This RCT conducted at 46 sites in the US, examined if treatment with divalproex sodium (valproate) could delay or prevent the emergence of agitation or psychosis in Alzheimer disease.

A total of 313 individuals with moderate Alzheimer disease who had not yet experienced agitation or psychosis were included in the study. They were randomised to valproate treatment at a target dose of 10 to 12 mg.kg/d or matching placebo for 24 months followed by a 2-month period of single-blind placebo treatment. The main outcome measure was time to emergence of clinically significant agitation or psychosis.

Overall, 122 subjects (59 valproate and 63 placebo) completed 24 months of treatment while taking study medication; 42 (27 valproate and 15 placebo) reached 24 months having discontinued study medication; 150 reached month 26. The following findings were reported:

• There was no difference between groups in time to emergence of agitation or psychosis (p=0.88) or in change on any secondary outcome.

• The valproate group had higher rates of somnolence, gait disturbance, tremor, diarrhoea, and weakness.

• 88 participants underwent MRI scans at baseline and 12 months: the valproate group showed greater loss in hippocampal and whole-brain volume, accompanied by greater ventricular expansion (p < 0.001).

This study concluded that valproate did not delay emergence of agitation or psychosis or slow cognitive or functional decline in patients with moderate Alzheimer disease and was associated with significant toxic effects