Introduction

Steven T. DeKosky and Bengt Winblad led this live discussion on how the addition of memantine to the clinician's toolbox will change the management of Alzheimer's disease.

Following its FDA approval last October, memantine is due to arrive in pharmacies this month.

• How should physicians use it?
• For whom should it be prescribed?
• What are good drug combinations?
• What side effects should doctors watch out for?
• Just how much of an improvement does this drug offer?
• Will this drug work for related forms of dementia?
• How long does its effect last?
• What is the best way to titrate the dose?

We have posted our summary adapted from the briefing document (.pdf) that the drug's U.S. distributor, Forest Laboratories Inc., submitted to the Food and Drug Administration (FDA) last September. Our recent news story reports on the results of a trial of memantine combined with AChE inhibitors. You may also be interested in our previous live discussion on cholinesterase inhibitors.

Steven T. DeKosky and Bengt Winblad led this live discussion on 29 September 2004. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

Transcript:

Steven T. DeKosky and Bengt Winblad led this live discussion on 10 February 2004. This discussion was co-organized by the Alzheimer's Association and the Alzheimer Research Forum.

Participants: Antonio Alvarez, caregiver; Steven T. DeKosky, University of Pittsburgh School of Medicine; Mike Faux, caregiver; Dale Grillot, caregiver; Lisa Gwyther, Duke University; Kevin Foley, Hauenstein Alzheimer's Disease and Memory Disorders Program, Grand Rapids, Michigan; Bev Jones, Clinical Assoc Prof, Wake Forrest University, Geriatric Psychiatrist; Jim Kallio, caregiver; Zaven Khachaturian, June Kinoshita, Executive Editor, Alzheimer Research Forum; Pallavi Kakulavar, MD, Cleveland Clinic Foundation; John C. Morris, Washington University; Phyllis O'Hara, Alzheimer Specialist, RNC, private practice, former president of the Western Massachusetts Alzheimer's Association; Jeff Paley, MD; Susan Scruby, caregiver; Lon Schneider; Gabrielle Strobel, Managing Editor, Alzheimer Research Forum; Bengt Winblad.

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

June
Thank you all for logging on today.

Bengt Winblad
I am sad that I cannot see all of you. This is my first experience with a chat room.

Dear friends, I do think we agree that we have evidence enough to believe that treatment of the disturbances in the glutamatergic system is important in AD.

June
I'd like to pose a question to Bengt. Can you give us a general description of the type of patient whom you find tends to benefit from memantine?

Bengt Winblad
My feeling is that most of our AD patients will respond on memantine. Certainly, we have most experience with patients who are in a more advanced dementia stage. We see a rather quick response within two to three weeks, and that is very positive.

Steve DeKosky
Bengt, if you could add.... What is the most likely signal of response seen by you and your staff?

John C. Morris
Bengt, what are the responses not only that you detect, but also that the families report?

Bengt Winblad
The earliest signs are that the patients take more interest in what is around them and take part in activities they have not done before. Examples could be that severely ill patients can start to eat by themselves, which they have not done for a long time.

June
What about effects on language and other types of cognitive functioning?

Bengt Winblad
Caregivers and family members say that their wives or husbands are more interactive, want to discuss more, take more initiatives. For example, one husband who is a taxi driver told that when he came home, his wife had been out shoveling the snow away from the garage entrance, which she had not done for a long time.

Jim_Kallio
Are we assuming in this discussion that Namenda is being used in conjunction with a cholinesterase inhibitor, too?

Steve DeKosky
The experience of the nursing home study was without cholinesterase inhibitors. Bengt, I assume your comment was for memantine alone?

Bengt Winblad
Yes, I have commented only for monotherapy.

Bev Jones
I see many patients in AD special care units whose Mini-Mental State Examination (MMSE) is Steve DeKosky
Bev, there will obviously be quite impaired people, non-mobile, perhaps with contractures, on whom determining a good response would be difficult. Much of the problem in designing these studies, and the reason that the early studies with cholinesterase inhibitors were done with mild-to-moderate patients, was because there was belief that it would be easier to show a positive effect on milder patients, and because there were no good tools to assess more severe cases for improvement or stabilization. We are now doing better in that regard.

Bengt Winblad
Bev, in our Latvian study we had a positive effect, also, on these patients. I have not initiated actual patients in nursing homes during the last year.

Bev Jones
Thanks. I realize data is limited on the most severely affected patients, but many families will be facing the question of whether to give Namenda a try.

June
Bengt, would you characterize the effects of memantine as being an overall improvement across the spectrum of symptoms, or is it more effective for certain aspects of the disease?

Bengt Winblad
June, I believe, without proof, that it has a good effect over the whole continuum.

Zaven
Bengt (Steve, Lon, and John, also), how much experience is there with this drug in the earliest stages of the disease (mild or even earlier)? Given the fact that the mode of action is through the glutamatergic system, one would expect it might be useful slowing disease progression by reducing putative calcium toxicity.

Bengt Winblad
Zaven, I agree about the possibility of disease modification. The preclinical data presented on memantine and its neuroprotective effects are really good and interesting.

I suppose we all have seen the new data on memantine with a possible effect also in mild and moderate stages of AD. Will that mean that we can treat the whole continuum of the disease?

Lon Schneider
The companies did not release any data, just their news releases. I don't think any of us have been able to evaluate the data. Lundbeck's trial was not positive.

Bengt Winblad
Lon, we all agree that our authorities will demand two pivotal studies that are positive. I have also seen a press release.

lhebert
Are the non-responders to acetylcholinesterase inhibitors in mild-to-moderate patients likely to respond to memantine?

Steve DeKosky
There are no published data on that question yet.

John C. Morris
I'm interested in what data are available to support benefits for memantine combined with cholinesterase inhibitors in patients with mild AD; does anyone know about such results?

Bengt Winblad
John, we have only 8-10 patients with combination. It seems to work well, but in two patients we have seen a confusional reaction that went away when dosage was reduced from 20 to 15 mg.

Lon Schneider
John, I think use of the term "combined with" acetylcholinesterase inhibitors is incorrect. The studies have only assessed the effect of memantine in patients who had been taking an AChEI for at least six months. This is an "add-on," not a combination.

Steve DeKosky
The Tariot et al. paper is the only published add-on study with AChE inhibitors and memantine. Other data have been reported in short communications but not yet published and peer-reviewed.

[Editor's Note: See ARF related news story.]

Lon Schneider
Steve, it is notable that in the moderate-to-severe stage, add-on patients had been on donepezil an average of 2.25 years before being randomized to memantine. They benefited from memantine, but the "placebo group"—those on donepezil alone—continued to deteriorate at a rather rapid rate, as though the donepezil was having no effect.

