Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

From monoamines to genomic targets: a paradigm shift for drug discovery in depression

Nature Reviews Drug Discovery volume 3, pages 136–151 (2004)Cite this article

Key Points

  • Depression is one of the world's most lucrative drug targets.

  • This common and complex disorder of gene–environment interactions affects more than 10% of the world's population.

  • In spite of the public health relevance and economic importance of depression, existing drug targets are based on the old monoamine theory.

  • All available drugs bind to targets identified more than 30 years ago. The enormous progress in neuroscience, molecular biology and genomics that has occurred in the past three decades has not been translated into novel treatment strategies.

  • We have created a conceptual framework that summarizes the progress in antidepressant drug development in terms of three 'waves'.

  • The first wave of antidepressant development took place in the early post-World War II period, in a time of therapeutic revolution that constituted the birth of modern pharmacology. The first antidepressant described was initially tested for its ability to treat tuberculosis, but was found to have the remarkable side effect of increasing patients' levels of energy. Research determined that the serendipitiously discovered tricyclic antidepressants target monominergic systems.

  • The second wave of antidepressant development consisted of the development of newer drugs acting on monoaminergic systems with increasing tolerability and safety. Selective reuptake inhibitors (SRIs) have been developed to enhance the function of specific monoamine systems by increasing the availability of a monoamine as a result of blockade of presynaptic transporters, which promote reuptake, thereby increasing transmitter availability at the synaptic cleft. SRIs have the same efficacy but are better tolerated than tricyclics.

  • The third wave of antidepressant development represents a paradigm shift, consisting in turn of three parallel strategies.

  • The first of those strategies is based on drug development based on candidate systems elucidated by contemporary translational neuroscience. Those systems include neuropeptides, such as corticotripin-releasing hormone (CRH) and substance P. Emerging targets are based on the neuroimmune, neuroprotection, and neurogenesis hypotheses of depression. The role of the transcription factor, cAMP response element-binding protein (CREB), as a potential target in depression has been increasingly investigated.

  • The second strategy consists of pharmacogenomic approaches to the identification of new targets for drug development and for prediction of treatment response.

  • The last strategy is still in its conceptual phase and will be based on aetiological models and opportunities emerging from genetics. Depression susceptibility genes might be targets for drug development or could identify previously unrecognized pathways for novel therapies.

Abstract

Depression, a complex psychiatric disorder that affects ∼15% of the population, has an enormous social cost. Although the disorder is thought to be the outcome of gene–environmental interactions, the causative genes and environmental factors underlying depression remain to be identified. All the antidepressant drugs now in use — the forerunner of which was discovered serendipitously 50 years ago — modulate monoamine neurotransmission, and take six to eight weeks to exert their effects, but each drug is efficacious in only 60–70% of patients. A conceptually novel antidepressant that acted rapidly and safely in a high proportion of patients would almost certainly become the world's bestselling drug. Yet such a drug is not on the horizon. Here, we cover the different phases of antidepressant drug discovery in the past, present and future, and comment on the challenges and opportunities for antidepressant research.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Melencolia by Albrecht Durer.
Figure 2: Strategies for antidepressant drug discovery.
Figure 3: Representative examples from different classes of antidepressant drugs.
Figure 4: A testable hypothesis is that different classes of antidepressants could have a final common pathway of action.
Figure 5: Six hypothalamic transcripts are regulated by chronic treatment with imipramine or St John's Wort, but not with control treatments.

Similar content being viewed by others

References

  1. Bloch, R. G. et al. The clinical effects of isoniazid and iproniazid in the treatment of pulmonary tuberculosis. Ann. Intern. Med. 40, 881–900 (1954).

  2. Keith, S. J. & Matthews, S. M. The value of psychiatric treatment: its efficacy in severe mental disorders. Psychopharmacol. Bull. 29, 427–430 (1993).

    CAS  PubMed  Google Scholar 

  3. Moller, H. J. & Volz, H. P. Drug treatment of depression in the 1990s. An overview of achievements and future possibilities. Drugs 52, 625–638 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Blazer, D. G., Kessler, R. C., McGonagle, K. A. & Swartz, M. S. The prevalence and distribution of major depression in a national community sample: the National Comorbidity Survey. Am. J. Psychiatry 151, 979–986 (1994).

    Article  CAS  PubMed  Google Scholar 

  5. Greenberg, P. E. et al. The economic burden of depression in the United States: how did it change between 1990 and 2000? J. Clin. Psychiatry 64, 1465–1475 (2003). Estimates the economic burden of depression to have been relatively stable from 1990 to 2000. Of the total economic cost of depression in 2000 (US $83.1 billion), US $26.1 billion (31%) were direct medical costs, US $5.4 billion (7%) were suicide related mortality costs, and US $51.5 billion (62%) were workplace costs.

