Designer drugs are the trend these days, but what of the classics? In the category of well-known medicines that don’t go out of style, consider valproic acid. This short-chain fatty acid came to market in the United States in 1983 to treat seizure disorders and found frequent off-label use as a mood stabilizer. Now this cheap and widely used compound is being retailored as a possible neuroprotective agent for Alzheimer disease (AD).

That effort may get a boost from a new study looking at valproic acid for dementia in HIV-infected people. In a small, placebo-controlled pilot trial, Giovanni Schifitto, Harris Gelbard, and colleagues at the University of Rochester Medical Center, New York, and the University of Nebraska Medical Center in Omaha report a trend toward improved cognitive performance and normalization of brain metabolism after valproate treatment of impaired, HIV-positive subjects. The results, appearing online this month in Neurology, may give hope to researchers who are midway through a larger trial to look at valproic acid in Alzheimer disease (see below).

The HIV trial enrolled 22 people, six without and 16 with cognitive impairment, who took 250 mg of valproic acid or placebo twice daily for 10 weeks. They were evaluated with neuropsychological tests and by magnetic resonance spectroscopy (MRS), which measured markers of neuronal metabolism in the brain. The treatment was well tolerated, and did not affect levels of HIV RNA or CD4 T cells.

Over the course of treatment, there were no statistically significant changes in any given cognitive measure, but the treated patients tended to show a better performance overall. MRS revealed that treatment resulted in a significant increase in the N-acetyl aspartate to creatine ratio in frontal white matter. (A decrease in the NAA/Cr ratio has been previously observed in HIV-infected people compared to non-infected controls, and may be a marker for neuronal dysfunction or death.)

In AD, valproate has been investigated for the treatment of agitation and aggressive behavior, with variable results in four placebo-controlled trials. An additional open-label study is ongoing to look for behavioral effects of the drug (see more at clinicaltrials.gov).

To assess the potential neuroprotective effects of valproate, the Alzheimer’s Disease Cooperative Study (ADCS) is recruiting patients for a Phase 3 trial that asks a slightly different question. The multicenter trial, led by Pierre Tariot, now at Banner Alzheimer's Institute in Phoenix, Arizona, aims to enroll 300 AD patients who do not display agitation or psychosis to determine if treatment can delay the development of those behaviors (see more information at clinicaltrials.gov). The study will also track disease progression with cognitive and functional measures. Tariot and coworkers recently published the results of a pilot dosing trial for the study (Profenno et al., 2005).

How might valproate work to protect neurons? The compound inhibits GSK3β activation by apoptotic stimuli. In viral infection or AD, valproate may reduce ER stress caused by misfolded proteins and promote cell survival (Kim et al., 2005). Inhibition of GSK3β could also reduce phospho-tau pathology, leading to a protective effect on neurons. Treatment with HIV protease cocktails, as well as intractable epilepsy, both lead to amyloid pathology (Achim et al., 2005 and Gouras et al. 1997), and perhaps valproate intervenes to prevent that. One report shows that valproate enhances neurogenesis in rats (Hao et al., 2004). Even this old faithful apparently still carries some secrets up its sleeve.—Pat McCaffrey

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  1. 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.

    References:

    . 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. PubMed.

    . Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1567-77. PubMed.

    View all comments by Pierre Tariot

References

Paper Citations

  1. . A randomized, double-blind, placebo-controlled pilot trial of safety and tolerability of two doses of divalproex sodium in outpatients with probable Alzheimer's disease. Curr Alzheimer Res. 2005 Dec;2(5):553-8. PubMed.
  2. . Valproate protects cells from ER stress-induced lipid accumulation and apoptosis by inhibiting glycogen synthase kinase-3. J Cell Sci. 2005 Jan 1;118(Pt 1):89-99. PubMed.
  3. . Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS. 2005 Mar 4;19(4):407-11. PubMed.
  4. . Increased apolipoprotein E epsilon 4 in epilepsy with senile plaques. Ann Neurol. 1997 Mar;41(3):402-4. PubMed.
  5. . Mood stabilizer valproate promotes ERK pathway-dependent cortical neuronal growth and neurogenesis. J Neurosci. 2004 Jul 21;24(29):6590-9. PubMed.

External Citations

  1. clinicaltrials.gov
  2. clinicaltrials.gov

Further Reading

Papers

  1. . Neuroprotective properties of valproate: potential benefit for AD and tauopathies. J Mol Neurosci. 2002 Dec;19(3):303-7. PubMed.

Primary Papers

  1. . Valproic acid adjunctive therapy for HIV-associated cognitive impairment: a first report. Neurology. 2006 Mar 28;66(6):919-21. PubMed.