I have worked with individuals with severe and enduring mental health problems in the community for the past three years. I also have experience of working with individuals who have complex needs such as drug and alcohol problems, offending history and mental health or learning disabilities. I have a BSc and MSc in Psychology and will be starting a PhD at Manchester University in October. The PhD I am doing looks at the neuropsychological mechanisms for resilience to depression in adults. Once I have completed my PhD I would like to pursue a career in postdoctoral research. I have a good understanding in areas such as statistics, quantitative analysis, biopsychology, neuropsychology, research methods, health, criminology, sociology and psychology.

Sample

Evaluate the evidence for the efficacy of drug treatment based on the ACh system in dementia.

The current review will focus primarily on the treatment of Alzheimer’s type dementia; the Alzheimer’s Society estimates that there are over 700,000 people in the United Kingdom with dementia. Alzheimer’s disease is the most common form of dementia that predominantly affects the elderly and is associated with memory loss.  Alzheimer’s disease is a progressive and fatal illness that causes parts of the brain to contract. Consequential symptoms start with memory loss, and it is episodic memory that is most affected by the disease. An individual who suffers from episodic memory loss generally forgets his or her own personal history, recent personal events, and current events. Other problems associated with diminished short-term memory include patients repeatedly asking the same questions, often after only a few minutes. Patients with short-term memory loss forget where they have placed belongings, and an inability to find them leads to paranoia that they have been stolen. (Morris 1996).

Alzheimer’s disease has been explained in stages, early, mid, and late stage. People may vary in the length of time spent in each stage and what symptoms they show. This is because the stages can overlap. The stages therefore are a way of identifying groups of symptoms that reflect the increasing decline in the brain’s ability to function. The stages also help identify the most appropriate intervention strategies. Alzheimer’s sufferers in the early stages of the disease experience other cognitive malfunctions, such as the inability to remember words. The individual might make up words or stop talking altogether in fear that he or she might make a mistake. Early stage sufferers are less able to plan events, think logically, solve problems and make judgements and decisions; they also show great difficulty in learning new information. However in the early stages of Alzheimer’s disease the symptoms are not so noticeable, which allows the person to function independently. Cognitive problems become more apparent as the disease progresses and the person moves from early-stage (mild) Alzheimer’s to mid-stage (moderate) Alzheimer’s. Here the person experiences greater difficulty in sorting out the names and faces of friends and relatives. However they still know their own name, but not personal details such as their home address. In the mid-stage the person loses all ability to think clearly or in a logical way, they show increasing difficulty in following written or oral instructions and learning new information. Memory problems escalate (Morris 1996). Late-stage Alzheimer’s or severe Alzheimer’s sees the person decline into a state of total dependence, cognitive functions shut down. The person no longer recognises familiar faces, including their spouse and other family members. Bodily functions deteriorate and communication in oral and written form becomes impossible. The end result of Alzheimer’s disease is death; this is usually due to the brain’s powerlessness to keep the body going.

The following review will examine up to date research on current treatments available on the NHS, paying particular attention to the drug treatment based on the acetylcholine system in dementia. Treatments under review are cholinesterase inhibitors, which include donepezil, galantamine and rivastigmine. The review will also look at a new treatment called memantine, this is the first glutamate antagonist used to treat Alzheimer’s disease. The review will focus on the efficacy of these drugs, and what improvements, if any, there are for patients receiving treatment. The cost-effectiveness will also be taken into consideration.

