC, OL

DPZ 5 or 10 mg/day (n=200), 24 wk

No change from BL after ≥140 days DPZ
Santens & Ventura 2003

This evidence is supported by two open-label trials that showed improvement or stabilization of NPI scores with donepezil treatment in the short to medium term ( Santens & Ventura 2003; Tanaka et al. 2004). In a study of 70 patients, the majority showed no behavioral change after 12 weeks (≤3-point decrease or increase in total NPI score), and nearly one third had improved symptoms (≥4-point reduction) ( Tanaka et al. 2004). In a study performed in a routine clinical setting, Santens and Ventura (2003) found no significant change in overall behavior score in 200 patients after 6 months of treatment with donepezil 5 mg/day or 10 mg/day. The NICE Assessment Group also comments that, in observational studies, use of donepezil appeared to show benefit on improvements in social behavior assessed by the caregiver diary ( NICE 2005).

No evidence was found showing that donepezil improves or maintains behavioral symptoms long term (beyond 6 months).

Disease progression

Disease progression has been assessed by monitoring both patient- and disease-oriented outcomes. Patient-oriented outcomes include progression of disability and death rate, while disease-oriented outcomes include regional cerebral blood flow (rCBF), ¹²³ I quinuclidinyl benzilate (QNB) uptake in the brain, quantitative electroencephalogram (qEEG), and the degree of hippocampal atrophy.

The results of two RCTs provide evidence (level 2) of an effect by donepezil on disease progression in terms of patient-oriented outcomes ( Courtney et al. 2004; Petersen et al. 2005). In the AD2000 study, there were no significant benefits with donepezil compared with placebo in progression of disability at 3 years or numbers of deaths ( Courtney et al. 2004). In a study of patients with mild cognitive impairment, the donepezil group (10 mg/day) had reduced likelihood of progression to Alzheimer's disease at 12 months in comparison with placebo ( P=0.04), but this difference was not maintained at 3 years ( Petersen et al. 2005).

Lower level evidence of an impact on mortality rate is available from a retrospective matched cohort study using a database of nursing home residents in six US states ( Gasper et al. 2005). A total of 5423 residents treated with donepezil were compared with 5423 nonusers of donepezil. Based on Cox proportional hazards models, donepezil users showed a lower mortality rate than nonusers [hazard rate ratio (HRR) 0.89]. This survival advantage remained after adjusting for sociodemographic factors, other psychotropic drugs, and comorbid conditions (HRR 0.9).

There is some level 2 evidence that donepezil may have an effect on the disease-oriented outcomes, rCBF ( Nakano et al. 2001), ¹²³I QNB uptake in the brain ( Kemp et al. 2003), and hippocampal volume ( Krishnan et al. 2003; ). Treatment with donepezil 5 mg/day reduced the decline in rCBF, possibly indicating preservation of functional brain activity ( Nakano et al. 2001). Kemp et al. (2003) demonstrated better uptake of ¹²³I QNB in patients who had received donepezil 10 mg/day for 4 months than in those on placebo; the authors suggest this shows cholinergic treatment may have a neuroprotective role. At the end of a 24-week study of patients treated with donepezil 10 mg/kg or placebo, donepezil-treated patients had significantly smaller mean decreases in total ( P<0.01) and right ( P<0.02) hippocampal volumes ( Krishnan et al. 2003). Again, these data suggest a possible neuroprotective effect of donepezil in Alzheimer's disease.

Table 10

1

Systematic review

In observational studies, DPZ appeared to show benefit on delayed time to NHP

2

MC, DB, RCT

DPZ 5 or 10 mg/day (n=283) or PL (n=283), ≤3 y

NSD vs PL for progression of disability or numbers of deaths

NSD vs PL (42 vs 44% at 3 y, P=0.4)
Courtney et al. 2004

2

MC, DB, RCT

DPZ 10 mg/day (n=253), vitamin E (n=257), or PL (n=259), 3 y

SD ( P=0.04) in favor of DPZ vs PL for disease progression at 12 mo (16 vs 38 pts) but not after 3 y
Petersen et al. 2005

2

DB, RCT

DPZ 10 mg/day (n=6) or PL (n=6), 4 mo

¹²³ I QNB uptake better preserved in DPZ-than in PL-treated pts
Kemp et al. 2003

2

RCT

DPZ 10 mg/day (n=34) or PL (n=33), 24 wk

SD in favor of DPZ vs PL for mean decreases in total ( P<0.01) and right ( P<0.02) hippocampal volume
Krishnan et al. 2003

3

OL, matched control

DPZ 5 mg/day (n=54), 1 y; untreated control (n=93)

SD ( P=0.008) vs control in mean annual rate of hippocampal volume loss (3.82 vs 5.04%)
Hashimoto et al. 2005

