When should one stop cholinesterase inhibitors in patients with Alzheimer's disease?

An 83-year-old woman with Alzheimer's disease (AD) has been taking a cholinesterase inhibitor for 3 years. When she started the medication, her Folstein Mini Mental State Exam score was 18. It is now 8. Should she continue taking the medication?

Although there are some subtle differences among tacrine, donepezil, rivastigmine and galantamine, the 4 cholinesterase inhibitors currently available to treat AD, they all work by inhibiting acetylcholine degradation. They do not affect the basic disease process and may be less effective in more advanced disease as more cholinergic neurons are lost. Some of the differences among them may be clinically important (e.g., the once-a-day dosing of donepezil makes it easier to use than medications with more frequent dosing intervals), whereas other differences are of unclear or unproven significance (e.g., galantamine also modulates nicotinic receptors, yet this does not clearly provide any clinical advantage over the other inhibitors). Whichever inhibitor one chooses, what one usually hopes for from these modestly effective medications is a temporary stay or slowing in symptomatic progression, which might then translate into prolongation of independence, maintenance of quality of life or less caregiver burden. It is not realistic, given the existing evidence, to hope for an actual clinical improvement. Nonetheless, they are generally well tolerated, and the risk-benefit ratio may favour the drugs if they are capable of delaying outcomes such as nursing home placement.

If a patient is not deteriorating cognitively or functionally and not suffering any adverse effects, one usually continues the medication. Assuming the patient can afford the medication (it can cost more than $100/mo in the US), why not continue it? One of the challenges in using these medications is that it is extremely difficult to tell in individual cases whether the medication is helping. If a patient remains stable clinically, then either the medication is helping, the disease is progressing very slowly or the diagnosis is incorrect. Under these circumstances, it may be easiest — and perhaps most appropriate given the apparent lack of long-term toxicity — to avoid risking clinical deterioration by discontinuing the medication.

What about the patient who has started to deteriorate? Here again, there are several possible interpretations. If deterioration represents treatment failure, it may be appropriate to discontinue the medication. It is not clear whether switching to a different inhibitor offers any advantage. On the other hand, the original medication may be “propping up” the patient above the level to which she or he would decline in the absence of cholinesterase inhibition. Again, it is usually difficult or impossible in individual cases to tell which interpretation is correct. Many families and clinicians may be reluctant to abandon the medication in case it is providing a marginal but significant benefit; the lack of clear benefit in these situations may be balanced by the apparent lack of risk, thus favouring continuation. There is very little research to guide the clinician in this territory.

In this patient's case, the bare facts do not lead to a clear answer. Many other details may be important, including the patient's medical status, whether she is still at home, the ease of administering medications and the patient's financial situation. Ultimately, it should come down to the patient's goals, if known, and the family's goals. With much clinical uncertainty and no clear answer, there is no substitute for full and honest discussion and shared decision making. The only “should” in a case like this is that individual goals should matter.