Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs

Neuropsychopharmacology. 2005 Jul;30(7):1223-37. doi: 10.1038/sj.npp.1300731.


Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Antidepressive Agents / therapeutic use
  • Antipsychotic Agents / pharmacology
  • Antipsychotic Agents / therapeutic use
  • Circadian Rhythm / physiology
  • Disease Models, Animal
  • Electroconvulsive Therapy / adverse effects
  • Electroconvulsive Therapy / methods
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / physiology*
  • Humans
  • Lithium / pharmacology
  • Lithium / therapeutic use*
  • Models, Biological
  • Mood Disorders / drug therapy*
  • Mood Disorders / enzymology
  • Mood Disorders / genetics
  • Neurotransmitter Agents / metabolism
  • Signal Transduction / physiology
  • Valproic Acid / pharmacology
  • Valproic Acid / therapeutic use


  • Antidepressive Agents
  • Antipsychotic Agents
  • Enzyme Inhibitors
  • Neurotransmitter Agents
  • Valproic Acid
  • Lithium
  • Glycogen Synthase Kinase 3