Cholinesterase Inhibitors for Alzheimer's & Related Dementias CME

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The Management of Alzheimer's Disease and Related Dementias: Part 2 -- The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease and Related Dementias

Steven G. Potkin, MD

Copyright © 2004 the Postgraduate Institute for Medicine.

This Continuing Medical Education (CME) activity "The Management of Alzheimer's Disease and Related Dementias" was developed as an online CME activity.
Faculty affiliations and disclosures are at the end of this activity.

Release Date: January 30, 2004; Valid for credit through January 30, 2005

Target Audience

This activity has been designed to meet the educational needs of neurologists, psychiatrists, primary care physicians, and allied healthcare professionals involved in the care of patients with dementia.

Goal

To review the role of acetyl- and butyrylcholinesterase inhibitors in the treatment of impairment of activities of daily living and behavioral and cognitive symptoms of Alzheimer's disease and their potential role in treating other forms of dementia.

Program Description

The degeneration of the cholinergic system results in progressive loss of attention, memory, behaviors, and the ability to perform activities of daily living. This presentation addresses the role of acetyl- and butyrylcholinesterase inhibitors in modifying activities of daily living, behaviors, and cognitive symptoms associated with Alzheimer's disease (AD). There is accumulating evidence that delay in treatment has long-term consequences on the course of illness and that the use of acetyl- and butyrylcholinesterase inhibitors can have a clinically important impact on the symptoms of AD and related dementias.

Learning Objectives

Upon completion of this activity, participants will be able to:

1. Review the extent of under-diagnosis and under-treatment of Alzheimer's disease and their potential consequences.

2. Describe the role of acetyl- and butyrylcholinesterase inhibitors in the treatment of impairment of activities of daily living and behavioral and cognitive symptoms of Alzheimer's disease.

3. Review the potential roles of acetyl- and butyrylcholinesterase inhibitors in treating other forms of dementia, including Parkinson's dementia, Lewy body dementia, and mixed and vascular dementia.

4. Review the importance of switching cholinesterase inhibitors as a therapeutic option.

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Contents of This CME/CE Activity

1. The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease and Related Dementias
by Steven G. Potkin, MD
Alzheimer's Disease: Symptom Domains and Disease Stages
Effects of Cholinesterase Inhibitors on Activities of Daily Living
Behavioral Symptoms in Alzheimer's Disease
Effects of Cholinesterase Inhibitors on Behavioral Symptoms
Titration-Related Adverse Effects of Cholinesterase Inhibitors
Molecular Forms of Cholinesterase Inhibitors
Tolerability, Adverse Events, and Pharmacokinetics of Cholinesterase Inhibitors
Vascular Risk Factors, Vascular Dementia
The Hippocampus and Alzheimer's Disease
Effects of Cholinesterase Inhibitors on Vascular Dementia
Lewy Body Dementia
Parkinson's Disease and Dementia
Medical Rationale for Switching Cholinesterase Inhibitors
Switching Cholinesterase Inhibitors
Concluding Remarks


Alzheimer's Disease: Symptom Domains and Disease Stages

Slide 1

Slide 1. The Management of Alzheimer's Disease and Related Dementias: The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer's Disease and Related Dementias

We'll be discussing the role of cholinergic therapies in the treatment of Alzheimer's disease (AD) and related dementias.

Slide 2

Slide 2. ABC: The Key Symptom Domains of AD and Their Assessment Instruments

In AD there are 3 key symptom domains: activities of daily living (ADLs), behavior, and cognition; and we have separate scales to measure these. Alzheimer's disease is a progressive, degenerative illness that involves loss of memory and interference with functioning in some other cognitive domain, such as executive functioning, language, or knowing what something is or how to use it, and this has clear impact on both behaviors and ADLs.

Slide 3

Slide 3. Potential to Increase Diagnosis and Treatment Across Disease Stages

Here we look at the disease stages and the number of patients with the illness, how frequently it's diagnosed, and how often treated. Approximately one third of patients with mild AD are diagnosed and only two thirds of those patients are treated.

In the moderate stage the same pattern appears; less than half are actually diagnosed and not all of those are appropriately treated.

In severe dementia the situation changes. It's quite easy to make a diagnosis at that point, so most of the patients who have the illness are diagnosed, but less than half of those with the diagnosis are treated.

Why is this the case? Why do we not diagnose more of the cases with mild AD? Why are not all the patients treated, and what are the reasons for abandoning treatment in the more severe cases? These are some of the issues we'll touch upon.

Slide 4

Slide 4. Increased Probability of Institutionalization by Disease Severity

Here we look at the stages of AD and the probability of institutionalization. If you have moderate AD, you have about a one third chance of being institutionalized, and almost a 90% chance if you have severe AD. Part of AD is the steps toward institutionalization. Can our treatments modify the need for institutionalization so that people can function at home longer?

