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.
Competing Interests: Dr. Giacino has received support via institutional awards from the James S. McDonnell Foundation and the National Football League (NFL). Dr. Hammond serves on the scientific advisory boards of Eli Lilly and Company and Otsuka Pharmaceutical. Dr. Zafonte serves on the scientific advisory boards of Kisbee, Myomo, and Nano Diagnostics, and he evaluates patients in the Massachusetts General Hospital Brain and Body–TRUST Program, which is funded by the NFL Players Association. The other authors report no financial relationships with commercial interests. Dr. Arciniegas is editor of the Journal of Neuropsychiatry and Clinical Neurosciences; accordingly, Consulting Editor Fred Ovsiew, M.D., served as editor, including refereeing the peer review process and decision making on publication of this article. Dr. Ovsiew has no institutional affiliations or competing obligations with the authors, the authors’ institutions, or the sponsor of this work.