Alzheimer's Drugs -- Fact & Fiction

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There are two main categories of drugs for treating Alzheimer's, i.e.:

(1) Cholinesterase inhibitors
These include the prescription drugs Aricept/donepezil, Razadyne/galantamine, and Exelon/rivastigmine, and the over-the-counter "supplement" huperzine A.

(2) NMDA antagonists
So far, there is only one drug in this category, i.e., Namenda/memantine.

These drugs do not cure Alzheimer’s, and there is scant evidence that they slow down the damage that is being done. What they can do, however, is help the damaged regions of the brain function better, which in turns slows down the emergence of symptoms and improves your loved one’s quality of life.

Some doctors believe that Alzheimer’s drugs provide little or no benefit. It is true that some patients do not appear to be affected by them; however, some of these may actually be stabilized, and for a long time. Others show a marked improvement. And some, sadly, are not helped much if at all, or may develop adverse effects. Because the benefits differ from patient to patient, the results from clinical trials indicate that average improvements in mental function are modest. The only way to find out how well your loved one will respond is to try them.

Some people believe that the drugs only help improve memory. This is not true, either. Clinical trial tests showed they can improve cognitive, social, and motor impairments, and participation in activities of daily living. They can help delay or prevent the onset of serious behavioral problems (anger, aggression, agitation, wandering, etc), and reduce or eliminate the need for antipsychotics, antidepressants, and anxiolytics.

And yet … the majority of Alzheimer’s patients are never given Alzheimer’s drugs, and even those for whom they are prescribed often receive them for less than three months.

Cholinesterase Inhibitors (ChEIs)

Aricept, Razadyne, and Exelon are the cholinesterase inhibitors (ChEIs) most commonly recommended by doctors. Another ChEI, Cognex (tacrine), was prescribed in the past but is no longer recommended because it can cause liver damage.

How they work: Alzheimer’s disease changes the brain in many ways. One of the changes results in a decrease in the levels of acetylcholine, a chemical messenger believed to be important for alertness, memory, thought and judgment. In the healthy brain, the enzyme cholinesterase destroys excess acetylcholine. Cholinesterase inhibitors (ChEIs) slow the activity of cholinesterase, making more acetylcholine available for communication between cells.

What can they do: Aricept has been approved for all stages of Alzheimer’s — mild, moderate, and severe. Razadyne and Exelon have only gone through the extensive clinical trials needed for FDA approval for treating mild to moderate Alzheimer’s and so have only been approved for the earlier stages. That does not mean that they are not beneficial for the later stages. In fact, there is reason to think that Exelon may be better than Aricept for loved ones with moderate to severe Alzheimer’s (see below).

ChEIs can alleviate apathy and anxiety, improve alertness and motivation, and improve memory. Some patients were able to perform tasks which they had forgotten how to do, such as going shopping.

Roughly 40 to 50 % of patients improve when prescribed these drugs. Most will experience a delay in the progression of the illness. However, it may take some months of treatment for there to be a noticeable improvement or slowing down of memory loss. Unfortunately, not everyone benefits from them, and sometimes the side effects are intolerable.

Which ChEI should be used: Doctors tend to be more familiar with Aricept, since it has been on the market longer and has been approved for treating all stages of Alzheimer’s, and therefore prescribe it much more often. In clinical studies involving large numbers of subjects with mild to moderate Alzheimer’s, on average, all cholinesterase inhibitors appear to work equally well. These drugs all have the same, basic mechanism of action; that is, they all inhibit the enzyme acetylcholinesterase (AChE).

However, there are some significant differences among the three drugs. For example, the elimination pathway is through the kidney for Exelon, through the kidney and liver for Razadyne, and through the liver for Aricept. This should be taken into account when selecting the ChEI and dosage for patients with liver or kidney disease, or elderly patients with reduced kidney or liver function.

In addition, Aricept and Razadyne only inhibit AChE, while Exelon targets butyrylcholinesterase (BuChE) as well as AChE. Razadyne also modulates nicotinic receptors. Researchers don’t yet know the full impact that these differences may have, when it comes to the individual patient.

While these three drugs appear to work equally well when the results from large clinical trials are averaged, it is well established that one ChEI may work better or produce fewer acute (near-term) side effects in a given individual than another. If your loved one is started on one ChEI and either does not appear to be improving or at least stabilized, and/or is suffering side effects that do not go away after a few weeks or are intolerable, consider asking your doctor to prescribe a different ChEI.

