Summary

John C. Morris, Murray Raskind, and Martin Farlow led this live discussion on 14 October 2003. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

John C. Morris, M.D. led this live discussion along with Murray Raskind and Martin Farlow on 14 October 2003.

Participants: Gabrielle Strobel, Alzheimer's Research Forum; John C. Morris, Alzheimer's Disease Research Center at Washington University in St Louis, Missouri; Catherine Roe, Washington University, Saint Louis, Missouri; Elana Sinsabaugh, Caregiver; Pete Nelson, University of Pennsylvania; Philip Fun Hon Chung, Chang Gung Medical Center, Taiwan; Roy D. Kelley, Phillips, Maine; Stefan Lichtenthaler, University of Munich, Germany; Quirong Xiao, Memory Pharma; Joel Price, Washington University, Saint Louis, Missouri; Paula Chabun, Elder Health, Peach Arch Hospital, White Rock, British Columbia, Canada; Michael Chiasson, University of Calgary, Canada; Martin Farlow, Indiana University at Indianapolis; Catherine Roe, Washington University, Saint Louis, Missouri; Keith Crutcher, University of Cincinnati, Ohio; Murray Raskind, VA Puget Sound Health Care System Mental Illness Research, Education and Clinical Center, Seattle, Washington.

Note: The transcript has been edited for clarity and accuracy.

Gabrielle Strobel
Hi, all; let's get started. I wonder would our esteemed chat leaders state in a nutshell what the major news is that came out of this set of reviews? What did we not know before?

John C. Morris
I'm not sure that the set of reviews provided that much new information; What I think they emphasized is that the three currently available acetylcholinesterase inhibitor (AChEI) agents all are effective in mild to moderate Alzheimer's, at least to some degree, but are under-used.

Gabrielle Strobel
The AChEIs command little respect in general public opinion. The line is "they help a little, for a little while," but then the patient declines even faster. I take it this is not true?

John C. Morris
Marty, would you like to take this one?

Martin Farlow
I would summarize that this group of papers details potential benefits of the cholinesterase inhibitors, with the data for each being appropriately advocated. The data is together in one place where the reader can make judgments and comparisons concerning characteristics and relevant studies for the various drugs.

Gabrielle Strobel
How long do these drugs help? I know it is ethically difficult to keep people on placebo past one year in trials of drugs which are known to work, but what would you say from your clinical experience and open-label follow-up?

John C. Morris
I think the lack of respect for the AChEI agents comes, at least in part, from an expectation that benefit is to be measured in terms of patient improvement, whereas the clinical benefit much more often is realized in terms of "stability" of function, at least for a while. The duration of benefit varies from patient to patient, but in general, patients can expect some "stability" for 6-12 months, and often longer.

Martin Farlow
Nobody knows how long they are effective; data exists covering mild to moderate stages and the nursing home studies would suggest these drugs continue to be effective into the later stages of the illness.

Gabrielle Strobel
But it seems we now know the drugs' effect is small but robust and consistent, not fickle and highly variable as one often hears?

John C. Morris
I don't know if I'd use the term "robust," but definitely consistent and meaningful for the patient and his/her family.

Martin Farlow
I do believe they should be given to all patients with AD who tolerate them until there is no longer real interaction between the patient and family or caregiver. I think previously, clinicians were looking at one leg of the Alzheimer's elephant and trying to determine how the drugs were affecting it. I think with recent studies, a broader picture of the effects of these drugs on the whole elephant is emerging.

Pete Nelson
Any issues of dosage and what particular drugs are more effective, which may not be in the literature?

Martin Farlow
Donepezil can clearly be given at higher doses and some patients will benefit from those doses.

Gabrielle Strobel
When should treatment start?

John C. Morris
I'd be interested, given the question about dosages, as to what Drs. Farlow and Raskind consider optimal doses. The package inserts give recommended "maximum" doses, but is it possible to increase beyond (as long as there are no side effects) and, if so, how high do you go?