To identify the key areas of the brain associated with Alzheimer’s disease, post mortem examinations on brains of patients with Alzheimer’s disease have been compared with age-matched individuals with normal mental functioning. The results showed that the level of most neurotransmitters were normal, the only anomaly was the level of acetylcholine. In Alzheimer’s patients the level of acetylcholine was very low (Snyder 1996). Post mortems also revealed that patients who died from Alzheimer’s disease suffered a massive degeneration of the basil nucleus. The ‘nucleus basalis’ is rich in acetylcholine neurons, which project into the cerebral cortex (Tortora and Grabowski 2000). Considering the fact that certain drugs, such as atropine, causes memory loss and blocks the action of acetylcholine, and other drugs, such as cognex, improves memory and inhibits acetylcholinesterase. We can infer that a deficiency in acetylcholine is responsible for the symptoms of Alzheimer’s disease and the basil nucleus regulates cognitive processes such as memory, which is impaired in Alzheimer’s patients (Snyder 1996). There is no cure for Alzheimer’s but there are treatments, which aim to improve symptoms such as memory loss and cognitive function. Drug therapy is the most widely used form of treatment, which include galantamine, donepezil, and rivastigmine, all of which are cholinesterase inhibitors. An inhibitor is a substance that binds to an enzyme and decreases its activity. So to inhibit the action of acetylcholinesterase the level of acetylcholine would increase, and memory should improve (Pinel 2006). Acetylcholine itself is a highly charged molecule that would not be able to pass the blood brain barrier; and would be destroyed in the body by acetylcholinesterase. This is just one method of promoting neurotransmission; there are cholinergic agonists’ as well. But inhibitors are mostly used in the treatment of Alzheimer’s disease. 

Research is ongoing into the efficacy of cholinesterase inhibitors (ChEI) on cognitive functions, paying particular attention to memory. Crowell et al (2006) looked at the beneficial effects of galantamine, donepezil, and rivastigmine on recognition memory performance. They compared learning, recall and recognition scores between two groups of mild to moderately demented Alzheimer’s disease patients. The patients in group one were receiving ChEI treatment, and patients in group two were not receiving ChEI treatment. Both groups were subjected to a comprehensive neuropsychological evaluation, such as the Alzheimer’s disease Battery Word-List Test; Consortium to Establish a Registry for Alzheimer’s disease battery (CERAD) word list memory test. The results showed that there was no significant difference between the two groups for learning and free recall, but the patients receiving ChEI treatment scored fewer errors on the CERAD recognition test compared to the group who were not receiving ChEI treatment. The results suggest that the inhibitory action of these drugs has a beneficial effect on aspects of cognition. However they do not differentiate between the types of cholinesterase inhibitors, research needs to look at the benefits of each inhibitor on cognition in order to determine which drug treatment posses the capacity to produce the necessary or desired results. A piece of research by Behl et al (2006) also grouped together the three cholinesterase inhibitors, but in this study the researchers looked at the long term effects of drug treatment. One hundred and thirty patients were put into two groups, 65 were receiving treatment and 65 were not. Both groups of patients were categorized as having mild to moderate Alzheimer’s disease. They were matched on education and baseline Mini Mental State Examination (MMSE) (Folstein et al 1975). Both groups were administered cognitive tests at the start of the study and then again twelve months later. Results from the MMSE and Mattis Dementia Rating Scale (DRS) demonstrated that over a one-year period the treated group showed fewer declines in overall cognition. Scores on the Disability Assessment for Dementia Scale (DAD) also showed fewer declines in basic activities of daily living in the treated group. However the long-term effects of drug treatment did not improve memory, which in the early to mid stages of Alzheimer’s disease declines more rapidly with other cognitive skills than daily living skills (Morris 1996). The researchers neglect to tell us the types of memory they were investigating, perhaps we are to assume that it is short term memory as this is most commonly associated with the disease. Further elaboration on cognitive improvement is also lacking in this study. The DRS is designed to measure cognitive function on five sub-scales, attention, initiation-perseveration, construction, conceptualisation and memory.