The chronic (long-term) side effects of the three drugs are different, too. Some researchers have reported that Aricept is more likely to cause sleep disturbances, cardiovascular problems such as bradycardia, extrapyramidal symptoms (EPS), and behavioral disturbances; and Razadyne is more likely to cause syncope (fainting). Again, if your loved one does not appear to be responding to a given ChEI any longer, or is developing one of these chronic side effects, don’t simply give up on ChEI therapy — switch to a different drug.

Switching drugs is commonly done for antidepressants and medicines for congestive heart failure and epilepsy, so it’s strange that so few doctors consider trying it with ChEIs. And there is even experimental evidence from several clinical trials that switching can often help, by providing superior efficacy, reducing side effects, or both.

If the reason for changing to a different ChEI is adverse effects, some doctors recommend a “wash out” period of one week before beginning treatment with another, to allow the adverse effects to resolve. No wash out period is needed for patients who tolerated a ChEI well but are switching because they failed to respond or did not respond as well as expected.

Sleep disturbances: Caregivers often report that a loved one who is on Aricept is distressed by vivid dreams. If that happens to your loved one, suspect the Aricept. This is a very common side effect of this ChEI, and one that is often resolved by simply giving the drug to your loved one in the morning rather than the evening. There is no reason to give the drug in the evening that I’ve been able to discover, other than, perhaps, the hope that the gastrointestinal side effects won’t be as bothersome when the patient is asleep.

However, you might want to consider not only giving your loved one’s medicine in the morning, but also switching to one of the other ChEIs as well. Both Razadyne and Exelon have been shown to be less likely to trigger sleep disturbances than Aricept, and any caregiver who has had to cope with sleep disturbances will tell you they are to be feared and avoided if at all possible. Acetylcholine — the chemical messenger whose levels are increased by ChEIs – plays an active role in maintaining a normal sleep pattern. The healthy brain has low levels of acetylcholine during slow-wave sleep, and high levels during wakefulness. High levels of ChEIs in the bloodstream at night, which result in high levels of acetylcholine in the brain, can sometimes trigger sleep disorders. (Since a normal sleep pattern is important for memory consolidation, disruption of the circadian rhythm can add to memory problems as well.) ChEIs that have short half-lives in the blood and are given in the morning will support the normal circadian cholinergic rhythm. Aricept has a very long half-life (70 hours) in comparison with Razadyne (7 hours) and Exelon (1.5 hours) (and huperzine A, 4.5 hours).

Why do different patients have different responses to ChEIs: The reasons why some patients respond well to a given drug and others develop intolerable side effects are not yet fully known. However, recent studies on Aricept indicate that the therapeutic response to this drug may be due to subtle differences in certain genes. Aricept is metabolized via CYP-related enzymes in the liver, especially CYP2D6, CYP3A4, and CYP1A2. Approximately 15-20% of Alzheimer’s patients may exhibit an abnormal metabolism of Aricept. Of these, ~50% show an ultrarapid metabolism, requiring higher doses of the drug to reach a therapeutic threshold, whereas the other 50% show a poor metabolism, exhibiting adverse side effects at low doses. Pharmacogenetic and pharmacogenomic factors may account for 75-85% of the therapeutic response to ChEIs that are metabolized via liver enzymes of the CYP family.

What about moderate to severe Alzheimer’s: As noted above, Aricept is the only ChEI that has been formally approved for treating the later stages of Alzheimer’s. The fact that Aricept was found to be helpful in the later stages tends to indicate that ChEIs, in general, might be beneficial in the later stages. Just because all three ChEIs showed equal benefits in the earlier stages, however, does not mean that they will all perform equally well in the later stages.

In fact, there is some reason to believe that Exelon might be more beneficial for loved ones with moderate to severe Alzheimer’s. As noted above, Exelon has dual activity against AChE and BuChE, whereas the other ChEIs are specific for AChE. This dual capability may become more important as the disease progresses, since the activity of AChE decreases the Alzheimer’s brain, while that of BuChE increases, particularly in the cortex and hippocampus. BuChE-positive neurons are thought to have roles in attention, executive function, emotional memory and behaviour. Therefore, inhibition of BuChE may provide additional benefits as time goes by. (Note: Oral Exelon is reported to be more likely to cause acute gastrointestinal side effects than the other ChEIs. However, many researchers believe that the drug would be just as readily tolerated as the others if the dose were ramped up more slowly than recommended. Also, using the Exelon patch rather than the oral pill is likely to cause fewer adverse events while the body is adjusting to the drug. With the patch, the Exelon enters the blood stream through the skin/muscle, rather than through the stomach and intestines. Ergo, the patch tends to have fewer gastrointestinal side effects.)

Until recently, all comparisons of these three ChEIs were done in patients who had mild to moderate Alzheimer’s. However, there has now been one head-to-head comparison of oral Exelon and Aricept, in nearly one thousand patients with moderate to moderately-severe Alzheimer’s. Adverse events were more frequent in the Exelon group during the titration phase, but similar in the maintenance phase. Centrally mediated adverse events such as nausea and vomiting tended to be higher in Exelon-treated patients (remember, this was the oral formulation, and the patients were titrated fairly quickly, as is “officially” recommended), whereas brainstem and peripherally mediated adverse events such as insomnia, muscle cramps and urinary incontinence had a low incidence overall, but tended to be higher in Aricept-treated patients. Results indicated that ChEI treatment was beneficial throughout the 2 years of the study. Although both drugs performed similarly on cognition and behaviour, Exelon appeared to provide greater benefit in activities of daily living and global functioning. Alzheimer’s patients who had genotypes that encoded for full expression of the BuChE enzyme, who were < 75 years of age, or who had symptoms suggestive of concomitant Lewy body dementia showed significantly greater benefits from Exelon treatment.

What about generics: Razadyne has been available as the generic galantamine in the US, and Aricept very recently became available as the generic donepezil. While generic products have the same active ingredients as the brand name drugs, they are not entirely identical. Historically, physicians have noted a variety of differences in individual responses — both positive and negative — to generic drugs for other health conditions. Therefore, a caregiver whose loved one has been receiving Razadyne or Aricept may notice a difference in effectiveness when switching to the generic product. If the generic does not appear to be as effective as the brand name, talk with the doctor about prescribing the brand name product instead. Patients who are trying a ChEI for the first time may choose a generic due to its lower cost. Those who do not appear to benefit from it may want to consider switching to Exelon.

What about the new 23 mg Aricept: A new, high-dose formulation of Aricept recently came on the market. There have been a number of misconceptions about this product.

First and foremost, the new 23mg Aricept is an extended release formulation. This means that you should not break it in half, crush it, or dissolve it to administer it.

It also means that the maximum levels of the drug in the blood are significantly lower than the levels you would achieve by taking two 10mg pills. So do not try doubling up on the 10mg pills instead!

Patients should be on a steady dose of one 10mg tablet for at least four to six weeks — and tolerating it well — before switching to the 23mg pill. Do not try to titrate up to 23mg using 5 and 10mg pills.

The overall benefits from switching to this new pill are, in my opinion, questionable. There was a 24-week, double-blind, placebo-controlled clinical trial of 1,467 patients with moderate-to-severe AD who had been on 10mg Aricept once daily for at least 3 months. Half were given the higher dose, the other half continued to take the 10mg. Tests used to evaluate efficacy were cognition (SIB) and global function (CIBIC+). It is interesting that they did not use the ADAS-Cog, which is the “gold standard” in clinical trials for treating dementia … and which Aricept has not been shown to affect in some of the earlier trials.

The SIB (Severe Impairment Battery) is similar to the MMSE but designed for use with severely demented patients (MMSE below 1-12 points). The MMSE cannot discriminate among patients in this severe AD range … and the SIB cannot discriminate among patients who have mild to moderate AD. The SIB takes only 20-30 minutes to administer, and consists of one-step questions and commands that are presented with gestural cues and can be repeated as needed by the patient. There was a statistically significant improvement in SIB scores on the higher dose.

The Clinician’s Interview-Based Impression of Change plus caregiver input (CIBIC-plus) is a much more extensive test, and involves detailed interviews of the caregiver regarding the ADLO’s abilities, behavior, and mood, etc, as well as direct assessments of the AD patient. There was no difference in CIBIC+ results between patients on the 23mg ER formulation and those who continued taking 10mg.

These results mean that, as far as the caregivers were concerned, on average, there were no detectable benefits from switching to the higher dose.

However, as might be expected, there were distinct disadvantages: i.e., switching to the higher dose caused more adverse side effects. So if you decide to try the higher-dose formulation to see whether your loved one might do better on it, be aware of this possibility and keep track of your loved one’s behaviors to see if new symptoms crop up or old symptoms are exacerbated.

Huperzine A: Huperzine A is an inexpensive alternative to the prescription ChEIs. It is an over-the-counter supplement that has been used to treat Alzheimer’s (and vascular dementia) in China for many years, and reportedly is well tolerated. It was recently evaluated in a double-blind, placebo-controlled Phase II clinical trial in the US, and found to be beneficial at the higher dose that was tested (i.e., 400 mcg 2x per day) over the six months of the blinded trial. As far as I’ve been able to tell, only the results from the initial six have been released. The trial went into a series of open-label stages which purportedly were going so well, they continued to increase the length of the study in six-month increments for two additional years. All told, interested patients were in the trial for two and a half years. My husband was in the trial for the entire time, in the cohort that received the lower dose (200 mcg x2). He responded well and, if given the drug after a full meal, did not have any noticeable side effects from it. Several years later, as his symptoms began to progress, his neuro recommended that we ramp up to the higher dose, which is what he is taking now. Huperzine A can be found at some online health food stores. If you and your doctor decide to try huperzine A instead of one of the prescription ChEIs, choose a formulation that does not contain any other supplements. Several trials are currently recruiting or preparing to recruit for a sustained-release tablet formulation.

Drug interactions: A number of drugs which are often prescribed for elderly people, such as those for treating urinary incontinence, have anticholinergic activity, i.e., they decrease the amount or activity of acetylcholine. Anticholinergics, in essence, have the opposite effect of ChEIs. The simultaneous use of both types of drugs is likely to lead to reduced effectiveness of one or both drugs. Many doctors are unaware of the potential problem, and as many as one-third of dementia patients are given both. Be sure to ask your pharmacist about the compatibility of any new drug or over-the-counter medicine or supplement before giving it to your loved one.

Should ChEIs be used to treat other dementias: In addition to Alzheimer’s, ChEIs may be effective for use in the treatment of Lewy body dementias (Parkinson’s dementia and dementia with Lewy bodies), especially for neuropsychiatric symptoms.

ChEIs are sometimes prescribed for vascular dementia (VaD), but the drugs have not been officially “blessed” by the FDA for this application. In fact, their use is discouraged since there is no consistent evidence that ChEIs are beneficial for “pure” VaD, and since at least one trial raised safety concerns, including the potential for a slightly higher death rate in this patient population. However, ChEIs are believed to be helpful to loved ones with “mixed dementia”, i.e., Alzheimer’s and VaD, which is very common and often misdiagnosed as “pure” VaD.

ChEIs are rarely, if ever, beneficial for patients with frontotemporal dementia (FTD) and may cause adverse effects, especially agitation. ChEIs are therefore not recommended for treating FTD. ChEIs have not been shown to be helpful in progressive supranuclear palsy.

Several meta-analyses of the studies conducted to date have concluded that ChEIs will not delay the conversion of mild cognitive impairment (MCI) to Alzheimer’s. However, these studies would have included many MCI patients who would not have converted to Alzheimer’s in any event. (See the Compendium article on MCI conversion rates.) There might be benefits to select individuals. The problem is discerning which individuals would be helped, and which would needlessly suffer adverse effects.

Namenda

How Namenda works: Namenda was the first drug approved by the FDA to treat the symptoms of moderate to severe Alzheimer’s. It is also the first of this new class of uncompetitive NMDA receptor antagonists that alter the brain’s response to glutamate, a messenger chemical involved in all brain function, including learning and memory. Excessive stimulation of the N-methyl-D-aspartate (NMDA) receptor by high levels of glutamate leads to increased flow of calcium cations into the cell through the receptor’s ion channel, resulting in excitotoxicity, a pathological process causing neuron injury or death. Namenda works by preferentially binding to the NMDA receptor-operated cation channels, thereby decreasing the effects of glutamate. Interestingly, there is also evidence that the drug may be able to improve cerebral glucose metabolism.

What it can do: Randomized clinical trial data indicate that Namenda can improve cognition, global assessment, and quality of life in patients with moderate to severe Alzheimer’s. Specific cognition sub-items that appear to respond most significantly to Namenda include memory, language, orientation, praxis and visuospatial ability. For example, a U.S. study found that outpatients with Alzheimer’s who were using Namenda were better able to use the phone, pay attention to conversation, get around outside the home, and perform daily tasks such as clearing the dishes after eating. There is also evidence that the drug helps in very advanced cases of Alzheimer’s. A European study that focused on nursing-home patients with severe dementia found that those who took the drug were more likely to be able to stand up, move, eat and drink, dress themselves, and use the toilet. Namenda has also been shown to reduce agitation/aggression and irritability/lability, on average. Clinical trial results are further supported by results from open-label extension studies and studies investigating combination therapy with ChEIs.

Namenda tends to be better tolerated and with fewer side effects than the ChEIs, based on several clinical trials and on use in Europe since 1989 — although, as with any drug, some individuals may experience significant side effects. It undergoes very little metabolism and is excreted mainly through the kidneys.

What about mild to moderate Alzheimer’s: There is evidence that Namenda may be beneficial to some patients in the earlier stages of Alzheimer’s, although the drug is not specifically approved for that application. Two clinical trials showed 60-70% therapy response rate, with minimal side effects, in mild-to-moderate Alzheimer’s. More recent studies with the new extended-release formulation concluded that patients with mild to moderate Alzheimer’s had modest improvements in their memory and thinking skills. It is my understanding that the American Academy of Neurology (AAN) Management of Dementia Guidelines were recently revised to suggest that Namenda be prescribed for early-stage Alzheimer’s patients who cannot tolerate ChEIs.

What about generics: Namenda is still under patent protection in the U.S.

Drug interactions: The combined use of Namenda with other NMDA antagonists (amantadine, ketamine, and dextromethorphan) has not been systematically evaluated and any such use should be approached with caution.

Since Namenda clearance is reduced by about 80% under alkaline urine conditions at pH 8, anything that alters urine pH toward the alkaline condition may lead to an accumulation of the drug with a possible increase in adverse effects. Urine pH is altered by diet, drugs (e.g. carbonic anhydrase inhibitors, sodium bicarbonate) and clinical state of the patient (e.g. renal tubular acidosis or severe infections of the urinary tract). Namenda should be used with caution under these conditions.

Should Namenda be used to treat other dementias: Several clinical trials indicated that Namenda is beneficial for patients with mild to moderate vascular dementia, including benefits associated with behavioral symptoms.

A recent study on Lewy-body-related dementias found that patients who have dementia with Lewy bodies who received Namenda showed significantly greater improvement in global clinical status and behavioral symptoms than those taking placebo. Interestingly, no significant differences were found between the two treatments in patients with Parkinson’s disease dementia in this particular study, even though earlier studies have shown a benefit for this dementia.

There is some evidence that Namenda may be beneficial for alcohol-related dementia, AIDS-related dementia, and Huntington disease.

There is anecdotal evidence that Namenda may be helpful to loved ones with FTD. However, the results from a very small, open-label study were not particularly promising. Larger clinical trials are now under way to help determine whether the drug may be broadly beneficial to FTD patients.

Combination Therapy

Studies have shown that, in general, Alzheimer’s patients do better on a combination of a ChEI and Namenda than they do on either one alone, even in the long term (five years or more). For example, in one of the first clinical trials on combination therapy, more than 400 patients with moderate to severe Alzheimer’s who were on stable doses of Aricept were randomly assigned to receive either Namenda or a placebo as well. Those who received Namenda had significantly better outcomes on measures of cognition, activities of daily living, global outcome, and behavior.

In a more recent study, 382 patients were given one of three treatments, i.e., standard care without either type of Alzheimer’s drug; ChEI monotherapy; or ChEI plus Namenda combination therapy. They were evaluated every six months for up to 4 years. The combination therapy group had significantly lower rates of deterioration than the monotherapy or no therapy groups, and the differences between combination therapy and the other groups increased with treatment duration over the course of the study.

An observational study published in 2009 found that Alzheimer’s patients who used cholinesterase inhibitors and Namenda were able to postpone nursing home admission significantly longer than those who only took cholinesterase inhibitors.

Since Namenda was originally tested for efficacy in the later stages of Alzheimer’s, doctors tend to start a patient on a ChEI, and then, once the patient is stabilized on that drug, introduce Namenda. However, there is no medical reason for starting patients in that order of which I’m aware. In fact, my husband started on Namenda — while he still had only moderate Alzheimer’s — and responded very well. It was only later that we added the huperzine A.

How Long Do They Work?

Some doctors are under the misapprehension that because the clinical trials that were used to obtain FDA approval were only designed to last for three to six months, Alzheimer’s drugs are only effective for a maximum of six months. This is not true.

In fact, every long-term study of which I am aware, whether conducted on a single Alzheimer’s drug or on combination therapy, and whether prospective or retrospective, concluded that the drugs were still beneficial — on average — for the full length of the study, i.e., up to ten years (the longest time that has been studied to date). However, results may be different for a given individual. Some respond better to the drugs than others; some develop serious adverse effects that others do not.

When Should Alzheimer’s Drugs be Discontinued?

It can sometimes be difficult to tell if Alzheimer’s drugs are providing any benefit, especially after they have been used for several years, because no one knows how quickly the disease would have progressed without them. Sometimes, caregivers believe the drugs are not doing any good and decide to discontinue them. Studies have found that some patients may decline rapidly once the drugs are discontinued; and even if the drugs are restarted, these patients may be stabilized at their new level of cognitive function but will not regain their former level of function. However, other patients show no discernible effects when the drugs are stopped; and some may actually improve when taken off one or both drugs if they have developed adverse effects from them.

If you decide to stop giving your loved one these drugs, it is always a good idea to slowly wean your loved one off the drugs, one drug at a time. That way, if the loved one experiences a sudden decline in abilities, the drug can be restarted before significant damage is done.

What about when the loved one is in the advanced stages of Alzheimer’s? There is no substantive evidence that these drugs prolong life. As far as is known, they simply help the damaged brain function better than it would without them. But sooner or later, there comes a time when it seems senseless to keep on administering these drugs.

When to discontinue Alzheimer’s drugs due to progression of the disease has not been studied per se, and many healthcare guidelines don’t even address the subject. The ISOA guidelines recommend that physicians discontinue Alzheimer’s drugs if patients reach “profound” stages of dementia, when the patients has no cognitive or functional skills left to preserve. Note that there is a distinction between “severe” and “profound” dementia. The guidelines from the American College of Physicians and the American Academy of Family Physicians indicate that “if slowing decline is no longer a goal, treatment with [Alzheimer's drugs] is no longer appropriate.” Others have stated that treatment should be withdrawn at the point were a patient is entirely dependent in all basic ADLs, and the family and physician believe that “meaningful social interactions and quality of life benefits are no longer possible.”
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Further reading:

“Official” Medical Guidelines
- O’Brien JT, Burns A. Clinical practice with anti-dementia drugs: a revised (second) consensus statement from the British Association for Psychopharmacology. J Psychopharmacol. 2010 Nov 18.

http://www.bap.org.uk/pdfs/Anti-dementia_2010_BAP.pdf

- Doody RS. Cholinesterase Inhibitors and Memantine: Best Practices. CNS Spectr. 2008;13:10(Suppl 16):34-35.

http://www.cnsspectrums.com/aspx/articledetail.aspx?articleid=1854

- VHA Pharmacy Benefits Management Service and the Medical Advisory Panel. Updated Criteria for Use: Cholinesterase Inhibitors to Treat Dementia.

http://www.pbm.va.gov/Clinical%20Guidance/Criteria%20For%20Use/Cholinesterase%20Inhibitors%20Criteria%20for%20Use%20Updated%207.31.08.doc

Cholinesterase Inhibitors
- Potkin S. The Management of Alzheimer’s Disease and Related Dementias: Part 2 — The Role of Cholinesterase Inhibitors in the Treatment of Alzheimer’s Disease and Related Dementias. Postgraduate Institute for Medicine CME 2004.

http://cme.medscape.com/viewarticle/467554_1

- Hitti M. Trio of Drugs May Improve Alzheimer’s. WebMD 2006.

http://www.webmd.com/alzheimers/news/20060125/trio-drugs-may-improve-alzheimers

- Lane RM, Potkin SG, Enz A. Targeting acetylcholinesterase and butyrylcholinesterase in dementia. Int J Neuropsychopharmacol. 2006 Feb;9(1):101-24.
- Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, Nagel J, Lane R. Rivastigmine and Donepezil Treatment in Moderate to Moderately- Severe Alzheimer’s Disease Over a 2-Year Period. Curr Med Res Opin. 2005 Aug;21(8):1317-27.

http://www.redorbit.com/news/health/267067/rivastigmine_and_donepezil_treatment_in_moderate_to_moderately_severe_alzheimers/

- Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, et al. A six-month double-blind, randomized, placebo-controlled study of a transdermal patch in Alzheimer’s Disease — rivastigmine patch versus capsule. Int J Geriatric Psychiatry 2007; 22:456-467.

http://www.ncbi.nlm.nih.gov/pubmed/17380489

Switching ChEIs
- Gauthier S, Emre M, Farlow MR, Bullock R, Grossberg GT, Potkin SG. Strategies for continued successful treatment of Alzheimer’s disease: switching cholinesterase inhibitors. Curr Med Res Opin. 2003;19:707–14.

http://www.medscape.com/viewarticle/466047

- Dantoine T, Auriacombe S, Sarazin M, et al. Rivastigmine monotherapy and combination therapy with memantine in patients with moderately severe Alzheimer’s disease who failed to benefit from previous cholinesterase inhibitor treatment. Int J Clin Pract. 2006;60:110–18.

http://www.medscape.com/viewarticle/521100

- Bartorelli L, Giraldi C, Saccardo M, et al. Effects of switching from an AChE inhibitor to a dual AChE-BuChE inhibitor in patients with Alzheimer’s disease. Curr Med Res Opin. 2005;21:1809–18. [

http://www.ncbi.nlm.nih.gov/pubmed/16307702

ChEI-Caused Sleep Disturbances
- Nieoullon A, Bentué-Ferrer D, Bordet R, Tsolaki M, Förstl H. Importance of circadian rhythmicity in the cholinergic treatment of Alzheimer’s disease: focus on galantamine*. Curr Med Res Opin. 2008 Dec;24(12):3357-67.

http://www.ncbi.nlm.nih.gov/pubmed/19032118

- Davis B, Sadik K. Circadian cholinergic rhythms: implications for cholinesterase inhibitor therapy. Dement Geriatr Cogn Disord. 2006;21(2):120-9.

http://www.ncbi.nlm.nih.gov/pubmed/16391473

- Robert P. Understanding and Managing Behavioral Symptoms in Alzheimer’s Disease and Related Dementias: Focus on Rivastigmine. Curr Med Res Opin. 2002;18(3).

http://www.medscape.com/viewarticle/439728

ChEIs for Mild Cognitive Impairment (MCI)
- Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. Effect of rivastigmine on delay to diagnosis of Alzheimer’s disease from mild cognitive impairment: the InDDEx study. Lancet Neurol. 2007 Jun;6(6):501-12.

http://industry.biomed.cas.cz/kamil/clanky/feldman%20et%20al%202007%20lancet%20neurology.pdf

Genes Affect ChEI Efficacy and Adverse Effects
- Cacabelos R. Donepezil in Alzheimer’s disease: From conventional trials to pharmacogenetics. Neuropsychiatr Dis Treat. 2007 June; 3(3): 303–333.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2654795/

Huperzine A
- Wang BS, Wang H, Wei ZH, Song YY, Zhang L, Chen HZ. Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer’s disease: an updated meta-analysis. J Neural Transm. 2009 Apr;116(4):457-65.

http://www.ncbi.nlm.nih.gov/pubmed/19221692

- Sabbagh MN. Drug development for Alzheimer’s disease: where are we now and where are we headed? Am J Geriatr Pharmacother. 2009 Jun;7(3):167-85.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2948028/

Anticholinergic Drugs
- Sink KM, Thomas J, Xu H, Craig B, Kritchevsky S, Sands LP. Dual Use of Bladder Anticholinergics and Cholinesterase Inhibitors: Long-Term Functional and Cognitive Outcomes. J Am Geriatr Soc. 2008;56(5):847-853.

http://www.medscape.com/viewarticle/578206

Namenda
- Blesa Rafael. Clinical experience of memantine in Alzheimer’s disease. European Neurology 2009; 3(2)

http://www.touchneurology.com/files/article_pdfs/blesa.pdf

- Jancin B. Memantine effective in mild to moderate Alzheimer’s. Internal Medicine News, June 15, 2004.