Bengt Winblad
I agree that it could be an effect of memantine alone in the Tariot paper.

Steve DeKosky
Well, it may be unfair to say that donepezil has no effect unless you removed it and saw a further decline.

June
Good point, Steve.

Gabrielle
Lon, do you mean to say the donepezil was no longer working in the Tariot et al. patients, and it was not really a combination therapy trial?

Lon Schneider
Gabrielle, a combination trial would randomize patients to donepezil alone, memantine alone, the combination of donepezil and memantine, and placebo.

Bengt Winblad
Good design, Lon.

June
So, Lon, do these data suggest that memantine has an effect on progression?

Lon Schneider
The studies haven't been done to assess progression. It's just that memantine has a clinical effect over six months in moderate-to-severe patients who had been on donepezil for 2.25 years.

June
Are there ongoing trials that can answer the question regarding progression?

Bengt Winblad
June, not that I know about.

Steve DeKosky
As for disease modification, that seems a plausible hypothesis. It awaits a disease modification study, of longer duration, to see if there is improvement. If you look at the article on neuroprotection in Parkinson's in JAMA last week by Schapira and Olanow, you can see what the problems are of interpreting such studies when there is also a symptomatic effect of the drug, as there clearly was with memantine. I am not aware of such a longitudinal study underway. Lon, do you know?

Lon Schneider
Steve, I am not aware of long-term trials.

June
Zaven asked about trials in mild cognitive impairment (MCI) or early AD patients. Are there any in progress?

Bengt Winblad
Zaven, I don't think they have started on MCI yet.

Jim_Kallio
We get many questions on the Alzheimer's list about memantine use with Exelon and Reminyl…. Will we see trials on those, too?

Antonio Alvarez
This question is for Dr. DeKosky or other doctors in the panel: Are there any data or do you have any opinion on the use of antiinflammatories together with memantine and acetylcholinesterase inhibitors? And specifically, do you think there will be any benefits on the use of Flurbiprofen as an antiinflammatory medicine together with memantine and an acetylcholinesterase inhibitor? My wife is in the early-mild stages of Alzheimer's.

Steve DeKosky
Antonio, the only treatment trial of use of antiinflammatories in AD (Naprosyn and ibuprofen) was not positive. There are no data yet in humans on Flurbiprofen, which people are interested in because of its potential effects on β amyloid.

Lon Schneider
The R-enantiomer of Flurbiprofen is an NSAID but doesn't inhibit COX1 or 2. It might modulate transcription pathways of NFκB, and it reduces Aβ42. Myriad Pharma is developing it, but there is no evidence that the use of antiinflammatories is helpful in people who already have AD. In fact, it appears harmful overall.

[Editor's Note: See ARF related news story].

Jeff Paley
Steve and Bengt, are you believers in the metal-chelation hypothesis and Bush/Tanzi's clioquinol study published recently in Archives of Neurology?

Bengt Winblad
Jeff, clioquinol is difficult to give; you have to add vitamins to avoid side effects.

Jeff Paley
Yes—B12 injections—but there is a second-generation compound without the optic toxicity; do you believe the data in terms of mechanism?

June
Hi, Jeff. I'd like to refer you to an ARF Live Discussion we had in January on clioquinol. I'd like to confine the discussion here to memantine. Thanks!

Bengt Winblad
I had an earlier question about experience of increasing dosage over 20 mg./day. My answer was that there is certainly some experience with memantine in trials on pain with 40 mg./day, but that there is a real risk that higher doses in dementia patients will lead to more side effects. Have you any experiences with higher doses?

June
Thanks for bringing this question up, Bengt. We posted a question before the chat from a woman whose husband seemed to benefit from a higher dose (40 mg.), but her physician doesn't want to go above 20 mg. (See Q & A)

Jeff Paley
To all, what does the 10-plus-year experience in Europe tell us about long-term use of memantine?

Bengt Winblad
Jeff, the European experience is that memantine also in the long-term studies is a safe drug and that really few interactions could be expected, and I think that was an important point in the European approval in 2002.

Kakulavar
In Europe, are they using memantine for mild Alzheimer's, and if so, do you know if it is effective?

Bengt Winblad
Kakulavar, it's only registered for more severe stages, but mainly in Germany it has been used for several years in milder stages of brain insufficiency and sold very well.

Kakulavar
You mean in Europe it is only approved for use for severe-stage Alzheimer's?

Steve DeKosky
Please remember, everyone, that when you ask whether a medicine is "effective," that the standard is a double-blind, placebo-controlled trial, not our clinical impression...and there are not a lot of those trials completed and reported.

June
Have any of you had clinical experience treating earlier-stage patients with memantine?

John C. Morris
I have no experience with memantine in early-stage patients. Moreover, I have no experience with memantine in "combination" (or as an add-on) with vitamin E, antiinflammatories, etc. I wonder if there are data from Europe, or if not data, at least clinical experience in this regard?

Bengt Winblad
John, in Europe we don't use vitamin E in dementia patients and are afraid of antiinflammatories due to the gastric problems. I'm sure, still, that Merz would have some data on combinations, but I don't know about them.

Gabrielle
Bengt, is it not also true that fewer people in Germany take cholinesterase inhibitors? Is memantine the drug of choice over there?

Bengt Winblad
Gabrielle, I think memantine, together with gingko, is having the largest market share in Germany.

Bev Jones
I'm interested in the prior European experience, too. For example, was there evidence in other uses that memantine helped moderate-to-severe disease more clearly than mild?

Kevin Foley
Steve, any trials underway looking at lower dosages or once-daily dosing, or reason beyond the Latvian study to believe that less than 20 mg. per day would be just as effective?

Steve DeKosky
Kevin, Bengt would be best to answer your question about lower dosing.

Bengt Winblad
Concerning dosage, I think that for glutamatergic drugs, in general, we believe in a U-shaped dose response curve. Still, 10 mg. gave a good effect in our nursing home study.

Jeff Paley
Is there any data from the European literature about use of the drug in severe disease?

Bev Jones
Are there any memantine data on frontotemporal Lewy body disease or Parkinson's?

Bengt Winblad
Bev, I would like to test in a trial for frontotemporal lobe dementia. I have treated three AD patients with severe frontal lobe atrophy and their reaction was rather modest or bad on the cholinergic drugs, but good on memantine, or actually, the addition of memantine.

Bev Jones
Good! It would seem the benefits would be not specific to AD.

Bengt Winblad
Bev, two European trials on vascular dementia with memantine gave very positive indications of effects (see Orgogozo et al., 2002 and Wilcock et al., 2002).

