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Is mood chemistry?

Abstract

The chemical hypothesis of depression suggests that mood disorders are caused by a chemical imbalance in the brain, which can be corrected by antidepressant drugs. However, recent evidence indicates that problems in information processing within neural networks, rather than changes in chemical balance, might underlie depression, and that antidepressant drugs induce plastic changes in neuronal connectivity, which gradually lead to improvements in neuronal information processing and recovery of mood.

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Figure 1: Monoamine hypothesis of mood disorders.
Figure 2: The chemical hypothesis of depression.
Figure 3: The network hypothesis of depression.
Figure 4: A combinatorial approach for treating depression based on the network hypothesis.

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References

  1. Bunney, W. E. Jr & Davis, J. M. Norepinephrine in depressive reactions. A review. Arch. Gen. Psychiatry 13, 483–494 (1965).

    Article  CAS  Google Scholar 

  2. Coppen, A. The biochemistry of affective disorders. Br. J. Psychiatry 113, 1237–1264 (1967).

    Article  CAS  Google Scholar 

  3. Schildkraut, J. J. The catecholamine hypothesis of affective disorders: a review of supporting evidence. Am. J. Psychiatry 122, 509–522 (1965).

    Article  CAS  Google Scholar 

  4. Wong, M. L. & Licinio, J. From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nature Rev. Drug Disc. 3, 136–150 (2004).

    Article  CAS  Google Scholar 

  5. Nestler, E. J. et al. Neurobiology of depression. Neuron 34, 13–25 (2002).

    Article  CAS  Google Scholar 

  6. Manji, H. K., Drevets, W. C. & Charney, D. S. The cellular neurobiology of depression. Nature Med. 7, 541–547 (2001).

    Article  CAS  Google Scholar 

  7. Coyle, J. T. & Duman, R. S. Finding the intracellular signaling pathways affected by mood disorder treatments. Neuron 38, 157–160 (2003).

    Article  CAS  Google Scholar 

  8. Kennedy, J. L., Farrer, L. A., Andreasen, N. C., Mayeux, R. & George-Hyslop, P. The genetics of adult-onset neuropsychiatric disease: complexities and conundra? Science 302, 822–826 (2003).

    Article  CAS  Google Scholar 

  9. Healy, D. The Antidepressant Era (Harvard Univ. Press, Cambridge, Massachusetts, 1997).

    Google Scholar 

  10. Duman, R. S. & Vaidya, V. A. Molecular and cellular actions of chronic electroconvulsive seizures. J. ECT 14, 181–193 (1998).

    Article  CAS  Google Scholar 

  11. Nestler, E. J. Antidepressant treatments in the 21st century. Biol. Psychiatry 44, 526–533 (1998).

    Article  CAS  Google Scholar 

  12. Delgado, P. L. How antidepressants help depression: mechanisms of action and clinical response. J. Clin. Psychiatry 65 Suppl. 4, 25–30 (2004).

    CAS  PubMed  Google Scholar 

  13. Booij, L., Van der Does, A. J. & Riedel, W. J. Monoamine depletion in psychiatric and healthy populations: review. Mol. Psychiatry 8, 951–973 (2003).

    Article  CAS  Google Scholar 

  14. Sulser, F., Vetulani, J. & Mobley, P. L. Mode of action of antidepressant drugs. Biochem. Pharmacol. 27, 257–261 (1978).

    Article  CAS  Google Scholar 

  15. Duman, R. S., Heninger, G. R. & Nestler, E. J. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54, 597–606 (1997).

    Article  CAS  Google Scholar 

  16. Knuuttila, J. E., Toronen, P. & Castrén, E. Effects of antidepressant drug imipramine on gene expression in rat prefrontal cortex. Neurochem. Res. 29, 1235–1244 (2004).

    Article  CAS  Google Scholar 

  17. Newton, S. S. et al. Gene profile of electroconvulsive seizures: induction of neurotrophic and angiogenic factors. J. Neurosci. 23, 10841–10851 (2003).

    Article  CAS  Google Scholar 

  18. Carlsson, A. A half-century of neurotransmitter research: impact on neurology and psychiatry. Nobel lecture. Nobelprize.org, <http://www.nobel.se/medicine/laureates/2000/carlsson-lecture.pdf> (2000).

  19. Buzsaki, G. Large-scale recording of neuronal ensembles. Nature Neurosci. 7, 446–451 (2004).

    Article  CAS  Google Scholar 

  20. Hua, J. Y. & Smith, S. J. Neural activity and the dynamics of central nervous system development. Nature Neurosci. 7, 327–332 (2004).

    Article  CAS  Google Scholar 

  21. Katz, L. C. & Shatz, C. J. Synaptic activity and the construction of cortical circuits. Science 274, 1133–1138 (1996).

