A Randomized Placebo-Controlled Discontinuation Study of Cholinesterase Inhibitors in Institutionalized Patients With Moderate to Severe Alzheimer Disease

Objectives: Cholinesterase inhibitors (ChEIs) offer modest benefits in Alzheimer disease (AD), which must be balanced against risks. Relatively few data delineate the benefits and risks of long-term ChEI administration in institutionalized patients with advanced AD. This study investigated the effects of ChEI discontinuation in institutionalized patients with AD.

Design: Institutionalized patients with moderate to severe AD (standardized Mini- Mental Status Examination ≤15) and treated with a ChEI for ≥2 years were randomized, double-blind, to ChEI continuation or placebo, with a 2-week tapering phase, for 8-weeks.

Measurements: The primary outcome of this pilot study was change on the Clinician's Global Impression of Change (CGI-C) scale. Secondary outcomes included safety, efficacy, and tolerability. Baseline (BL) predictors of clinical deterioration were also determined.

Results: Forty patients (mean ± standard deviation age = 89.3 ± 3.5 years, standardized Mini-Mental Status Examination = 8.1 ± 5.2, Neuropsychiatric Inventory-Nursing Home version total score = 21.1 ± 15.9, 80% male) were randomized to ChEI continuation (n = 21) or placebo (n = 19). There was no significant difference in clinical worsening in the ChEI continuation (28.6%) and placebo groups (36.8%) on CGI-C (odds ratio for worsening 1.58, 95% confidence interval .38-6.55, P = .53). The occurrence of adverse events was similar in both groups. There were no significant differences in any of the secondary outcome measures. In the placebo group, BL hallucinations predicted CGI-C worsening [F(1,17) = 6.4, P = .02], and there was a trend for BL delusions to predict CGI-C worsening [F(1,15) = 3.5, P = .08].

Conclusions: These results suggest that ChEI discontinuation is safe and well tolerated in the majority of institutionalized patients with moderate to severe AD. When discontinuing ChEI, the presence of hallucinations and delusions may predict clinical deterioration, suggesting the need for increased caution.