Slide 5

Slide 5. Effects of Disease Severity on Impairment of ADL in Patients With AD

This shows the impairment of ADLs by patients with mild, moderate, and severe AD. If we look at the inability to handle money (on the left), the patients with severe AD have many more problems with that. The lower the score, the more problems they have.

Inability to tell time is the same, as is difficulty doing hobbies, and dressing. There's really no problem undressing in patients with mild AD, but in severe AD, there is a problem. This goes on through even things like confusion, and ability to use a telephone. With each stage of AD there's more and more loss of these ADLs.



Effects of Cholinesterase Inhibitors on Activities of Daily Living

Slide 6

Slide 6. Effects of Galantamine on ADL: ADCS/ADL Scores Mean Change From Baseline

This shows the effects of galantamine on ADLs. In this study, over 20 weeks, patients who were treated with 16 mg and 24 mg of galantamine were able to prevent the emergence of loss of ADLs. The patients treated with placebo, in the triangles, showed deterioration in ADLs, while the higher doses of galantamine were able to prevent this.

Slide 7

Slide 7. Effect of Donepezil on ADL at Endpoint: Change in Assessment Scale Score From Baseline

These are data for donepezil showing that there was inability to improve ADL scores in some patients treated with donepezil.

Slide 8

Slide 8. Effects of Rivastigmine on ADL: Progressive Deterioration Scale (PDS)

Here the effects of rivastigmine on ADLs are shown, with patients on placebo deteriorating, but the 6- to 12-mg dose maintaining very close to baseline for a 6-month period.

Slide 9

Slide 9. Improvement in ADL: Rivastigmine Treatment vs Placebo (PDS)

This talks about what changed. When we compare rivastigmine vs placebo, patients in the mild stages of AD showed an enhanced ability to handle money, to tell time, and to spend time on their hobbies.

In the moderate stages, they were able to participate in family discussions of financing, able to dress, had decreased forgetfulness, and could remember where objects were.

In the severe stage, the ability to use a telephone was improved by rivastigmine. They were comfortable in different settings, weren't anxious when their caregiver left, and their eating manners improved.

So depending on the stage of illness that one's in, you'll expect different changes in symptoms. For example, you don't see any changes in the ability to handle money in the severe stage. One of the reasons for that is that once you take the checkbook away, you're not likely to give it back. The same thing is for driving. However, by stage of illness you can have a different expectation of the kind of symptoms that you'll see improvement in relative to placebo. This is also useful in instructing families about what they might see over the stages of illness and how the medication may be useful.



Behavioral Symptoms in Alzheimer's Disease

Slide 10

Slide 10. Peak Frequency of Behavioral Symptoms as AD Progresses

This is an autopsy-confirmed diagnosis of AD. On the x-axis, time 0 was when the diagnosis was made; to the left is months before the diagnosis, and to the right, months after the diagnosis. What's surprising is that the peak frequency of social withdrawal was 3 years before the diagnosis was made; suicidal ideation, 24 months; depression, 20 months; paranoia, 18 months; and day/night reversals, 9 months. So many of these symptoms occurred a long time before the diagnosis was made. I think we, as physicians, when we see a patient sitting in front of us, elderly with social withdrawal, all think of depression, but we don't all think of the question, could this be the first symptom of AD? And we don't necessarily proceed with the appropriate workup.

Once the diagnosis has been made, we'll see the characteristic agitation, irritability, wandering, hallucinations, and aggression; aggression is usually one of the main reasons leading to institutionalization.

Slide 11

Slide 11. Psychotic Symptom Frequency Increases With Disease Severity

This is the Clinical Dementia Rating Scale (CDR). A CDR .5 would be mild cognitive impairment, 1 would be mild, 2 moderate, and 3 severe. The frequency of psychotic symptoms is greater than 50% in the moderate and the severe, and actually quite high in even the mild patients. So behavioral psychotic symptoms are not rare in AD.



Effects of Cholinesterase Inhibitors on Behavioral Symptoms

Slide 12

Slide 12. Effect of Galantamine on Behavioral Symptoms: NPI Total Scores

If we look at galantamine's ability to prevent the emergence of behavioral symptoms, patients treated with placebo and a low dose of galantamine had emergence of behavioral symptoms, but this was prevented by treatment with galantamine at 16 mg/d and 24 mg/d.

Slide 13

Slide 13. Donepezil Behavior Effects in Nursing Home Patients at Week 24: Mean Change From Baseline in NPI-NH Individual Items

Donepezil, in a non-nursing home population and community, was able to show benefit on behavioral symptoms over a 24-week period. However, when donepezil was given to nursing home patients in the next stage, there was no overall improvement. One symptom, aggression and agitation, showed a slight advantage for donepezil, while the others did not. Overall there was no improvement in patients in the nursing home study.

