Drugs for cognitive disorders - technical
- Alzheimer's disease
- Attention-deficit hyperactivity disorder
Cognitive disorders are among the most difficult of all nervous system illnesses to treat as they affect the most complex and least clearly understood aspects of brain function. Animal studies cannot accurately mirror the complexities of human cognition, and there are few, if any, animal models of human cognitive illnesses. As so few drugs have been found to exert clinically significant effects, animal models for testing novel cognition-enhancing agents have unknown predictive value. However, progress has been made in recent years with improved international agreement on the criteria used to approve new cognition-enhancing drugs, and the introduction of new drugs for the treatment of dementia.
It is important to define the objective of drug treatment in this, the most common of all forms of senile dementia. Alzheimer's disease (AD) is a progressive illness; drug treatment could treat the symptoms without influencing the course of the disease, or it might seek to delay or arrest the progressive cognitive deterioration which such patients suffer. Although the latter aim is the subject of intensive research in academic and industrial laboratories, there are currently no drugs available that target the underlying pathology of dementias and only palliative treatments are, as yet, available.
The approval of new medicines for the treatment of AD in recent years has led regulatory agencies to define more clearly what criteria should be used in assessing the clinical benefits derived from drug treatment. AD is a disease characterized by disturbances in higher cortical function, including disorders of recent memory, language function, praxis, visual perception, abstract thinking, and decision making. A variety of cognitive tests and other assessment tools are available to assess and quantify these deficits. These include composite dementia assessments designed to provide an overall summary of cognitive status, for example Blessed Rating Instruments, the Mini Mental State Examination, Alzheimer's Disease Assessment Scale–Cognition (ADAS–Cog), and the Brief Cognitive Rating Scale. There are also a variety of neuropsychological tests designed to assess particular aspects of cognitive function, and some of these are designed to permit the assessment of severely impaired patients who are unable to perform standard tests. Space does not permit any detailed description of these test batteries here; they are reviewed elsewhere. (1) Most studies with cholinesterase inhibitors in AD have used ADAS–Cog (a 70-point scale), and a four-point improvement for the drug-treated group versus placebo at 6 months has generally been accepted. This, in effect, means that patients with AD have been stabilized, since they suffer a progressive decline in cognitive scores of 7 to 10 points per annum on the ADAS–Cog scale. However, a statistically significant, but small, drug-induced improvement in a cognitive assessment score does not necessarily represent a clinically significant improvement to the patient or to their doctor. Therefore cognitive test score results must be supplemented by evidence of clinical improvement, using some form of Clinical Global Impression of Change as an outcome measure. This is usually rated by a clinician on a seven-point scale, in which 4 represents ‘no change', 1 is a ‘marked improvement', and 7 is ‘markedly worse', using a semistructured clinical interview format (e.g. the Clinician's Interview-Based Impression of Change (CIBIC)).
The development of agreed scientific and clinical standards for the approval of new drugs has largely eclipsed most of the older drugs that had been used in the treatment of AD and other dementias, since none of them can meet these standards. The older drugs include a range of cerebral vasodilators (e.g. dihydroergotoxin, papaverine, isoxsuprine, cinnarizine) and the so-called ‘nootropics' (e.g. piracetam, oxiracetam, aniracetam), which were widely used in some European countries, as well as the so-called ‘metabolic enhancers' (e.g. idebenone and indeloxazine) which were popular for a while in Japan (the latter drugs were removed from the Japanese reimbursable list in 1998).