    Article  PubMed  Google Scholar 

  6. Pincus, H. A. & Pettit, A. R. The societal costs of chronic major depression. J. Clin. Psychiatry 62 (Suppl. 6), 5–9 (2001). Updated the estimates of the total cost of depression to exceed US $100 billion per year in 2001.

    PubMed  Google Scholar 

  7. Healy, D. The Antidepressant Era (Harvard Univ. Press, Cambridge, 1997). A detailed historical account of the discovery of the first antidepressants and the development of subsequent second-wave compounds.

    Google Scholar 

  8. Loomer, H. P., Saunders, J. C. & Kline, N. S. A Clinical and pharmacodynamic evaluation of iproniazid as a psychic energizer. Psychiatr. Res. Rep. Am. Psychiatr. Assoc. 8, 129–141 (1957).

    CAS  PubMed  Google Scholar 

  9. Kuhn, R. Uber die behandlung depressives zustande mit einem iminobenzylderivat (G 22,355). Schweiz. Med. Wochenschr. 87, 1135–1140 (1957).

    CAS  PubMed  Google Scholar 

  10. Glowinski, J., Axelrod, J., Kopin, I. J. & Wurtman, R. J. Physiological disposition of H3-norepinephrine in the developing rat. J. Pharmacol. Exp. Ther. 146, 48–53 (1964).

    CAS  PubMed  Google Scholar 

  11. Carlsson, A., Lindqvist, M. & Waldeck, B. Mechanism of release of alpha-methylated noradrenaline analogues by monoamine oxidase inhibitors. Eur. J. Pharmacol. 3, 34–39 (1968).

    Article  CAS  PubMed  Google Scholar 

  12. Broekkamp, C. L., Leysen, D., Peeters, B. W. & Pinder, R. M. Prospects for improved antidepressants. J. Med. Chem. 38, 4615–4633 (1995).

    Article  CAS  PubMed  Google Scholar 

  13. Kent, J. M. SNaRIs, NaSSAs, and NaRIs: new agents for the treatment of depression. Lancet 355, 911–918 (2000).

    Article  CAS  PubMed  Google Scholar 

  14. Anderson, I. M. SSRIS versus tricyclic antidepressants in depressed inpatients: a meta-analysis of efficacy and tolerability. Depress. Anxiety 7 (Suppl 1), 11–17 (1998).

    Article  PubMed  Google Scholar 

  15. Thase, M. E., Entsuah, A. R. & Rudolph, R. L. Remission rates during treatment with venlafaxine or selective serotonin reuptake inhibitors. Br. J. Psychiatry 178, 234–241 (2001).

    Article  CAS  PubMed  Google Scholar 

  16. Entsuah, A. R., Huang, H. & Thase, M. E. Response and remission rates in different subpopulations with major depressive disorder administered venlafaxine, selective serotonin reuptake inhibitors, or placebo. J. Clin. Psychiatry 62, 869–877 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Bymaster, F. P., McNamara, R. K. & Tran, P. V. New approaches to developing antidepressants by enhancing monoaminergic neurotransmission. Expert Opin. Investig. Drugs 12, 531–543 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Selye, H. A syndrome produced by diverse nocuous agents. Nature 138, 32 (1936). In this landmark article, Selye introduced the concept of stress into biology. Selye described common responses to various types of stressors.

    Article  Google Scholar 

  19. Chrousos, G. P. & Gold, P. W. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA 267, 1244–1252 (1992).

    Article  CAS  PubMed  Google Scholar 

  20. Gold, P. W., Wong, M. L., Chrousos, G. P. & Licinio, J. Stress system abnormalities in melancholic and atypical depression: molecular, pathophysiological, and therapeutic implications. Mol. Psychiatry 1, 257–264 (1996).

    CAS  PubMed  Google Scholar 

  21. Brady, L. S., Whitfield, H. J. Jr, Fox, R. J., Gold, P. W. & Herkenham, M. Long-term antidepressant administration alters corticotropin-releasing hormone, tyrosine hydroxylase, and mineralocorticoid receptor gene expression in rat brain. Therapeutic implications. J. Clin. Invest. 87, 831–837 (1991).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Brady, L. S., Gold, P. W., Herkenham, M., Lynn, A. B. & Whitfield, H. J. Jr. The antidepressants fluoxetine, idazoxan and phenelzine alter corticotropin-releasing hormone and tyrosine hydroxylase mRNA levels in rat brain: therapeutic implications. Brain Res. 572, 117–125 (1992).

    Article  CAS  PubMed  Google Scholar 

  23. Michelson, D. et al. Chronic imipramine is associated with diminished hypothalamic–pituitary–adrenal axis responsivity in healthy humans. J. Clin. Endocrinol. Metab. 82, 2601–2606 (1997). References 21–23 describe attenuation of hypothalamus–pituitary–adrenal axis activity as a pharmacological effect of antidepressants.

    Article  CAS  PubMed  Google Scholar 

  24. Nemeroff, C. B. et al. Elevated concentrations of CSF corticotropin-releasing-factor-like immunoreactivity in depressed patients. Science 226, 1342–1344 (1984).