Slide 14

Slide 14. Rivastigmine: Change on NPI-NH at Week 52 for Patients Who Had the Symptom at Baseline

This shows an open-label nursing home study for 1 year for patients with AD who were treated with rivastigmine. There were improvements in irritability, anxiety, useless wandering and motor behaviors, delusions, disinhibition, hallucinations, nighttime behaviors, etc. A variety of symptoms showed improvement over the 52 weeks. This is important because, once behavioral symptoms begin, they tend to persist. They tend to become multiple and they tend not to go away on their own.

Slide 15

Slide 15. NPI Improvement Following AChE Inhibitors and Dual AChE and BuChE Inhibitors Treatment in Five Studies (Mean Change per Item After Approximately 6 Months)

We compared the studies, which is difficult and there are problems in doing that, to get an idea of the type of changes we're seeing in outpatients. On the left, galantamine was able to prevent the emergence of behavioral symptoms in a community-assisted setting. Donepezil was able to improve behaviors, but not in a nursing home study. And 2 nursing home studies, a European and a United States study, show the changes associated with rivastigmine treatment.

Slide 16

Slide 16. Effects of Rivastigmine on Psychotropic Medication Use

I think another important point in one of the nursing home studies with rivastigmine was the effects of using cholinesterase inhibitors on the need for other medications. Over the 26 weeks, 7% of the time the dose for antipsychotics was increased. However, 13% of the time the dose was reduced, and 31% of the time there was no need for antipsychotic medication; the antipsychotic medication that was present could be terminated. This was true not only for antipsychotics, but also for antianxiety agents and antidepressant agents, showing that the use of cholinesterase inhibitors was able to reduce the need for other medications commonly used to treat patients with AD and related dementias.

Slide 17

Slide 17. Rivastigmine and Donepezil Administration Increases Basal ACh Release in Aged Rats

This is an animal study. There was a microcannula placed in the cortex or hippocampus, and samples of acetylcholine were taken to measure the amount of acetylcholine release. On the left, the control shows that with 21 days of donepezil there was an increase, and an even larger increase with rivastigmine, in the cortex, and the same pattern was observed in the hippocampus. This suggested that large amounts of baseline acetylcholine release could be induced by chronic treatment with cholinesterase inhibitors.

When you increase acetylcholine, one of the effects in the brain is to cause an imbalance between acetylcholine and dopamine. The brain sometimes pumps out dopamine in the area postrema in order to compensate for the large increase in acetylcholine, which can cause transient nausea or vomiting.



Titration-Related Adverse Effects of Cholinesterase Inhibitors

Slide 18

Slide 18. Most Frequent Adverse Events With 1-Week Dose Titration of ChE Inhibitors

In this study we are looking at the effects of, not what's recommended, but 1-week dose titration of the cholinesterase inhibitors. There's about a 3-fold increase in nausea when you go from placebo to 10 mg of donepezil in a week. When you go from placebo to 24 mg of galantamine, there's about a 3-fold increase, and a 3- to 4-fold increase for rivastigmine, when you go from placebo to 6 to 12 mg. The same is true for the other symptoms. However, 1-week dose titration is not recommended. The idea is to start slow, start low, and go slow.

Slide 19

Slide 19. Adverse Events With 1- vs 4-Week Titration of Galantamine

For example, if we look at the galantamine data with 1-week titration, there was a 3-fold increase in nausea. However, with a 4-week titration to 24 mg, that could be cut in half.

Slide 20

Slide 20. Tolerability of Donepezil: Incidence of Common Adverse Events by Titration Rate

This shows donepezil with no titration. There is a large increase in nausea, diarrhea, etc with 1-week titration. However, with the 6-week titration to 10 mg, these rates are markedly reduced and not very different from placebo.

Slide 21

Slide 21. Slow (4 Weeks)-Dose Titration With Rivastigmine Provides Low Potential for AEs

These emerging data with rivastigmine show that with a 4-week titration between dose levels, the amount of nausea, vomiting, and other side effects is much lower than reported in the pivotal studies using shorter-term titration and fixed mandated titration.

Slide 22

Slide 22. Acute Titration-Related AEs With ChE Inhibitor Therapy

To summarize, there are acute titration-related adverse events (AEs) with cholinesterase inhibitors, and they include nausea, vomiting, some abdominal pain, diarrhea, and anorexia. These tend to be transient, usually during the dose escalations, and almost always of mild to moderate intensity. I guess the point is, they're not life threatening. They're inconvenient to the patient and they're caused by increases in acetylcholine in the brain. They're not peripheral. They're centrally mediated side effects. You can avoid them by slow dose escalation, particularly by giving Exelon (rivastigmine) and Reminyl (galantamine) with food. These are proven ways to decrease the incidence of these AEs.



Molecular Forms of Cholinesterase Inhibitors

Slide 23

Slide 23. Molecular Forms of AChE

There also are different isoforms of acetylcholinesterase, and it has to do with brain selectivity and why these drugs tend to work more in the brain than in the periphery. In the red cell there are dimers of acetylcholinesterase. There's a series of tetramers on collagen stalks in the muscle. In the brain there's primarily the monomer G1 form or the tetramer G4 form. The drugs have different effects on these isomers.