John C. Morris
Bengt, Lon, Steve, Gabrielle, Zaven, Lisa, June, et al., I must sign off now for another commitment. Thanks for hosting this Web chat!

Zaven
Good-bye, John.

Steve DeKosky
There is a great deal of work that has been done in Europe on memantine, and those studies, Bengt's nursing home study, and the two U.S. studies did indeed indicate the memantine appears low in side effects. I think that is why, even with questions about the magnitude of the effect of the medication in terms of changes in behavior or cognition, people are enthusiastic about it and want to try it immediately in milder cases and in other diseases. The clinical experiences will lead to decisions about doing the controlled trials that must be done to demonstrate clearly that it works. Again, the issue of a symptomatic effect versus a neuroprotective effect will complicate the design.

Bengt Winblad
Steve, I agree!

Dave Grillot
Dale Grillot here from Columbus, Ohio. I'm a caregiver and researching for a book on caregiving. I have read a number of reports of patients who have become violent when started on memantine. Can anyone comment?

Bengt Winblad
Dave, we haven't seen that with monotherapy. I have heard about one case on the combination.

Steve DeKosky
I think there have been some suggestions of agitation in the studies. I do not know of "violence." It is also difficult to characterize what might have led to agitation in many cases of more severe disease. But it deserves continuing monitoring in post-approval assessments of effectiveness.

Lon Schneider
Where do the reports of "violence" come from? Anybody have citations?

Bengt Winblad
Lon, I have seen confusion in two patients, but only heard about more intense psychiatric problems in one.

Dave Grillot
I have seen a number of posts on caregiving messenger boards about families that had to stop memantine because of violent behavior. Sorry, not anything published.

MikeFaux
So is there any data on how long memantine is effective, or what unexpected effects may occur upon withdrawal?

Bengt Winblad
Mike, there is no real long-term data, except that the Barry Reisberg study had an open-labeled phase IV for another 18 months, I believe (personal communication).

Dr. Kevin Foley
How does a busy doctor in primary care define "moderate" disease in the office, i.e., a candidate for memantine? Not all doctors use the MMSE or functional scales.

Bengt Winblad
Kevin, I still think that the MMSE is useful on the GP level. A moderately severe demented patient has a need for support in more complicated tasks, but manages well to live at home.

June
Bengt and Steve, I was struck by the data on adverse events (AEs). In many cases, the memantine group had fewer AEs than the placebo did, which suggests to me that these AEs are actually disease effects that memantine was ameliorating. Would you agree with this interpretation?

Bengt Winblad
June, I think the reduction in, for example, agitation is due to the patient's experience of thinking a bit more clearly; that reduces the problems in the interaction.

Debra Katt-Lloyd
Steve and Bengt, what has been the typical titration in practice? Do you find doctors giving a 5-mg. increase per week, or do they tend to spread it out over a longer period, e.g., waiting a month in between?

Steve DeKosky
The dose packs have a very slow increase up to 20 mg. Most people were starting with 10, then going to 10 bid when buying the drug from European pharmacies. In the U.S., the increase has been slower in those packs. But I did not see a problem starting with 10 and going to 10 bid a week later. I am curious about Bengt's greater experience in this regard.

Gabrielle
Debra, good question. I think for galantamine, the speed with which the doctor ramps up to the full dose affects how well the patient responds and the side effects (see recent ARF Live Discussion on cholinesterase inhibitors).

Bengt Winblad
Debra, in practice, I have seen everything going from 10 mg. and after one week directly to 20 mg. In the patients with frontal lobe engagement, we went much slower than the recommended 5-mg. increase per week.

Debra Katt-Lloyd
Thank you, both—my experience with MDs prescribing the cholinesterase inhibitors is often that they would be slow to titrate up even without side effects.

Zaven
I have to log out. Good-bye Bengt, Steve, Lon, June, and Nico!

June
Thanks for being here, Zaven! Good-bye.

Bengt Winblad
Good-bye, Zaven.

Jeff Paley
Steve and Bengt, is there a downside to adding memantine to acetylcholinesterase inhibitors for all mild-to-moderate patients, since the safety profile is so clean?

Bengt Winblad
In many of the European countries, the downside would be that there is no reimbursement, and the drugs are certainly very expensive.

Steve DeKosky
In addition to expense, we have a responsibility to figure out how to answer the questions in careful ways, such as in the incredibly difficult study Bengt did in Latvia in the nursing home. All our other speculation is just that, and AD patients are, as you know, very variable. The next data that will likely emerge will be from the completed studies of memantine in mild-to-moderate AD.

Kim
I don't understand. The package insert refers to three studies and the only one with significant results is when memantine is used in combination with donepezil. How can anyone consider using it in monotherapy?

Steve DeKosky
Kim, see Reisberg, 2003.

Lon Schneider
The package insert refers to three trials, all positive. The Latvia trial had patients with both AD and vascular dementia.

Kim
What about the Neuropsychiatric Inventory (NPI), Clinician's Interview-Based Impression of Change-plus (CIBIC-plus), and MMSE? Not significant?

Jeff Paley
How might you account for the fact that one study in mild-to-moderate was negative, but there was a recent one that was positive?

Lon Schneider
NPI was not a primary; the co-primaries included Aβ-derived diffusible ligands (ADDLs).

Bengt Winblad
Lon, a subanalysis of the Latvian study showed that memantine had as good an effect in both Alzheimer's and vascular dementia.

Lon Schneider
Yes, in fact, both the FDA's and Forest Laboratories' subanalyses showed that. I was reacting to the idea that two trials in the package insert were "negative." This is not the case.

Gabrielle
With cholinesterase inhibitors, clinical experience is exposing an interesting tension between the need to boost ACh levels in the AD brain and to lower them peripherally, for example, to treat incontinence. Anticholinergic drugs are quite commonly prescribed in geriatric care. This can be a dilemma. Do any of you see inklings of a similar mechanistic "tug-of-war" for memantine on the horizon, where you want to dampen N-methyl-d-aspartate (NMDA) receptors in AD, but might need to up them for other conditions?

Lon Schneider
Given memantine's action as an NMDA antagonist, you would expect it to reduce the various gastrointestinal symptoms due to acetylcholinesterase inhibitors.

Kevin Foley
Bengt, at what MMSE score would you recommend starting memantine? At 14?

Bengt Winblad
Kevin, I would start on patients with MMSE Bev Jones
As a clinician, I expect will be hard to tell patients and families they should wait until they hit an MMSE Jim_Kallio
You're right…. Waiting for 15 will be very difficult.

Dr. Kevin Foley
So are you going to treat everyone?

