Cholinesterase Inhibitors -- Assessing Their Effects

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Management of Alzheimer's Disease: Assessing the Effects of Cholinesterase Inhibitors

(From: The Canadian Journal of Diagnosis, Vol. 20, No. 6, p. 49-52.)

Editorial Consultant
Bernard Groulx, M.D., CSPQ, FRCPC
Chef Psychiatrist, Ste. Anne's Hospital
Associate Professor, McGill University
McGill Centre for Studies in Aging, Montreal, Quebec

Alzheimer's disease (AD) is the most common form of dementia. It affects approximately 20% of the population over 65 years of age.[1-2] Although the precise cause of AD is not known, the pathologic changes associated with the disease have been well documented, mostly through autopsies of AD patients. AD is associated with the presence of neurofibrillary tangles and neuritic plaques throughout the brain, but particularly in the cortex and hippocampus.[3] Research has also shown that patients with AD and other dementias have decreased acetylcholine (ACh) levels, as a result of the loss of cholinergic neurons, which results in a decline in cognition and has a deleterious impact, on mood and behaviour.[3]

Cholinesterase inhibitors (ChEIs) are the only agents indicated for the symptomatic treatment of AD and related dementias. There are currently three such agents available to Canadian physicians: donepezil, rivastigmine and galantamine. Although these agents are all grouped together in one therapeutic class, there are several notable differences in their pharmacologic profiles. These differences may have a significant clinical impact with respect to their effects on cognition, mood, behavioural symptoms and, ultimately, patient quality of life.

What are the differences in the mechanisms of action of the ChEIs?

Under normal circumstances, the brain maintains a healthy level of ACh required for normal cognitive and behavioural function. The ACh produced by cholinergic neurons is broken down by enzymes known as cholinesterases. There are two such enzymes of importance in regulating cholinergic levels: acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE).

As their names suggest, the ChEIs (donepezil, rivastigmine and galantamine) work by inhibiting the cholinesterase enzymes, preserving ACh in the brain and thus slowing the progression of symptoms. ChEIs are not a cure – hey cannot restore lost neurons; they are used to enhance the function of the remaining cholinergic neurons.

From a mechanistic perspective, there are important differences between the three agents.[4] Donepezil and galantamine are selective inhibitors of AChE; galantamine also modulates nicotinic receptors. Rivastigmine is a dual inhibitor, targeting both enzymes AChE and BuChE.[5] Table 1 summarizes some of the major differences between the three available ChEIs.


Table 1 : Mechanism of Action of Currently Available Cholinesterase Inhibitors

Property Donepezil Rivastigmine Galantamine
Enzyme inhibition AChE AChE & BuChE AChE
Brain regions selective No Yes No
Allosterice modulation Yes Unknown Yes

Adapted from: Emre M. et al. Int J Clin Pract, 2001; Suppl. 127:64-72



Figure 1: Comparative Effects of ChEIs on Cognitive Symptoms in Mild to Moderate AD



In the healthy brain, AChE accounts for approximately 80% of ACh hydrolysis, with BuChE making up the remainder. As dementia progresses, however, the activity of AChE diminishes, while that of BuChE increases, particularly in the cortex and hippocampus.[5] Recently, researchers have found some brain areas where BuChE completely dominates AChE in terms of ACh metabolism. These findings suggest an increased importance for BuChE as a therapeutic target in dementia, in the treatment of mood and behavioural symptoms related to AD.

How effective are ChEls in addressing cognitive problems of dementia?

The ChEIs have each demonstrated efficacy in the short-term improvement of cognitive function in AD. There have, however, been differences observed in the relative degree of benefit for the three agents. Figure 1 shows data taken from three studies, each examining the effects of one of the three agents in mild to moderate AD.[6-8] Each of these three studies used the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and each showed a significant increase in values from baseline to week 24-26, with the largest treatment effect being observed in the rivastigmine study at week 26.