Slide 24

Slide 24. Inhibitory Influence of ChE Inhibitors on Molecular Forms

We can see, in the upper left-hand panel, that there's mostly G4 and a little G1 in the normal brain. On the lower left we see that the G4 peak disappears in AD, and AD becomes a G1 illness. And on the right-hand panel we can see that rivastigmine, in contrast to the other compounds, is G1 preferring. It prefers the isoform that is most prevalent in AD.

Slide 25

Slide 25. AChE Isoforms in Normal and AD Brains

This is really a repeat of what you saw before. In the frontal cortex and nucleus basalis the normal G4 peak drops away and the G1 peak emerges. The caudate nucleus is, however, different. In the caudate nucleus there is little G1 with and without AD. This has some implications in terms of side effects. What it implies is that the G1-preferring drug, rivastigmine, will affect and increase the acetylcholine in the frontal cortex and nucleus basalis without causing increases of acetylcholine in the caudate. This is important because one doesn't want to have movement disorders or tremors associated with increasing acetylcholine in the caudate nucleus.



Tolerability, Adverse Events, and Pharmacokinetics of Cholinesterase Inhibitors

Slide 26

Slide 26. ChE Inhibitors: Tolerability

This summarizes the tolerability of donepezil, rivastigmine, and galantamine; and with all compounds acute AEs are cholinergically mediated. The chronic AEs are a bit different. There's greater sleep disturbance with donepezil and greater cardiovascular problems, such as bradycardia with donepezil, and syncope with galantamine, compared with rivastigmine. There are few extrapyramidal symptoms (EPS) with rivastigmine and galantamine, but more with donepezil, and more behavioral disturbances reported with donepezil and galantamine according to the publication by Inglis.

Slide 27

Slide 27. Adverse Events per 100,000 Prescriptions for Rivastigmine and Donepezil

This compares the adverse reactions reported to the US Food and Drug Administration (FDA) in the first 6 months that each of these compounds was on the market. There were more reported adverse reactions for donepezil and more serious AEs for donepezil than for rivastigmine.

In contrast to the commonly held idea that rivastigmine is a less well-tolerated drug, I think this has to do with the acute titration-mediated side effects rather than the long-term side effects. This is quite important because I think sometimes patients are willing to tolerate chronic diarrhea, some other symptoms, or insomnia, not being aware that there are other alternatives.

Slide 28

Slide 28. Significance of Drug-Drug Interaction

This takes a look at drug-drug interactions, and points out that the primary metabolism of most drugs is through 3A4 or 2D6, and that this is responsible for 85% of drug metabolism. It's quite important because most of the treatments that we use for AD, in addition to cholinesterase inhibitors, involve the use of drugs that are metabolized through 3A4 or 2D6, including most of the atypical antipsychotic medications and many of the antidepressants and mood stabilizers.

Slide 29

Slide 29. ChE Inhibitors: Pharmacokinetic Characteristics

This continues our comparison between donepezil, galantamine, and rivastigmine. The elimination pathway for rivastigmine is through the kidney, through the kidney and liver for galantamine, and through the liver for donepezil. And metabolism of donepezil and galantamine is through the 2D6/3A4 isoenzymes.

Galantamine and rivastigmine are better tolerated when administered with food. That is not the case for donepezil.

Slide 30

Slide 30. Linear Dose Response of Rivastigmine in ADAS-Cog, PDS, and MMSE Mean Change From Baseline at Week 26

This shows that there are advantages with rivastigmine in increasing the dose. There is a dose relationship between improvements in the cognitive portion of the Alzheimer's Disease Assessment Scale (ADAS-Cog), in the upper left, ADLs, in the upper right, and the Mini-Mental State Examination (MMSE) scale, on the bottom.



Vascular Risk Factors, Vascular Dementia

Slide 31

Slide 31. Effects of Rivastigmine on Cognition in Patients With AD (MHIS Score = 0) and AD With Vascular Risk Factors (MHIS > 0)

I'd like to change focus and talk about vascular risk factors. In the rivastigmine studies there were patients who had vascular risk factors and those who did not. The modified Hachinski score of 0 meant no vascular risk factors, and greater than 0 meant hypertension, a transient ischemic attack (TIA), or some other associated vascular risk factor.

Interesting enough, the right-hand panel shows that the patients with vascular risk factors had a more potent response compared with placebo than those without vascular risk factors, suggesting that the presence of vascular risk factors should not dissuade someone from using cholinesterase inhibitors.

Slide 32

Slide 32. Effects of Rivastigmine on ADL in Patients With AD (MHIS Score = 0) and AD With Vascular Risk Factors (MHIS > 0)

In terms of ADLs the same pattern is seen, with at least as much response in patients with vascular risk factors as those without vascular risk factors.

