Drugs for cognitive disorders
Leslie Iversen
Introduction
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.
Alzheimer’s disease
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,(1) there are no drugs that target the underlying pathology, and only palliative treatments are, as yet, available.
The approval of new medicines for the symptomatic 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 composite dementia assessments designed to provide an overall summary of cognitive status, for example the Mini Mental State Examination (MMSE), Alzheimer’s Disease Assessment Scale-Cognition (ADAS-Cog), and the Brief Cognitive Rating Scale are used.(2) Most studies with cholinesterase inhibitors in AD have used ADAS-Cog (a 70-point scale), and a two to three-point improvement for the drug-treated group versus placebo at 6 months has generally been accepted. However, statistically significant, but small, drug-induced improvements in cognitive assessment scores do not necessarily represent a clinically significant improvement to the patient or to their doctor; they must be supplemented by evidence of clinical improvement, using some form of Clinical Global Impression of Change as an outcome measure, usually rated by a clinician on a seven-point scale.
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.
Cholinergic agents
Attention has focused instead on the cholinergic agents. The ‘cholinergic hypothesis’ of dementia. 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.(3) 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. The most successful approach so far has been the use of inhibitors of the enzyme acetylcholinesterase.
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.(4) The first clinical trials in patients with AD were performed with physostigmine, and confirmed that the drug had significant beneficial effects on cognitive performance in AD patients.(5) 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 was very narrow.
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.(4) The first clinical trials in patients with AD were performed with physostigmine, and confirmed that the drug had significant beneficial effects on cognitive performance in AD patients.(5) 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 was very narrow.
Subsequently four other cholinesterase inhibitors with improved profiles have gained approval for use in AD: tacrine, donepezil, rivastigmine, and galantamine, but tacrine is no longer actively marketed owing to liver toxicity. Clinical data from several thousand patients with AD involved in trials with these cholinesterase inhibitors are now available.(6,7,8) The first of these to gain approval in 1997 was donepezil. Results of large-scale clinical trials with donezepil and the other cholinesterase inhibitors over periods of 15 and 24 weeks have yielded similar results for the three compounds in patients with mild to moderately severe AD. The drugs caused small but significant improvements in the ADAS-Cog, CIBIC, and MMSE scores. The most common side-effects were transient mild nausea, insomnia, and diarrhoea. Not all patients with AD will benefit from treatment with cholinesterase inhibitors; the proportion ranges from 30 to 50 per cent; although the clinical benefits of drug treatment in patients showing a response can persist for up to 24 months.
The approval of cholinesterase inhibitors for the treatment of Alzheimer’s disease was an important landmark. They are reasonably well tolerated and produce significant, if modest, beneficial effects in patients with mild to moderately severe AD. However, they have not gained immediate and universal acceptance. In some countries (e.g. the United Kingdom) it has been argued that the drugs are too costly and provide at best only a modest improvement.
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