3

OL, matched control

DPZ 5 mg/day (n=20) for 1 y; untreated control (n=11)

SD vs control in MMSE ( P<0.01) and qEEG ratio ( P<0.01)
Rodriguez et al. 2002

3

OL, matched control

DPZ, NR (n=130), TAC, NR (n=22), RIV, NR (n=6), control (n=135), follow-up at 2 and 3 y

At 2 y, NHP 16% in control vs 1% in treated group (relative risk, 0.06; P=0.001). At 3 y, 50 vs 11% ( P<0.001)
Lopez et al. 2005

This evidence is supported by several 1-year, open-label trials that included matched control groups ( Nobili et al. 2002; Rodriguez et al. 2002; Hashimoto et al. 2005; ). In one study, 54 patients who received donepezil 5 mg/day underwent MRI twice at a 1-year interval ( Hashimoto et al. 2005). The results were compared with those from a matched control group of 93 untreated patients. The mean annual rate of hippocampal atrophy in the treated group was significantly lower than in the control group (3.82 vs 5.04%, P=0.008), suggesting a neuroprotective effect with donepezil. Similarly, rCBF was preserved in 25 patients undergoing donepezil treatment (5 mg/day) for 1 year but was reduced in 13 untreated patients ( Nobili et al. 2002). Long-term treatment with donepezil 5 mg/day has also been shown to lead to lesser deterioration of qEEG in comparison with an untreated group of patients ( Rodriguez et al. 2002).

On balance, donepezil appears to have an effect on biomarkers of disease progression, but further RCT evidence is needed to confirm if these translate into clinical effects reflecting disease modification.

Time to institutionalization

There is limited and conflicting evidence that donepezil treatment has an effect on the patient-oriented outcome of delayed time to institutionalization (). The AD2000 RCT found no significant difference between the donepezil group and placebo group in institutionalization at 1 or 3 years ( Courtney et al. 2004). However, the small number of patients remaining in this study at 3 years must be taken into account (n=57 and 60 in donepezil and placebo groups, respectively).

Lower level evidence (level 3) from two large studies supports a delay in or reduced risk of nursing home placement among patients treated with donepezil ( Geldmacher et al. 2003; Beusterien et al. 2004), particularly those who complied well with their treatment regimen ( Geldmacher et al. 2003; ). In a smaller study, 135 pairs of patients with probable Alzheimer's disease were matched to compare those on AChEIs (130 on donepezil) with untreated patients ( Lopez et al. 2005). Within 2 years of study entry, 16% of untreated patients were in a nursing home, compared with 1% of treated patients (relative risk, 0.06; 95% confidence interval 0.008, 0.48; P=0.001). This significant difference in nursing home admissions was maintained at 3 years (50 vs 11%, P<0.001). These results are supported by a systematic review which notes that, in observational studies, use of donepezil appeared to show a benefit on delayed time to nursing home placement ( NICE 2005).

Quality of life

Evidence is divided on whether donepezil improves patients' quality of life (). The systematic reviews reported mixed results, with the most recent (conducted by the NICE Assessment Group) pointing to improvements, no change, and worsening quality of life in three RCTs, and the impact of the dose used for donepezil being unclear ( NICE 2005). Only one open-label study was identified beyond those covered in the systematic reviews, and this study did not use a validated quality-of-life scale for dementia ( Frölich et al. 2002). Instead, investigators were asked to answer the question, "How did therapy with donepezil influence the quality of life of the patient and/or his family over the observation period?", offering three possible outcomes: improved, unchanged, or worsened. After 3 months of treatment, quality of life was judged as "improved" in 70% of patients overall.

Caregiver burden

There is some evidence that donepezil lessens caregiver burden in terms of caring time spent each day (). However, only one systematic review mentions this aspect ( Birks & Harvey 2003), reporting that caregiver stress was assessed in one study, but the results were reported without any measure of precision. This review also highlights the results of an RCT, which showed significant benefit with donepezil treatment in comparison with placebo in time spent each day by the caregiver assisting with ADL.

Level 2 evidence from RCTs is conflicting ( Courtney et al. 2004; Wimo et al. 2004). At 12 months, Wimo et al. (2004) reported a significant difference in caring time relative to baseline between caregivers of donepezil-treated patients and caregivers of placebo-treated patients of 1.1 h per day ( P=0.03) ( Wimo et al. 2004). In the AD2000 study, however, there were no significant differences between the donepezil and placebo groups in any of the caregiver parameters assessed ( Courtney et al. 2004).