Slide 33

Slide 33. Evolution of VAD Symptoms

Let's talk about vascular dementia as a syndrome. Alzheimer defined it as arteriosclerotic brain degeneration, and that maintained into the mid-1960s when one spoke of the volume of the brain infarction. Hachinski's contribution was pointing out that it was really the accumulation of multiple small strokes and, therefore, the definition was multi-infarct dementia.

This was further enhanced by Roman, who talked about vascular dementia; not only the number of infarcts, but the size and where they were located, whether at watershed areas or not.

The risk factors for vascular dementia are very similar to the risk factors for vascular disease: diabetes, hypertension, and hyperlipidemia.

Slide 34

Slide 34. Prevalence of Dementias: European Study of 2346 Cases

This speaks to the prevalence of dementia, with AD being the primary factor, vascular dementia being about 16%, and there's quite a lot of overlap as well.

Slide 35

Slide 35. Vascular Risk Factors

The vascular risk factors are the ones that you'd expect: hyperlipidemia, hypertension, diabetes, obesity, alcohol, smoking history, TIA, having an increased hematocrit or having a coagulopathy, family histories, atrial fibrillation, or other electrocardiogram (EKG) abnormalities. All these vascular risk factors are risk factors for the development of AD as well.

Slide 36

Slide 36. VAD: MRI Required for Clinical Diagnosis

Here you can see some magnetic resonance imaging (MRI) evidence of vascular disease in terms of the white periventricular showing evidence of hypertension from microvascular disease.



The Hippocampus and Alzheimer's Disease

Slide 37

Slide 37. Hippocampal ChAT Activity

Here we look at the choline acetyltransferase (ChAT) levels, the enzyme that makes acetylcholine, and find that it is depressed in AD, multi-infarct dementia, as well as the combination. So it shouldn't surprise us that cholinesterase therapies would be useful in AD and mixed dementia, as well as multi-infarct dementia.

Slide 38

Slide 38. Hippocampal Muscarinic Receptors

In terms of the muscarinic receptors, they're only decreased in multi-infarct dementia, once again suggesting that cholinergic therapies might be useful.



Effects of Cholinesterase Inhibitors on Vascular Dementia

Slide 39

Slide 39. Effects of Galantamine Treatment for 26 Weeks on Cognition in VAD and AD Patients With CVD

A very interesting paper by Erkinjuntti compared people with vascular dementia vs those with mixed dementia, and found that there was a statistically significant benefit of galantamine in those with mixed dementia, although this was not seen in patients with vascular dementia.

Slide 40

Slide 40. Rivastigmine in Subcortical VAD: Efficacy up to 22 Months in an Open-Label Study

Rivastigmine has open-label data for 22 months, which are interesting. It compared patients on rivastigmine vs aspirin. The patients on rivastigmine showed continued improvement in their Neuropsychiatric Inventory (NPI) behavioral scores compared with those on cardioaspirin, who were stable.

Slide 41

Slide 41. Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

This was also true for the clock drawing test; you see continued, sustained improvement over the 2 years of the study for the patients on rivastigmine compared with a slight deterioration for those on aspirin alone.

Slide 42

Slide 42. Rivastigmine in Subcortical VAD: Efficacy up to 22 Months

Importantly, just as AD is a family illness, the same is true for AD-related dementias. The Relative Stress Scale continued to show improvements for the patients treated with rivastigmine vs those treated with aspirin.

Slide 43

Slide 43. Decreased Cholinergic Activity Associated With Neuropathy of AD, DLB, and PD

We've been talking about the cholinergic pathology in AD, in vascular dementia. There's also a cholinergic deficit in dementia with Lewy bodies and dementia of Parkinson's disease, at least as great as that seen with AD. This shows that ChAT, the enzyme that makes acetylcholine, decreases in the other dementias.

Slide 44

Slide 44. Brain Infarction and the Clinical Expression of Alzheimer Disease: The Nun Study (N=61)

The Nun Study has been very useful in understanding the role of premorbid educational achievement, and also shows the overlap and synergy between brain vascular disease and the clinical expression of AD.

Participants who had AD pathology and brain infarcts together had a higher prevalence of dementia than those without infarcts; so the 2 together made for worse cognitive functioning. Fewer neuropathologic lesions of AD resulted in dementia with those who had existing lacunar infarcts. So having vascular lesions, all you needed was minimal AD lesions to produce AD, where it would have taken more neuropathologic lesions of AD in the absence of these lacunar infarcts. This shows that cerebrovascular disease can play an important role in determining the severity of the clinical symptoms of AD.



Lewy Body Dementia

Slide 45

Slide 45. Dementia With Lewy Bodies

Lewy body dementia is very interesting. Previously rarely diagnosed, it has been increasingly diagnosed in the past several years, thanks to the Newcastle upon Tyne, England group, which has defined the syndrome.

The key symptoms include fluctuating cognitive impairment; the family would report that one day they are much better than another day, more than normal variation. Persistence of visual hallucinations is very common, usually of small objects or people. They have systematized delusions, a high incidence of depression, and they're very sensitive to neuroleptic medication. Either they have Parkinson's symptoms that are observable on examination or, because of their visual hallucinations, are given a neuroleptic medication. They become quite rigid, often develop a fever, and have an increased risk of mortality. This is less so with atypical antipsychotic medications, but they still show a strong response and increased sensitivity to these medications.