There was more research available on the use and efficacy of the cholinesterase inhibitor donepezil (aricept). According to guidance of the National Institute for Health and Clinical Excellence (NICE), donepezil should be made available within the NHS as one part of the management of some people with mild and moderate Alzheimer’s disease.  Patients should be examined using the Mini Mental State Examination (MMSE) (Folstein et al 1975), and if they score 12 points or above, donepezil and other inhibitors should be made available. In general donepezil and other cholinesterase inhibitors improve cognition, alertness and behaviour in about 5% of Alzheimer’s patients in the earlier stages of the disease. This is a very small percentage and what does it mean for the other 95% of Alzheimer’s sufferers? Wallin et al (2007) investigated the effects of donepezil in a clinical setting over a three-year period. They argued that clinical short-term trails have shown a positive effect of donepezil in treating Alzheimer’s disease, but more work needs to be done to assess the efficacy of the continuous use of donepezil. Four hundred and thirty-five outpatients attending The Swedish Treatment study centre, received treatment with donepezil. They were assessed every six moths for three years with the Mini-Mental State Examination (MMSE) (Folstein et al 1975), Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog), global rating (CIBIC) and the Instrumental Activities of Daily Living (IADL). The results demonstrated that three-year donepezil treatment has a positive effect on global and cognitive function, compared to those who did not receive treatment. Again the researchers do not detail the types of cognitive function; furthermore the results are only applicable in a clinical setting. Peterson (2005) also measured the effect of donepezil over a three-year period; his research however was focused primarily on participants with “probable” Alzheimer’s disease. They had not been diagnosed with the disease but did have a mild cognitive impairment or memory loss beyond normal aging. His aim was to see whether donepezil could delay the onset of Alzheimer’s by inhibiting the action of acetylcholinesterase, the enzyme that inactivates acetylcholine. Seven hundred and sixty nine participants were assigned to three groups, group one received a daily 10 milligram dose of donepezil, group two received 2000 IUs of vitamin E daily and group three were given a placebo. After the first year of treatment 38 participants in group three receiving the placebo developed Alzheimer’s disease, 33 participants in group two receiving vitamin E were also diagnosed with Alzheimer’s. Only 16 of those participants receiving donepezil progressed to Alzheimer’s. However after three years the number of participants who developed Alzheimer’s disease was similar, 73 in the placebo group, 76 in the vitamin E group and 63 in the donepezil group. Although donepezil cut the risk of developing Alzheimer’s by one-third, the final result suggests that a sugar pill and vitamin E has similar potential. The research so far only really details the effect of donepezil on cognition and memory (and these terms are used very broadly), it does not assess whether the drug improves the quality of life of the sufferer. Does it make the completion of everyday tasks, such as having a bath, brushing teeth, and combing hair any easier?

The cost-effectiveness of a drug therapy can determine who is prescribed the treatment and at what point is it available on the NHS. As previously discussed NICE made the recommendation that donepezil should only be made available to patients who have mild to moderate Alzheimer’s disease. Loveman et al (2006) reported the benefits of donepezil as well as the cost on the NHS. They found that donepezil treatment has a cost per quality-adjusted life-year (QALY) in excess of £80,000, and delays the progress of the disease by 1.42-1.59 months over a five-year period.  Donepezil is not available for patients with severe Alzheimer’s, even though research suggests that it is just as effective in improving cognition and function. Wingblad et al (2006) argued that the efficacy of cholinesterase in severe Alzheimer’s has not been assessed and so they conducted a randomized placebo-controlled trial of donepezil for patients with severe Alzheimer’s disease. Those who participated in the trial had a score between 1 and 10 on the MMSE (Folstein et al 1975), and lived in nursing homes. After six months of treatment, patients who were administered the donepezil did significantly better on the primary cognitive and functional tests than those who were assigned to the placebo condition. There were however no significant differences in behavioural measures between the two groups. The study by Wingblad et al (2006) suggests to us that individuals with severe Alzheimer’s disease will experience similar cognitive benefits with donepezil as those who suffer from mild and moderate Alzheimer’s disease. However Hogan (2006) asks whether we should be prescribing cholinesterase inhibitors to patients with severe Alzheimer’s disease, or do the financial costs out weigh the benefits? Richard Gray et al (2004) claims that donepezil does not produce the necessary or desired results for people with Alzheimer’s disease and therefore is not cost-effective. Wingblad et al (2006) comment further by saying that this topic is highly controversial.