Attention has focused instead on the cholinergic agents. This approach has its basis in the ‘cholinergic hypothesis' of dementia. (2,3) The ability of the cholinergic blocking drug scopolamine to disrupt learning and memory in animals and in healthy human volunteers indicates that acetylcholine plays a key role in attention and short-term memory functions in the brain. The cholinergic hypothesis was boosted by the discovery in the 1970s that cholinergic neurones are particularly damaged or absent from the brains of patients dying with AD, and that the extent of damage to the cholinergic system correlates with the severity of dementia in life. In AD the damage appears to be particularly severe in the system of cholinergic neurones located deep in the forebrain in the nucleus basalis of Meynert, whose fibres branch extensively and innervate most areas of the cerebral cortex. This neuronal system forms part of the ascending reticular activating system, which plays a key role in the process of selective attention—essential for the laying down of new memories. Consequently, there has been considerable interest in the possibility that ‘cholinergic replacement therapy' might relieve the symptoms of AD, in the same way that dopamine replacement therapy has successfully been employed in the treatment of Parkinson's disease.
One approach has been to develop drugs that mimic acetylcholine and act as agonists at the muscarinic cholinergic receptors in brain, but which, unlike acetylcholine itself, are bioavailable and brain-penetrant. Attention has focused on the discovery and development of muscarinic agonists that show selectivity for the m 1-receptor subtype, which is the predominant form present in the cerebral cortex. The most thoroughly studied cholinomimetic to date is xanomeline, a compound that acts as a highly potent and selective m 1-receptor agonist. Clinical effects were assessed in a multicentre study of 343 patients with AD. (4) Those patients on the highest dose (75 mg three times a day) who completed the study showed significant improvement when assessed using the ADAS–Cog scale (p = 0.045), and this group also showed a significant overall global improvement using CIBIC ( p = 0.022). In addition to cognitive improvements, patients receiving xanomeline also exhibited significant behavioural improvement, with dose-dependent reductions in vocal outbursts, suspiciousness, delusions, agitation, and hallucinations. Xanomeline is unlikely to be used in the treatment of AD because of its relatively short duration of action, but these results suggest that further research on cholinomimetics may still be justified.
The most successful approach so far has been the use of inhibitors of the enzyme acetylcholinesterase. Such drugs boost the function of acetylcholine after its release from cholinergic nerve terminals by slowing the normally rapid enzymatic inactivation of the neurotransmitter. Inhibitors of acetylcholinesterase have been known since the nineteenth century with the discovery of physostigmine, a plant product used as an arrow-tip poison. Irreversible organophosphate inhibitors of acetylcholinesterase were later developed as chemical warfare agents (‘nerve gases'), and for more peaceful uses as insecticides. Despite their colourful past, low doses of this class of compounds have proved effective as cognitive enhancers in a wide range of animal tests, including those in which cholinergic function is deliberately impaired. (5) The first clinical trials in patients with AD were performed with physostigmine, and there is now an extensive literature on this topic. Most of the clinical trials have confirmed that physostigmine has significant beneficial effects on cognitive performance in AD patients. However, it has limited usefulness because, although it is absorbed rapidly, it has only a very short half-life in plasma. This means that to obtain any sustained cognitive benefit it has to be given in doses that are sufficiently high to elicit a number of adverse side-effects. Thus, the therapeutic window is very narrow. (3,6) A slow-release formulation of physostigmine may improve its profile and is now under development. Other cholinesterase inhibitors with longer duration of action have also been assessed, and three of these have so far gained approval for use in AD, with others in advanced stages of development. The first to be approved was tacrine, a drug first described some 50 years ago, which was then given a new lease of life. (7) It was the first cholinesterase inhibitor to be tested in large-scale properly controlled clinical trials in AD, eventually involving several thousand patients. (8) It led to modest, but significant, improvements in cognitive performance and global clinical ratings, and was approved for human use in 1993. Although this was an important milestone, tacrine clearly had several limitations. One problem is that the drug can cause hepatocellular injury, and therefore patients using tacrine require careful clinical monitoring by means of regular blood tests to look for signs of liver toxicity. Elevated plasma transaminase levels were the main reasons for drop-out in the major tacrine trials, and this together with other adverse side-effects means that more than 50 per cent of patients with AD were unable to tolerate the drug. Tacrine is chemically an acridine and thus has carcinogenic potential, although this may not be of particular relevance to elderly patients with AD it is another undesirable property. Having enjoyed a brief period of clinical use in AD, tacrine has now been withdrawnfrom most major pharmaceutical markets, as it is clear that second-generation cholinesterase inhibitors have clear advantages.
