Multicenter Evaluation of Memory Remediation in Traumatic Brain Injury With Donepezil: A Randomized Controlled Trial

Memory impairments are common chronic and functionally important consequences of traumatic brain injury (TBI). Among patients with persistent verbal memory impairments due to TBI-related cholinergic deficits, donepezil (an acetylcholinesterase inhibitor) may improve these and related problems. The Multicenter Evaluation of Memory Remediation in TBI with Donepezil (MEMRI-TBI-D) study, a four-site, randomized, parallel-group, double-blind, placebo-controlled, 10-week clinical trial, evaluated the efficacy of donepezil on verbal memory impairments, co-occurring cognitive and noncognitive neuropsychiatric problems, and functional status among persons with severe, persistent, and functionally limiting verbal memory problems at least 6 months after mild, moderate, or severe TBI. Efficacy, safety, and tolerability measures were assessed. Seventy-five participants were randomly assigned to donepezil (N=37) and placebo (N=38) groups. In both modified intent-to-treat and per-protocol analyses, donepezil significantly improved memory (i.e., verbal learning, as measured by the Hopkins Verbal Learning Test–Revised Total Trials 1–3, the primary outcome measure) when compared with placebo. Treatment-responder rates in the donepezil and placebo groups were 42% and 18%, respectively, yielding a number needed to treat of 3.5. Among donepezil responders, delayed recall and processing speed also improved significantly. Treatment-emergent adverse event rates for donepezil and placebo were 46% and 8%, respectively, and mild or moderate (85%); diarrhea and nausea were significantly more common in the donepezil group, yielding a number needed to harm of 6.25 and a likelihood to be helped or harmed ratio of 1.79. These results suggest that donepezil is an efficacious treatment for severe, persistent memory impairments after predominantly severe TBI, with a relatively favorable safety and tolerability profile.