    Article  CAS  Google Scholar 

  22. Varela, F., Lachaux, J. P., Rodriguez, E. & Martinerie, J. The brainweb: phase synchronization and large-scale integration. Nature Rev. Neurosci. 2, 229–239 (2001).

    Article  CAS  Google Scholar 

  23. Gaspar, P., Cases, O. & Maroteaux, L. The developmental role of serotonin: news from mouse molecular genetics. Nature Rev. Neurosci. 4, 1002–1012 (2003).

    Article  CAS  Google Scholar 

  24. Gross, C. et al. Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult. Nature 416, 396–400 (2002).

    Article  CAS  Google Scholar 

  25. Brunner, H. G., Nelen, M., Breakefield, X. O., Ropers, H. H. & van Oost, B. A. Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262, 578–580 (1993).

    Article  CAS  Google Scholar 

  26. Cases, O. et al. Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268, 1763–1766 (1995).

    Article  CAS  Google Scholar 

  27. Cases, O. et al. Lack of barrels in the somatosensory cortex of monoamine oxidase A-deficient mice: role of a serotonin excess during the critical period. Neuron 16, 297–307 (1996).

    Article  CAS  Google Scholar 

  28. Xu, Y., Sari, Y. & Zhou, F. C. Selective serotonin reuptake inhibitor disrupts organization of thalamocortical somatosensory barrels during development. Dev. Brain Res. 150, 151–161 (2004).

    Article  CAS  Google Scholar 

  29. Ansorge, M. S., Zhou, M., Lira, A., Hen, R. & Gingrich, J. A. Early-life blockade of the 5-HT transporter alters emotional behavior in adult mice. Science 306, 879–881 (2004).

    Article  CAS  Google Scholar 

  30. Feng, P., Ma, Y. & Vogel, G. W. The critical window of brain development from susceptive to insusceptive. Effects of clomipramine neonatal treatment on sexual behavior. Brain Res. Dev. Brain Res. 129, 107–110 (2001).

    Article  CAS  Google Scholar 

  31. Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during sensory development. Curr. Opin. Neurobiol. 10, 138–145 (2000).

    Article  CAS  Google Scholar 

  32. Bremner, J. D. et al. Reduced volume of orbitofrontal cortex in major depression. Biol. Psychiatry 51, 273–279 (2002).

    Article  Google Scholar 

  33. Botteron, K. N., Raichle, M. E., Drevets, W. C., Heath, A. C. & Todd, R. D. Volumetric reduction in left subgenual prefrontal cortex in early onset depression. Biol. Psychiatry 51, 342–344 (2002).

    Article  Google Scholar 

  34. Drevets, W. C. Neuroimaging and neuropathological studies of depression: implications for the cognitive–emotional features of mood disorders. Curr. Opin. Neurobiol. 11, 240–249 (2001).

    Article  CAS  Google Scholar 

  35. MacQueen, G. M. et al. Course of illness, hippocampal function, and hippocampal volume in major depression. Proc. Natl Acad. Sci. USA 100, 1387–1392 (2003).

    Article  CAS  Google Scholar 

  36. Sheline, Y. I., Gado, M. H. & Kraemer, H. C. Untreated depression and hippocampal volume loss. Am. J. Psychiatry 160, 1516–1518 (2003).

    Article  Google Scholar 

  37. Sheline, Y. I. Neuroimaging studies of mood disorder effects on the brain. Biol. Psychiatry 54, 338–352 (2003).

    Article  Google Scholar 

  38. Frodl, T. et al. Hippocampal changes in patients with a first episode of major depression. Am. J. Psychiatry 159, 1112–1118 (2002).

    Article  Google Scholar 

  39. Mervaala, E. et al. Quantitative MRI of the hippocampus and amygdala in severe depression. Psychol. Med. 30, 117–125 (2000).

    Article  CAS  Google Scholar 

  40. Drevets, W. C., Bogers, W. & Raichle, M. E. Functional anatomical correlates of antidepressant drug treatment assessed using PET measures of regional glucose metabolism. Eur. Neuropsychopharmacol. 12, 527–544 (2002).

    Article  CAS  Google Scholar 

  41. Vythilingam, M. et al. Childhood trauma associated with smaller hippocampal volume in women with major depression. Am. J. Psychiatry 159, 2072–2080 (2002).

    Article  Google Scholar 

  42. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus. J. Neurosci. 20, 9104–9110 (2000).

    Article  CAS  Google Scholar 

  43. Santarelli, L. et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science 301, 805–809 (2003).

    Article  CAS  Google Scholar 

  44. van Praag, H. et al. Functional neurogenesis in the adult hippocampus. Nature 415, 1030–1034 (2002).

