VIENNA — Valproate treatment over 2 years does nothing to delay the onset of agitation or psychosis in patients with Alzheimer's disease, and patients taking the anticonvulsant showed significantly more brain volume loss on MRI at year 1 than did those taking placebo, based on the results of a randomized trial.
But because the changes in brain volume did not correlate with any clinical differences between the groups, it's difficult to know just what to make of the observed volume loss, Dr. Pierre Tariot said at the International Conference on Alzheimer's Disease.
“Interpretation of these results really isn't possible at this juncture,” said Dr. Tariot of the Banner Alzheimer's Institute, Phoenix, in an interview. “It could theoretically represent damage to the brain, but that seems unlikely due to the absence of correlation with clinical decline that is seen in natural history studies. There are case reports of 'pseudoatrophy' associated with valproate use, which may be relevant here. We have an ongoing analysis, and the full details will be presented at a later time.”
The trial randomized 313 patients with mild-moderate Alzheimer's disease who lacked agitation or psychosis at baseline to either placebo or an extended-release form of divalproex sodium (Depakote ER) at a dose of 10-12 mg/kg per day. The primary outcome was time until the emergence of agitation and/or psychosis. The symptoms had to last at least 2 weeks, and had to be clinically significant in the opinion of the site physician.
MRI of the brain was performed on a subset of 90 patients at baseline and 1 year.
The patients' mean age was 75 years; their mean Mini Mental State Exam at baseline was 17 and the mean Neuropsychiatric Inventory score was 3. Most of the patients (70%) were positive for the high-risk apolipoprotein E e4 allele.
There were no between-group differences in time to agitation or psychosis. In fact, although the study assumed an incidence of 50% by the end of the trial, only 17% of the entire cohort developed either of these symptoms, said Dr. Tariot, who received consulting fees and research funding from Abbott Laboratories, which manufactures Depakote ER. Abbott supplied the drugs for the trial and funded the MRI portion of the trial.
There also were no between-group differences in any of the secondary end points, confirming that valproate confers no clinically discernible neuroprotective benefit. Patients taking placebo had a slightly better score on the Alzheimer's Disease Cooperative Study activities of daily living at 24 months, Dr. Tariot said, but that difference did not reach significance after adjustment for multiple comparisons.
Consistent with known effects of the medication, patients taking valproate had significantly more central nervous system side effects (gait disturbance, tremor, and sedation), and gastrointestinal side effects (abdominal pain, loose stool).
In the MRI substudy, total brain volume and bilateral hippocampal volume were significantly decreased in the valproate group, compared with placebo, while ventricular volume was significantly increased in the active treatment group, compared with the placebo group. However, Dr. Tariot noted, there were no differences in clinical outcomes between these two subgroups.
The conference was sponsored by the Alzheimer's Association.
Valproate appeared to reduce brain volume, but this difference did not correlate with clinical outcomes.
Source Dr. Tariot