Slide 46

Slide 46. Dementia With Lewy Bodies (cont'd)

Supportive features would include falls and syncope, and depression characteristics.

Slide 47

Slide 47. Neuropsychiatric Symptoms in DLB vs AD

If we look at the actual number of behavioral symptoms in dementia with Lewy bodies vs AD, Lewy body dementia patients have more visual and auditory hallucinations, more depression, and more delusions of misidentification, where the patient will say, "You're not my spouse. Where did she go?" when speaking to their spouse, forgetting who their spouse is. These delusions of misidentification are quite devastating to the caregiver, who is already stressed, having spent so much effort in a never-ending day in caring for someone with Lewy body dementia or AD.

Slide 48

Slide 48. Behavioral Symptoms at Baseline (NPI)

So the sine qua non of behavioral symptoms associated with dementias might be considered Lewy body dementia. More than half the patients have aberrant motor behavior, irritability, aggression and agitation, delusions, depression, apathy/indifference, and anxiety.

Slide 40

Slide 49. Behavioral and Cognitive Responses to Donepezil in AD and DLB (Open-Label, 5 mg/d for 6 Months)

When these patients were treated with donepezil, there was no behavioral improvement noted in the study by Samuel.

Slide 50

Slide 50. Effects of Rivastigmine on Behavioral Symptoms in DLB (Double Blind)

However, in a careful, double-blind study done for 20 weeks in 120 patients, there was no change on placebo, but a marked improvement on patients with rivastigmine. More than 60% of the patients had an improvement of greater than 30% from baseline, which would be an obvious dramatic improvement, when treated with rivastigmine.



Parkinson's Disease and Dementia

Slide 51

Slide 51. PD and Dementia

Dementia is also seen in patients with Parkinson's disease. At least one third, and maybe up to half, of the patients with Parkinson's disease develop dementia. And this dementia is not improved by dopaminergic therapies.

Many people think that cholinergic therapy would be inappropriate in patients with Parkinson's disease because you may increase the tremor and some of the movement disorders by increasing acetylcholine, and recall that we previously used anticholinergic drugs in treating Parkinson's disease.

Slide 52

Slide 52. NPI Hallucination and Sleep Scores in PD Patients Receiving Rivastigmine

In this study by Reading, compared with baseline there was an improvement in hallucinations and sleep in patients with Parkinson's dementia who received rivastigmine.

Slide 53

Slide 53. Rivastigmine in PD: Cognition, Motor Function, and Caregiver Burden

Their MMSE scores also showed a robust improvement. The Parkinson's disease rating scales did not show any deterioration of movement disorder at all. And importantly, the caregiver stress for these patients dramatically decreased when the patients were given rivastigmine.

Slide 54

Slide 54. Effects of Rivastigmine on ADAS-Cog and UPDRS Motor Scores in PDD

Another study, recently published, looked at patients with Parkinson's disease dementia and compared them over 26 weeks. The motor score, the Unified Parkinson's Disease Rating Scale, was stable over the 26 weeks despite the rivastigmine treatment, and the ADAS-Cog, the improvement in cognition, was marked with improvements in naming, recognition, word finding, and concentration.

One of the things that's very interesting is that the subjects were able to remember the instructions better, and the persons administering the neurocognitive assessments spontaneously reported that the subjects participating could do much better in terms of following through with the directions for the testing.

Slide 55

Slide 55. Effects of Rivastigmine Treatment on Clinical Global Impression of Change From Baseline

In terms of their mean dose, it was a little over 7 mg of rivastigmine a day. And interestingly enough, the patients, the caregivers, and the neurologists all agreed that the patients had shown a moderate improvement over the 26 weeks of the study. It may be the first time that the neurologists, caregivers, and patients uniformly agreed on how the patients were doing.

What we've shown is that cholinesterase inhibitors can be useful in not only AD, both mild and moderate, but also in patients with vascular risk factors and vascular dementia or mixed dementia, and in patients with Parkinson's disease dementia and Lewy body dementia.

Despite this efficacy many cases of AD are not diagnosed. When diagnosed, they're not treated, and particularly are not treated in the later stages, although there's no evidence to support this idea.

An additional factor that we haven't addressed is that when cholinesterase therapy is initiated, it often is discontinued after several months or within the first year. The rationale for this is related to the expectations that the physician and the family have.

We must keep in mind that this is a progressive, incurable disease and that, in fact, stabilization is terrific therapy. Rather than seeing the downward trend continue, if we can attenuate the slope of the downward progression or stabilize the patient or, in some circumstances, get improvement for a period of time in some symptoms, this would be considered excellent medicine in most areas. Not being aware of this, sometimes family and physicians give up when the patient continues to show some decline, not keeping in mind what the progression would have been otherwise.


