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Published on 1 March 2006

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Advances in the treatment of Alzheimer’s disease

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Peter Passmore
BSc MD
FRCP(Lond, Glasg) FRCPI
Senior Lecturer in Geriatric Medicine
Queen’s University Belfast
Consultant, Care of the Elderly
Belfast City Hospital
Northern Ireland
UK
E:p.passmore@qub.ac.uk

Alzheimer’s disease (AD) is the most common cause of dementia. It is a progressive neurodegenerative disorder characterised by loss of memory, deterioration in function, emergence of neuropsychiatric symptoms and eventual deterioration in mobility and increased dependence. Survival from diagnosis ranges from 3.1 to 7.1 years. There is no diagnostic test for AD. Diagnosis in the clinical situation is based on clinical assessment and is of probable or possible AD. AD is characterised by the presence of senile plaques and neurofibrillary tangles, and the subsequent development of neurotransmitter abnormalities, which are responsible for the clinical presentation. Successful treatment of AD would involve an interruption of the processes that produce the plaque/tangle pathology. At present, therapies are available based on alleviation of symptomatic deficits.(1)     These involve acetylcholine and glutamatergic systems. Great problems are associated with the management of patients with neuropsychiatric symptoms. This often involves the use of typical and atypical antipsychotics that are not licensed specifically for neuropsychiatric symptoms in dementia and that have significant adverse effects on cognition. Both typical and atypical antipsychotics have been associated with an increased incidence of cerebrovascular events.

Acetylcholinesterase inhibitors
Treatments for AD have been developed based on neurotransmitter deficiencies. The principal deficiency is in the cholinergic system. Attempts to increase the synthesis of acetylcholine were unsuccessful, and efforts focused on the inhibition of acetylcholinesterase. Donepezil was the first acetylcholinesterase inhibitor launched in the UK, in 1997. This was followed by rivastigmine in 1998 and galantamine in 2000. Donepezil is a reversible inhibitor of acetylcholinesterase, and rivastigmine is a reversible noncompetitive inhibitor that inhibits acetyl- and butyrylcholinesterase, while galantamine allosterically modulates at the nicotinic receptor and reversibly inhibits acetylcholinesterase. Donepezil is used once daily, rivastigmine twice daily, and galantamine is available in a twice-daily formulation; a once-daily form of galantamine, Reminyl XL, has recently been made available.

Acetylcholinesterase inhibitors are licensed for use in mild to moderately severe AD. They have been shown to improve cognition, activities of daily living, neuropsychiatric symptoms and global impression. Initial studies focused on cognition, function and global assessments, while subsequent studies examined neuropsychiatric symptoms. The medications are started at the lowest dose and titrated upwards, usually at four-weekly intervals. It is usual clinical practice to try to achieve the highest dose tolerated. Adverse effects of nausea/vomiting are treated with concomitant domperidone.

Adverse effects are mainly cholinergic in nature – nausea, vomiting and diarrhoea. Muscle cramps are rarely observed. These drugs should be used with caution in people with asthma/chronic obstructive pulmonary disease and cardiac conduction disorders, and are contraindicated in peptic ulcer disease. Because of their mode of action, it is important to flag up their use in patients who are scheduled for anaesthesia.

There is now a considerable clinical experience with acetylcholinesterase inhibitors and, in general, they appear to be safe and well tolerated.

In 2001 the National Institute for Health and Clinical Excellence (NICE) recommended that, in patients with AD whose mini-mental state examination (MMSE) was above 12 points, these drugs should be available under the following conditions:

  • Diagnosis should be made by a specialist. There should be assessment of cognitive, global and behavioural functioning, activities of daily living and the likelihood of compliance with treatment.
  • Specialists should initiate treatment, and GPs may continue using shared-care protocols.
  • Carers’ views should be sought before and during drug treatment.
  • Response should be reviewed after two to four months, and treatment continued if cognition has improved or has not deteriorated, and if behavioural or functional assessment shows improvement.
  • Review with MMSE, global, functional and behavioural assessment every six months, and continue only if cognitive assessment remains above 12 points and if treatment is considered to have a worthwhile effect on global, functional and behavioural condition.

It has been evident in clinical trials, and subsequently in clinical practice, that discontinuation of acetylcholinesterase inhibitors can be associated with a rapid decline in cognition and worsening of behaviour. Many clinicians are reluctant to discontinue treatment because of this risk, but when treatment is stopped families are advised to restart medication as soon as possible in case of clinical decline.

Specialist clinicians are generally working in agreement with the NICE issues guidance. This guideline is currently under review, and a definitive statement on new recommendations is expected in December 2005. The draft statement issued in Spring 2005 did not recommend donepezil, rivastigmine or galantamine for use in mild to moderately severe AD. This controversial decision was probably based mainly on a cost-effectiveness calculation using stipulations that did not permit a full recognition of the social implications of dementia.

Memantine
Memantine is an N-methyl-d-aspartate (NMDA) receptor antagonist that affects glutamate transmission. It is licensed for treatment of moderate-to-severe AD. Memantine was available for years in Germany and was then developed as a drug for dementia. It is a twice-daily preparation and is titrated up at weekly intervals, starting at 5mg once daily until 10mg twice daily is reached. Memantine is generally well tolerated. It should be used with caution in renal impairment and epilepsy. Some studies show that memantine prescribed in addition to donepezil has effects on cognition and behaviour.

The draft NICE statement indicated that ­memantine was not recommended for the management of AD at the moderate- to-severe stage.

Additional treatments
Patients will often self-medicate with Ginkgo biloba. There is some evidence that this product has beneficial effects on cognition. In practice, patients taking aspirin need to know that there is an interaction with Gingko. There is no evidence that vitamin E has any cognitive benefits; it was shown to delay death or nursing home placement in one study when used at very high doses (2,000 IU daily). Vitamin E is also associated with a bleeding diathesis. There is no evidence that oestrogen or nonsteroidal anti- inflammatory drugs are beneficial. A number of therapies are currently undergoing early-stage development. They are based on the interruption of the abnormal amyloid processing that is thought to be the main problem in AD. Therapies in development include inhibitors of secretase, inhibitors of amyloid aggregation, vaccination against amyloid and agents which may clear amyloid from the brain.

Conclusion
Acetylcholinesterase inhibitors and memantine are currently the only available licensed therapies for AD. These drugs have modest effects, which are, however, meaningful for patients and carers, particularly in those who respond well initially. They play a useful role in the modulation of some neuropsychiatric symptoms. Their use is highly regulated and, as a result, there is a significant amount of control in their prescribing. In the UK, the NICE process has resulted in the controversial draft conclusion that the drugs are not recommended. If this proves to be the final recommendation, there will be major implications for primary and secondary care organisations, due to difficulties in the management of AD problems, particularly neuropsychiatric symptoms, in the former, and to issues around reconfiguration of “Memory Clinics” in the latter. Patients already on treatment will continue to receive medication, while new referrals will not be eligible for treatment. In the UK, postcode prescribing issues could resurface (eg, Scotland vs England), and the demands for private consultation and prescription would be likely to increase.

Reference

  1. Cummings JL. Alzheimer’s disease. N Engl J Med 2004;351:56-67.

Resources
Royal College of Psychiatry – Faculty for the Psychiatry of Old Age.
Atypical anti‑psychotics and behavioural and psychiatric symptoms of dementia
W:www.rcpsych.ac.uk/college/faculty/oap/BPSD.pdf
American Academy of Neurology
Dementia
W:www.aan.com/publications/continuum/feb_2004.cfm



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