Clinical data from several thousand patients with AD involved in trials with ‘second-generation' cholinesterase inhibitors are now available (7,9). The first of these to gain approval in 1997 was donepezil. This is a potent inhibitor that demonstrates selectivity for acetylcholinesterase over the plasma butyrylcholinesterase enzyme, although it is not clear that this conveys any particular clinical advantage. Donepezil has a very long half-life in animals and humans (plasma half-life of more than 48 h) and consequently it causes a long-lasting inhibition of the enzyme. This probably explains why it is better tolerated than any of the first-generation cholinesterase inhibitors by both animals and human subjects. Results of large-scale clinical trials over periods of 15 weeks (10) and 24 weeks (11) have been reported. The 15-week study was a double-blind placebo-controlled multicentre outpatient trial involving 468 patients with mild to moderately severe AD. Patients were randomized to receive placebo, 5 mg donepezil, or 10 mg donepezil once a day. Both doses of the drug were well tolerated and caused significant improvements in the ADAS–Cog, CIBIC, and Mini Mental State Examination scores. With the higher dose of donepezil, 38 per cent of all the patients treated demonstrated clinical improvement (scores of 1, 2, or 3) compared with 18 per cent of those receiving placebo. The most common side-effects were transient mild nausea, insomnia, and diarrhoea. An important finding was that there was no evidence of any hepatotoxicity. The 24-week study involved another 473 patients and the same doses of donepezil. Again, there were significant improvements in cognitive test scores and in global clinical assessments (CIBIC).
The approval of donepezil was another landmark. It is well tolerated and produces a significant, if modest, beneficial effect in patients with mild to moderately severe AD. However, donezepil will not necessarily gain immediate and universal acceptance. In some countries (e.g. the United Kingdom) it is argued that the drug is too costly, that it provides at best only a modest improvement, and that longer-term studies are needed before its safety can be properly assessed. On the other hand, the availability of an officially approved medicine will certainly encourage physicians to pay more careful attention to the diagnosis of AD in their patients, and even a modest improvement may be considered worthwhile. Donepezil is only the first of a series of acetylcholinesterase inhibitors likely to be approved for use in AD over the next few years. Eptastigmine is closely related chemically to physostigmine, but has a much-improved duration of action. Rivastigmine is another carbamate that causes a long-lasting inhibition of the enzyme, and it has already been approved for use in some European countries. Galanthamine and huperzine are examples of plant-based medicines. Metrifonate is a very long-lasting cholinesterase inhibitor of the organophosphate type, used previously as an antiparasitic agent.
Some general conclusions can be drawn from the results now available on the use of cholinesterase inhibitors in AD. (12) These drugs cause, at best, modest improvements in cognition and overall clinical condition. Not all patients with AD will benefit from them, the proportion ranges from 30 to 50 per cent; although the clinical benefits of drug treatment in patients showing a response persist for up to 24 months. It is unlikely that any further major improvements will be seen with this class of drugs. There is a bell-shaped dose–response curve; low doses cause too little inhibition of the enzyme to be effective, while high doses cause too much enzyme inhibition leading to adverse side-effects. The maximum inhibition of acetylcholinesterase that is achievable varies with each drug, from levels of less than 50 per cent for physostigmine, eptastigmine and tacrine, to levels of 50 to 80 per cent for galanthamine, donepezil, and metrifonate. All the drugs act by the same mechanism, and are consequently likely to suffer from the same side-effects and limitations. However, this situation is an improvement on the position just a few years ago when no medicines were available for treating patients with AD.