Long-term placebo-controlled data on the effectiveness of ChEI therapy are mainly available as extrapolations from short-term placebo data or open-label-design extensions of randomized placebo-controlled trials. In a one-year placebo-controlled study of donepezil in 431 patients with mild to moderate AD (average baseline mini-mental state examination [MMSE] score: 17), mean changes in baseline MMSE score were not significant in either the donepezil or placebo groups. The last observation carried forward (LOCF) analysis, however, presented a positive significant difference of 1.2 points at study endpoint.[9] Donepezil is also associated with a slower rate of decline in cognitive performance (ADAS-Cog) than predicted in untreated patients.[7] In an open label-design extension, rivastigmine resulted in a decline of approximately two points on the ADAS-Cog after one year, versus seven points for a projected placebo group. Follow-up at 142 weeks showed sustained efficacy.[10] Rivastigmine also appears to maintain improvements in cognitive function over the long term, as measured by change in MMSE score.[11] Galantamine has shown in an open-label extension study that cognitive function and activities of daily living (ADL) were unchanged for most patients, at one year from baseline, when galantamine was administered continuously at 12 mg twice daily.[8]

How effective are ChEls in addressing mood and behavioural problems of dementia?

Approximately 80% of patients with AD experience mood or behavioural symptoms of dementia.[12] Once experienced, the symptoms tend to worsen over time. The most frequently reported symptoms are mood disorders, agitation, aggression, paranoid delusions, hallucinations, sleep disorders (including nocturnal wandering), incontinence, stereotyped vocalizations and screaming.[13]

Before discussing pharmacologic treatments, consideration should be taken with respect to improving patient quality of life nonpharmacologically. In the case of a patient with agitation, for example, the following evaluation may be useful for determining the causes of this symptom, and if nonpharmacologic treatment is appropriate: Is the agitation a reaction to something going on "inside" or "outside" the patient? Is he/she hungry or thirsty, constipated or – the most common cause of all – in pain, but unable to say so due to loss of the capacity to express him/herself? Does the patient have an infection or any occult medical problem? Is the milieu too complex? Are the demands (physical, emotional, interactional, architectural, etc.) of the environment beyond the patient's capacities?

In the typical patient with mild to moderate disease, the first symptoms to appear are usually social withdrawal and/or depression. Anxiety, irritability and mood changes are also common symptoms early in the course of disease.

Like the core cognitive decline seen in AD and related dementias, mood and behavioural problems are thought to be related to loss of cholinergic neurons and associated with cholinergic deficits in the neocortex, hippocampus and limbic system – areas associated with behaviour and emotion, among other functions.[14]

All three ChEIs have demonstrated a positive effect on certain symptoms. All three, for example, have shown that they can provide benefit for anxiety, depression, agitation and apathy in AD. Of the three, however, only rivastigmine has demonstrated positive effects across the spectrum of symptoms, including psychotic symptoms (e.g., hallucinations, delusions).[13]

As is the case with the data on cognition, many of the published ChEI studies that report mood and behaviour scores do not go beyond one year of treatment duration.

Rivastigmine is the only ChEI that has data showing effects on mood and behaviour symptoms to two years. An open-label extension study of rivastigmine's effects showed an improvement from the beginning of the open-label portion of the study to 52 weeks. (Prior to this, patients were randomized to either rivastigmine or placebo in a 26-week double-blind study.) Scores were still improved from baseline after the next year (at 104 weeks; Figure 2).[15]


Figure 2: Rivastigmine on Mood and Behaviours: Significant Long-term Benefits in Mild to Moderate Patients


Figure 3: Effect of Rivastigmine on ADL by Diease Severity


One should also be aware that cholinesterase inhibition itself, by delaying the development of behavioural symptoms or reducing their severity, can reduce the need for psychotropic medications.

What is the overall effect of improved cognitive, mood and behavioural symptoms in dementia?

To this point, ChEIs have been examined in terms of their effects on several different symptoms in AD and related dementias. Improvements in cognition and in mood and behavioural symptoms each have their own individual benefits depending on the degree of deficit facing a patient.

Since there is no cure for AD, the true test of a particular agent's efficacy in AD and related dementias is the cumulative effect of the improvements in cognition, mood and behaviour on patient quality of life.

Quality of life is typically analyzed in AD by using scales that document patient function in ADL.

Some trials with donepezil and galantamine have demonstrated benefits with respect to ADL. For example, donepezil has shown benefit in non-institutionalized ambulatory patients with moderate to severe AD, but these benefits have not been shown in nursing-home patients.[16] In the case of galantamine, short-term (three-and five-month) studies in patients with mild to moderate AD have shown positive effects on ADL, however, in six-month trials in the recommended dose range, galantamine was not shown to be effective.[16]

In the case of rivastigmine, benefits have been shown in patients with mild and moderate AD. Additionally, long-term data demonstrate these beneficial effects may be maintained for periods of at least two years.[16] As shown in Figure 3, rivastigmine demonstrated benefits on the Global Deterioration Scale (GDS) compared to placebo over 26 weeks of therapy.[17] The GDS measures the impact of AD on a patient's ability to carry out everyday tasks, using a caregiver or nurse's assessment.

