Cholinesterase inhibitors: The earlier, the better

Cholinesterase inhibitor treatment should be started as early as possible in the course of dementia and continued as long as the perception of benefit outweighs the cost and side-effect profile. Decisions about which cholinesterase inhibitors to use in which patients, when to start using them, and whether to stop using them are "empirical", based on negotiation between the patient, physician, and family. They offered his recommendations based on the published data and common practice of dementia specialists in the United States and Europe. As a general rule, cholinesterase inhibitors should be stopped when adverse events are severe or persistent or when the physician and patient/caregiver see no benefit after six months of therapy. The drugs should not be stopped merely on the basis of a decline in Mini-Mental State Examination score, since the decline have been worse. If the patient had not been taking the drug. And, the drugs should never be stopped at the time of nursing home placement – a highly stressful event for the patient and family members. There is a risk of worsening. It’s certainly not the time to stop treatment.

When the drug is stopped, patients should be carefully monitored and the drug restarted if there is a significant decline in function after 2-3 weeks. The currently available cholinesterase inhibitors – tacrine, donepezil, revastigmine, and galantamine – have been shown to be about equally effective in slowing decline in cognitive and global functioning in trials lasting 6-12 months, and open-label extension trials suggest continuing benefit for up to two years. Tacrine is rarely used any more because of its high rate of liver toxicity. Among the other three, dosing is a bit easier for donepezil than for the others. Individual patients may differ in tolerance and clinical response to each of the agents, so it may be worthwhile to empirically switch from one to another if the patient’s response or tolerance to one is inadequate. Cholinesterase inhibitors are labeled only for use in patients with mild to moderate Alzheimer’s disease. However, recent data suggest that they may be effective in other groups of patients, including those with more severe dementia, mild cognitive impairment, vascular dementia, and mixed dementia.

In one 24-week trial, 290 patients with moderate to severe Alzheimer’s disease were randomized to receive either donepezil (5mg/day for the first 28 days and 10mg day thereafter) or placebo. The donepezil group showed benefits on the Clinician’s Interview-Based Impression of Change (with caregiver input) scale at all visits up to week 24. Other measures, including the standardized Mini-Mental State Examination, the Disability Assessment for Dementia, the Functional Rating Scale, and the Neuropsychiatrics Inventory, were all significantly different in favor of donepezil. Rivastigmine showed similar benefit in a 52-week study.

Of course, it would be unethical to conduct a formal prospective randomized trial in which cholinesterase inhibitors were withheld until the patient progresses to moderate or severe disease. But, at the very least, the data show that you don’t lose efficacy with increased severity. Ongoing studies are examining whether the drugs might preserve higher function longer if started when individuals have mild cognitive impairment. These studies may be tricky, because it’s hard to show benefit in milder disease.