VALPROATE TRIAL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study represents a novel clinical trial strategy designed to assess both prospective "prophylactic" therapy for psychopathology in AD and also to assess an approach that may alter several aspects of the pathophysiology of AD, thereby perhaps resulting in neuroprotective effects, which would be assessed by monitoring clinical progression of illness as well as relevant biomarkers and imaging data. The primary objective of this study is to demonstrate in a randomized, placebo-controlled clinical trial whether chronic valproate therapy delays the emergence of agitation and/or psychosis in outpatients with probable Alzheimer's disease (AD) who have not yet experienced agitation or psychosis during the course of their illness. The chief secondary aim is to determine whether chronic valproate therapy for up to two years delays the progression of cognitive, functional, other behavioral, and global measures of illness. We hypothesize that active therapy will result in slowing of decline in these measures. Other secondary aims: The study will address the tolerability and safety of low-dose, long-term valproate therapy versus placebo by the assessment of adverse experiences, comorbid events, vital signs, and laboratory measures. We hypothesize that active treatment will be well tolerated. We will measure possible drug-placebo differences in quality of life. We hypothesize that active treatment will be associated with higher quality of life ratings. We will study biological markers selected for their possible relevance to the pathophysiology of Alzheimer's disease, as well as the postulated mechanism of action of valproate. We will conduct repeated MRI scans in a subset of patients enrolled to assess whether there may be possible drug-placebo differences in brain volumetric measurements. (Note that our UCI site will not participate in this MRI substudy). We hypothesize that specific valproate-mediated biochemical alterations will correlate with clinical and structural imaging responses. Finally, we will examine the effects of withdrawal of active treatment vs placebo treatment after two years of treatment. We hypothesize that withdrawal of active vs placebo treatment will not yield differences in change in behavioral, cognitive, functional, or global measures of disease from month 24 to month 26.