Steve DeKosky
Bev, you are right; we all have that dilemma. The issue is how much data you need or trust, and what the expectations are. That is why I think doing the neuroprotection trial is important.

Bengt Winblad
Bev, we can, after the press release from Forest Laboratories, already see that clinicians are using it outside the approved indication on more mild patients.

Jim_Kallio
We have the dilemma, too, of when Blue Cross will quit paying for Aricept.

Jeff Paley
Again, Steve or Bengt, any idea why the mild-to-moderate studies were mixed—some positive and some negative?

Bengt Winblad
Steve, I am not sure a study in MCI will be done, as it is only recognized as an early Alzheimer's diagnosis, and they certainly will have the indications from mild to severe after some further studies.

Steve DeKosky
Bengt, is it likely that Merz or Forest, or both, will do a neuroprotection (long-term) trial to see if it slows progression?

Bev Jones
Gotta go; thanks, everyone. Steve, enjoyed seeing you on the PBS special.

[Editor's note: The PBS special is "The Forgetting."]

Gabrielle
On the future outlook: Investigational drugs called cognitive enhancers, or ampakines, modulate synaptic transmission via AMPA receptors, vaguely similar perhaps to the mechanism of memantine. What do you think of these? Do you foresee future use for AD from these candidates in the pipeline?

Phyllis O'Hara
Thanks for the Ampalex update. Wondered what happened to it!

Steve DeKosky
The AMPA receptor is different from the NMDA receptor, and we first need to see positive studies before deciding about any combination therapies aimed at the glutamate receptor subtypes.

Bengt Winblad
Phyllis, I am not so sure that influencing the AMPA receptor is as good an approach, possibly due to more side effects.

Gabrielle
Bengt, what sorts of side effects?

Bengt Winblad
Gabrielle, side effects more toward the psychotic domain. What is your feeling about effect in vascular dementia (VaD)?

Gabrielle
Steve, you are testing amyloid imaging with Pittsburgh compound B (PIB). Could you do a small study identifying people early and treating them with memantine versus not?

Steve DeKosky
We need to determine what the levels of amyloid are in the brains at different stages of disease, and longitudinally what the rates of increase are in relation to cognition, and then if all goes well, try to see if that intervention slows or reverses amyloid load. I do not think there is a mechanism currently wherein memantine would affect amyloid. But I am sure someone will think of one.

Gabrielle
Ha ha, Steve! Everyone's favorite thing eventually affects amyloid, does it not? Currently, everything is affecting BACE. I thought of it not directly as memantine affecting amyloid, but of presymptomatic amyloid as an early marker.

June
Is there any neuropathology data on patients who have been treated with memantine (and for that matter, AChE inhibitors) regarding effects on plaque load?

Bengt Winblad
June, I am not aware of reduction of plaques. We have run the Pittsburgh PIB ligand in 25 early-AD and 20 MCI patients, and in some of these on more occasions, so I am sure Agneta Nordberg will present these data in Philadelphia in July.

Gabrielle
All, we have extensive coverage of the published study by Bengt, Bill Klunk with numerous comments by other scientists, on the Alzforum news section (see ARF related news story).

June
Thanks, Bengt.

Bengt Winblad
Steve, in the ECNP meeting there were data presented both on an effect on β-amyloid production and also on diminishing the phosphorylation of tau in a report from Khalid Iqbal.

Steve DeKosky
Aha! See? It happened already. Very interesting.

June
Bengt, were you addressing your vascular dementia question to anyone in particular?

Bengt Winblad
June, I am happy if anyone will answer if we should do more trials with memantine in vascular dementia.

Lon Schneider
You should distinguish ischemic disease and continue trials in that. That's where the evidence is in Wilcock and Orgogozo's memantine trials.

Bengt Winblad
Lon, yes, perhaps "vascular dementia" is too broad and heterogeneous.

June
So what would be the inclusion criteria for a vascular dementia trial?

Bengt Winblad
June, probably we have to pick out, as Lon said, a group of patients that on imaging shows a more pronounced subcortical damage indicating that the blood-brain barrier of the penetrating vessels is not intact.

Steve DeKosky
I agree that the cases to focus on may be the subcortical ischemia/lacunar infarction cases...also easier to track longitudinally, I believe.

Phyllis O'Hara
Thanks for letting this 75-year-old nurse eavesdrop on your fascinating discussion. Later!

Antonio Alvarez
Thank you very much to Dr. DeKosky and other doctors for participating. I have to go now.

June
Thanks, Antonio. Good luck.

Jim_Kallio
Yes...what about using memantine in combination with Exelon or Reminyl?

Steve DeKosky
I suspect the companies are doing those. I do not have a lot of experience with the combination with Exelon; I have a few patients on Reminyl and memantine without problems. But we do very much need a larger experience with these to know that they are okay to use together.

Jim_Kallio
How about efficacy, too, on the Exelon and Reminyl used with memantine?

Bengt Winblad
Jim, a large study is ongoing in Germany with a combination with Reminyl. I do think we will see similar effects as with Aricept. I am not sure about the design; perhaps Lon has an idea about that?

Steve DeKosky
There are no data on efficacy. By that, I mean the type that might emerge from a controlled trial.

June
Yes, efficacy data are difficult to obtain. In the meantime, people must also worry about potential adverse effects from combining two approved therapies.

Jim_Kallio
So do we even know yet about synergistic effects of adding the cholinesterase inhibitor with memantine?

Steve DeKosky
I think there are many cases in which people have done that—added memantine to ongoing donepezil or galantamine. The former case would be like the Tariot study. I do not know if you can get an answer about "synergy" from that. Combined effects may depend on the stage at which you initiate the therapies.

Jim_Kallio
A lot of caregiver concern is about whether it's worth the money to add memantine therapy…. It can be expensive without insurance.

Lon Schneider
Again, no evidence that memantine and donepezil together provide additive effects, but strong evidence that memantine provides effects in people who had been taking donepezil for an average of two years or so.

Dave Grillot
I think the big questions for families are: When should it be started and when is it no longer worthwhile, and apparently, should the person stay on cholinesterase inhibitors?

Steve DeKosky
Dave, specific data on which to make recommendations about your important questions are not available yet. No one knows when to take off the cholinesterase inhibitors. And although we know that the studies show effects of memantine on AD subjects with MMSE of 15 and below, we don't know "how high" to go—or won't with certainty until the mild-to-moderate AD studies are completed and reported, which we hope will be soon. The answer to when to stop is not a simple or unitary one, and requires careful discussion with your doctor and consideration of the status of the patient.

June
If a patient is already on, say, donepezil or Reminyl, can a physician feel comfortable about adding memantine to the treatment, in terms of potential adverse effects?

