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 Unpublished clinical trials using memantine at this stage yielded equivocal overall results.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.