Martin Farlow
Rivastigmine has a lot fewer adverse effects if titration is slower. Galantamine has greater benefits at 16 mg BID dose than recommended dosing, but at the cost of greater side effects in some patients.

Murray Raskind
I have not pushed beyond the highest recommended doses: For galantamine, 32 mg /day offered no advantage in trials compared with 24 mg, and caused more adverse effects. There may be occasional benefit from going beyond 10 mg of donepezil.

Martin Farlow
In patients who are failing after being on drug for 6-12 months, I will routinely take patients to levels above FDA recommendations for all of these drugs.

Murray Raskind
I have trouble knowing when a patient is "failing," given that even if they are obviously declining cognitively, the rate of decline may still be less than if they were untreated.

Martin Farlow
Rather than failing, perhaps "progressing more rapidly than family previously had appreciated," which, granted, may be an effect of disease progression.

John C. Morris
There was a question about which drug is more effective. I believe that the benefit of the three drugs is basically is the same for all; the issue is which is better or less well-tolerated than the other. As Marty indicates, the titration scheme can affect tolerability, but in practice I find that perhaps donepezil has slightly less frequent side effects than the other two. What is the experience of others in this regard?

Martin Farlow
I would agree with regards to tolerability. I would say rivastigmine may have greater effects in patients with subcortical dementias, but they have not established this in head-to-head trials. I would agree for rivastigmine, particularly patients with hallucinations and attention problems, given the DLBD study data.

Keith Crutcher
To anyone, in this era of "pharmacogenomics," is there any clear evidence for genotypic variability accounting for the responders? I remember some data indicating that E4 carriers were less responsive, but don't know the specifics or if it has held up.

John C. Morris
Marty, didn't you investigate the issue of factors, including ApoE status, that might affect response to treatment? Murray and Marty, can either of you respond to Keith's query about genotype and differential response to therapy?

Murray Raskind
I have been unimpressed that genotype data can yet help us.

Martin Farlow
The data has not held up in terms of guiding drug therapy, though I suspect ApoE genotyping may make a resurgence when the full implications of ongoing mild cognitive impairment (MCI) trials are digested.

Philip Fung
Which of these three drugs would you suggest to be the first drug to apply? And are there any guidelines or factors helping our decision process?

Murray Raskind
The drug with which you are most familiar probably should be your first choice. There are no convincing data for superiority of one versus another.

John C. Morris
Very practically, I go with "ease of use" in recommending which drug to initiate. We have the most experience with donepezil, it has a favorable side effect profile, the titration is simple, and it is once a day—I think these factors (together with the belief that no one drug clearly has more benefit than the others) result in donepezil being the most commonly prescribed.

Martin Farlow
I do think that for many AD patients living alone, donepezil use once a day offers an advantage in compliance and/or supervision.

Gabrielle Strobel
AD is heterogeneous: Some call it a syndrome, with symptoms and their time course varying among patients. The drugs have slightly different effect profiles. Are there corresponding "profiles" of patients who fit a given AChE inhibitor over another? For example, rivastigmine for those with more psychiatric symptoms and for those with advanced disease? Can one match patient profiles with drugs?

Murray Raskind
Suggestions of differential profiles may be a function of studies unique to a drug; for example, rivastigmine is the only one studied versus placebo in dementia with Lewy bodies (DLB) (a psychiatric symptom-"heavy" disorder). The positive results of this study on psychiatric symptoms are encouraging for rivastigmine, but may be a drug class effect when other agents are studied in DLB.

Gabrielle Strobel
Many AD patients develop major depression along with their AD symptoms. Is one AChEI more suited than another to help these depressed patients? Or must this depression be treated separately?

Martin Farlow
Depression deserves to be treated separately.

Gabrielle Strobel
When should treatment start? Do recent findings about a compensatory increase in the cholinergic system early in the disease (by DeKosky's group and others) suggest something about when to start donepezil treatment?

