Department of Old Age Psychiatry and Kingshill Research Centre, Avon and Wiltshire Mental Health Trust, Victoria Hospital, Swindon SNI 4HZ, UK. Tel: +44 (0)1 793 437501; Fax: +44 (0)1 793 437521
Correspondence: e-mail: roger.bullock{at}kingshill-research.org
Declaration of interest R.B. has worked on clinical trials in dementia for all the major pharmaceutical companies.
See editorial, pp.
9798, this issue.
ABSTRACT
Background Alzheimer's disease management involves symptomatic drug treatments passed by the National Institute for Clinical Excellence. Disease modification is now the goal.
Aims To review current and developmental drugs for Alzheimer's disease, their usage, and the clinical context of known facts and proposed specific models.
Method A brief evidence-based review was made, using literature where available, or evidence from consensus groups where it was absent.
Results There is good evidence to support the use of cholinesterase inhibitors, and perhaps vitamin E. Oestrogen and anti-inflammatory agents show possibility, but there is not enough evidence to support routine use.
Conclusions Symptomatic treatments exist for Alzheimer's disease. Observational studies and increasing knowledge of brain biology are leading towards further treatment options. Old age psychiatrists have valuable treatments they now have to learn to use.
The cholinergic hypothesis of Alzheimer's disease (Davies & Maloney, 1976) has led to the development of a number of strategies to enhance the failing cholinergic neurons and thus the neurotransmitter, acetylcholine. The most consistent therapeutic effect has been seen using inhibitors of the enzyme acetylcholinesterase, which cleaves the transmitter in the cholinergic synapse. Three such compounds have now been licensed for the treatment of Alzheimer's disease: donepezil, rivastigmine and galantamine. These have increased awareness of Alzheimer's disease, but unfortunately cost pressures have hindered their development in the UK, even though experienced users of donepezil and rivastigmine have found consistent results (Cameron et al, 2000; Evans et al, 2000; Matthews et al, 2000). The acetylcholinesterase inhibitors (AChEIs) were considered to be a stepping-stone to better disease-modifying compounds (Bullock, 1998). Although they undoubtedly are, no other class of drug has yet reached the clinic, and AChEIs will remain the main treatment option for some time. A variety of protocols for treatment (Harvey, 1999) have been superseded in the UK by the National Institute for Clinical Excellence (2001) guidelines on the use of these three drugs.
PRACTICAL DILEMMAS IN THE USE OF ACETYLCHOLINESTERASE INHIBITORS
The AChEI class of drugs all affect the measured domains of dementia in much the same way. The consistency of effect is evident from Fig. 1, which shows the cognition scores averaged from the pivotal trials of the three licensed compounds. This is a symptomatic response lasting approximately 8 months, followed by a decline that remains significantly above that of the placebo group for longer periods. This supports the preclinical cholinergic hypotheses (Davies & Maloney, 1976). Exciting as this is, it is only symptomatic treatment at the end of a complex disease process analogous to the use of levodopa in Parkinson's disease. The AChEI class continues to present practical and scientific challenges that clinicians need to have resolved; meanwhile, different treatments continue in development.
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Who?
In all trials of AChEIs, a response, as measured by the
scales used, was found in an average of 40% of the patients studied
(Corey-Bloom et al,
1998; Rogers et al,
1998; Raskind et al,
2000). This compares favourably with most drugs for chronic
illness, and all AChEIs have low numbers needed to treat (NNTs)
(Livingston & Katona,
2000). Using the scores from published data, donepezil has an NNT
of 4, rivastigmine 7 and galantamine 3. The high placebo response is often
questioned, but this is common in mental health studies, where it masks a
large non-drug treatment effect. Responders and non-responders are identified
but our criteria may be too harsh and the nature of a
response needs more research and definition. Currently no hard
predictor of response or non-response has been identified
(Schneider & Farlow,
1995). The APOE4 allele was once suggested as a marker of
poor response, but subsequent studies suggested no correlation.
In the absence of valid biological markers for Alzheimer's disease, measuring the effect intervention may have on the disease itself requires all patients to be treated for a reasonable length of time perhaps up to 6 months. In reality, this depends on economics; so UK prescribers tend to work in subsets of mild to moderate dementia, excluding institutional patients with more advanced disease, and only prescribing to community-based patients who can have their medication supervised as now ratified in the NICE guidelines.
How?
Various models of prescribing exist, all involving titration of the dose to
minimise side-effects particularly gastrointestinal ones. Donepezil
has the advantage of having only two dose steps, while rivastigmine and
galantamine offer a wider range, making tailoring to individual patients
perhaps more precise. Whichever drug is chosen, the dose should be taken to
the maximum tolerated (within the licence), after which at least 3 months of
treatment should be given before considering whether there has been inadequate
response. Rigidity may mean that late responders miss out on potential benefit
but within a limited budget, it will allow more patients exposure to
treatment.
