Psychiatric journals from the 1950s are full of adverts for treatments for dementia with stimulants such as dexamphetamine or methylphenidate and a group of related compounds that were called analeptics rather than stimulants. These included pipradrol and pentylenetetrazol.
Since the 1960s, the discussion has centred on the cholinomimetic drugs. There is no evidence that damage to the cholinergic pathway is the central deficit in Alzheimer’s dementia. Indeed, many other neurotransmitters are affected in both Alzheimer’s and other dementias. Given the interactions between various neurotransmitter systems, it is almost impossible to manipulate one neurotransmitter without affecting the others, and hence cholinergic drugs were never likely to be specifically helpful for dementia.
In addition, current research suggests that many cortical dementias may in part involve cell-protective mechanisms that have been thrown out of gear. Normally, there is a range of mechanisms within cells aimed at neutralising toxins of various sorts and in generally sculpting the nervous system. 3 These frequently involve the binding of a protein to the toxin, which labels it so that the cell’s own degradative processes destroy the offending agent. In the dementias, such mechanisms appear to have been stimulated to the point where large amounts of these cell-protective proteins are produced – to the point that they themselves poison the cell. Whether the stimulus to this production is genetic, viral, toxic (as in aluminium) or some combination of these and other factors, is uncertain. It may even represent a feature of normal ageing, with some people programmed to age quicker than others. The treatment options are to find compounds that will either switch off the process or else compensate for it, or, as the evidence of a reduced frequency of dementia on aspirin hints, compounds that suppress inflammatory responses in general.
Historically however, the aim of dementia treatment has always been one of giving a boost to the cholinergic system. Early efforts to do this clinically included the following:
• Choline. This is a precursor of the neurotransmitter acetylcholine (ACh). The rationale has been that, by increasing supplies of choline in the body, the brain might synthesise more ACh. Early studies reported some success, but this has not been confirmed. Choline is also present in the essential fatty acid lecithin. For this reason, lecithin supplements have also been given in dementia, but with little benefit.
• Piracetam/oxiracetam/aniracetam/pramiracetam. In animal studies these nootropic drugs release ACh within the brain. They appear to be mildly stimulant in humans but relatively ineffective in dementing conditions. It has been claimed that combining them with lecithin and an anticholinesterase does give some benefit.
• Cholinesterase inhibitors. These block the breakdown of ACh. The first drug of this type was physostigmine. But this has an extremely short half-life, and doses that bring about improved performances in one person produce deterioration in others. Tetrahydroaminoacridine (THA; tacrine) is a longer-acting cholinesterase inhibitor that was licensed for Alzheimer’s disease in the USA. There are suggestions that this type of compound may be of greater benefit in senile dementia of Lewy body type (SDLT) than in other dementias. If there are benefits they may stem from the effects of tacrine on potassium channels. The benefits, if present, are slender when set against the drug’s significant liver toxicity.
• Angiotensin-converting enzyme (ACE) inhibitors. The best-known ACE inhibitors, captopril, enalapril and lisinopril, are used in the treatment of hypertension and cardiac failure. They also bring about a release of acetylcholine in the brain. The marketing of ACE inhibitors for blood pressure heavily emphasises the fact that these drugs both lower blood pressure and provide some sort of ‘zest for life’. There appears to be some stimulant quality or mild cognitive-enhancing quality to these compounds. In studies with aged rats, the ACE inhibitors appeared to improve performance in some behavioural tasks back to the performance level shown by young rats. A number of open studies at present have suggested that the drugs may be helpful in some cases of dementia but not sufficiently so to warrant further development.
SECOND-GENERATION CHOLINOMIMETICS
A second generation of agents acting on the cholinergic system has proved more successful but the use of these agents has been controversial because of their cost. Critics claim that the clinical trials provide barely perceptible benefits in dementing disorders and that the widespread and indiscriminate use of such agents, given the modest benefits set against the high costs, would be crippling financially.
