Effects of augmenting cholinergic neurotransmission on balance in Parkinson's disease

Introduction: Degeneration of cholinergic systems may contribute to impairments of balance and gait in Parkinson's disease (PD) and phase 2 clinical trials have suggested that centrally acting cholinesterase inhibitors reduce falls. Here, we examined the effects of augmenting cholinergic neurotransmission on static and dynamic balance, indices of fall risk.

Methods: A single-site, randomized, double-blind, crossover trial examined the effect of donepezil in patients with PD. Forty-nine participants with idiopathic PD were randomized and 45 completed the trial. Each treatment period was 6 weeks with a 6-week washout between treatments. Donepezil in 2.5 mg capsules, or identical appearing placebo capsules, was increased from two per day (5 mg) to four capsules (10 mg) after 3 weeks. The primary outcome measures were the range of the medio-lateral sway when standing (static balance) and the variability of the stride duration when walking (dynamic balance). A linear mixed model was used to investigate whether the change in outcomes between weeks 0 and 6 differed between phases.

Results: There were no significant differences in treatment effects between placebo and donepezil for medio-lateral sway range during quiet standing (p = 0.28), nor in gait variability (p = 0.31). None of the secondary outcome measures or exploratory analyses were significant although one secondary measure of static balance was increased by donepezil.

Conclusions: Contrary to our hypothesis, cholinergic augmentation with donepezil at 10 mg/day for 6 weeks did not affect measures of static or dynamic balance in people with PD. These results are compared with other phase 2 trials of cholinesterase inhibitors and considerations for future trials are discussed.