Valproate (Depakote, divalproex, valproic acid), another small molecule FDA-approved mood stabilizer and anti-epileptic, was also found to inhibit GSK3β, [48] and, in amyloid transgenic mice, it rescued behavioral deficits [49]. However, in a Phase 3 study involving 313 patients with probable AD, treatment with valproate for 24 months resulted in accelerated brain atrophy and cognitive impairment [50], with significant toxic effects, and no effect on agitation or psychosis [51]. A later Phase 2 study in 28 patients with PSP showed no difference in disease progression, with possible worsening on measures of gait, suggesting valproate was poorly tolerated and inefficacious in this population [52]. Due to these negative results, valproate is no longer in clinical development for treatment of tauopathies, and available evidence recommends against its use. It should be noted that both lithium and valproate are non-specific for GSK3β, and thus observed toxicity may be due to off-target effects, and it is also possible that GSK3β was not inhibited to the extent that would be predicted to have a significant effect on tau phosphorylation and therefore a clinically meaningful effect.