    Article  CAS  Google Scholar 

  45. Sairanen, M., Lucas, G., Ernfors, P., Castrén, M. & Castrén, E. BDNF and antidepressant drugs have different but coordinated effects on neuronal turnover, proliferation and survival in the adult dentate gyrus. J. Neurosci. 25, 1089–1094 (2005).

    Article  CAS  Google Scholar 

  46. Vaidya, V. A., Siuciak, J. A., Du, F. & Duman, R. S. Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures. Neuroscience 89, 157–166 (1999).

    Article  CAS  Google Scholar 

  47. Fujioka, T., Fujioka, A. & Duman, R. S. Activation of cAMP signaling facilitates the morphological maturation of newborn neurons in adult hippocampus. J. Neurosci. 24, 319–328 (2004).

    Article  CAS  Google Scholar 

  48. Altar, C. A. Neurotrophins and depression. Trends Pharmacol. Sci. 20, 59–61 (1999).

    Article  CAS  Google Scholar 

  49. Castrén, E. Neurotrophic effects of antidepressant drugs. Curr. Opin. Pharmacol. 4, 58–64 (2004).

    Article  Google Scholar 

  50. Thoenen, H. Neurotrophins and neuronal plasticity. Science 270, 593–598 (1995).

    Article  CAS  Google Scholar 

  51. Poo, M. M. Neurotrophins as synaptic modulators. Nature Rev. Neurosci. 2, 24–32 (2001).

    Article  CAS  Google Scholar 

  52. Nibuya, M., Morinobu, S. & Duman, R. S. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J. Neurosci. 15, 7539–7547 (1995).

    CAS  PubMed  Google Scholar 

  53. Russo-Neustadt, A. A., Beard, R. C., Huang, Y. M. & Cotman, C. W. Physical activity and antidepressant treatment potentiate the expression of specific brain-derived neurotrophic factor transcripts in the rat hippocampus. Neuroscience 101, 305–312 (2000).

    Article  CAS  Google Scholar 

  54. Saarelainen, T. et al. Activation of the TrkB neurotrophin receptor is induced by antidepressant drugs and is required for antidepressant-induced behavioral effects. J. Neurosci. 23, 349–357 (2003).

    Article  CAS  Google Scholar 

  55. Shirayama, Y., Chen, A. C., Nakagawa, S., Russell, D. S. & Duman, R. S. Brain-derived neurotrophic factor produces antidepressant effects in behavioral models of depression. J. Neurosci. 22, 3251–3261 (2002).

    Article  CAS  Google Scholar 

  56. Siuciak, J. A., Lewis, D. R., Wiegand, S. J. & Lindsay, R. M. Antidepressant-like effect of brain-derived neurotrophic factor (BDNF). Pharmacol. Biochem. Behav. 56, 131–137 (1997).

    Article  CAS  Google Scholar 

  57. Van der Does, A. J. W. The effects of tryptophan depletion on mood and psychiatric symptoms. J. Affect. Disord. 64, 107–119 (2001).

    Article  CAS  Google Scholar 

  58. Wirz-Justice, A. & Van den Hoofdakker, R. H. Sleep deprivation in depression: what do we know, where do we go? Biol. Psychiatry 46, 445–453 (1999).

    Article  CAS  Google Scholar 

  59. Treatment for Adolescents With Depression Study Team. Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with depression: Treatment for Adolescents With Depression Study (TADS) randomized controlled trial. JAMA 292, 807–820 (2004).

  60. Wolpaw, J. R. & Tennissen, A. M. Activity-dependent spinal cord plasticity in health and disease. Annu. Rev. Neurosci. 24, 807–843 (2001).

    Article  CAS  Google Scholar 

  61. Levi-Montalcini, R. The nerve growth factor: thirty-five years later. EMBO J. 6, 1145–1154 (1987).

    Article  CAS  Google Scholar 

  62. Barde, Y. -A. Trophic factors and neuronal survival. Neuron 2, 1525–1534 (1989).

    Article  CAS  Google Scholar 

  63. Huang, E. J. & Reichardt, L. F. Neurotrophins: roles in neuronal development and function. Annu. Rev. Neurosci. 24, 677–736 (2001).

    Article  CAS  Google Scholar 

  64. Cohen-Cory, S. The developing synapse: construction and modulation of synaptic structures and circuits. Science 298, 770–776 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

I would like to thank H. Rauvala, M. Saarma, M. Castrén and R. Galuske for their comments to the manuscript, and the Sigrid Jusélius Foundation, Sohlberg Foundation and the Academy of Finland and for support.

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Castrén, E. Is mood chemistry?. Nat Rev Neurosci 6, 241–246 (2005). https://doi.org/10.1038/nrn1629

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