The modest clinical trial effects, however, may stem from two sources. One possibility is that these drugs are debatably effective. The other possibility is that they work reasonably well in some patients but not at all in others; adding up scores across the whole group in this case would underestimate the benefits that can be obtained in some patients. In dementia, some clinicians claim that the latter option is the correct one. If so, there is no reason to believe that the cognitive-stimulating effects such drugs produce will be of benefit only in clear dementia. There is a potential for patients with difficulty following head injury to respond, as well as the cognitive decline found in many other states.
Donepezil (Aricept)
The claims are that this cholinesterase inhibitor given in 5mg or 10mg doses can produce cognitive benefits in patients with mild to moderate dementia and that it sustains functional ability and delays the emergence of behavioural symptoms. (Similar claims have been made for rivastigmine and galantamine.) Donepezil’s main selling point is that it comes in a single dose.
Rivastigmine (Exelon)
This cholinesterase inhibitor is used in doses of 3–12mg per day. It has a similar profile of side effects and precautions to donepezil.
Galantamine (Reminyl)
Galantamine is also a cholinesterase inhibitor, used in doses of 16–32mg per day, again with a similar profile of side effects and precautions to donepezil and rivastigmine. Its selling point is that it also has direct effects on cholinergic receptors in addition to enhancing ACh, but it is not known whether this produces a real clinical benefit or is simply a piece of mythology.
Side effects of cholinesterase inhibitors
The commonest side effects are diarrhoea, muscle cramps, fatigue, nausea and insomnia. There is a potential to slow the heart so patients with cardiac conditions should be monitored. Another possibility is that treatment may provoke confusion or other neuropsychiatric disturbances. At present, there is little established about the possible interaction of these drugs with the many others that elderly patients are likely to be taking.
Overdosage produces nausea, vomiting, diarrhoea, confusion, convulsions, and cardiac and respiratory depression. Overdosage can be treated with atropine.
At present there may be many other effects of these drugs that are side effects in one setting but useful in others waiting to be discovered – see Section 8.
CHOLINOMIMETICS IN OTHER THERAPEUTIC AREAS
In addition to providing a possible benefit in Alzheimer’s dementia, clinicians and patients have not surprisingly tried drugs such as the cholinesterase inhibitors in a range of other areas. At present there is evidence for benefits in the cognitive failures associated with multiple sclerosis, Parkinson’s disease and Huntington’s chorea. Claims have also been made for benefits in minimal cognitive or age-associated memory impairment.
In addition there is reported use of and reported benefits for these agents in the treatment of cognitive decline in schizophrenia and in depression. The drugs have also been used to minimise any electroconvulsive therapy-linked memory loss.
There are preliminary reports of benefits in tardive dyskinesia. 4 There are also reports of benefits in Tourette’s syndrome and in attention-deficit/hyperactivity disorder (ADHD). But of perhaps even greater interest are reports of benefits in autism and Asperger’s syndrome. 5
It needs to be borne in mind also that cholinesterase inhibitors were brought on to the market for dementia, unlike imipramine and chlorpromazine, which were later found to be antidepressant and antipsychotic. In the same way, there is preliminary evidence that the cholinesterase inhibitors may in fact do more for disorders that have little to do with higher cognitive function such as erectile impotence – see Section 8.
MEMANTINE (EVISTA)
Unlike other drugs for dementia, memantine works on the glutamate system, through the N-methyl-D-aspartate (NMDA) receptor. Glutamate is in fact the most common excitatory neurotransmitter in the brain, and there has been considerable evidence for some time that acting on the glutamate system might produce memory-enhancing effects, although the discovery of the benefits of memantine was made by accident, as was the fact that it had actions on the glutamate system.
Memantine began life in the 1970s as a glucose-lowering drug, which it was hoped would be a treatment for adult-onset diabetes. It failed for this purpose but drifted into use in Germany as a geriatric tonic (Akatinol). Impressions developed that it seemed to be best in the presence of neurodegenerative disease, which led to trials in Alzheimer’s disease.
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