John C. Morris
Regarding "when to initiate," the data for very early stages of dementia have yet to be thoroughly analyzed. At this point, it is fair to say that we don't know whether the AChEIs "work" in very early-stage AD or MCI. My clinical experience suggests that they do; however, because rate of decline is slower in the very mild stages, one needs to observe individuals over long periods. To the extent that individuals with MCI actually have underlying Alzheimer's disease, it makes sense that the ChEI may be beneficial. How the one report of compensatory cholinergic activity in very early-stage AD factors in here, I don't know.

Gabrielle Strobel
Should MCI/incipient, early AD be treated with AChEIs? Or should one "keep the powder dry" in this phase?

Murray Raskind
I treat "MCI" at the first evidence (even historical) of convincing progression of cognitive deficit.

Martin Farlow
The one presented trial to date was with donepezil and suggested some symptomatic benefit, but also higher gastrointestinal adverse effect rates. The issue is still under study. I do put many MCI patients on cholinesterase inhibitor therapy after fully explaining the pros and cons and getting patients' wishes.

Philip Fung
Practically, we do only have a 12~15 percent conversion rate annually of MCI to AD, and different subtypes of MCI, according to Dr. Petersen, have different conversion rates. Then how could we know to whom we should give the drug, apart from the individual's desire?

John C. Morris
Philip, I think it is possible to identify the MCI individuals who have a high probability of having underlying AD. This subset sometimes is termed "MCI of the Alzheimer's type." These are the patients who should be considered for ChEI therapy. I wouldn't worry about conversion rates; the diagnosis of AD is highly variable (i.e., different clinicians have different thresholds for "calling" the diagnosis).

Murray Raskind
Time of "conversion" from MCI to AD is still somewhat arbitrary; any decline within MCI encourages me to begin AChEI treatment.

Martin Farlow
I agree with John and Murray. It may be possible to predict by MRI evaluation of hippocampus, and ApoE genotype, which patients with MCI are more likely to convert.

Pete Nelson
Dr. Farlow, how high do you go with donepezil, and have you seen many respond well to this higher dose?

John C. Morris
Pete, I don't know whether Marty saw your query. What I have done occasionally is increase the donepezil dose to 20 mg a day. The few patients for whom I've done this seem to tolerate it well and may have responded (this is all subjective/anecdotal).

Gabrielle Strobel
Retreating early, I'd want a drug as soon as I have a reasonably certain diagnosis. But I wonder if one might run into a similar situation as with PD, where the effect of L-dopa wears off later on in the disease when the patients need the symptomatic relief the most...?

Martin Farlow
Nobody knows, but it is a great topic to write papers about.

Murray Raskind
Recent galantamine data (now in press in Arch. Neurology) suggests that the drug keeps "working" for at least three years.

Gabrielle Strobel
Murray, that is great news, indeed. We will look out for that paper and link to it from this chat. Who is the first author?

Murray Raskind
I am!

Gabrielle Strobel
Donepezil is more specific than rivastigmine, which is "dirtier" in that it inhibits both AChE and butyrylcholinesterase. Is that good or bad?

Murray Raskind
These are all complicated drugs working on an only partially described brain cholinergic system in AD. Therefore, it is difficult to know theoretically which agent is more specific.

Martin Farlow
Specificity used to be thought of as the best way to decrease adverse effects. In reality, the longer half-life of donepezil is more important. The effects of rivastigmine on AChE are probably good, particularly as the disease progresses, but nobody has designed a convincing study to prove it yet.

Gabrielle Strobel
I understand there are new acetyl- and butyrylcholinesterase inhibitors being studied and tested in human trials. These are not the three we are talking about today, right? What are they? How are they better?

Murray Raskind
I am unaware of any "new" AChEI agents in development that theoretically would offer substantial advantage, but we can always be pleasantly surprised.

