Glycogen synthase kinase (GSK)-3β, an important component of the Wnt signaling pathway, is involved in numerous cellular functions. That GSK-3β may be involved in the pathophysiology of bipolar (BP) illness is based on the observation that lithium, a mood-stabilizing drug, inhibits GSK-3β both in vitro and in vivo.We determined the protein expression of GSK-3β in the cytosol and membrane fractions of the platelets obtained from patients with major depressive disorder (MDD) and BP illness, before treatment and after treatment with antidepressants or mood-stabilizing drugs, respectively. Protein expression was determined using the Western blot technique.We observed that the protein expression of GSK-3β was significantly reduced in the membrane and cytosol fractions of platelets from drug-free patients with BP illness, but not from the drug-free patients with MDD, compared with normal control subjects. Treatment with mood-stabilizing drugs significantly increased the protein expression of GSK-3β in the membrane and cytosol fractions of platelets from BP patients compared with pre-treatment levels, and the post-treatment levels were similar to those observed in normal control subjects. On the other hand, there was no significant effect of treatment with antidepressants on GSK-3β protein expression either in the membrane or in the cytosol fractions of platelets from MDD patients.These results suggest that GSK-3β may play an important role in the pathophysiology of BP illness but not MDD and that its abnormality may be corrected by treatment with mood-stabilizing drugs, suggesting that GSK-3β may be a state rather than a trait marker for BP illness. © 2009 Elsevier Ltd.