Lon Schneider
The evidence, as thin as it is, is that memantine added to donepezil reduces adverse effects, that it doesn't add AEs.

June
Lon, that's good to know. Based on what we know about the mechanism of memantine, are there any classes of drugs, foods, etc., that people should not combine with memantine?

Bengt Winblad
June, there are really few precautions to be taken, but certainly we have to be more careful with patients with reduced kidney function, recent heart infarction and, according to the recommendations, it should not be used in patients with epilepsy.

Susan Scruby
For what it's worth, my mother has been on Aricept for some time, though at a low dosage. She seems unable to tolerate the higher dosage (we've tried three times). She started on the titration pack of Namenda on January. 31—it may just be wishful thinking on my part, but she does seem to be more engaged. Many of her conversations don't make sense, but she is more alert and aware, and more interested in talking with people and participating. This may pass, too, but I'll take what I can get.

Steve DeKosky
Susan, so will we. Amen!

Bengt Winblad
Susan, I think what you report is exactly what caregivers report for us in Stockholm.

June
Sadly, our time is up. I want to thank our guests for participating in today's chat, and our audience for being here.

MikeFaux
Thanks, Bengt, Steve, Lon, June, et al. for all your work!

Steve DeKosky
June, I'm pleased by the thoughtful questions and concern of both the clinicians and caregivers in this session, and for Bengt to do this. Many thanks.

lisagwyther
This has been interesting.

June
You may also send questions by e-mail: junekino@alzforum.org. Thank you, Bengt, Steve, and all! I have to say farewell. Bye!

Background

Background Text

The Medical Need
Alzheimer's disease is the most common form of dementia in the elderly and is the fourth-leading cause of death for patients aged 65 or older. The prevalence of AD is estimated to be about four million people in the U.S. alone, and approximately one million elderly Americans have severe dementia. Moderate to severe AD represents an identifiable stage of AD and can be reliably diagnosed. A hallmark of the transition to the moderate and severe stages of AD is the progressive loss of the ability to perform activities of daily living.

The current therapeutic options for AD approved by the FDA are the cholinesterase inhibitors (ChEIs), which are indicated for the treatment of mild to moderate AD. However, it is believed that seventy percent of diagnosed dementia patients already have advanced dementia symptoms. The time that the average AD patient spends in the mild stages, where episodic memory loss is the primary clinical finding, is relatively brief. Once the patient reaches the moderate stage, the remaining three to 12 years of life (depending on the age of onset, see related ARF news story) are spent experiencing further deterioration in cognition and activities of daily living (ADLs). There is no approved anti-dementia treatment in the U.S. for patients with advanced AD (MMSE During the mild-to-moderate stages, cognitive skills show deterioration and this decline leads to impaired ADLs. Instrumental ADLs begin to be affected in the mild-to-moderate stages of AD, followed by pronounced deterioration in physical or self-care functions during the moderate-to-severe stage. The progressive decline in the patient's ADLs ultimately lead to nursing home placement. Decline in ADLs and cognition further burden caregivers. In severe AD, all intellectual functions are severely compromised, and the clinical picture is dominated by the patient's limited function and disruptive behavior. The estimated annual cost of patient care rises from $18,408 in mild to $36,132 in severe stages. Thus, there is a need for therapeutic agents that will slow decline, potentially reduce care costs, and delay institutionalization.

Preclinical and postmortem studies of AD have associated changes in glutamatergic function with memory deficits, a hallmark of AD. Moreover, the excitotoxicity hypothesis holds that chronic glutamatergic overstimulation leads to neurodegeneration. Thus, the glutamatergic neurotransmitter pathway has been implicated in AD pathology and serves as a target for therapeutic intervention.

About Memantine

Memantine is a novel therapeutic agent that represents a new class of AD treatment options. Memantine has shown efficacy and safety in the symptomatic treatment of patients with moderate-to-severe AD. Memantine has recently been approved for the treatment of moderately severe to severe AD in the European Union and Australia. (Section 2.1 of the full briefing summarizes the history of the clinical development of memantine.)

Memantine has been available in Germany since 1982 (originally approved for the treatment of organic brain syndrome) and is currently available outside the U.S. in 42 countries. As of February 2003, there were over 600,000 patient-years of exposure to memantine.

Memantine is a low-to-moderate affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist with strong voltage dependency and rapid blocking/unblocking kinetics. These pharmacological features appear to allow memantine to block the sustained activation of the receptor by glutamate that may occur under pathological conditions, and to rapidly leave the NMDA receptor channel during normal physiological activation. In humans, memantine is 100 percent bioavailable after an oral dose, undergoes minimal metabolism, and exhibits a terminal elimination half-life of 60 to 80 hours (75 percent or more of the dose is eliminated intact in the urine). It rapidly crosses the blood-brain barrier with a CSF/serum ratio of 0.52. Memantine does not inhibit cytochrome P-450 (CYP 450) isoenzymes in vitro, and its pharmacokinetics are not affected by food, sex, or age.

Efficacy

Memantine demonstrated efficacy in the treatment of moderate-to-severe AD using a dose of up to 20 mg/day in two key double-blind, placebo-controlled trials (Trials 9605 and MD-02) of 6-month duration in patients with probable AD. Also, efficacy of 10 mg/day of memantine was shown in an earlier trial (Trial 9403) of 12-week duration in dementia patients. AD patients were defined as having Hachinski Ischemia Scale [HIS] scores ² 4; (see Panel 1 in briefing pdf). In these studies, memantine was titrated from a starting dose of 5 mg/day (weekly titration by 5 mg/day increments) to a target dose of 20 mg/day administered as 10 mg twice daily in the two six-month trials, and a target dose of 10 mg/day administered once daily in the 12-week trial. Patients were diagnosed with probable AD using National Institute of Neurological and Communicative Disorders and Stroke- Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria in Trials 9605 and MD-02, and with dementia using the Diagnostic and Statistical Manual for Mental Disorders, 3rd revised edition (DSM-III-R) criteria in Trial 9403. AD stages were identified as moderate to severe based on scores on the Mini Mental State Examination (MMSE scores of 3-14 in Trial 9605; 5-15 in Trial MD-02; and These three key memantine clinical trials are the first to evaluate the treatment of moderate-to-severe AD. Outcome measures were chosen to reflect the symptomatology of the more severe dementia patient. Specifically, in Trials 9605 and MD-02, the Severe Impairment Battery (SIB) and the 19-item version of the ADCS-Activities of Daily Living Inventory (ADCS-ADL19), which is modified for more advanced AD patients, were used as the indices of cognitive and functional change, respectively, and a global assessment of change was made by the clinician using the Clinician's Interview-Based Impression of Change Plus Caregiver Input (CIBIC+).