Medical Rationale for Switching Cholinesterase Inhibitors

Slide 58

Slide 56. Reasons to Consider Switching ChE Inhibitors

Also, there's the issue of switching medication, and I think switching is not considered enough. When a patient fails to show an initial response to treatment, (is put on a treatment which doesn't show much of an effect), one should consider switching, or when someone's had a period of response for 6 months or a year and now no longer has it. What I mean by that is, even though it's progressive -- someone shows some changes, more changes in cognition, loss of another ADL, or some behavioral problems emerging -- I think it's appropriate that one consider switching, and not as a last resort, but when a patient's no longer responding to current treatment.

Slide 59

Slide 57. Switching: Medical Rationale

We actually use the idea of switching for most illnesses. If someone is on a serotonin reuptake inhibitor and doesn't respond after 3 months, one would switch to another antidepressant or even another serotonin reuptake inhibitor and a good response can be found. We do this for antibiotics. We certainly do this for congestive heart failure and epilepsy. So in most aspects of medicine we're used to the concept of switching. For some reason this hasn't been widespread in the treatment of AD. Why do you switch? To maximize the benefits of treatment.



Switching Cholinesterase Inhibitors

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Slide 58. Changing From Donepezil to Galantamine and Rivastigmine

The data also suggest that switching can be quite useful. Let's review that. In the open-label study of Robillard (on the left), of 17 patients, a little more than half of them showed an improvement when switched from donepezil to galantamine. Keep in mind that these were nonresponders to donepezil, but when switched to galantamine, showed an improvement.

The same was shown in a larger study (on the right). When patients had side effects of donepezil and were switched, about 65% of them responded to rivastigmine. When patients had lost their efficacy, roughly 50% showed a response.

These 2 studies have been criticized because they're small studies, and we're looking at the switching from donepezil to galantamine, or donepezil to rivastigmine, and not the reverse. And that's because donepezil is the most widely prescribed treatment. But I think it may be beneficial to switch no matter what.

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Slide 59. Lack of Tolerability and Efficacy With Donepezil Do Not Preclude Response to Rivastigmine

In a large study of almost 400 patients, there were patients who discontinued donepezil because they were unable to tolerate it or because of a lack of efficacy. Of the patients who discontinued because of lack of efficacy, shown on the left, 55% of them were able to respond to rivastigmine and 11.5 % discontinued because of AEs associated with rivastigmine.

On the right side are patients who had diarrhea or other symptoms where they couldn't tolerate donepezil), and 15% of those discontinued rivastigmine due to side effects. This means that 85% of those who didn't tolerate donepezil were able to tolerate rivastigmine; making the point that inability to tolerate one cholinesterase inhibitor doesn't predict that you'll be unable to tolerate another. And interestingly enough, almost three quarters of those patients who had discontinued donepezil for AEs were able to respond to rivastigmine.

The point of this is, if you have a side effect that can't be tolerated (and I think that many patients don't understand that they don't have to tolerate insomnia, bradycardia, falls, or muscle cramps), switching can eliminate those side effects most of the time. And if one is dissatisfied with a therapeutic response to their current cholinesterase inhibitors, at least half the time they're going to get a better response by switching to another cholinesterase inhibitor.

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Slide 60. Guidelines for Switching ChEIs

What are the guidelines for switching? If patients are doing well, leave them. If patients are having problems with either safety or tolerability, I think the question is how do you switch to galantamine or rivastigmine? One of the things to consider if they've had side effects: you might want to wash out the medication they've been on for 7 days and then begin treatment with the alternative cholinesterase inhibitor.

However, for patients who have been on a cholinesterase inhibitor and had no problems with tolerability, but are being switched because they failed to respond or are not responding as well as anticipated, no washout period is required. You can immediately switch to either, in this case, galantamine, 4 mg twice a day, or rivastigmine, 1.5 mg twice a day.

There is evidence that you can switch from donepezil to rivastigmine at a much faster rate, and that patients used to a cholinergic load can be immediately switched to 3 mg twice daily. This is not the recommended titration schedule although there's much clinical experience to support this more rapid change.

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Slide 61. Medical Rationale for Switching

Let's summarize switching. Switching, for odd reasons, is a relatively new concept in AD treatment. Typically physicians stop a cholinesterase inhibitor if the patient doesn't show a robust response or starts to lose a response. And that's often mediated by the family saying, "Well, the patient's no longer responding." I think it's important to educate the patient and their family in advance, particularly the family, of what to expect. This is a progressive illness and what we're trying to do is ameliorate the rate of progression, to slow down the rate of progression.

The evidence suggests that switching represents an important option and can maximize response and even minimize side effects.



Concluding Remarks

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Slide 62. Memantine in Moderate-to-Severe AD

I wanted to mention 2 other treatments. One is memantine (Namenda), which has recently been approved for the treatment of moderate-to-severe AD. This appears to work as monotherapy and when combined with cholinesterase inhibitors. It works by blocking the N-methyl-D-aspartate (NMDA) glutamatergic pathway by blocking NMDA glutamatergic receptors.

