Medicines for dementia

There is a wide range of drugs used to treat the variety of symptoms that can present with dementia. For example, psychotic symptoms may develop and be treated with antipsychotics although olanzapine and risperidone should not be used as they increase risk of stroke in older people with dementia. These drugs used to treat secondary symptoms are examined elsewhere in this chapter. Dosing may be lower than normal due to lower metabolic rates in older people who make up the majority of dementia sufferers. This section examines those drugs designed to treat the cognitive impairment – largely memory defi  cits, which are characteristic of dementia.

Memory and learning is a highly complex function involving a multitude of pathways and a variety of neurotransmitters. As yet there is only an incomplete understanding of the processes involved. However, research has implicated the degeneration of cholinergic neurons originating in part of the amygdala called the nucleus basalis of Meynert as a major factor in the impairment of short-term memory and there seems an overall reduction in acetylcholine activity. This has led to the development of drugs designed to boost cholinergic activity to enhance cognitive function and memory impairment. These drugs are termed cholinesterase inhibitors. Three are currently licensed for use in mild –to moderate dementia in Alzheimer’s disease: donepezil, galantamine and rivastigmine. One further drug, memantine, is licensed for use in moderate–to severe dementia in Alzheimer’s disease but it is not a cholinesterase inhibitor.

The prescribing of these drugs has been the subject of considerable public debate. At the moment a technology appraisal by NICE recommends that they are made available in mild –to moderate Alzheimer’s disease as long as certain criteria are met (see below). This has proved controversial and a legal challenge was mounted, albeit unsuccessfully, by a number of bodies including the Royal College of Nursing, the Royal College of Psychiatry, Age Concern and the Alzheimer’s Society. It is of interest that a cost effectiveness study of memantine in Finland concluded that the extended independence and delay of institutionalisation amply offset the cost of treatment.

Mechanisms of action

Cholinesterase inhibitors inhibit the enzyme that breaks down acetylcholine called acetylcholinesterase (AChE). By doing this there is an increase in the amount of acetylcholine available. The three drugs, although achieving the same therapeutic goal, are different from one another. Donepezil is a long acting, reversible AChE inhibitor, rivastigmine is intermediate acting and pseudo-irreversible, and galantamine may have a dual action in not only inhibiting acetylcholine breakdown in a similar way, but through its agonist activity at nicotinic receptors may induce acetylcholine release. Memantine has a different action altogether. It is thought that a mechanism responsible for neuronal injury or death is over-exposure to the excitatory neurotransmitter glutamate. This is termed �?excitotoxicity’. One receptor involved in this process is the glutamate N-methyl-d-aspartate (NMDA) receptor. Memantine is a non-competitive, low affi nity, NMDA antagonist, allowing normal activity but having the ability to regulate excess Ca2+ ion influx under conditions of over-activation. This impedes the progression of symptoms.

Evidence of effectiveness

A systematic review of studies of cholinesterase inhibitors used to treat mild to moderate dementia shows that there is no notable variation between the three drugs. Small benefi  ts were noted in activities of daily living and behaviour as well as assessment scales. Similar benefi  ts were also noted in cases of severe dementia but the number of studies (two) is too small to draw conclusions. However small the benefi ts may appear, it can be argued that small or indeed no benefi ts over a period of 6 months, the timescale of a number of trials, constitutes a therapeutic success in what is a progressively degenerative disease.

Side effects

The most common side effects of cholinesterase inhibitors are gastrointestinal. These include nausea, vomiting and diarrhoea. Others such as headaches, insomnia, dizziness and psychiatric disturbances may also occur. Memantine can cause constipation, headaches, drowsiness and dizziness. Less commonly it can induce vomiting, confusion, hallucinations and fatigue. Seizures have also been reported but very rarely.

Interactions

The drugs for dementia have few strong interactions. Memantine has an increased risk of causing CNS toxicity when given with amantadine, ketamine or dextromethorphan and it is recommended that they are not used together. Galantamine may have its plasma concentration levels increased by a number of drugs, notably paroxetine and erythromycin. Key points regarding dementia and Alzheimer’s disease can be found in Boxes 2.5 and 2.6, respectively.

Dementia – key points

• Prescribing should concur with the relevant guidance.
• Co-morbidity is common in older people and care should be taken with possible interactions.
• Lower metabolic rates may affect dosing regimes.

NICE guidance

The three drugs donepezil, rivastigmine and galantamine should be made available in the NHS as one component of the management of those people with mild and moderate Alzheimer’s disease (AD) whose mini mental state examination (MMSE) score is above 10 points under the following conditions:
• Diagnosis that the form of dementia is AD must be made in a specialist clinic according to standard diagnostic criteria.
• Assessment in a specialist clinic, including tests of cognitive, global and behavioural functioning and of activities of daily living, should be made before the drug is prescribed.
• Clinicians should also exercise judgement about the likelihood of compliance; in general, a carer or care-worker that is in suffi cient contact with the patient to ensure compliance should be a minimum requirement.
• Only specialists (including old-age psychiatrists, neurologists and care of older people physicians) should initiate treatment. Carers’ views of the patient’s condition at baseline and follow-up should be sought. If general practitioners are to take over prescribing, it is recommended that they should do so under an agreed shared-care protocol with clear treatment end points.
• A further assessment should be made, usually 2 to 4 months after reaching maintenance dose of the drug. Following this assessment the drug should be continued only where there has been an improvement or no deterioration in MMSE score, together with evidence of global improvement on the basis of behavioural and/or functional assessment.
• Patients who continue on the drug should be reviewed by MMSE score and global, functional and behavioural assessment every 6 months. The drug should normally only be continued while their MMSE score remains above 10 points, and their global, functional and behavioural condition remains at a level where the drug is considered to be having a worthwhile effect. When the MMSE score falls below 10 points, patients should not normally be prescribed any of these three drugs. Any review involving MMSE assessment should be undertaken by an appropriate specialist team, unless there are locally agreed protocols for shared care.
• The benefits of these three drugs for patients with other forms of dementia (e.g. Dementia with Lewy Bodies) was not assessed in the guidance.