Schifitto G, Peterson DR, Zhong J, Ni H, Cruttenden K, Gaugh M, Gendelman HE, Boska M, Gelbard H.
Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report.
Neurology. 2006 Mar 28;66(6):919-21.
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I was involved with this work as chairman of the Data and Safety Monitoring Committee, so I will not comment on the trial specifically but offer a general perspective here. There is a modest amount of information from placebo-controlled trials in patients with dementia addressing whether valproate may relieve agitation. Overall, the results are inconclusive, with the most recent multicenter trial failing to show benefit after earlier trials suggested benefit on secondary outcomes (1). The average dose tended to be about 750 mg/d, with average levels of about 50 mcg/ml. In most cases, sedation, gastrointestinal distress, and thrombocytopenia were the most common side effects noted. Using insensitive measures of cognitive function, no improvement was seen. The report of Schiffito et al. is encouraging in that it suggests that, in another vulnerable population, valproate was well tolerated, although we do not know what blood levels were achieved. Blood concentration achieved may matter, since some of the particular cell signaling pathways of interest may be affected in a concentration-dependent manner. The study also, importantly, has shown a lack of interaction with antiretroviral therapy and a lack of effect on viral replication.
There is an explosion of literature suggesting that valproic acid and its various formulations, including divalproex sodium, as well as related compounds such as lithium, may have clinically relevant neuroprotective properties in a variety of human conditions including, for instance, HIV-associated cognitive impairment, bipolar disorder, and Alzheimer disease, among others. The preliminary evidence in the report of Schiffito et al. is insufficient to draw conclusions as to the degree to which meaningful cognitive improvement can be expected with this treatment in this population, but there is no evidence of harm as yet, and the potential for benefit in this and other populations merits further investigation.
On the strength of somewhat overlapping rationales, a multicenter clinical trial of divalproex sodium in several hundred people with probable Alzheimer disease is under way (2). The Valproate Neuroprotection Trial, funded by the NIA and conducted by the Alzheimer’s Disease Cooperative Study Group (with Leon Thal as the PI), is now in its third year. It addresses whether low-dose divalproex sodium may attenuate the clinical progression of illness in people with mild to moderate probable Alzheimer disease. In addition to examining critical clinical measures addressing behavioral, cognitive, and functional outcomes, the trial incorporates peripheral biomarkers and repeated static cerebral imaging to further explore the possible impact of therapy. The results from the trial in people afflicted with Alzheimer's will be helpful in further understanding the impact of this treatment in people with HIV and vice versa. It is too soon to know what the true impact will be. Completing these studies in a timely fashion is a priority.
Tariot PN, Raman R, Jakimovich L, Schneider L, Porsteinsson A, Thomas R, Mintzer J, Brenner R, Schafer K, Thal L, Alzheimer's Disease Cooperative Study, Valproate Nursing Home Study Group.
Divalproex sodium in nursing home residents with possible or probable Alzheimer Disease complicated by agitation: a randomized, controlled trial.
Am J Geriatr Psychiatry. 2005 Nov;13(11):942-9.
Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S.
Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales.
Adv Drug Deliv Rev. 2002 Dec 7;54(12):1567-77.