When to call it quits

By Betty Zou

In the first study of its kind, researchers at Sunnybrook Research Institute (SRI) have shown that discontinuing cholinesterase inhibitors (ChEI) in institutionalized patients with Alzheimer’s disease (AD) and other dementias does not lead to a worsening of symptoms.

Cholinesterase inhibitors are a class of drugs that prevent the breakdown of acetylcholine, a chemical messenger that relays signals between neurons in the brain where it plays a role in cognition. Levels of this neurotransmitter are lower in the brains of patients with AD compared to people without AD. By inhibiting the degradation of acetylcholine, ChEI allow the neurotransmitter to accumulate to higher levels, which, in turn, enhance communication between neurons. Treatment with ChEI can temporarily improve or stabilize dementia symptoms, and they are one of the most common medications used to treat patients with AD and other types of dementia. Although ChEI are generally well tolerated, some patients experience nausea, diarrhea, vomiting and weight loss, which can be particularly worrisome in a frail and elderly patient population. While there is a checklist to help clinicians decide whether ChEI treatment should be stopped, there have been few studies directly evaluating the health effects of ChEI discontinuation.

The pilot study, led by Dr. Krista Lanctôt, a senior scientist in the Hurvitz Brain Sciences Research Program at SRI, was a randomized, double-blind, placebo-controlled trial involving 40 residents in long-term care at Sunnybrook’s Veterans Centre. All patients were diagnosed with probable AD and primary degenerative dementia, and had been receiving ChEI treatment for at least two years. The patients were randomly assigned to one of two groups. The placebo group tapered off their ChEI medications for two weeks and continued on placebo for the remaining six weeks. The continuation group continued to receive their current dose for eight weeks. Patients in both groups were assessed at the start of the study and at two-week intervals throughout.

To determine the effects of ChEI discontinuation, the researchers used the Clinician’s Global Impression of Change score, a seven-point scale that measures the degree to which a patient’s condition improved or worsened relative to a baseline state. Clinicians assess this based on cognitive, behavioural or functional changes observed in the patient. At the end of the eight-week trial, the researchers found no difference between the scores of the placebo group and the continuation group. That is, patients taken off ChEI did not worsen more than patients who continued their treatments. There was also no difference in the occurrence of adverse events, such as unintentional weight loss and falls, between the two groups.

Another important finding was that patients who experienced delusions or hallucinations prior to the study were more likely to have worsening symptoms after ChEI discontinuation; this highlights the need for close monitoring of patients with psychotic symptoms if ChEI discontinuation is attempted.

Based on these findings, Lanctôt anticipates that 63% of patients in long-term care facilities can be safely discontinued from ChEI. With an estimated 20% of approximately 14,800 long-term care residents in Ontario receiving these medications, discontinuing ChEI could lead to $17.4 million per year in cost savings. The study had several limitations including the small number of participants, 80% of whom were male. It was published in the Journal of the American Medical Directors Association.

Lanctôt is working with Dr. Nathan Herrmann, an associate scientist in the Hurvitz Brain Sciences Research Program, to see if their findings can be replicated in a larger and more gender-balanced population. She stresses that the ultimate decision to discontinue ChEI treatment should be highly individualized. Studies such as this one provide clinicians and patients with the safety data they need to make informed decisions and to anticipate negative outcomes.

Lanctôt’s research is funded by the Alzheimer’s Society of Canada.