Increasing Donepezil Dosage Improves Cognitive Function in Patients with Dementia

By John Henry Dreyfuss, MDalert.com staff.

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  • Plasma donepezil concentration increased proportionally with dose (5–10 mg/day).
  • Plasma donepezil concentration was affected mainly by dose and partially by age.
  • Change in cognitive function correlated positively with plasma concentration.
  • Safety parameters were not significantly related to plasma concentration.
  • Increasing plasma donepezil concentration further improves cognitive function.

Increased plasma concentrations of donepezil resulted in improved cognitive function in patients with dementia with Lewy bodies (Figure 1). The increased plasma concentration correlated positively with improved cognitive function without affecting safety, and was affected mainly by dose and to a lesser extent by age. “Therefore, for patients in whom safety concerns are not found at donepezil 5 mg/day, increasing the dose to 10 mg/day to increase plasma concentration is worthwhile to further improve cognitive function,” the authors concluded. The results were published recently in the Journal of the Neurological Sciences.

Figure 1. Combination of 2 brain diagrams in one for comparison. In the left normal brain,
in the right brain of a person with Alzheimer's disease.
(Sources: Wikipedia/By Garrondo [Public domain], via Wikimedia Commons.)

The Analysis

The researchers analyzed data from a 12-week phase 3 trial of donepezil (5 mg/day and 10 mg/day) in patients with dementia with Lewy bodies (DLB; Figure 2). They conducted a multivariate regression analysis in order to identify contribution of factors affecting plasma donepezil concentration and the relationship between plasma concentration and cognitive function. The relationships between plasma donepezil concentration and cognitive function were measured using the Mini-Mental State Examination (MMSE), as well as the rate of hallucination and cognitive fluctuation. They also evaluated the safety of varying plasma concentration by tracking blood pressure, pulse rate, body weight, and parkinsonism as measured by the Unified Parkinson's Disease Rating Scale part III. These evaluations were assessed by scatterplots and Pearson correlation.

Figure 2. Photomicrographs of regions of substantia nigra in a patient showing
Lewy bodies and Lewy neurites in various magnifications.
(Sources: Wikipedia/By Suraj Rajan (Own work)/Creative Commons,
via Wikimedia Commons CC BY-SA 3.0.)

Overall, the data from 87 patients were used in the analyses. Plasma donepezil concentration increased proportionally with increasing dosages. The dose contribution rate was 0.39, (P<0.0001). Age also contributed to the rate at 0.12, (P=0.0003). Both age and dose were statistically significant contributing factors affecting plasma donepezil concentration. Furthermore, plasma donepezil concentration was found to correlate significantly with improvement of MMSE score (P=0.040). No significant correlations were found with the change in other tested parameters.

Figure 2. Immunohistochemical staining of Lewy Neurites in a case of Lewy Body Dementia (DLB). (Sources: Wikimedia/By Jensflorian (Own work)/Creative Commons CC BY-SA 3.0/
or GFDL, via Wikimedia Commons.)

Conclusions

“Plasma donepezil concentration correlated positively with change in cognitive function without affecting safety, and was affected mainly by dose and to a lesser extent by age. Therefore, for patients in whom safety concerns are not found at donepezil 5 mg/day, increasing the dose to 10 mg/day to increase plasma concentration is worthwhile to further improve cognitive function,” the authors concluded.