Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling

Pharmacogenomics J. 2012 Aug;12(4):328-41. doi: 10.1038/tpj.2011.9. Epub 2011 Mar 8.


The overall neurobiological mechanisms by which lithium and valproate stabilize mood in bipolar disorder patients have yet to be fully defined. The therapeutic efficacy and dissimilar chemical structures of these medications suggest that they perturb both shared and disparate cellular processes. To investigate key pathways and functional clusters involved in the global action of lithium and valproate, we generated interaction networks formed by well-supported drug targets. Striking functional similarities emerged. Intersecting nodes in lithium and valproate networks highlighted a strong enrichment of apoptosis clusters and neurotrophin signaling. Other enriched pathways included MAPK, ErbB, insulin, VEGF, Wnt and long-term potentiation indicating a widespread effect of both drugs on diverse signaling systems. MAPK1/3 and AKT1/2 were the most preponderant nodes across pathways suggesting a central role in mediating pathway interactions. The convergence of biological responses unveils a functional signature for lithium and valproate that could be key modulators of their therapeutic efficacy.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Bipolar Disorder / drug therapy*
  • Humans
  • Intercellular Signaling Peptides and Proteins / therapeutic use
  • Lithium Compounds / therapeutic use*
  • Mice
  • Nerve Growth Factors / drug effects*
  • Phosphoric Monoester Hydrolases / drug effects
  • Proto-Oncogene Proteins c-akt / drug effects
  • Rats
  • Signal Transduction / drug effects
  • Transcriptome / drug effects
  • Valproic Acid / therapeutic use*


  • Intercellular Signaling Peptides and Proteins
  • Lithium Compounds
  • Nerve Growth Factors
  • Valproic Acid
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • myo-inositol-1 (or 4)-monophosphatase