Potential Role of the Sigma-1 Receptor Chaperone in the Beneficial Effects of Donepezil in Dementia with Lewy Bodies

With great interest, I read the article by Mori et al.1) about a randomized, placebo-controlled trial of the cholinesterase (ChE) inhibitor donepezil for dementia with Lewy bodies (DLB). The study randomly assigned 140 DLB patients to receive placebo or donepezil hydrochloride (3, 5, or 10 mg, daily for 12 weeks). The effects on cognition were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician’s Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Donepezil at 5 or 10 mg was significantly superior to placebo on both the MMSE and CIBIC-plus, and 3 mg donepezil was significantly superior to placebo on the CIBICplus, but not on the MMSE. Furthermore, a beneficial effect of donepezil was evident in each symptom domain characteristic of delusion, hallucination, and cognitive fluctuation (in DLB). Moreover, patients who received donepezil showed improved global function, as measured by the CIBIC-plus. These results suggest that donepezil (5 and 10 mg/day) produces significant cognitive, behavioral, and global improvements in DLB patients, and that at the highest dose, this drug reduces the caregiver burden. 1)