Glycogen synthase kinase-3: a target for novel bipolar disorder treatments

The enzyme glycogen synthase kinase-3 (GSK-3) is a direct target of lithium. While originally recognized as an important molecule in a limited number of cellular processes, with unclear significance for the treatment of bipolar disorder, recent evidence suggests it has critically important cellular functions in the adult brain. GSK-3 has an essential role in a number of signaling pathways and regulates the function of a diverse number of proteins, notably transcription factors and cytoskeletal elements. The most important functions of the enzyme in regard to bipolar disorder may be critical effects on cellular resilience and neuronal plasticity. There is tremendous interest in GSK-3 inhibitors as novel therapeutic agents, and selective, small-molecule compounds are rapidly being developed for a broad range of other maladies including diabetes, Alzheimer's disease, stroke, and inflammatory conditions. In this perspectives article, we provide an overview of the molecular targets of lithium, focusing on GSK-3-regulated signaling pathways and the important functions of GSK-3 that may have relevance for the treatment of bipolar disorder. We conclude with a discussion of the GSK-3 inhibitors furthest in development and the clinical trials that may emerge.