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Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers

  • Husseini K. Manji (a1), Gregory J. Moore (a1) and Guang Chen (a1)

New research is dramatically altering our understanding of the molecular mechanisms underlying neuronal communication.


To elucidate the molecular mechanisms underlying the therapeutic effects of mood stabilisers.


Results from integrated clinical and laboratory studies are reviewed.


Chronic administration of lithium and valproate produced a striking reduction in protein kinase C (PKC) isozymes in rat frontal cortex and hippocampus. In a small study, tamoxifen (also a PKC inhibitor) had marked antimanic efficacy. Both lithium and valproate regulate the DNA binding activity of the activator protein 1 family of transcription factors. Using mRNA differential display, it was also shown that chronic administration of lithium and valproate modulates expression of several genes. An exciting finding is that of a robust elevation in the levels of the cytoprotective protein, bcl-2.


The results suggest that regulation of signalling pathways may play a major part in the long-term actions of mood stabilisers. Additionally, mood stabilisers may exert underappreciated neuroprotective effects.

Corresponding author
Dr Husseini K. Manji, Director, Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bld 49, Room BIEE16, 49 Convent Drive, MSC 4405, Bethesda, MD 20892, USA. Tel: + 1 301 496 0373; fax + 1 301 480 0123; e-mail:
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Declaration of interest

Support from the National Institute of Mental Health, The Stanley Foundation, NARSAD and the Joseph Young Sr Foundation.

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Bipolar disorder: leads from the molecular and cellular mechanisms of action of mood stabilisers

  • Husseini K. Manji (a1), Gregory J. Moore (a1) and Guang Chen (a1)
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