When Trial 9403, the earliest of the three, was conducted, the ADCS-ADL19 and SIB instruments were not generally available. Trial 9403 used the care dependency subscale of the Behavioral Rating Scale for Geriatric Patients (BGP) as a functional assessment, along with a co-primary measure of global change, the Clinical Global Impression of Change (CGI-C). The BGP-cognitive subscale, which was a subset of items from the BGP-care dependency subscale, was retrospectively defined and analyzed as a cognitive measure. (Panel 1 in briefing .pdf summarizes efficacy of memantine as measured in cognition, function, and global status from these three trials. See simplified Table below, full table in .pdf)

Efficacy Results from 3-Key, Double-Blind, Placebo-Controlled Dementia Studies

Safety

Memantine has exhibited an acceptable safety and tolerability profile in 2,297 patients in 27 clinical trials involving a variety of neurodegenerative disorders (e.g., dementia, neuropathic pain, spasticity, and Parkinson's disease). This overall safety database, including studies with limited safety information, European postmarketing clinical practice experience, and other postmarketing drug experience studies, contains no evidence for rare, serious safety findings. A total of 1,748 patients were exposed to memantine in the core dementia and neuropathy safety studies. Adverse events, vital signs, and laboratory tests were systematically evaluated in the core safety trials, and electrocardiograms (ECGs) were assessed in two dementia (Trials MD-02 and 9605) studies and the two neuropathic pain studies.

The core double-blind, placebo-controlled dementia trials (AD or VaD patients) included 922 placebo patients and 940 memantine patients. Approximately 80 percent of patients in both treatment groups completed the studies. Serious adverse events that were reported in more than 1 percent of either treatment group were confusion (memantine 1.6 vs. placebo 0.9 percent), inflicted injury (memantine 1.1 vs. placebo 1.7 percent), cerebrovascular disorder (memantine 1.0 vs. placebo 1.5 percent), fall (memantine 0.6 vs. placebo 1.1 percent), and agitation (memantine 0.5 vs. placebo 1.1 percent). Most of these were considered unrelated or unlikely to be related to the trial drug. The most common reason for discontinuation in both placebo and memantine patients was adverse events (11.5 percent in the placebo group and 10.1 percent in the memantine group). The most frequent adverse events (AEs) leading to discontinuation in this trial group were agitation (memantine 1.2 vs. placebo 2.0 percent), confusion (memantine 1.2 vs. placebo 1.1 percent), and cerebrovascular disorder (memantine 0.7 vs. placebo 1.1 percent).

Treatment-emergent adverse events (TEAE) reported most frequently (>5 percent in incidence) by memantine-treated dementia patients and at an incidence greater than placebo patients were dizziness, confusion, headache, and constipation. None of the TEAEs were reported by >7 percent of memantine-treated patients or at a rate two times higher than in the placebo group (see Table below, or Panel two in .pdf). Most TEAEs were considered mild or moderate in severity and not related to the trial drug in either the placebo- or memantine-treated patients. The percentage of AD patients reporting TEAEs was similar in placebo- and memantine-treated groups. Patients with moderate to severe dementia had an overall TEAE profile similar to that of the entire dementia group. The profile and incidence of TEAEs (as compared to placebo) reported for AD patients receiving memantine as concomitant treatment with donepezil (Trial MD-02) was not different overall from that observed in AD patients receiving memantine alone (Trial 9605).

Analyses of vital sign measurements, clinical laboratory data, and ECG results in the placebo-controlled trials revealed no clinically relevant differences between treatment groups. There was no evidence for any special safety concerns based on the preclinical safety trial results and specific assessments of possible psychotomimetic, neurologic, ophthalmologic, and cardiovascular effects from the clinical trials.

In summary, the sponsor writes, memantine at its recommended dosage of 10 mg BID is well-tolerated with a safety profile similar to that of placebo treatment and is effective in providing clinical benefit for patients with moderate-to-severe AD. —Edited by Gabrielle Strobel.

TEAEs in ≥ 5.0 of Patients in Either Treatment Group—Core Double-Blind, Placebo-Controlled Dementia Trials

Additional References—Posted 29 September 2004
Note: Please see original references in Briefing Document Full Text (.pdf)

Periclou AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of Pharmacokinetic or Pharmacodynamic Interaction Between Memantine and Donepezil (September). Ann Pharmacother. 2004 Sep ; 38(9):1389-94. Abstract

Doody, R, Wirth, Y, Schmitt, F, Möbius, HJ. Specific Functional Effects of Memantine Treatment in Patients with Moderate to Severe Alzheimer's Disease. Dement Geriatr Cogn Disord. 2004 ; 18(2):227-32. Abstract
 

Interventions Working Group for the Alzheimer's Association

Steven T. DeKosky, University of Pittsburgh School of Medicine. Dr. DeKosky serves on advisory boards for AstraZeneca, Cephalon, and Eisai Pfizer. He performs clinical research sponsored by Eisai Pfizer and Janssen. He serves as a consultant for Forest Laboratories, Eisai-Pfizer, Cephalon, Janssen, Novartis, AstraZeneca, Daiichi, and Teva Pharmaceuticals.

Lisa Gwyther, MSW, Associate Clinical Professor, Dept. of Psychiatry, Education Director, Bryan ADRC, Duke University Medical Center. No conflicts.

Zaven Khachaturian, KRA, Inc. We KRA, Inc., have consulting agreements with the Alzheimer’s Association, Toyama Chemical Co. (Japan), and GSK. No direct or specific conflicts regarding memantine, other than a theoretical one as the author of the “Calcium Hypothesis,” the presumed mode of action for memantine.

John C. Morris, MD. Neither Dr. Morris nor his family owns stock or has equity interest (outside of mutual funds or other externally directed accounts) in any pharmaceutical or biotechnology company. From July 2002 to July 2003, Dr. Morris participated in clinical trials of antidementia drugs sponsored by Elan, Eli Lilly, and Merck. He has also served as a consultant or received speaking honoraria for the following companies: Celera, Forest Labs, Janssen, Neurochem, Novartis, and OCC/Johnson & Johnson.

Lon S. Schneider, M.D. Consultant for Forest. He received travel reimbursement from Lundbeck Consultant for JNJ, Pfizer, and Novartis. He also received grant and clinical trials related funds from JNJ, Pfizer, Novartis.

Kathleen Anne Welsh-Bohmer, Ph.D. Professor of Psychiatry and Behavioral Sciences, Duke University.

