Lithium increases platelet serine-9 phosphorylated GSK-3ß levels in drug-free bipolar disorder during depressive episodes.

BACKGROUND: Glycogen synthase kinase-3 ß (GSK3ß) is an intracellular enzyme directly implicated in several neural processes relevant to bipolar disorder (BD) pathophysiology. GSK3ß is also an important target for lithium and antidepressants. When phosphorylated at serine-9, GSK3ß becomes inactive. Few studies evaluated serine-9 phosphorylated GSK3ß (phospho-GSK3ß) levels in BD subjects in vivo and no study has assessed it specifically in bipolar depression. Also, the effect of lithium monotherapy on GSK3ß has never been studied in humans. METHODS: In 27 patients with bipolar depression, total GSK3ß and phospho-GSK3ß were assessed in platelets by enzyme immunometric assay. Subjects were evaluated before and after 6 weeks of lithium treatment at therapeutic levels. Healthy subjects (n = 22) were used as a control group. RESULTS: No differences in phospho-GSK3ß or total GSK3ß were observed when comparing drug-free BD subjects in depression and healthy controls. Baseline HAM-D scores were not correlated with phospho-GSK3ß and total GSK3ß levels. From baseline to endpoint, lithium treatment inactivated GSK3ß by significantly increasing phospho-GSK3ß levels (p = 0.010). Clinical improvement (baseline HAM-D - endpoint HAM-D) negatively correlated with the increase in phospho-GSK3ß (p = 0.03). CONCLUSION: The present results show that lithium inactivates platelet GSK3ß in BD during mood episodes. No direct association with pathophysiology of BD was observed. Further studies are needed to clarify the role of GSK3ß as a key biomarker in BD and its association with treatment response as well as the relevance of GSK3ß in other neuropsychiatric disorders and as a new therapeutic target per se.