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

The Pharmacogenomics Journal volume 12, pages 328–341 (2012)Cite this article

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Abstract

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.

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Acknowledgements

This research was supported by the Intramural Research Program of the National Institute of Mental Health, National Institutes of Health.

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Authors and Affiliations

  1. Human Genetics Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    A Gupta, N Akula, W Corona, X-y Jiang, N Hunter, F J McMahon & S D Detera-Wadleigh

  2. Department of Psychiatry and Psychotherapy, University Medical Center, Georg-August-Universität, Göttingen, Germany

    T G Schulze

  3. Bioinformatics and Computational Biosciences Branch, Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA

    V Nagarajan

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Correspondence to S D Detera-Wadleigh.

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Gupta, A., Schulze, T., Nagarajan, V. et al. Interaction networks of lithium and valproate molecular targets reveal a striking enrichment of apoptosis functional clusters and neurotrophin signaling. Pharmacogenomics J 12, 328–341 (2012). https://doi.org/10.1038/tpj.2011.9

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  • DOI: https://doi.org/10.1038/tpj.2011.9

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