Question—Posted 31 January 2007

My dad has been taking Reminyl for years. Recently, the nursing home doubled the dose, and he has been much more agitated. That made me wonder whether he should try memantine. He has never tried memantine and he is definitely in the moderate to severe stage of AD or dementia. My question is, would he start that with the Reminyl? Would it be best to eliminate Reminyl altogether and start memantine? Or perhaps reduce the Reminyl and add the memantine?

Reply by Doug Galasko—Posted 31 January 2007

The only published study on the combination of Namenda with a cholinesterase inhibitor is the one that was used by Forest as part of their package to obtain FDA-approval for Namenda in moderate to severe AD. That study combined memantine (Namenda) with donepezil versus donepezil alone, and found benefits regarding slower progression of cognitive test scores and ADL scores. The combination was well-tolerated with no suggestion that behavioral symptoms were related to using both medications. In principle, memantine could be combined with a different cholinesterase inhibitor, for example, galantamine or rivastgmine, although there have not been published clinical trials to formally make this comparison. There is an ongoing clinical trial to investigate the combination of rivastigmine and memantine, sponsored by Novartis.

An open-label extension study to one of the original memantine clinical trials was reported by Reisberg et al. (2006). In that study, 175 (96.7 percent) of 181 subjects who completed the 28-week randomized trial entered the open-label study for a further 24 weeks. The mean age was 75 years old, and most subjects were female. Nearly 90 percent of the study population was Caucasian. The mean MMSE score was about 7. The group that were previously taking placebo and switched to memantine showed a significant benefit in functional, global, and cognitive efficacy assessments compared with their mean rate of decline during placebo treatment. Data suggested that the group in treatment for 12 months continued to show clinical benefit even though they declined on outcome measures. Memantine was well-tolerated for 12 months of treatment overall. This indicates sustained beneficial effects from memantine in AD.

What is not clear is whether memantine helps patients with milder AD. Unpublished clinical trials using memantine at this stage yielded equivocal overall results. This does not mean that milder patients will never show a response to memantine; it simply means that the likelihood of their doing so is smaller than it is for moderate to severe dementia.

Question from Lauretta W.—Posted 6 February 2004

My husband began using Memantine (brought in from a buyers club in NY) from Germany over a year ago. He used 10 mg bid. In 9 days he began speaking again and eating again without help. A year later the disease progressed to the point where he had lost 30 lbs and was not eating or drinking. We considered a feeding tube and then decided against it, but increased his medication first to 3 [doses] a day, and then 4 [doses of 10 mg] per day. At 4 per day he began eating by himself and started to gain weight again. His doctor is refusing to prescribe any more than 2 a day without literature saying it would be okay to do. I feel it is a matter of life or death. Do you have anything I could send to my doctor to help convince him? My husband is 55 and in great health otherwise.

Reply from Bengt Windblad— Posted 6 February 2004

There are no published data on memantine doses above 20 mg in AD. Some of the older studies in "organic brain syndrome" used higher doses, but it is difficult to recommend more than 20 mg/d based on these sometimes poorly documented studies. In neuropathic pain, on the other hand, we have (so far unpublished) data showing that efficacy of memantine in pain is better with 40 mg/d - but adverse-event rates clearly increase and more patients drop out than with 20 mg/d. Overall, we are not very happy with the recommendation of higher doses in dementia patients. Based on the mode of action, we do not expect a major increase in efficacy with higher doses in this indication and, in contrast, the safety and tolerability profile may worsen. (There probably is a U-shaped dose-response curve with very high doses worsening cognition via an impairment of the physiological function of the NMDA receptors). Things seem to be different in pain, and perhaps for patients with a high BMI / body weight (as plasma levels decrease with weight).

Question from J.M.— Posted 25 March 2004

My husband was diagnosed with "probable early stage AD" two years ago. Since that time, his regimen includes Reminyl to offset cognitive losses and Paxil to dampen anxiety-driven personality deficits. About a year ago, he began using .5mg of clonapine to minimize his nocturnal myoclonic jerking. His only other medical condition is a "non-pathologically induced prostate enlargement" which is easily managed by Proscar, a supplemental hormone.

With that said, we continued down the AD road, all the while researching both the disease and alternative treatments. We discovered Memantine about a year or so ago and have tracked it with the hopes of adding it to his regimen. His geriatric psychiatrist agreed to this once it was officially approved for use by the FDA. During this last month, Alan successfully titrated Namenda and it is now another part of his daily regimen at 10mg twice a day. Based on our research and the discovery that Memantine could enhance activity of SSRI drugs, we went one step further and also reduced his Paxil during the titration process.

The results are phenomenal. His first response was increased energy and renewed interest in activities and socialization. He is much calmer and is able to concentrate with minimal distraction. He can follow abstract conversation with more ease as well as learn and retain new information. The latest thing we noticed was that he no longer waivers upon rising, even when he is fatigued during the evening.

So... What is my question? I would like to know how our geriatric psychiatrist could reach researchers like Dr. John Morris, to present his clinical findings which would, as I understand it, help argue for the need for additional studies related to long-term use of Namenda. Admittedly, my husband is his first patient to be prescribed Namenda but since our doctor is the head of our local hospital's psychiatric facility, this information may prove to be beneficial to many.

Any help you could provide would be welcome. — J.M.

Q. Why is Memantine "not recommended for patients with epilepsy"?—Posted 30 June 2004

My husband (58) has moderately severe AD and it was recommended that we apply to the Special Access Program for Memantine. He was denied on the grounds that "he's an epileptic." He is not, but does take Epival "off label" as an aid in controlling agitation as well as a prophylatic against potential seizures which the Dr says are common in advancing AD. Is it the disorder of epilepsy or the interaction of drugs which precludes the use of Memantine?

A. Reply from Lon Schneider

Memantine belongs to a class of drugs known as NMDA antagonists. Some NMDA antagonists may be pro-convulsant. That is, they may tend to increase the likelihood of or cause seizures in people who have epilepsy. The available NMDA antagonists, memantine, dextromethorphan, and amantadine, however, are probably less likely to worsen epilepsy although they have not been systematically evaluated for this effect. In memantine clinical trials in patients with moderate to severe Alzheimer's disease there does not appear to be an increased risk for seizures, although the numbers studied are few.

Divalproex (brand names Epival in Canada and Depakote in the US) is an anticonvulsant medication used to treat seizures and migraine headaches. Divalproex, however, is also approved by the FDA as a mood stabilizer to treat mood swings and hyperactivity in people with bipolar depression. It is helpful for treating what are known as manic episodes. Some physicians use divalproex to treat agitation and aggression in people with dementia, although it is not officially approved for this use and some clinical trials have been not shown efficacy.