Gabrielle Strobel
I think I read that in an abstract of a paper by Marty? That's what prompted the question.

Martin Farlow
Phenserine may actually decrease APP levels as an additional mechanism. Phenserine, in addition to being a cholinesterase inhibitor, actually interacts at a promoter site to block transcription of APP.

Gabrielle Strobel
Marty, that is very interesting. So APP and all its cleavage products would go down.... Is this in clinical trials, by whom?

Martin Farlow
Phenserine has been tested in one Phase 2 trial. The company is Axonyx.

Elana Sinsabaugh
I have heard that an increase in donepezil will slow down the heart. Is this true?

John C. Morris
I'm sure Murray and Marty know more than I, but I think the decreased heart rate with AChEI therapy is only 1-3 beats per minute, and practically has not been a major problem. Of course, if an individual has cardiac compromise or is syncopal, then it could be a factor.

Martin Farlow
Donepezil does slow heart rate, but the effect is seldom clinically significant.

Murray Raskind
I agree with John. Heart-rate changes in either direction are sometimes seen, but are small unless one is dealing with an overdose.

John C. Morris
I send all my complicated patients to Marty and Murray!

Murray Raskind
When John sends me a DLB or demented Parkinson's patient, I start an AChEI.

Gabrielle Strobel
Murray, but anticholinergics are used very widely in the elderly, no? And Marty, while we are on new drugs, what is neotrophin. What's it doing?

Martin Farlow
It is dead, dead. Very large trial showed neotrophin had no clinical benefits in AD.

Gabrielle Strobel
Thanks, Marty; good to know. I'll check our Drugs in Clinical Trials section to see if we have a skeleton in the closet there....

Murray Raskind
Anticholinergics remain overused in elderly patients, and should be avoided when possible. They are a common cause of acute delirium in patients with, or even without, an underlying dementia.

John C. Morris
The issue of anticholinergics (e.g., those used for bladder dysfunction) is a tough one; some are more likely than others to cross the blood-brain barrier (BBB) and have a deleterious effect on cognition—these drugs can aggravate "confusion" in demented individuals and presumably counter any benefit of the AChEIs. On the other hand, bladder "leakage" or frank incontinence is problematic, also, so we're often left with trying to reduce the dose or even eliminate the anticholinergics.

Gabrielle Strobel
There are many other dementias which overlap with AD, and the AChEI inhibitors are being tested for them. Can you say if any particular drug is more useful for a particular condition, or are they all pretty much the same for these related conditions, too?

Martin Farlow
Sometimes Detrol or Ditropan is the difference in a given caregiver being willing and able to keep a patient at home. I don't use anticholinergics unless they are the only practical management tool in a given patient.

Gabrielle Strobel
I see, Marty. What a dilemma!

John C. Morris
Personally, I think all the current AChEIs are equally effective in the "overlap" syndromes or mixed dementias (e.g., dementia with Lewy bodies/AD, vascular dementia, and AD).

Martin Farlow
Maybe it sounds like a good RO-1 that should be done, but that won't be funded because it is not a sexy enough topic.

Murray Raskind
Dear all, I must sign off now to go to my typing lesson (just kidding, but I do need such a lesson and do have to depart).

Pete Nelson
Thanks for the chat, Gabrielle et al.; it was very informative!

John C. Morris
Gabrielle, I'm going to need to sign off, also. I thank you for all your coordination and moderating, and everyone for their questions and responses.

Gabrielle Strobel
Before everyone is leaving, let me just thank our stellar, and busy clinicians for making time.

Keith Crutcher
Thanks to all.

Philip Fung
Thanks from Taiwan.

Martin Farlow
Very good. Bye, everyone

 

Background

Background Text: Update on Approved Drugs for the Symptomatic Treatment of Alzheimer Disease: Introduction
By John C. Morris, M.D., Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and Professor of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO.
Reference: Neurolog. 2003 Sep;9(5):223-4:

Posting courtesy of Lippincott William & Wilkins. The Alzheimer Research Forum gratefully acknowledges their permission to make this series available to a wider audience.

