Objective: To complete a Double-Blind, Placebo-Controlled Study of the Efficacy and Safety of Divalproex sodium ER augmentation of Donepezil for Cognition, Hippocampal Volume, and Behavior in Alzheimer's Disease.
Design: Divalproex sodium has been studied in terms of decreasing the behavioral complications in AD patients; however, no clinical data exists on the cognitive enhancing ability of Divalproex sodium, despite some positive basic science data. This protocol provides data on the use of Divalproex sodium as an augmenting agent to donepezil for improving cognition (assessed with the MMSE and ADAS-cog) in mild/moderate AD patients. Changes in hippocampal volume (volumetric MRI) and in behavioral complications (Neuropsychiatric Inventory and BEHAVE-AD) were also examined. Divalproex sodium ER 500-mg qhs was used due to the ease of administration in this population, and the safety and tolerability of this was also assessed.
Materials and Methods: Subjects were enrolled if they met NINCDS/ADRDA criteria for the diagnosis of AD and had a MMSE score within the range of 10 to 24 inclusive at baseline. No concomitant psychotropics were allowed. All subjects entered the protocol on a stable dose of donepezil for at least 6 months. Following an eight-week open-label assessment period with donepezil only, subjects were randomized to an 18-week double-blind treatment period of augmentation with Divalproex sodium ER or placebo.
Results: An interim analysis of the composite data revealed these initial characteristics: mean age of 73.0, 50% female, and mean MMSE=21.5. At baseline the mean NPI was 16.75, the BEHAVE-AD was 3.75, and the ADAS-cog was 48.25. At week 26 the cohort on the combination of Divalproex sodium ER and donepezil versus the cohort on placebo and donepezil had the following respective results: NPI of 8 versus 12.33; BEHAVE-AD of 0 versus 3; MMSE of 20 versus 18.67, and ADAS-cog of 68.0 versus 59.0. One patient experienced two days of nausea after entering the randomization phase and insisted on discontinuing the protocol – the individual was on placebo. This was the only adverse event reported.
Conclusion: This interim analysis of a double-blind, placebo-controlled trial of the augmentation of donepezil with Divalproex sodium ER revealed a decrease in the NPI and BEHAVE-AD, consistent with both the literature and clinical practice. Divalproex sodium ER 500 mg qhs was well tolerated in this population, a finding not previously reported. Although the MMSE declined less in the cohort on combination treatment, the ADAS-cog increased in both cohorts. The full data set and both volume and shape anlayses of the hippocampal changes will be available for presentation. The protocol will likely be extended for an additional year to obtain longer term neuropsychiatric and neuroimaging results.
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