The differences in quality of life assessments noted with the three ChEIs are reflective of their differences in treating the cognitive, mood and behavioural symptoms of dementia. As per quality of life assessments (e.g., GDS), agents that are more effective at alleviating symptoms across the spectrum of disease would appear to have a greater positive impact on quality of life.

CASE STUDY

Patient Profile

Mrs. MJ is a 67-year-old woman living in the community with her husband. Both Mrs. MJ and her husband have been retired for many years and have enjoyed travelling across Canada and the United States. Mrs. MJ presented to her primary-care physician two years ago, complaining of a six-month-long decline in cognitive function that she and her husband first noticed when she had difficulty reading a map. Typically, Mrs. MJ would navigate their road trips while her husband did the driving. Since this original observation, she and her husband have also noted that she often misplaces things and has exhibited uncharacteristic major changes in mood.

Medical History

Mrs. MJ is being treated for dyslipidemia and hypertension, both diagnosed when she was in her late 50s. At the time of her presentation for the cognitive difficulties, she was being satisfactorily treated with an angiotensin converting enzyme (ACE) inhibitor for control of mild hypertension, and a statin agent to address lipid abnormalities.

She has no family history of dementia and had not experienced any cognitive difficulties of her own prior to her initial complaint.

Diagnosis

The physician, who treats a number of older adults, immediately suspected Mrs. MJ was experiencing the early stages of dementia. He administered an MMSE. Mrs. MJ scored 26/30, which is consistent with early-stage dementia. The physician performed a full physical examination and ordered a complete blood workup, which showed no signs of other disease. Her previous problems (hypertension and high cholesterol) were still controlled to acceptable levels.

The physician made the diagnosis of mild Alzheimer's disease (AD).

Treatment and Course of Therapy

Discussion

Studies have shown that treatment with ChEIs can maintain or, in some cases, improve cognition, mood and behavioural symptoms of dementia. By slowing the steady decline that characterizes AD, cholinesterase inhibition can thereby improve the quality of life of both the patient and the caregiver(s).

Furthermore, even though Mrs. MJ is still in the mild stage of disease, studies have indicated that more benefit can be gained by initiating treatment earlier, in the course of disease, delaying and attenuating the onset of cognitive decline and the emergence of mood or behavioural symptoms.

The physician opted to prescribe the ChEI rivastigmine, starting at 1.5 mg BID, titrated to 3 mg BID one month later. Rivastigmine has been shown to be effective in treating cognitive and mood symptoms in AD. Furthermore, it is not metabolized through the liver's CYP450 system. Donepezil and galantamine are metabolized through CYP450, which might be a concern for Mrs. MJ in that she is taking a statin for dyslipidemia.

Over the first six months, Mrs. MJ and her husband noted an improvement in her ability to read maps and a stabilization of her mood. MMSEs performed at 12 and 18 months were 26 and 25, respectively. Twenty months after diagnosis, Mrs. MJ noted that she had begun to feel anxious and agitated on a daily basis, despite continued ability to function cognitively. She reported this to her doctor, who explained to her that mood and behavioural symptoms can often emerge during the course of disease and that these can sometimes be helped by increasing the dose of the ChEI. At that time, her MMSE score was 24.

Mrs. MJ and her husband agreed to try increasing the dose. The physician therefore titrated the rivastigmine dose to 4.5 mg BID.

Mrs. MJ reported that the anxiety and agitation subsided over the next several weeks. The physician elected to maintain the dose at 4.5 mg BID. Her most recent MMSE score held steady at 24.

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References

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Copyright 2003 STA HeaIthCare Communications Inc. All rights reserved. This program is published by STA HeaIthCare Communications Inc. as a professional service to physicians through an unrestricted educational grant by Novartis Pharmaceuticals Canada Inc. The information and opinions contained herein reflect the views and experience of the authors and not necessarily those of Novartis Pharmaceuticals Canada Inc. or STA Healthcare Communications Inc. Any products mentioned herein should be used in accordance with the prescribing information contained in their respective product monograph.