The NMDA glutamatergic receptors are important in long-term potentiation (LTP), which is preserving or making long-term memories. However, if there's too much excitatory glutamatergic input, there can be a loss of brain cells and brain function. Memantine is hypothesized to modulate the activity of that receptor. However it works, it does work in moderate to severe patients, improving their ADLs, behavior, and cognition.

This is an evaluable adjunctive to using cholinesterase therapies. Just like we treat cardiac illness with more than 1 medication, I think there are good reasons to consider using cholinesterase inhibitors combined with memantine for patients with moderately severe or severe AD.

The side effects of memantine compared with cholinesterase inhibitors are comparable. The effects with rivastigmine in moderately severe patients were quite robust.

Another treatment that has been tried is vaccines. I think the importance of the vaccines, even though these trials were abandoned, is that some of the patients who received vaccines were able to decrease their amyloid load. Therefore, this could be important in determining whether the plaques that we see in AD are causal and if removed, we would see improved cognition. The data from these trials are not conclusive, but it offers a potential other avenue of decreasing the pathology associated with AD.

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Slide 63. Summary

Acetylcholinesterase inhibitors, galantamine and donepezil, and the dual acetyl- and butyrylcholinesterase inhibitor, rivastigmine, are a proven value in treating AD. They treat not only the cognitive symptoms, but also the behavioral and the ADLs.

Patients with severe AD can maintain a robust response to cholinesterase inhibitors. The data for this are most evident with rivastigmine.

Behavioral disturbances are important because the behavioral disturbances are what lead to people being institutionalized. It's the aggression or the other behaviors that cause people to be removed from their homes, because the caregivers can no longer take care of them. As AD gets worse, the number of behavioral symptoms increases, and once the symptoms are there, they tend to persist.

One of the advantages of using cholinesterase inhibitors is that they can decrease the need for antipsychotic medications and antidepressant medications, which are costly and in their own rights can interfere with cognition.

At some stage in the illness cholinesterase inhibitors need to be augmented by other treatments, but there is much to offer patients with AD. It's unfortunate that too few are diagnosed, that treatments are often not initiated, that treatments are abandoned too early, and that there's this notion that patients with moderate AD cannot respond when, in fact, there's been robust responses in patients with moderate AD.

I think there's much that we have to offer now for patients with AD and their families. The major goal for us is early detection, because early detection can result in early treatment, which has a long-term beneficial consequence.

We can decrease the burden on the caregiver, and the burden on the caregiver is related to numerous health problems that the caregiver has.

Patients can stay at home having meaningful interactions with their families for longer periods of time before institutionalization is necessary, which is almost always the case. Delaying institutionalization not only has important consequences in human benefits, but also can decrease the overall cost of the illness, given the enormous cost of institutionalization for patients with dementia.

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Slide 64. Summary

In addition to these benefits in AD, there's increasing evidence that cholinesterase inhibitors can be very effective in AD-related dementias. Alzheimer patients with vascular risk factors or vascular pathology also respond to cholinesterase inhibitors. In mixed dementia, they work. There's increasing evidence for cholinesterase inhibitors being important in dementia with Lewy bodies, and for the dementia related to Parkinson's disease, which suggests an important extended role for these agents.

Lastly, all the cholinesterase inhibitors have different modes of action and different pharmacokinetic profiles, so switching can be efficacious. I think too often we forget to use this option when either side effects develop or side effects become intolerable. When long-term side effects or loss of efficacy occur or patients continue to deteriorate, often one gives up treatment. I think a more appropriate choice would be to switch to a different cholinesterase inhibitor and see if, in fact, optimal benefit or enhanced benefit can be obtained.

What we have shown is that the cholinergic system is involved in not only AD, but also in vascular dementia, Lewy body dementia, and Parkinson's disease. Changing the tone in the cholinergic system can have beneficial effects on cognition, behaviors, and improvement in ADLs. The available cholinesterase inhibitors are not the same, and some patients may respond better to one than another. And when one fails to work, one should consider switching to another agent.


Authors and Disclosures

Author

Steven G. Potkin, MD
Professor, Department of Psychiatry and Human Behavior; Director, Clinical Psychiatric Research; Robert R. Sprague Director of UCI Brain Imaging Center, University of California, Irvine, CA

Disclosure: Grants/Research Support: Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Forest Laboratories, Janssen Pharmaceutica, Novartis Pharmaceuticals Corporation, Organon, Otsuka, Pfizer Inc., Sanofi-Synthelabo; Consultant/Advisory Board Member: Acadia Pharmaceuticals, Arena Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, Janssen Pharmaceutica, Novartis Pharmaceuticals Corporation, Organon, Otsuka, Pfizer Inc., Praecis; Speakers' Bureau: AstraZeneca, Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, Pfizer Inc.

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