Rivastigmine is a second cholinesterase inhibitor available to patients with mild and moderate Alzheimer’s disease. The recommendations for the availability of rivastigmine have been set out by the National Institute for Health and Clinical Excellence, and they are the same recommendations as donepezil. Rivastigmine (exelon) is a dual cholinesterase inhibitor; it inhibits both acetylcholinesterase and butyrlcholinesterase. Butyrlcholinesterase is also referred to as pseudocholinesterase, which is an enzyme that breaks down the action of acetylcholine. In this way it is very similar to acetylcholinesterase, however butyrlcholinesterase is primarily found in the liver. Rozzini et al (2007) reviewed the effect of rivastigmine as a treatment for cognitive impairment and behavioural and psychological symptoms of dementia; they assessed 30 Alzheimer’s patients and 30 patients with dementia with Lewy bodies. After treatment both groups showed cognitive and psycho-behavioural improvement, which suggests that rivastigmine produces the desired results with cognition in the ACh system in dementia. However, this conclusion would be strengthened if we knew how cognition was assessed. Jill Stein (2006) introduces a novel idea that was presented at the International Conference on Alzheimer’s disease and Related Disorders in July 2006. This piece of research demonstrated the efficacy of a rivastigmine patch; the results suggest that rivastigmine delivered in patch formation may be just as valuable as the capsule for the treatment of moderately severe Alzheimer’s disease. The patch comes in two sizes, the size ten patches and the size twenty patches. Participants were aged from 50 to 85 and had a score between 10 and 20 on the Mini Mental State Examination. Both patch sizes produced a more positive effect than those who received the placebo. Furthermore the dose in a size ten patch showed similar efficacy to the highest dosed rivastigmine capsule, the patch also produced fewer side effects such as nausea and vomiting. However this piece of research does not tell us what the positive effects were and how they were assessed.

The research on the patch investigated the efficacy of rivastigmine treatment for patients with moderately severe Alzheimer’s disease. However, according the guidelines set out by NICE, rivastigmine treatment is only available to patients with mild to moderate Alzheimer’s disease. Could this be due to the costs associated with this method of intervention? Loveman et al (2006) also investigated the cost-effectiveness of rivastigmine treatment; they calculated that this drug has a cost per QALY in excess of £57000, and delays the progress of the disease and time spent in full-time care by 1.43-1.63 months over a five-year period. They also found that this drug was more beneficial in higher doses, which increases costs on the NHS. The cost of rivastigmine treatment has been deemed costly, and NHS policy makers do not consider the savings associated with the delayed progress of the disease as acceptable.

Both donepezil and rivastigmine have a broad spectrum of side effects including, vomiting, diarrhoea, headaches, dizziness, insomnia, skin rashes and tremors. A major drawback of these drugs is the relatively short duration of their effectiveness. Although they do boost acetylcholine levels, they become less effective the longer they are used. After about one year, the nicotinic receptors become desensitized to Ach and no longer respond well to it. When this happens, the patient is almost back to square one, and dementia tends to accelerate. Unlike these prescription drugs galantamine seems to have no limit in its ability to maintain the sensitivity of nicotinic receptors to Ach. Since the receptors continue to respond indefinitely, galantamine may help slow the progression of the disease down.

Galantamine works is different from donepezil and rivastigmine in one very important way. In addition to boosting acetylcholine levels by inhibiting the action of acetylcholinesterase, galantamine has the unique ability to increase the receptiveness of nicotinic receptors to acetylcholine. Nicotinic receptors are one of the two major classes of neuronal acetylcholine receptors; the other class is called muscarinic receptors. This gives galantamine a major advantage in combating the impairments caused by a decline in cholinergic function. It is an alkaloid derived from the bulbs of daffodils and snowdrops. NICE recommended in 2001 that this drug along with other cholinesterase inhibitors be made available to patients suffering from mild to moderate Alzheimer’s disease. The efficacy of Galantamine has been shown across several areas such as cognition, behaviour, and daily living (Wilcock et al 2000). Erkinjuntti et al (2002) examined the efficacy of galantamine in probable vascular dementia and Alzheimer’s disease combined with cerebrovascular disease. Patients included in the study met the criteria of probable vascular dementia of National Institute of Neurological Disorders and Stroke and the Association Internationale pour la Recherché et l’Enseignement en Neurosciences (NINDS-AIREN) or possible Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA). They had score 10-25 on the MMSE (Folstein et al 1975), and 12 or more on the Alzheimer’s disease assessment scale cognitive subscale (ADAS-COG). 592 patients were randomly assigned to either the placebo or Galantamine condition. When the study began the Galantamine patients were administered 4mg/day in the first week, and this was increased by 4mg/day each week until they reached 24 mg/day in week 6. Efficacy was assessed using the ADAS-cog (ADAS-cog/11) at week 6, month 3, and month 6. At 6 months, patients assigned Galantamine had improved in cognitive function compared with the placebo patients. Again the term cognitive function is used very broadly, and the results suggest that the drug needs to be administered in higher doses for there to be any noticeable changes or improvements. 