Further evidence suggesting a positive effect of donepezil on caregiver burden comes from an open-label study in which a self-administered, nationwide survey was used to match 274 caregivers of patients treated with donepezil to 274 caregivers of untreated patients ( Fillit et al. 2000). There were significant differences between the groups in favor of donepezil on the total difficulty scale ( P=0.004), mainly due to differences in assisting with walking ( P≤0.001), providing emotional support ( P≤0.001), and managing behavioral problems ( P=0.05). However, there was no significant difference on the demand scale, which measured the frequency of engaging in caregiving activities.

Tolerability

Poor drug tolerability is a serious concern in patients with Alzheimer's disease because of their advanced age and the high prevalence of comorbid disease ( Jackson et al. 2004). There is level 1 evidence that donepezil is well tolerated and that adverse events are usually cholinergic in nature (e.g. nausea, vomiting, and diarrhea) and generally mild and transient ( Clegg et al. 2002; Wolfson et al. 2002; Birks & Harvey 2003; Warner et al. 2004; Whitehead et al. 2004). Adverse events were recorded more often in patients receiving donepezil than in those on placebo, and there was an increased frequency with the higher dose of 10 mg/day ( Birks & Harvey 2003; Whitehead et al. 2004; NICE 2005). Also, in the short term, more patients discontinued donepezil treatment on account of adverse events than in placebo groups. However, when treatment was longer than 12 weeks, there was no evidence of a difference in numbers of patients leaving the trials ( Birks & Harvey 2003).

A dose-dependent effect was confirmed in a meta analysis of individual patient data from 10 RCTs ( Whitehead et al. 2004). In 821 patients treated with donepezil 5 mg/day, only the incidence of diarrhea was significantly higher in the donepezil group in comparison with placebo (7 vs 4%, P<0.01). Among patients treated with donepezil 10 mg/day (n=662), nausea (21%), diarrhea (16%), headache (13%), insomnia (12%), vomiting (11%), dizziness (8%), and pain (8%) (all P<0.01), and rhinitis (8%, P<0.05) had significantly higher incidences compared with placebo. However, the authors note that, of the adverse events that occurred in at least 5% of patients, only diarrhea, nausea, vomiting, and dizziness were considered related to study medication in a majority of patients in each treatment group. Also, most adverse events were mild, only occasionally moderate in intensity, and generally transient in nature.

In the larger open-label studies (n>100), reported incidences of adverse events ranged widely, from 9.3 to 96% (). Gastrointestinal and psychiatric/neurologic adverse events were reported most frequently, and the frequency of discontinuations due to adverse events was less than 10% in most studies. In the two largest studies conducted, donepezil treatment was regarded as well tolerated, despite high concomitant medication use and extensive comorbidity among the patient groups ( Hager et al. 2003; Relkin et al. 2003). However, there was inconsistency in incidences of adverse events; while Relkin et al. (2003) reported incidences in line with those in RCTs, Hager et al. (2003) reported considerably lower incidences. The latter authors suggest that this may be explained by the naturalistic nature of the postmarketing surveillance study, where the treating physician is likely to not ask for adverse events as specifically as in a controlled trial. Also in this study, most patients whose donepezil dose was increased to 10 mg were able to tolerate the treatment as well as those who continued on the 5 mg dose ( Hager et al. 2003). In contrast, Relkin et al. (2003) found the occurrence of cholinergic-induced adverse events appeared to be directly related to the timing of dose increase from 5 to 10 mg/day at 4 weeks ( Relkin et al. 2003).

Table 12

256, 9 mo

NR

No major drug-related AEs observed. No detail given

8 patients (3%): behavioral (4 patients) gastrointestinal (3), pulmonary (1)

SD between DPZ and RIV (3 vs 17%, P<0.01), DPZ and GAL (3 vs 21%, P<0.01) in percentage discontinuation
Mossello et al. 2004

2094, 3 mo

12.2%

Nausea (2.2%), diarrhea (1.4%), trembling inside (1.4%), vomiting (1.1%)

6.1% (55.4% of discontinuations)

Global tolerability judged by investigators as "very good" or "good" in 91.3% of patients assessed (n=1989). SAEs reported in 46 patients (2.2%); 10 considered possibly/probably related to DPZ treatment

The tolerability profile of donepezil appears be qualitatively similar to that of rivastigmine and galantamine in terms of the nature of adverse events. However, in terms of relative frequency of adverse events, there is level 1 evidence that fewer people had at least one adverse event with donepezil compared with rivastigmine, although the difference was not significant (43 vs 58%, relative risk 0.74) ( Warner et al. 2004). The between-group difference in number of patients discontinuing treatment, however, was significant in favor of donepezil (11 vs 31%, relative risk 0.35). Similar rates of adverse events, severe adverse events, and adverse events leading to withdrawal were reported in galantamine- and donepezil-treated patients ( Warner et al. 2004). This is supported by level 3 evidence from 6- and 9-month open-label trials ( Aguglia et al. 2004; Mossello et al. 2004). In one study, patients were administered donepezil (n=256), rivastigmine (n=132), or galantamine (n=19) ( Mossello et al. 2004). The percentage of patients that discontinued treatment was significantly lower in the donepezil group (3%) than in the rivastigmine (17%, P<0.01) or galantamine groups (21%, P<0.01), although the number of patients in the galantamine group was low. In another study of patients treated with donepezil (n=70), rivastigmine (n=121), or galantamine (n=51), the most common adverse events were gastrointestinal and the frequency of these events were similar in all treatment groups (<6% for each event) ( Aguglia et al. 2004).

