Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

Mol Psychiatry. 2003 Feb;8(2):135-44. doi: 10.1038/


The clinical efficacy of lithium in the prophylaxis of recurrent affective episodes in bipolar disorder is characterized by a lag in onset and remains for weeks to months after discontinuation. Thus, the long-term therapeutic effect of lithium likely requires reprogramming of gene expression. Protein kinase C and glycogen synthase kinase-3 signal transduction pathways are perturbed by chronic lithium at therapeutically relevant concentrations and have been implicated in modulating synaptic function in nerve terminals. These signaling pathways offer an opportunity to model critical signals for altering gene expression programs that underlie adaptive responses of neurons to long-term lithium exposure. While the precise physiological events critical for the clinical efficacy of lithium remain unknown, we propose that linking lithium-responsive genes as a regulatory network will provide a strategy to identify signature gene expression patterns that distinguish between therapeutic and nontherapeutic actions of lithium.

Publication types

  • Review

MeSH terms

  • Antimanic Agents / therapeutic use*
  • Bipolar Disorder / drug therapy*
  • Bipolar Disorder / genetics
  • Bipolar Disorder / physiopathology*
  • Calcium-Binding Proteins
  • Gene Expression / drug effects
  • Glucosidases
  • Glycogen Synthase Kinase 3 / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins*
  • Lithium / therapeutic use*
  • Membrane Proteins*
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Phosphoproteins / metabolism
  • Protein Kinase C / metabolism
  • Signal Transduction / drug effects*


  • Antimanic Agents
  • Calcium-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Phosphoproteins
  • Myristoylated Alanine-Rich C Kinase Substrate
  • Lithium
  • Protein Kinase C
  • Glycogen Synthase Kinase 3
  • Glucosidases
  • PRKCSH protein, human