If one drug does not work or has intolerable side-effects, then another should be tried; although the three drugs belong to the same class, they are all different. There is no published information on switching the drugs. Convention when switching drugs is to leave an interval of five times the half-life of the first drug before commencing the second (that is, 60 hours for rivastigmine and 15 days for donepezil). Consensus suggests that 3 days should be left after treatment with rivastigmine or galantamine, while a week should be left following donepezil treatment. This is based on clinical practice no controlled trial has been published.
Which?
The three drugs are similar yet have different individual characteristics
(Table 1). How clinically
relevant the differences are is unproven but interesting hypotheses are
arising out of them.
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Donepezil
Donepezil is very selective for acetylcholinesterase (AChE). This
selectivity is claimed to reduce its side-effect profile, but published
clinical data have not shown increased tolerability. Paradoxically, in
Alzheimer's disease the level of AChE falls as the disease progresses
(Arendt, 1992), matched by a
rise in butyrylcholinesterase (BuChE) the function of which is
unknown, but it forms part of the plaques and appears to come from the
activated glial cells. What BuChE inhibition means is unclear, but
rivastigmine and galantamine inhibit it, donepezil does not they may
work differently in later disease, although no published evidence has
supported this.
Rivastigmine
Rivastigmine preferentially inhibits one of the four AChE subtypes
G1, found particularly in the hypothalamus and cortex. This subtype is
implicated in plaque maturation, but whether there is any added clinical
benefit to this specificity is again unproven.
Galantamine
Galantamine produces an effect on presynaptic nicotinic receptors called
allosteric modulation (as does physostigmine and codeine). This produces
increased amounts of acetylcholine in the synapse by a direct effect on
presynaptic release, but again, the clinical impact is unknown and published
evidence as to its significance and desirability is required. It may be that
modulation, rather than agonism, protects against downregulation of
post-synaptic receptors. This may allow the drug to work longer, but further
studies are needed to confirm this. Modulation also improves attention, and
this has been demonstrated with galantamine but not with donepezil or
rivastigmine in Alzheimer's disease.
When?
The drugs are licensed for mild to moderate Alzheimer's disease. Patients
with mild disease already have significant illness and should receive
treatment, even with minimal symptoms. Treating mildly affected patients will
mean smaller responses, and protocols should reflect this long-term
follow-up being needed to show any continuing effect beyond that expected from
clinical trials. Moderate disease covers a wide range of morbidity: in trials
down to a Mini-Mental State Examination (MMSE;
Folstein et al, 1975) score of 10, but in NICE guidelines down to 12. Patients scoring at the lower
end of the range have a host of symptoms, and AChEIs here may be as valuable
for their symptomatic effects on behaviour as for their effect on the
underlying disease. Trial data with metrifonate (another AChEI, which was
withdrawn because of side-effects) showed improvement in neuropsychiatric
symptoms in Alzheimer's disease especially in apathy, hallucinations
and agitation (Cummings et al,
1998). This effect is more noticeable in dementia with Lewy bodies
where improvements in both MMSE scores and neuropsychiatric symptoms have been
demonstrated with rivastigmine (McKeith
et al, 2000). This suggests that dementia should be
treated at any time, with symptomatic delay and retention of qualify of life
being the aim early in the disease, moving towards symptomatic relief as
progression occurs. No published results are available for severe dementia,
though open-label follow-up from trials suggests that these drugs continue
working as the cholinergic deficit increases.
What?
What about AChEIs in other dementias, plus other cholinergic therapies?
Clinical trials are ongoing with AChEIs in vascular dementia and mixed
dementia. No result is available as yet, but as the cholinergic system is
implicated in these disorders it is hoped that findings will be positive. A
study of rivastigmine in dementia with Lewy bodies has produced positive
results (McKeith et al,
2000). Acetylcholinesterases are being studied as a potential
treatment in mild cognitive impairment a rational assumption as 55% of
patients with this problem go on to develop Alzheimer's disease, and
intervention here may have a profound effect on the burden of disease overall.
No study of anticholinergic therapy in frontotemporal dementia is under way at
present.
Muscarinic agonists have been tried in Alzheimer's disease, but these drugs have a narrow therapeutic window before side-effects become intolerable, and to date no clinical trial has shown significant effects on cognition. Nicotinic drugs are also still in early trial stages, with similar tolerability problems to overcome, but more promising efficacy data.
NON-CHOLINERGIC DRUG THERAPY
Research into Alzheimer's disease has led to understanding of some of the pathological mechanisms involved. Inflammation occurs, as evidenced by the inflammatory markers found for example, complement attack complex at levels similar to those found in ischaemic heart disease (McGeer & McGeer, 1998). Basic science coupled with the observation that sufferers from rheumatoid arthritis have a lower rate of Alzheimer's disease (Stewart et al, 1997) has led to trials of anti-inflammatory drugs in the treatment of Alzheimer's disease. Trials with prednisolone have not been successful, but ongoing work with the cyclo-oxygenase inhibitors (especially Cox-2) in animal and now in human clinical trials may show benefit. These drugs are not without long-term side-effects, so current practice is not to recommend their use routinely.
