A common mechanism of action for three mood-stabilizing drugs


Lithium, carbamazepine and valproic acid are effective mood-stabilizing treatments for bipolar affective disorder. The molecular mechanisms underlying the actions of these drugs and the illness itself are unknown. Berridge and colleagues1 suggested that inositol depletion may be the way that lithium works in bipolar affective disorder, but others have suggested that glycogen synthase kinase2,3 (GSK3) may be the relevant target. The action of valproic acid has been linked to both inositol depletion4,5 and to inhibition of histone deacetylase6 (HDAC). We show here that all three drugs inhibit the collapse of sensory neuron growth cones and increase growth cone area. These effects do not depend on GSK3 or HDAC inhibition. Inositol, however, reverses the effects of the drugs on growth cones, thus implicating inositol depletion in their action. Moreover, the development of Dictyostelium is sensitive to lithium7 and to valproic acid, but resistance to both is conferred by deletion of the gene that codes for prolyl oligopeptidase, which also regulates inositol metabolism. Inhibitors of prolyl oligopeptidase reverse the effects of all three drugs on sensory neuron growth cone area and collapse. These results suggest a molecular basis for both bipolar affective disorder and its treatment.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Structural changes in sensory neuron axons following treatment with mood-stabilizing drugs.
Figure 2: Inositol reverses the effects of mood-stabilizing drugs on growth cone collapse and spread area.
Figure 3: VPA effects on Dictyostelium aggregation are due to modulation of InsP3 signalling.
Figure 4: Inhibitors of prolyl oligopeptidase enzyme activity block the action of mood-stabilizing drugs on growth cone collapse and spread area.


  1. 1

    Berridge, M. J., Downes, C. P. & Hanley, M. R. Neural and developmental actions of lithium: a unifying hypothesis. Cell 59, 411–419 (1989)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2

    Klein, P. S. & Melton, D. A. A molecular mechanism for the effect of lithium on development. Proc. Natl Acad. Sci. USA 93, 8455–8459 (1996)

    ADS  CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3

    Lucas, F. R. & Salinas, P. C. WNT-7a induces axonal remodeling and increases synapsin I levels in cerebellar neurons. Dev. Biol. 192, 31–44 (1997)

    CAS  Article  PubMed  Google Scholar 

  4. 4

    O'Donnell, T. et al. Chronic lithium and sodium valproate both decrease the concentration of myo-inositol and increase the concentration of inositol monophosphates in rat brain. Brain Res. 880, 84–91 (2000)

    CAS  Article  PubMed  Google Scholar 

  5. 5

    Vaden, D. L., Ding, D., Peterson, B. & Greenberg, M. L. Lithium and valproate decrease inositol mass and increase expression of the yeast ino1 and ino2 genes for inositol biosynthesis. J. Biol. Chem. 276, 15466–15471 (2001)

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Phiel, C. J. et al. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. J. Biol. Chem. 276, 36734–36741 (2001)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7

    Williams, R. S., Eames, M., Ryves, W. J., Viggars, J. & Harwood, A. J. Loss of a prolyl oligopeptidase confers resistance to lithium by elevation of inositol (1,4,5) trisphosphate. EMBO J. 18, 2734–2745 (1999)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  8. 8

    Kerwin, R. The Bethlem and Maudsley NHS Trust Prescribing Guidlines (Duntiz, London, 1999)

    Google Scholar 

  9. 9

    Hall, A. C., Lucas, F. R. & Salinas, P. C. Axonal remodeling and synaptic differentiation in the cerebellum is regulated by WNT-7a signaling. Cell 100, 525–535 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10

    Goold, R. G., Owen, R. & Gordon-Weeks, P. R. Glycogen synthase kinase 3beta phosphorylation of microtubule-associated protein 1B regulates the stability of microtubules in growth cones. J. Cell Sci. 112, 3373–3384 (1999)

    CAS  PubMed  Google Scholar 

  11. 11

    Takei, Y., Teng, J., Harada, A. & Hirokawa, N. Defects in axonal elongation and neuronal migration in mice with disrupted tau and map1b genes. J. Cell. Biol. 150, 989–1000 (2000)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12

    Stambolic, V., Ruel, L. & Woodgett, J. R. Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6, 1664–1668 (1996)

    CAS  Article  Google Scholar 

  13. 13

    Yost, C. et al. The axis-inducing activity, stability, and subcellular distribution of beta-catenin is regulated in Xenopus embryos by glycogen synthase kinase 3. Genes Dev. 10, 1443–1454 (1996)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14

    Tillner, J., Nau, H., Winckler, T. & Dingermann, T. Evaluation of the teratogenic potential of valproic acid analogues in transgenic Dictyostelium discoideum strains. Toxicol. Vitro 12, 463–469 (1998)

    CAS  Article  Google Scholar 

  15. 15

    Maes, M. et al. Lower serum prolyl endopeptidase enzyme activity in major depression: further evidence that peptidases play a role in the pathophysiology of depression. Biol. Psychiatry 35, 545–552 (1994)

    CAS  Article  PubMed  Google Scholar 

  16. 16

    Maes, M. et al. Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs. Psychiatry Res. 58, 217–225 (1995)

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Augustyns, K. et al. Synthesis of peptidyl acetals as inhibitors or prolyl endopeptidase. Bioorg. Medicinal Chem. Lett. 5, 1265–1270 (1995)

    CAS  Article  Google Scholar 

  18. 18

    Demuth, H. U. et al. Design of (omega-N-(O-acyl)hydroxy amid) aminodicarboxylic acid pyrrolidides as potent inhibitors of proline-specific peptidases. FEBS Lett. 320, 23–27 (1993)

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Cheng, L. & Mudge, A. W. Cultured Schwann cells constitutively express the myelin protein P0. Neuron 16, 309–319 (1996)

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Cramer, L. P., Siebert, M. & Mitchison, T. J. Identification of novel graded polarity actin filament bundles in locomoting heart fibroblasts: implications for the generation of motile force. J. Cell Biol. 136, 1287–1305 (1997)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  21. 21

    Kypta, R. M., Su, H. & Reichardt, L. F. Association between a transmembrane protein tyrosine phosphatase and the cadherin-catenin complex. J. Cell Biol. 134, 1519–1529 (1996)

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Harwood, A. J., Plyte, S. E., Woodgett, J., Strutt, H. & Kay, R. R. Glycogen synthase kinase 3 regulates cell fate in Dictyostelium. Cell 80, 139–148 (1995)

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23

    Sambrook, J., Fritsch, E. F. & Maniatis, T. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Press, 1989)

    Google Scholar 

Download references


This study was an equal collaboration between the Harwood and Mudge research groups, and the paper was co-written by A.W.M. and A.J.H. The neuron experiments were carried out by L.C., and Dictyostelium experiments by R.S.B.W. and A.J.H. The neuron analysis was designed by A.W.M., and carried out by R.S.B.W. and A.W.M. The work was supported by both MRC (L.C., A.W.M.) and Wellcome Trust funding (A.J.H. and R.S.B.W.). We thank L. Cramer for discussions. We also thank M. Shipman and B. Mudge for help with microscopy and graphics, respectively.

Author information



Corresponding author

Correspondence to Anne W. Mudge.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Williams, R., Cheng, L., Mudge, A. et al. A common mechanism of action for three mood-stabilizing drugs. Nature 417, 292–295 (2002). https://doi.org/10.1038/417292a

Download citation

Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.


Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing