It has now been a full ten years since the first of the second-generation cholinesterase inhibitors (CIs), Aricept (donepezil) was approved for Alzheimer’s dementia. (The original CI, tacrine, is rarely prescribed these days because of the risk of bradycardia and hepatotoxicity). Soon after Aricept’s approval, other companies got busy producing their own me-too drugs, including Exelon (rivastigmine) in 2000, and Razadyne (IR and ER) (galantamine) in 2001. Namenda (memantine) came along in 2003 and is an NMDA receptor antagonist rather than a CI. Unfortunately, the initial burst of enthusiasm for these drugs diminished in response to an influential study questioning the magnitude of their clinical effectiveness. The British AD2000 study randomized 486 patients with AD to two doses of Aricept (5 mg and 10 mg) or placebo and followed them for three years. At the end of the study, there were no differences in rates of institutionalization or progression to severe disability among the groups, although Aricept patients averaged a 1 point higher score on their MMSEs (Lancet 2004;363:2105-2115). By contrast, the latest systematic reviews published by the Cochrane database endorse all three CIs as being modestly effective for AD. They all lead to about a 2 point improvement in the ADAS-Cog, (the standard research instrument used in the field), and they produce small benefits in activities of daily living. There are no detectable efficacy differences among them (Birks J, Cochrane Database of Systematic Reviews, updated 8/2006). While they may be equivalently effective, each has its own character, so let’s go through all of the currently available AD meds, in turn (see table, “Current Medications for Dementia”). But first, some general notes. Every so often, CIs will lead to rapid and noticeable improvement in cognition and behavior (“my mother is herself again!”). Usually, however, they act by slowing the rate of cognitive decline. Patients and family understandably become impatient if all they have to look forward to is a more gradual worsening. It sometimes helps to compare CIs to blood pressure medications—“you take them everyday and you don’t feel any different, but having a lower blood pressure will eventually prevent you from having a stroke.” In the same way, taking a CI will cause imperceptible neurotransmitter changes that may prevent a dementia catastrophe, like getting lost, or causing a fire in the kitchen. All CIs commonly cause nausea, vomiting, and dizziness, and this is why the recommended dosing schedule is excruciatingly slow, generally no faster than one increment every 4 weeks. (For more detailed side effect information, see our medication fact sheets on www.TheCarlatReport.com, free to subscribers.) Aricept (donepezil). Mnemonic to remember generic name: the first letters juxtaposed are “AD” for Alzheimer’s Disease. The first to be approved, it is also the most prescribed of the three CIs. It recently got a boost from the FDA when it was approved for use in severe dementia (in addition to its current mild-to-moderate dementia approval). Start at 5 mg QAM, and go up to 10 mg QAM after 4 weeks. The company recommends PM dosing, but giving it in the morning may prevent the insomnia and vivid dreams that some patients report with Aricept. Key advantages: Once a day dosing, easy titration. Exelon (rivastigmine). Mnemonic: “Excellent river!” Exelon recently won a second FDA indication for dementia associated with Parkinson’s Disease (PD) on the strength of a single placebo-controlled trial of 541 patients with PD and dementia. Clinically meaningful improvement occurred in 5% of PD patients on Exelon, whereas 10% of patients on placebo worsened. Unfortunately, Exelon is a pain to use, both because it requires BID dosing (start at 1.5 mg BID, go to 3 mg BID after one month and finally to 6 mg BID) and because it leads to unacceptably high rates of nausea (47%) and actual vomiting (31%). Titrating it very slowly may reduce nausea. Word on the street has it that an Exelon patch will soon receive FDA approval, which will be more convenient for patients and possible easier on the GI tract. Key advantage: No cytochrome p450 interactions, unlike other CIs. Razadyne (galantamine) and Razadyne ER. Mnemonic: “Lots of Razzamatazz at a gala!” The relative newcomer, Razadyne was approved in 2001. Its original name was “Reminyl” but the company changed it because pharmacists were sometimes confusing written scripts with Amaryl, a diabetes medication. Razadyne’s claim to fame is that it has a “dual” mechanism of action, modulating cholinergic nicotinic receptors in addition to inhibiting acetylcholinesterase. Drug reps from Ortho McNeil will use this factoid to argue that Razadyne is more effective than the other CIs and will even trot out a company-sponsored study or two to back it up. But when all studies from all companies are analyzed, there is no significant outcome difference. Razadyne recently released its ER (extended release) version, which is what most clinicians prescribe. Start at 8 mg QD, increase to 16 mg QD after one month and then to 24. Key advantages: Once a day dosing with ER form, dual mechanism of action (possible advantage). Razadyne got burned recently when the company’s own clinical data showed a 1.5% mortality rate in patients taking the medication for mild cognitive impairment (MCI) versus a 0.5% mortality rate in the placebo arm. According to the FDA, the two treatments did not differ in the main outcome variable, which was percent progressing to dementia (see http://www.fda.gov/cder/drug/InfoSheets/HCP/galantaminelHCP.pdf.). The significance of the mortality findings has been questioned, because the placebo mortality rate was abnormally low. Namenda (memantine). Namenda is stuck with a bum indication (moderate to severe dementia only) but it does boast a unique mechanism of action (NMDA receptor antagonist) and it has some data to support its usefulness as an augmenter of Aricept (JAMA, 2004; 291:317-324). Thus, many specialists will put the majority of their demented patients on the combination of one of the CIs and Namenda, starting at 5 mg QAM and titrating up by 5 mg each week, up to a maximum of 10 mg BID. Side effects of Namenda? Look for dizziness, sedation, transient confusion, headache, and constipation. However, it tends to be well-tolerated over the long term. Coming soon? Alzhemed and Flurizan. Neurochem Pharmaceutical has just completed a large Phase III trial of the new drug Alzhemed (tramiprosate), which works by binding to the peptide Amyloid-Beta, thereby slowing the formation of amyloid plaques. According to business publications, the company will release the results sometime soon (http://www.pharmaceutical-business-review.com). Flurizan (tarenflurbil), manufactured by Myriad Pharmaceuticals, is an SALA, or “Selective Amyloid-Beta Lowering Agent.” Currently in Phase III clinical trials for the treatment of mild AD, it is reportedly ineffective for moderate AD. See the company’s web site, http://www.myriad.com, for an entertaining video clip about how flurizan works.

Current Medications for Dementia
Trade name	Generic name	Supplied as…	Starting dose	Target dose
Aricept	donepezil	5, 10	5 QPM	10 QPM
Exelon	rivastigmine	1.5, 3, 4.5, 6	1.5 BID	3 – 6 BID
Namenda	memantine	5, 10	5 QD	5 – 10 BID
Razadyne	galantamine	4, 8, 12	4 BID	8 – 12 BID
Razadyne ER	galantamine ER	8, 16, 24	8 QD	16 – 24 QD

Note: Dosing information from Physician’s Desk Reference; all doses are in milligrams.

TCPR Verdict:

CIs: Gains are modest, but real.