Thus, there is strong evidence that donepezil is well tolerated and that the most common adverse events can be predicted from its cholinergic mechanism of action. Also, the frequency of these adverse events appears to be dose related. There is some evidence that the incidence of adverse events is lower outside of the clinical trial setting, although a wide variation in percentages was observed in open-label studies.

Table 13

Direct medical costs
Preventive services (including screening of high-risk individuals)

Productivity losses (for both patients and caregivers)

Monetarized value of the psychologic burden and stress on patients and caregivers and of the decrease in quality of life

Diagnostic services
Doctor consultations (generalist and specialist)
Laboratory and imaging tests (e.g. MRI, SPECT)

Opportunity costs of time spent by patients and caregivers (travel, waiting for providers, hospital stays)

Treatment and care services
Physician services
Pharmaceuticals/drugs
Medical and nursing procedures
Physiotherapy and other allied professional (e.g. rehabilitation) services
Hospitalization and day hospitals
Nursing home care
Respite care
Caregiver support and training programs

Direct personal costs
Transportation
Homecare services (personal and nursing)
Equipment and aid supplies used in the home
Home modifications/alterations

Direct nonhealthcare costs
Social services and allowances
Meal delivery services
Group homes/special care units

# data[].attributes.attachment_link.title
Donepezil in Alzheimer's disease: an evidence-based review of its impact on clinical and economic outcomes

# data[].attributes.attachment_link.description
Donepezil is indicated for the symptomatic treatment of mild to moderate Alzheimer's disease. It is a specific and reversible inhibitor of acetylcholinesterase (AChE); by increasing levels of available acetylcholine, donepezil may compensate for the loss of functioning cholinergic brain cells.

# data[].attributes.body
Galantamine
-Positive
slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

-Negative
-Chest pain or discomfort.
-lightheadedness, dizziness, or fainting.
-shakiness in the legs, arms, hands, or feet.
-shortness of breath.
-slow or irregular heartbeat.
-unusual tiredness.

https://www.mayoclinic.org/drugs-supplements/galantamine-oral-route/side-effects/drg-20067458?p=1

# data[].attributes.attachment_link.readable_text
Description and Brand Names

Drug information provided by: IBM Micromedex

US Brand Name

Descriptions

Galantamine is used to treat mild to moderate dementia (memory loss and mental changes) that is a sign of Alzheimer's disease. Galantamine will not cure Alzheimer's disease, and it will not stop the disease from getting worse. However, galantamine can improve the thinking ability in some patients with Alzheimer's disease.

In Alzheimer's disease, many chemical changes take place in the brain. One of the earliest and biggest changes is that there is less of a chemical called acetylcholine (ACh). ACh helps the brain to work properly. Galantamine slows the breakdown of ACh, so it can build up and have a greater effect. However, as Alzheimer's disease gets worse, there will be less and less ACh, so galantamine may not work as well.

This medicine is available only with your doctor's prescription.

This product is available in the following dosage forms:

Portions of this document last updated: Aug. 01, 2022

Copyright © 2022 IBM Watson Health. All rights reserved. Information is for End User's use only and may not be sold, redistributed or otherwise used for commercial purposes.

# data[].attributes.attachment_link.description
Drug information provided by: IBM Micromedex Galantamine is used to treat mild to moderate dementia (memory loss and mental changes) that is a sign of Alzheimer's disease. Galantamine will not cure Alzheimer's disease, and it will not stop the disease from getting worse. However, galantamine can improve the thinking ability in some patients with Alzheimer's disease.

# data[].attributes.body
United States
1 of every 9 people
10.7% of people over the age of 65
Worldwide
50 million people
Researchers think the number of people with Alzheimer's it will continue to grow

United States
WorldWide

# data[].attributes.body
- age
-changes in your brain
-genetics
Causes

# data[].attributes.body
-Age
-Family history
-Downs syndrome
-head injuries
-cardiovascular disease
-smoking
-diabetes
-obesity
-high blood pressure
-high cholesterol

# data[].attributes.body
-Memory loss

-losses track of dates

-poor judgment

-taking longer to complete everyday tasks

-increased anxiety

-mood and personality changes

-wandering and getting lost

symptoms