Objective: This paper offers a case study of “reverse translational research,” in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimer's disease (AD) ultimately led to a mechanism-based trial designed to delay or prevent the emergence of psychopathology.
Design: Review and synthesis of research.
Results: Clinical trials evidence is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed.
Conclusion: These findings lead to the surprising conclusion that neuroprotective properties may account for some valproate's clinical effects. Clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimer’s Disease Cooperative Study. The design addresses valproate’s potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.
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