Attention-deficit hyperactivity disorder
Attention-deficit hyperactivity disorder ( ADHD) is one of the most thoroughly studied disorders in child psychiatry, and the increasingly common use of stimulant drugs to treat this disorder has become the focus of much public attention and debate in recent years. (13) ADHD is defined in terms of three key features: lack of sustained attention, impulsivity, and hyperactivity. According to the earlier DSM-III diagnostic definition, ADHD affects approximately 5 per cent of all school-age children. However, the DSM-IV definition includes subcategories (e.g. primarily inattentive), and the diagnosis of ADHD now includes more than 10 per cent of children. (14,15)
Because of the interest in the drug treatment of ADHD, a number of assessment tools have been developed. These include the widely used Conners Teacher Rating Scale, the Conners Parent Rating Scale, and a variety of tests designed to measure hyperactivity, problem behaviour, attention, and other aspects of cognition, as well as academic performance. (16)
The most commonly used drugs are the psychostimulants D-amphetamine, methylphenidate, and pemoline, and of these methylphenidate is by far the most widely prescribed. In more than 100 published trials these drugs have been found to have significant beneficial effects on all three key symptoms of ADHD in approximately 70 per cent of the treated children. The clinically effective dose range is between 0.2 and 0.5 mg/kg for D-amphetamine and from 0.3 to 1.0 mg/kg for methylphenidate.
The mechanism of action of all three agents is similar; they act principally as inhibitors of the dopamine-uptake mechanism in the brain and, in addition, promote the release of this neurotransmitter, thus stimulating dopaminergic mechanisms. The drugs also act to an important extent on noradrenaline-containing neurones to promote an increased release of this monoamine. (17) It is paradoxical that stimulant drugs, whose actions include an ability to promote hyperactivity, should have a calming effect on hyperactive children. However, there are a number of explanations for this. One is that actions of these amphetamine derivatives show the ‘rate dependency' typical of other central nervous system agents, i.e. they tend to stimulate low rates of behaviour and to suppress high rates. (18) An alternative view is that the relatively low doses of amphetamines used in the treatment of ADHD would not have stimulant effects even in normal healthy adults. (17)
There are few animal models that can be used in the study of psychostimulant use or ADHD. Gainetdinov et al.(19) have recently described an animal model in mice which were genetically engineered to delete the gene for the dopamine transporter. Such animals have elevated levels of dopamine in their brains and are behaviourally hyperactive. Paradoxically, D-amphetamine decreases activity in these animals, in keeping with the ‘rate-dependency' hypothesis. The use of amphetamines, particularly methylphenidate, has increased rapidly during the past 25 years, particularly in the United States where 3.5 million children were reported to be receiving the drug in 1997. The largest increases in use in recent years have been among girls and teenagers. It is becoming clear that the beneficial effects of these drugs in prepubertal children continue into adolescence. (14) Indeed, one of the still unanswered questions is when should such treatment stop? The use of amphetamines in Europe has been at a much lower level so far, although their use in ADHD has also been increasingly rapidly. In the United Kingdom, for example, only 2000 prescriptions for methylphenidate were written in 1990, but this number had risen to 92 000 by 1997. In turn, such widespread use provokes other problems. The relatively free availability of psychostimulant drugs in the classroom has led to some ‘trafficking' and a small, but worrying, increase in intravenous abuse. (20)
1. Gershon, S., Ferris, S.H., Kennedy, J.S., et al. (1994). Methods for the evaluation of pharmacological agents in the treatment of cognitive and other deficits in dementia. In Clinical evaluation of psychotropic drugs: principles and guidelines (ed. R.F. Prien and D.S. Robinson), pp. 467–99. Raven Press, New York.
2. Bartus, R.T., Dean, R.L., Beer, B., and Lippa, A. (1982). The cholinergic hypothesis of geriatric memory dysfunction. Science, 217, 408–17.
3. Sahakian, B.J. (1988). Cholinergic drugs and human cognitive performance. In Handbook of psychopharmacology, Vol. 20 (ed. L.L. Iversen, S.D. Iversen, and S.H. Snyder), pp. 393–424. Plenum Press, New York.
