This study tested if sodium valproate or lithium, two agents used to treat bipolar mood disorder, altered the regulatory phosphorylations of Akt or glycogen synthase kinase-3beta (GSK3beta) in human neuroblastoma SH-SY5Y cells. Treatment with sodium valproate caused a gradual but relatively large increase in the activation-associated phosphorylation of Akt on Ser-473, and a similarly gradual but more modest increase in the inhibition-associated phosphorylation of GSK3beta on Ser-9. Two other inhibitors of histone deacetylase, a recently identified target of sodium valproate, also caused gradual increases in the phosphorylation of Akt and GSK3beta. Lithium treatment increased the Ser-9 phosphorylation of GSK3beta both in cells and in mouse brain after chronic administration, but did not alter the phosphorylation of Akt. These results identify novel effects of sodium valproate on the Akt/GSK3beta signaling pathway, indicating that histone deacetylase inhibition is linked to activation of Akt, and show that two anti-bipolar agents have a common action, the increased inhibitory phosphorylation of Ser-9-GSK3beta. The latter finding, along with previous reports that lithium directly inhibits GSK3beta, reveals the possibly unique situation where a single target, GSK3beta, is inhibited by two independent mechanisms, directly and by phosphorylation following lithium administration, and further, that two mood stabilizers have inhibitory effects on GSK3beta.