SIR: Thank you for the opportunity to respond to Dr. Base-XML-tag-lib and colleague's letter. The open-label pilot study that these authors describe adds to the data from other reports/investigations reviewed in our paper1 that suggest some promise for acetylcholinesterase inhibitors in treating the neurobehavioral sequelae of traumatic brain injury (TBI). We agree with Dr. Base-XML-tag-lib's conclusion that additional research into the efficacy of donepezil (and other acetylcholinesterase inhibitors) in TBI is warranted. Like many of the uncontrolled studies that we reviewed, positive findings in Dr. Base-XML-tag-lib's report (i.e., increase in clinical global improvement ratings) are difficult to disentangle from the potential effects of placebo, spontaneous recovery, and/or concurrent treatment. Negative findings (i.e., no significant improvement on a memory measure) are similarly difficult to interpret, in the context of a short follow-up period.
Based on our review of the literature, we believe that there is now sufficient theoretical and preliminary empirical evidence to move beyond pilot studies to large-scale clinical trials. We recommend that such trials incorporate methodological considerations, including: a) randomized double-blind placebo-controlled design; b) sample size selection based on the hypothesized degree of improvement on the primary outcome measure; c) selection of subjects based on specific cognitive inclusion criteria (e.g., demonstrable impairment at baseline in those cognitive realms that are hypothesized to be responsive to cholinesterase inhibition); and d) sufficient duration of intervention to allow for measurement of cognitive and functional improvement. Additionally, we would like to underscore recommendations made in our review article that stress the importance of selecting outcome measures that: a) are sensitive to the type of cognitive impairment observed following TBI; b) have been associated with cholinergic deficit; c) have been shown to be responsive to acetylcholinesterase inhibition; and d) address outcomes other than cognition, including affect, behavior, and functional outcome. Certainly, Dr. Base-XML-tag-lib's call to include cognitive outcome measures targeting executive functioning (i.e., "cognitive flexibility, verbal abstract reasoning, learning from mistakes") is supported by the literature relating to the mechanisms of action of acetylcholinesterase inhibitors. In keeping with the above recommendations, we are in the process of conducting a double-blind randomized controlled trial (RCT) to study the effects of donepezil on cognitive, behavioral, functional, and quality of life outcomes during a 6-month follow-up period in 92 subjects with TBI. We look forward to reporting our data when the study is complete.