4. Bodick, N.C., Offen, W.W., Levey, A.I., et al. (1997). Effects of xanomeline, a selective muscarinic receptor agonist, on cognitive function and behavioral symptom in Alzheimer's disease. Archives of Neurology, 54, 465–73.
5. Rupniak, N.M.J., Steventon, M.J., Jennings, C.A., and Iversen, S.D. (1989). Comparison of the effects of four cholinomimetic agents on cognition in primates following disruption by scopolamine. Psychopharmacology, 99, 189–95.
6. Davis, K.L. and Mohs, R.S. (1982). Enhancement of memory processes in Alzheimer's disease with multiple-dose intravenous physostigmine. American Journal of Psychiatry, 139, 1421–4.
7. Giacobini, E. (1998). Cholinesterase inhibitors for Alzheimer's disease therapy: from tacrine to future applications. Neurochemistry International, 32, 413–19.
8. Qizilbash, N., Whitehead, A., Higgins, J., Wilcock, G., Schneider, L., and Farlow, M. (1998). Cholinesterase inhibition for Alzheimer's disease? A meta-analysis of the tacrine trials. Journal of the American Medical Association, 280, 1777–82.
9. Farlow, M.R. and Evans, R.M. (1998). Pharmacological treatment of cognition in Alzheimer's dementia. Neurology, 51 (Supplement 1), S36–44.
10. Rogers, S.L., Doody, R.S., Mohs, R.C., and Friedhoff, L.T. (1998). Donepezil improves cognition and global function in Alzheimer's disease: a 15 week, double blind placebo controlled study. Archives of Internal Medicine, 158, 1021–31.
11. Rogers, S.L., Farlow, M.R., Doody, R.S., Mohs, R.C., and Friedhoff, L.T. (1998). A 24 week, double blind, placebo controlled trial of donepezil in patients with Alzheimer's disease. Neurology, 50, 136–45.
12. Benzi, G. and Moretti, A. (1998). Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease? European Journal of Pharmacology, 346, 1–13.
13. Gibbs, N. (1998). The age of Ritalin. Time, 30 November, 86–9.
14. Garland, E.J. (1998). Pharmacotherapy of adolescent attention deficit hyperactivity disorder: challenges, choices and caveats. Journal of Psychopharmacology, 12, 385–3.
15. Sagvolden, T. and Sergeant, J.A. (1998). Attention deficit/hyperactivity disorder—from brain dysfunctions to behaviour. Behavioural Brain Research, 94, 1–10.
16. Klein, R.G., Abikoff, H., Barkley, R.A., et al. (1994). Clinical trials in children and adolescents. In Clinical evaluation of psychotropic drugs: principles and guidelines (ed. R.F. Prien and D.S. Robinson), pp. 501–46. Raven Press, New York.
17. Solanto, M.V. (1998). Neuropsychopharmacological mechanism of stimulant drug action in attention-deficit hyperactivity disorder: a review and integration. Behavioural Brain Research, 94, 127–52.
18. Robbins, T.W. and Sahakian, B.J. (1979). Paradoxical effects of psychomotor stimulant drugs in hyperactive children from the standpoint of behavioural pharmacology. Neuropharmacology, 18, 931–50.
19. Gainetdinov, R.R., Wetsel, W.C., Jones, S.R., Levin, E.D., Jaber, M., and Caron, M.G. (1999). Role of serotonin in the paradoxical calming effect of psychostimulants on hyperactivity. Science, 283, 397–401.
20. Musser, C.J., Ahmann, P.A., Theye, F.W., Mundt, P., Broste, S.K., and Mueller-Rizner, N. (1998). Stimulant use and the potential for abuse in Wisconsin as reported by school administrators and longitudinally followed children. Journal of Development and Behavior in Pediatrics, 19, 187–92.