“The results of this trial, along with inconclusive results of preliminary trials as well as subsequent negative findings from a large trial, should discourage prophylactic or symptomatic use of valproate in dementia,” the researchers conclude in their report in the Archives of General Psychiatry for August.
Dr. Pierre N. Tariot, with the Banner Alzheimer’s Institute in Phoenix, Arizona, and colleagues note the great burden of psychosis and agitation in patients with Alzheimer’s disease. While treatments have been largely ineffectual, there was some evidence that divalproex sodium might prevent or slow the development of these behavioral disturbances.
To investigate, the team conducted a randomized double-blind trial in 313 Alzheimer’s patients who had not developed agitation or psychosis. They were randomized to placebo or valproate treatment at a target dose of 10-12 mg/kg per day for 24 months. Ultimately, 122 participants completed 24 months on study medication.
The primary endpoint was a score of 3 or more on at least one of the Neuropsychiatric Inventory (NPI) items assessing delusions, hallucinations, and agitation/aggression. This was reached by 29 patients receiving placebo compared with 25 given valproate (hazard ratio 0.96, p=0.88), the researchers found.
Furthermore, the change in Alzheimer Disease Assessment Scale–cognitive subscale scores at 12 months favored placebo treatment, according to the report.
In addition, participants on valproate were more likely than those given placebo to experience somnolence, gait disturbance, tremor, diarrhea, constipation, weakness, asthenia, and dyspnea, Dr. Tariot and colleagues report.
Despite these negative results, they conclude: “Given the public health significance of the behavioral features of dementia and the limited safety and efficacy of available psychotropic agents, it is still appropriate to pursue the goal of secondary prevention of agitation and psychosis. Other agents may merit investigation with this type of trial design.”
Arch Gen Psychiatry. 2011;68:853-861.