Tacrine in 1993 was the initial drug approved by the Food and Drug Administration (FDA) for symptomatic therapy for Alzheimer disease (AD). Subsequent FDA approval was obtained for donepezil (1996), rivastigmine (2000), and galantamine (2001). All four drugs are centrally acting cholinesterase inhibitors (cholinesterase inhibitors) and all consistently demonstrate efficacy for mild-moderate AD. Therapeutic benefit, although modest, is clinically meaningful and generally equivalent for all four drugs. Tacrine no longer is marketed by its manufacturer in the United States as the newer drugs (donepezil, rivastigmine, and galantamine) have superior tolerability and safety profiles and are easier to use (e.g., bid or qd dosing for the newer drugs versus qid dosing for tacrine).

Are there clinically relevant differences in the therapeutic ratios of donepezil, rivastigmine, and galantamine? There is no definitive answer to this question. Only a very few limited studies have attempted to directly compare these agents. Comparing published findings of pivotal trials for each drug is problematic because variable patient selection criteria and study designs, rather than actual drug effect, may be responsible for any small differences in results. Clinical experience suggests that several factors will determine which drug(s) ultimately will emerge as the most favored: 1) therapeutic superiority (symptomatic benefit is very nearly equal for all three, but it is possible that 1 or more may demonstrate additional disease-modifying effects); 2) tolerability and safety profiles (all are safe but share peripheral and central cholinergic side effects; distinctions may rest on the frequency rather than type of side effects); 3) ease of use (including dosing frequency and dose escalation requirements); and 4) cost (currently, all three drugs cost about $150/mo). Clinical experience with rivastigmine and galantamine still is insufficient to know how well they compare with donepezil, the current industry "leader" by virtue of the fact that it was launched several years before rivastigmine and galantamine were approved.

Several features are shared in common by donepezil, rivastigmine, and galantamine. All have therapeutic benefit in AD. Modest efficacy consistently is shown for each drug in the multiple domains affected by AD: cognition, performance of activities of daily living, behavior, and "global" function. Duration of benefit varies but can be demonstrated in some cases for at least a year. The cholinesterase inhibitors may be efficacious for patients with either less or more severe stages of AD than the mild-moderate stage for which the drugs are approved. They also may be beneficial in dementing disorders that overlap with AD, including dementia with Lewy bodies and vascular and mixed dementia.

Although the cholinesterase inhibitors are efficacious, safe, and readily available in the United States, many patients with AD are untreated with these drugs; those who are often discontinue therapy after only brief drug exposure. Because the drugs generally are well tolerated by patients with AD, especially with current dose escalation paradigms, it is unlikely that unacceptable side effects explain the underutilization of the drugs. Instead, the high nontreatment and discontinuation rates may relate to unwarranted therapeutic nihilism ("the drugs don't work") and to unrealistic expectations of drug benefit (anticipating clinical improvement rather than "stability" of function).

This group of papers is intended to provide up-to-date, clinically relevant information for each agent. The Neurologist is fortunate to have each of the three cholinesterase inhibitors discussed by highly regarded clinical investigators. Drs. Doody, Farlow, and Raskind are leaders in dementia research with extensive experience in the pharmacotherapy of AD. As such, their advice frequently has been sought by companies involved in drug discovery and development for AD. They (and I) have served as consultants, advisory panel members, and site investigators in clinical trials for several companies, including those that manufacture and market the drugs that are the focus of the present contributions.

See the following articles (.pdfs) also posted courtesy of Lippincott William & Wilkins.

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References

Webinar Citations

  1. Therapeutic Nihilism: Widespread Yet Passé? AD Acetylcholinesterase Inhibitors Are Better Than Their Reputation

Other Citations

  1. John C. Morris, M.D.

External Citations

  1. Lippincott William & Wilkins

Further Reading

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