In 2006, the National institute for Health and Clinical Excellence (NICE) recommended that the use of another drug called memantine should be used only in clinical studies for people with moderately severe to severe Alzheimer’s disease. This drug is both cost effective (between £37,000 and £52,000 per QALY) and beneficial as far as delaying the disease progression is concerned. Memantine is the first glutamate antagonist used to treat Alzheimer’s disease. It works by slowing down the increasing symptoms. The process of memantine however has not been fully established, but there is evidence to suggest that a malfunction of the glutamatergic neurotransmission contributes to the symptoms and progression of the disease (Loveman et al 2006). The process of learning and memory function are thought to involve the release of high levels of glutamate. Schmitt et al (2006) examined the cognitive response to memantine in moderate to severe Alzheimer disease patients who are already receiving donepezil. The efficacy of memantine was measured using the Severe Impairment Battery (SIB). The SIB results showed that patients receiving memantine scored significantly better on measurements of memory, language and praxis when compared to the placebo group. Hong-tao Hu et al (2006) also evaluated the efficacy as well as the safety of akatinol memantine treatment. However they looked specifically at treatment of mild to moderate Alzheimer’s disease. Their study involved one hundred patients with possible or probable Alzheimer’s disease; they also had a score between 10 and 26 on the Mini Mental State Examination. The participants were randomly assigned into two groups; group one received 5 mg/d in the first week, 10 mg/d in the second week, 15 mg/d in the third week and 20 mg/d from week four to sixteen. The increasing dosage aids the toleration of the drug and produces more noticeable changes.  The second group were given donepezil. The MMSE (Folstein et al 1975) was used to measure cognitive function; the Blessed-Roth scale was used to measure behaviour, mood and activity of daily life. DRS measured the severity of dementia. By week sixteen there had been significant improvement in cognition for those receiving akatinol memantine and donepezil. There was also an improvement in behaviour, mood and activity of daily life. However, there was no improvement in the serious level of dementia. The researchers concluded that akatinol memantine has a similar effect as donepezil in the treatment of mild to moderate Alzheimer’s disease, and can significantly improve cognition, mood and behaviour in Alzheimer’s disease patients. This drug is cheap and effective in the management of Alzheimer’s disease, however because of its complex action compared to cholinesterase inhibitors it can only be administered as part of a clinical study.

In 2006, NICE changed its recommendations for the use of donepezil, rvastigmine, and Galantamine. It ruled that cholinesterase inhibitors should be available on the NHS to patients with moderate Alzheimer’s only. This means that there are no interventions available to patients with mild Alzheimer’s disease. There is also very little hope for those who are in the later stages of the disease as memantine (ebixa) is only available in clinical studies. The efficacy of the cholinesterase inhibitors and glutamate antagonists has been confirmed in several pieces of research, they improve the quality of life in the majority of Alzheimer’s patients. However, the costs of cholinesterase inhibitors appear to out weigh the benefits and the complex action of glutamate antagonists limits its access. More research needs to be done on the process of akatinol memantine; so far research has demonstrated its efficacy in both the mild to moderate and the moderate to severe stages of Alzheimer’s disease. It has a similar effect on cognition and behaviour as donepezil, and it is up to £43,000 cheaper per QALY. This is, however, a highly controversial topic, as the burden of cost on the NHS determines what method of intervention is most appropriate and at what point should it be made available to Alzheimer’s disease patients. Costs are likely to escalate as the number of people who are diagnosed with the disease increases. Alzheimer’s is a progressive disease and the progression of the disease is always toward a worsening of symptoms. The end result of Alzheimer’s is death, therefore it is up to the National Institute for Health and Clinical Excellence to decide at what point the cost effectiveness of a drug takes priority over the patient. In the earlier stages of the disease the person experiences small relapses in memory and noticeable cognitive decline, however the person is able to compensate for them and continue to function independently. Therefore it appears that drug treatment is not imperative. In the severe stages of Alzheimer’s the person is at the point of no return, brain cells are severely damaged and communication is non-existent. Perhaps drug treatment is an ineffective use of resources and other alternative arrangements such as full-time care would be more appropriate.