http://findarticles.com/p/articles/mi_hb4365/is_12_37/ai_n29133473/

- Just S. Namenda™ (Memantine) for Moderate-to-Severe Alzheimer’s Disease. Pharmacotherapy Update 2004; 8(3).

http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2004/namenda.htm

Combination Therapy
- Trial of Memantine/Donepezil Paves the Way for Combination Therapy

http://www.alzforum.org/new/detail.asp?id=950

- McGreevey S. Study confirms benefit of combination therapy for Alzheimer’s disease. 2008.

http://www.eurekalert.org/pub_releases/2008-09/mgh-scb092208.php

- Lopez OL, Becker JT, Wahed AS, Saxton J, Sweet RA, Wolk DA, Klunk W, Dekosky ST. Long-term effects of the concomitant use of memantine with cholinesterase inhibition in Alzheimer disease. J Neurol Neurosurg Psychiatry. 2009 Jun;80(6):600-7.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2823571

Long-Term Benefits
- Cassels C, Lie D. Long-Term Combination Alzheimer’s Therapy Slows Decline CME. Medscape 2008.

http://www.medscape.com/viewarticle/581273

- Rountree SD, Chan W, Pavlik VN, Darby EJ, Siddiqui S, Doody RS. Persistent treatment with cholinesterase inhibitors and/or memantine slows clinical progression of Alzheimer’s disease (AD). Alzheimer’s Research & Therapy 2009, 1:7

http://alzres.com/content/1/2/7

- Donepezil — Relief for Patients with Severe AD? (Be sure to read Dr Schneider’s comments as well as the article)

http://www.alzforum.org/new/detail.asp?id=1364

- Seltzer B. Is long-term treatment of Alzheimer’s disease with cholinesterase inhibitor therapy justified? Drugs Aging. 2007;24(11):881-90.

http://www.ncbi.nlm.nih.gov/pubmed/17953456

- Bullock R, Dengiz A. Cognitive performance in patients with Alzheimer’s disease receiving cholinesterase inhibitors for up to 5 years. Int J Clin Pract. 2005 Jul;59(7):817-22.

http://www.ncbi.nlm.nih.gov/pubmed/15963209

Treating Behavioral Problems
- Cholinesterase Inhibitors Reduce Aggression, Wandering And Paranoia In Alzheimer’s Disease. Medical News Today 2008.

http://www.medicalnewstoday.com/articles/132476.php

- Beier MT. Treatment Strategies for the Behavioral Symptoms of Alzheimer’s Disease: Focus on Early Pharmacologic Intervention. Pharmacotherapy. 2007;27(3):399-411.

http://www.medscape.com/viewarticle/555408

- Masterman DL. Role of Cholinesterase Inhibitors in Managing Behavioral Problems in Alzheimer’s Disease. Prim Care Companion J Clin Psychiatry. 2004; 6(3): 126-131.

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=474736

- Gauthier S, Loft H, Cummings J. Improvement in behavioural symptoms in patients with moderate to severe Alzheimer’s disease by memantine: a pooled data analysis. Int J Geriatr Psychiatry 2008; 23: 537–545.

http://www.legemiddelsiden.no/Lundbeck/microsite/Gauthier_pooled_data.pdf

- Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD005593. DOI: 10.1002/14651858.CD005593.

http://www.cochrane.org/reviews/en/ab005593.html

- Grossberg GT, Pejovi? V, Miller ML, Graham SM. Memantine therapy of behavioral symptoms in community-dwelling patients with moderate to severe Alzheimer’s disease. Dement Geriatr Cogn Disord. 2009;27(2):164-72.

http://www.ncbi.nlm.nih.gov/pubmed/19194105

Discontinuing Alzheimer’s Drugs
- Fillit HM, Hofbauer RK, Setyawan J, et al. Memantine Discontinuation and the Health Status of Nursing Home Residents With Alzheimer’s Disease. Journal of the American Medical Directors Association, 2010; 11 (November) 636-644.e1

http://www.jamda.com/article/S1525-8610%2809%2900522-2/abstract

- Doody RS, Geldmacher DS, Gordon B, et al. Open-label, multicenter, phase 3 extension study of the safety and efficacy of donepezil in patients with Alzheimer’s disease. Arch Neurol. 2001;58:427-33.

http://archneur.ama-assn.org/cgi/content/full/58/3/427