Seizures occur in some people with advancing Alzheimer's dementia. Many experts however would not use an anticonvulsant such as divalproex as a prophylactic in order to protect against possible seizures for several reasons: (1) it cannot be predicted who with Alzheimer's disease will get seizures; (2) a single seizure may not require ongoing use of anticonvulsants; (3) physicians try to minimize medications used; (4) anticonvulsants have side effects including sedation, somnolence, and confusion, and in the case of divalproex there may be other side effects such as liver toxicity and a decrease in blood platelets needed for clotting. As with all medications used to treat behavioral symptoms in people with dementia, divalproex should be tapered and discontinued at intervals to assess whether it is helping.

There is no known contraindication to combining divalproex with memantine. In the absence of detailed information and an examination, we cannot speak specifically about whether memantine or divalproex is indicated in any particular person.

Comment by Bengt Winblad —Posted 1 July 2004

I agree with Lon that anti-epileptic medication should not be used in Alzheimer's disease or at least be extremely restricted. We all know that anti-epileptic drugs reduce considerably the cognitive capacity remaining in our patients. Concerning combining divalproex with memantine, Lon states that there is no contra indication but with what I said above I would be very restrictive with the combination.

Question: Is Memantine's effectiveness sufficient to replace Aricept, or are both required for effective treatment? —Posted 12 July 2004

This is a serious question, since my mother is not wealthy, and each of these drugs costs about $150/month.

My mother, age 85, was diagnosed with probable AD two years ago. She has been taking Aricept for two years with good effect. She has good function for ADL, and is able to function without much assistance, however she had major memory impairment, some confusion and some agitation. Her physician has now suggested Memantine.

Reply from Steven T. DeKosky —Posted 12 July 2004

Memantine has never been tested in a direct “head to head” test against Aricept. The double-blind, placebo-controlled studies of memantine either have been done vs. placebo, or as an add-on people taking Aricept already. In the latter case, everyone was on Aricept and randomized to either memantine or placebo. Those studies showed evidence that in moderate to severe AD adding it to the Aricept results in some improvement on average.

The level of severity of the dementia is also important. Memantine is still in testing in mild to moderate AD, and approved for use in moderate to severe AD. Aricept is approved for (and has been extensively tested in) mild to moderate AD and studies are underway or just completed looking at its effectiveness in moderate to severe AD. If the patient has moderate to severe AD the studies have shown a benefit, albeit a small one, for memantine alone. However there is no perfect way to know if substituting memantine for Aricept would be equivalent or better.

Disclosure: I consult for both Pfizer and Forest Laboratories.

Reply from a concerned neurologist (anonymity requested)—Posted 12 July 2004

It's sad that pharma's hype about Alzheimer drugs leads families that cannot afford these top shelf drugs to feel so guilty. Patients know that a drug exists for their loved one and believe it would be negligent to withhold it. The industry preys upon the dire needs of AD victims by charging them outrageous prices for drugs that do little or nothing. Even if a percentage of patients gets a tiny bit better, that in no way dents the tragedy of the disease, salvages the person's dignity, or improves prognosis. These drugs are the emperor's new clothes. They not only let pharma reap billions, but they assuage the physicians' sense of helplessness before his or her patients. Most physicians base their judgement of drug efficacy on a simple enquiry of a family member as to whether they see improvement. On the basis of an anecdotal remark the physician is all too ready to place a significant financial burden on the family.

Even worse is the common occurrence when the drug is having no observable effect, but the physician keeps the patient on the medication according to the purely hypothetical unsubstantiated rationale that the patient would be doing worse off drug. The blind trust put in us by many of our patients translates into gratitude, and hence a double deception that the patient has a remedy and the doctor has a happy patient. How can such a small increment in an ADAS-Cog score justify such a furious marketing campaign? The minuscule benefits do not justify the costs for many patients. I can easily think of a gizillion better ways to spend money on drugs which do have an impact—like delivery of AIDS meds to the third world. Alzheimer meds are an example of our distorted priorities.

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References

News Citations

1. Age Factors into Survival after AD Diagnosis 22 Nov 2002
2. Trial of Memantine/Donepezil Paves the Way for Combination Therapy 22 Jan 2004
3. Naproxen/Rofecoxib Trial Results Published 5 Jun 2003
4. Pittsburgh Compound-B Zooms into View 21 Jan 2004

Webinar Citations

1. Memantine: Implications for Treating Alzheimer's 29 Sep 2004

Paper Citations

1. Periclou AP, Ventura D, Sherman T, Rao N, Abramowitz WT. Lack of pharmacokinetic or pharmacodynamic interaction between memantine and donepezil. Ann Pharmacother. 2004 Sep;38(9):1389-94. PubMed.
2. Doody R, Wirth Y, Schmitt F, Möbius HJ. Specific functional effects of memantine treatment in patients with moderate to severe Alzheimer's disease. Dement Geriatr Cogn Disord. 2004;18(2):227-32. PubMed.
3. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ. A 24-week open-label extension study of memantine in moderate to severe Alzheimer disease. Arch Neurol. 2006 Jan;63(1):49-54. PubMed.
4. Tariot PN, Farlow MR, Grossberg GT, Graham SM, McDonald S, Gergel I, . Memantine treatment in patients with moderate to severe Alzheimer disease already receiving donepezil: a randomized controlled trial. JAMA. 2004 Jan 21;291(3):317-24. PubMed.
5. Ritchie CW, Bush AI, Mackinnon A, Macfarlane S, Mastwyk M, MacGregor L, Kiers L, Cherny R, Li QX, Tammer A, Carrington D, Mavros C, Volitakis I, Xilinas M, Ames D, Davis S, Beyreuther K, Tanzi RE, Masters CL. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: a pilot phase 2 clinical trial. Arch Neurol. 2003 Dec;60(12):1685-91. PubMed.
6. Orgogozo JM, Rigaud AS, Stöffler A, Möbius HJ, Forette F. Efficacy and safety of memantine in patients with mild to moderate vascular dementia: a randomized, placebo-controlled trial (MMM 300). Stroke. 2002 Jul;33(7):1834-9. PubMed.
7. Wilcock G, Möbius HJ, Stöffler A, MMM 500 group. A double-blind, placebo-controlled multicentre study of memantine in mild to moderate vascular dementia (MMM500). Int Clin Psychopharmacol. 2002 Nov;17(6):297-305. PubMed.
8. Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ, Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003 Apr 3;348(14):1333-41. PubMed.

Other Citations

1. Steven T. DeKosky

External Citations

1. .pdf
2. briefing document (.pdf)
3. Schapira and Olanow

Further Reading