There were no statistically significant changes between baseline evaluation and postdrug administration at the 1.25 mg dose for the following measurements: TST, stage 1, stage 2, stage 3, wake after sleep onset time, sleep latency, or sleep efficiency. Subjects experienced a statistically significant (p
0.02, two-tailed) increase in REM % at the initial 1.25
mg dose as depicted in . Mean REM % at baseline for the group of 5 subjects was 10 (standard deviation
4.2). Mean REM % after treatment with 1.25
mg donepezil was 19 (5.6). Subjects also experienced a statistically significant decrease in latency to REM sleep from baseline (p
0.02) with an observed mean of 230.9 minutes (37) before treatment and an observed mean of 142.6 minutes (25.6) after 1 month at the 1.25
mg dose. No other sleep parameters were found to have statistically significant changes pre- and post-treatment.
Table 1. Comparing Sleep Parameters of Subjects at Baseline and 1.25mg Donepezil
presents plots of REM % versus dose for each subject (plots are labeled with numbers indicating the temporal sequence of doses). Subject 1 was a 4.9-year-old boy with a nonverbal cognitive ratio IQ (NVDQ) of 55.18. He experienced a modest increase in REM % from baseline at the 1.25
mg dose and was increased to the 2.5
mg dose and restudied 1 month later. His 2.5
mg study revealed a decrease in REM %. He was further increased to 5
mg with a resultant further decline. At this dose, parents reported that he was “not himself” and his polysomnogram examination revealed a significant increase in wake after sleep onset time at this dose versus baseline (131 minutes vs. 48). The clinical decision was made to return his dose to 1.25
mg and he was reevaluated by PSG after a month on that dose (depicted as point “4” in , subject 1). When re-evaluated at 1.25
mg, REM sleep returned to above the baseline value and exceeded the values obtained at the 2.5 and 5
mg doses. Mother reported child “back to himself” at this dose.
FIG. 1. Response of REM % to dose, by subject. Note: Points are labeled in temporal order (0=baseline).
Subject 2 was a 2.5-year-old boy with an NVDQ of 72.35. He experienced an increase in REM % at the initial dose. He was increased to the 2.5
mg daily dose and restudied 4 weeks later as per protocol. At this dose, his REM % reached >30% of his total sleep time. As this result was greater than two standard deviations outside the target range for age, a clinical decision was made to increase his dose to 5
mg/day as per protocol and restudy him in 4 weeks. His PSG at 5
mg revealed an REM % of 20. The subject was maintained at 5
mg/day for 8 more weeks. He returned for his final study, but spiked a temperature while in hospital. His final PSG evaluation is not used in this data set as fever can alter sleep organization (Kryger et al. 2005
Subject 3 was a 5.3-year-old boy with an NVDQ of 45.74. He had an initial drug study at the 1.25
mg dose that could not be used in this dataset as he slept for <6 hours during that examination. Given that his mother reported that he was “better,” described as “more attentive” and “less frustrated” since beginning the trial, a clinical decision was made to maintain him at this entry dose for a further 2 months and restudy him at the end of that time. On his final examination, his REM % had normalized at 22.6%.
Subject 4 was a 6.9-year-old boy with an NVDQ of 93.37. He tripled his REM % from baseline after 1 month at 1.25
mg donepezil. As he was still well below standard norms for age at 12.2%, his dose was increased to 2.5
mg daily. His 2.5
mg follow-up study revealed normalization at 22.2% REM. He was held at this dose for 2 more months and restudied at this dose. His final REM % was 25.2%.
Subject 5 was a 5.8-year-old boy with an NDVQ of 47.22. He increased his REM % from 7.9% to 27% after 1 month at 1.25
mg/day. He was held at this dose and restudied after 2 months. His final REM % at 1.25
mg maintained normalization of REM at 24.8%. Mother reported that child was “much better” at the end of the study. She reported that subject began to wake up spontaneously after having slept for 9 or 10 hours, whereas previously he would be “dead tired” in the mornings. She also reported that he became continent overnight during the course of the study where previously he had “wet the bed almost every night.”
In addition, as depicted in , each subject had an initial decrease in REM latency at the 1.25
mg dose. The parents of all 5 subjects who completed the study opted to continue taking donepezil at their final study dose, and a further 3-month supply was furnished by the NIH. There were no adverse side effects other than the unspecified behavioral change noted above in subject 1 at the 5
The 5 subjects reported here had a total of 18 separate sleep studies at 3 possible doses. Despite the small sample size, it is possible to use this additional data to make a rough estimate of the (possibly nonlinear) response in REM % and latency to REM to doses over the entire observed range. Accordingly,
we fit independent quadratic regression models for the two outcome measures (yi
) of the form:
The two models were estimated using least squares with robust (“sandwich”) standard errors clustered by subject (to account for nonindependence of observations). All coefficients in each model were found to be statistically significant (p
0.05, two-tailed) and the models appear to fit the data reasonably well overall (R2
0.52 and 0.54, respectively, and the omnibus F
test was rejected at p
0.05 for both models). Based on the results of these models, the ideal dose for maximizing REM % and minimizing the REM latency appears to be approximately between 2.5 and 3.5
mg. Complete results are available on request.