Donepezil, a medication that boosts brain acetylcholine levels, has been FDA approved for many years to improve memory and independence in mild to moderate Alzheimer’s disease. The hippocampus is frequently damaged in TBI, and many individuals have memory difficulties. These facts led to an interest in whether donepezil might benefit individuals with TBI-related memory impairment.
Jefferson Moss-Magee Rehabilitation/Jefferson Moss Rehabilitation Research Institute was one of four centers that participated in a study led by David Arciniegas, MD (University of Colorado Anschutz Medical Campus). Tessa Hart, PhD, Emeritus Faculty, served as our site principal investigator, and John Whyte, MD, PhD, Emeritus Faculty and Founding Director of our Institute served as a co-investigator. “Right now, there is a major gap in treatment options for people with memory impairments after TBI. Joining with other high-caliber TBI Model System institutions to conduct multi-center drug trials is essential,” explained Dr. Whyte.
Results from this clinical trial were recently published in The Journal of Neuropsychiatry. The study enrolled a total of 75 patients who had a TBI at least six months previously, had significant memory complaints, and scored abnormally on the Hopkins Verbal Learning Test (HVLT), which requires remembering a list of words. Individuals were excluded for a variety of reasons but significant depression or anxiety or the need to be treated with certain psychoactive medications were frequent reasons for exclusion. Participants were assigned to receive donepezil or placebo in randomized double-blind fashion, for 10 weeks, with 5 mg/day for the first 2 weeks and 10 mg/day for the remaining 8 weeks.
Donepezil had a statistically significantly positive effect on the number of words participants were able to learn and remember. The size of this effect varied, but 42% of participants in the donepezil group — compared to 18% of the placebo group — showed a large improvement from baseline in their HVLT score. Donepezil also produced a side effect of nausea, which resolved in most patients but led to discontinuation in three participants. Overall, the study found the safety and tolerability profile of donepezil was favorable. Although the drug produced a statistically significant improvement in the primary outcome of the study (the HVLT score), it did not have a significant effect on the Everyday Memory Questionnaire or any caregiver functional ratings which are arguably more relevant to clinical benefit.
Indeed, this is the recurring problem in drug treatment studies of cognitive impairment: in order to show a clear drug effect, one often must select study participants who have a very specific profile (in this case, hippocampal memory impairment), without other confounding problems (like anxiety or depression). But many of the individuals seeking treatment have a combination of problems. And in many cases, their “everyday memory” complaints may stem for multiple sources, only one of which is addressed by donepezil. Future research will be needed to identify the profile of patients who can experience meaningful functional benefit from treatment with donepezil.