Background
** This review is awaiting update with a new protocol. The methods used for the review were acceptable when the review was published but do not meet contemporary standards, and the review is also considerably out of date. Therefore, readers should note that the review may not represent a reliable basis for decision making. **

Since the introduction of the first cholinesterase inhibitor (ChEI) in 1997, most clinicians and probably most patients would consider the cholinergic drugs, donepezil, galantamine and rivastigmine, to be the first line pharmacotherapy for mild to moderate Alzheimer's disease.

The drugs have slightly different pharmacological properties, but they all work by inhibiting the breakdown of acetylcholine, an important neurotransmitter associated with memory, by blocking the enzyme acetylcholinesterase. The most that these drugs could achieve is to modify the clinical manifestations of Alzheimer's disease. Cochrane reviews of each ChEI for Alzheimer's disease have been completed.

Objectives
To assess the effects of donepezil, galantamine and rivastigmine in people with mild, moderate or severe dementia due to Alzheimer's disease based on evidence summarised in three existing Cochrane Reviews

Search methods
The Cochrane Dementia and Cognitive Improvement Group's Specialized Register was searched using the terms 'donepezil', 'E2020' , 'Aricept' , galanthamin* galantamin* reminyl, rivastigmine, exelon, "ENA 713" and ENA-713 on 12 June 2005. This Register contains up-to-date records of all major health care databases and many ongoing trial databases.

Selection criteria
All unconfounded, blinded, randomized trials of at least six months in which treatment with a ChEI at the usual recommended dose was compared with placebo or another ChEI for patients with mild, moderate or severe dementia due to Alzheimer's disease.

Data collection and analysis
Data were extracted by one reviewer (JSB), pooled where appropriate and possible, and the pooled treatment effects, or the risks and benefits of treatment, estimated.

Main results
The results of 10 randomized, double blind, placebo controlled trials demonstrate that treatment for 6 months, with donepezil, galantamine or rivastigmine at the recommended dose for people with mild, moderate or severe dementia due to Alzheimer's disease produced improvements in cognitive function, on average -2.37 points (95%CI -2.73 to -2.02, p<0.00001), in the midrange of the 70 point ADAS-Cog Scale. Study clinicians rated global clinical state more positively in treated patients. Benefits of treatment were also seen on measures of activities of daily living and behaviour. None of these treatment effects are large.

The effects are similar for patients with severe dementia, although there is very little evidence, from only two trials.

More patients leave ChEI treatment groups, (29%), than leave the placebo groups (18%).

There is evidence of more adverse events in total in the patients treated with a ChEI than with placebo. Although many types of adverse event were reported, nausea, vomiting, diarrhoea, were significantly more frequent in the ChEI groups than in placebo.

There is only one randomized, double blind study in which two ChEIs are compared, donepezil compared with rivastigmine.
There is no evidence of a difference between donepezil and rivastigmine for cognitive function, activities of daily living and behavioural disturbance at two years. Fewer patients suffer adverse events on donepezil than rivastigmine.

Authors' conclusions
The three cholinesterase inhibitors are efficacious for mild to moderate Alzheimer's disease. Despite the slight variations in the mode of action of the three cholinesterase inhibitors there is no evidence of any differences between them with respect to efficacy. The evidence from one large trial shows fewer adverse events associated with donepezil compared with rivastigmine.

Cholinesterase inhibitors for Alzheimer's disease

Background: A recent Cochrane review of reality orientation therapy identified the need for large, well-designed, multi-centre trials. 
Aims: To testthe hypothesis that cognitive stimulation therapy (CST) for older people with dementia would benefit cognition and quality of life. 
Method: A single-blind, multi-centre, randomised controlled trial recruited 201 older people with dementia. The main outcome measures were change in cognitive function and quality of life. An intention-to-treat analysis used analysis of covariance to control for potential variabilityin baseline measures. 
Results: One hundred and fifteen people were randomised within centres to the intervention group and 86 to the control group. At follow-up the intervention group had significantly improved relative to the control group on the Mini-Mental State Examination (P=0.044), the Alzheimer’s Disease Assessment Scale – Cognition (ADAS–Cog) (P=0.014) and Quality of Life – Alzheimer’s Disease scales (P=0.028). Using criteria of 4 points or more improvement on the ADAS–Cog the number needed to treat was 6 for the intervention group. 
Conclusion: The results compare favourably with trials of drugs for dementia. CST groups may have worthwhile benefits for many people with dementia.

/pdf/efficacy-of-an-evidence-based-cognitive-stimulation-therapy-2669vmy987.pdf

Efficacy of an evidence-based cognitive stimulation therapy programme for people with dementia: randomised controlled trial

Raina and associates reviewed the evidence for the effectiveness of cholinesterase inhibitors and memantine in achieving clinically relevant improvements in patients with dementia Consistent diffe

Effectiveness of Cholinesterase Inhibitors and Memantine for Treating Dementia: Evidence Review for a Clinical Practice Guideline

Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.

Polymorphism of human cytochrome P450 enzymes and its clinical impact

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(02)08267-3.pdf

Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial

Objective: To evaluate the efficacy and safety of galantamine in the treatment of Alzheimer9s disease. Design: Randomised, double blind, parallel group, placebo controlled trial. Setting: 86 outpatient clinics in Europe and Canada. Participants: 653 patients with mild to moderate Alzheimer9s disease. Intervention: Patients randomly assigned to galantamine had their daily dose escalated over three to four weeks to maintenance doses of 24 or 32 mg. Main outcome measures: Scores on the 11 item cognitive subscale of the Alzheimer9s disease assessment scale, the clinician9s interview based impression of change plus caregiver input, and the disability assessment for dementia scale. The effect of apolipoprotein E4 genotype on reponse to treatment was also assessed. Results: At six months, patients who received galantamine had a significantly better outcome on the 11 item cognitive subscale of the Alzheimer9s disease assessment scale than patients in the placebo group (mean treatment effect 2.9 points for lower dose and 3.1 for higher dose, intention to treat analysis, P Conclusion: Galantamine is effective and well tolerated in Alzheimer9s disease. As galantamine slowed the decline of functional ability as well as cognition, its effects are likely to be clinically relevant.

https://www.bmj.com/content/bmj/321/7274/1445.full.pdf

Els Gaens

Papers

Efficacy and safety of galantamine in patients with mild to moderate Alzheimer's disease: multicentre randomised controlled trial