Another observational study has shown that women on hormone replacement
therapy (HRT) have a reduced rate of Alzheimer's disease
(Robinson et al,
1994). The protective effect of oestrogen on the nervous system
and its vasculature is well-documented
(Birge, 1997), so clinical
trials are now in progress to test the efficacy of oestrogen therapy
(17-oestradiol particularly). Early treatment study results are not
encouraging (Mulnard et al,
2000), so again, in the absence of published positive studies, HRT
cannot be recommended for use as a treatment in Alzheimer's disease
although it does seem that its use is increasing in Alzheimer's disease
prophylaxis, particularly in the USA.
Antioxidants have shown benefit in several areas of chronic ill health, including Alzheimer's disease, after a study of selegiline and vitamin E and their effect on disease progression (Sano et al, 1997). This showed a positive effect on the rate of increasing dependency and delayed institutionalisation. However, this has yet to be replicated. Vitamin E is inexpensive and relatively safe the trial was high dosage (2000 IU). Institutionalisation is expensive, so the return on this treatment is potentially high but not rigorously proven. Many clinics are now routinely suggesting the use of vitamin E to patients with Alzheimer's disease usually at about 1000 IU. It is possible that this may benefit other dementias and neurodegenerative disease as well.
Nootropic drugs are available for prescription in Germany the best-known being Gingko biloba extract, nicergoline and piracetam. Precise modes of action are unclear, yet they do seem to produce an effect in some well-controlled studies.
Glutamate is increasingly implicated in dementia pathogenesis, with N-methyl-D-aspartate (NMDA) blockade a putative therapy. Memantine, an NMDA blocker, has had positive results reported in severe Alzheimer's disease (e.g. Winblad & Poritis, 1999), leading to application for regulatory approval for its use in dementia.
Nerve cell destruction seems secondary to activation of glial cells, so stabilisation of these glial cells may reduce the rate of Alzheimer's disease and other dementias. Several compounds such as propentofylline purportedly have this effect, especially in vitro, but to date have shown no therapeutic effect clinically. It remains a potential area of research.
The cortical cholinergic system is diffusely spread and a long way from its cell bodies. It is therefore dependent on nerve growth factor (NGF) to sustain it, and a reduction in NGF may be associated with Alzheimer's disease. Studies injecting NGF by cannulae into the cerebrospinal fluid showed some effect, but this is not a practical solution. Attempts to formulate the active portion of NGF into an oral preparation that crosses the bloodbrain barrier are ongoing; meanwhile a xanthine derivative (leteprinim potassium) that seems to have a stimulating effect on NGF is about to start clinical trial.
WHAT OF PLAQUES AND TANGLES?
The pathological basis of Alzheimer's disease is the presence of amyloid plaques and neurofibrillary tangles. Most work has focused on the amyloid cascade that produces the plaques, and various drugs are in development to modify amyloid metabolism. The most imminent clinical trial is the injection of beta-amyloid protein to vaccinate the individual and produce an antibody response that might remove amyloid from the nervous tissue. In mice this procedure relieved symptoms in genetic Alzheimer's disease animal models (Schenk et al, 1999) and prevented plaque formation in younger mice. This method is being tried in humans in both the UK and the USA, and represents the first true attempt at disease modification.
The other classical pathological change is the development of tangles, made up of abnormal tau protein. Tau pathology is known to exist in other neurodegenerative conditions and is an important area of research in treating other dementing diseases such as frontotemporal dementia and progressive supranuclear palsy. The hyperphosphorylation that occurs in Alzheimer's disease may be amenable to therapeutic intervention, and while there are some experimental models now to support this, no drugs are in clinical trials as yet.
FUTURE CHALLENGES
Basic science research is gradually unlocking some of the pathological sequences in dementia (especially in Alzheimer's disease) to provide theoretical treatment opportunities. This began with the AChEIs and is now at the stage of amyloid modification. For the first time therapeutic options exist in Alzheimer's disease and will soon be available in other dementias. These may be as simple as using vitamin E, through to combinations of therapy to maximise benefit (Table 2). Although these treatments are still predominantly symptomatic, they offer relief to patients and have increased clinicians' awareness of the condition. This has taken old age psychiatry from its roots in social psychiatry to a point at which psychopharmacology has an important role. The challenge now is to learn how to use these treatments most effectively. This means that everyone in the speciality who uses these treatments has the opportunity to contribute to the debate, and the prospects of development over the next 10 years make this one of the most exciting and dynamic areas of medicine in which to work.
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Clinical Implications and Limitations
CLINICAL IMPLICATIONS
LIMITATIONS
ACKNOWLEDGMENTS
The author thanks colleagues who have used these drugs to date for their participation in various consensus groups in order to fill in the gaps in this review where evidence remains weak.
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Received for publication April 20, 2000. Revision received May 29, 2000. Accepted for publication June 8, 2001.
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