Glycogen synthase kinase-3: A new therapeutic target in mood disorders

Abstract

Mood disorders, including major depressive disorder and bipolar disorder, are common and largely inadequately treated. Additionally, little is known about their etiologies. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase, interacting with many signaling pathways. In 1996, lithium was found to inhibit GSK-3 and this discovery led us to the possibility that impaired GSK-3 inhibition is related with mood disorders. In time, animal and human studies encouraged this finding. Evidence is reviewed that depression may be associated with impaired inhibitory control of GSK-3, and mania with hyperstimulation of GSK-3. Mood disorders may result in part from impairments in mechanisms controlling the activity of GSK-3 or GSK-3-regulated functions and substantial evidence supports the conclusion that bolstering the modulatory control of GSK-3 is an important component of the therapeutic actions of drugs used to treat mood disorders and that GSK-3 is a valid target for developing new therapeutic interventions. Future research should identify the causes of dysregulation of GSK-3 in mood disorders and the actions of GSK-3 that contribute to these diseases.