    Article  CAS  PubMed  Google Scholar 

  25. Wong, M. L. et al. Pronounced and sustained central hypernoradrenergic function in major depression with melancholic features: relation to hypercortisolism and corticotropin-releasing hormone. Proc. Natl Acad. Sci. USA 97, 325–330 (2000). Documents increased activity of sympathetic systems in depression.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Gold, P. W. et al. Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. Am. J. Psychiatry 141, 619–627 (1984). References 24 and 26 show the involvement of the hypothalamus–pituitary–adrenal axis in major depression by finding inappropriately high levels of corticotropin-releasing factor in the cerebrospinal fluid for the levels of cortisol.

    Article  CAS  PubMed  Google Scholar 

  27. Gold, P. W. et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing's disease. Pathophysiologic and diagnostic implications. N. Engl. J. Med. 314, 1329–1335 (1986).

    Article  CAS  PubMed  Google Scholar 

  28. Hiroi, N. et al. Expression of corticotropin releasing hormone receptors type I and type II mRNA in suicide victims and controls. Mol. Psychiatry 6, 540–546 (2001).

    Article  CAS  PubMed  Google Scholar 

  29. Raadsheer, F. C., Hoogendijk, W. J., Stam, F. C., Tilders, F. J. & Swaab, D. F. Increased numbers of corticotropin-releasing hormone expressing neurons in the hypothalamic paraventricular nucleus of depressed patients. Neuroendocrinology 60, 436–444 (1994).

    Article  CAS  PubMed  Google Scholar 

  30. Habib, K. E. et al. Oral administration of a corticotropin-releasing hormone receptor antagonist significantly attenuates behavioral, neuroendocrine, and autonomic responses to stress in primates. Proc. Natl Acad. Sci. USA 97, 6079–6084 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Zobel, A. W. et al. Effects of the high-affinity corticotropin-releasing hormone receptor 1 antagonist R121919 in major depression: the first 20 patients treated. J. Psychiatr. Res. 34, 171–181 (2000). Reports the first indication that corticotropin-releasing hormone receptor antagonists could effectively treat depressive symptoms.

    Article  CAS  PubMed  Google Scholar 

  32. Whybrow, P. C. & Prange, A. J. Jr. A hypothesis of thyroid–catecholamine–receptor interaction. Its relevance to affective illness. Arch. Gen. Psychiatry 38, 106–113 (1981).

    Article  CAS  PubMed  Google Scholar 

  33. Gold, P. W. & Chrousos, G. P. The endocrinology of melancholic and atypical depression: relation to neurocircuitry and somatic consequences. Proc. Assoc. Am. Physicians 111, 22–34 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Joffe, R. T. Refractory depression: treatment strategies, with particular reference to the thyroid axis. J. Psychiatry Neurosci. 22, 327–331 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Vaupel, R., Jarry, H., Schlomer, H. T. & Wuttke, W. Differential response of substance P-containing subtypes of adrenomedullary cells to different stressors. Endocrinology 123, 2140–2145 (1988).

    Article  CAS  PubMed  Google Scholar 

  36. Coiro, V. et al. Stimulation of ACTH/cortisol by intravenously infused substance P in normal men: inhibition by sodium valproate. Neuroendocrinology 56, 459–463 (1992).

    Article  CAS  PubMed  Google Scholar 

  37. Kramer, M. S. et al. Distinct mechanism for antidepressant activity by blockade of central substance P receptors. Science 281, 1640–1645 (1998). This study represents a paradigm shift in the treatment of depression: it shows that substance P antagonists could be effective in the treatment of depression.

    Article  CAS  PubMed  Google Scholar 

  38. Ranga, K. & Krishnan, R. Clinical experience with substance P receptor (NK1) antagonists in depression. J. Clin. Psychiatry 63 (Suppl 11), 25–29 (2002).

    CAS  PubMed  Google Scholar 

  39. Argyropoulos, S. V. & Nutt, D. J. Substance P antagonists: novel agents in the treatment of depression. Expert Opin. Investig. Drugs 9, 1871–1875 (2000).

    Article  CAS  PubMed  Google Scholar 

  40. Campos, D. et al. Prevention of cisplatin-induced emesis by the oral neurokinin-1 antagonist, MK-869, in combination with granisetron and dexamethasone or with dexamethasone alone. J. Clin. Oncol. 19, 1759–1767 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. New drug helps relieve chemotherapy-related symptoms. FDA Consum. 37, 3 (2003).

  42. Holsboer, F. Corticotropin-releasing hormone modulators and depression. Curr. Opin. Investig. Drugs 4, 46–50 (2003).

    CAS  PubMed  Google Scholar 

  43. Peterson, L. & Weber, M. S. Report of the American Psychiatric Association meeting 2002. [online], (cited 13 Jan 2003) <http://www.trends-in-medicine.com/May2002/APA052p.pdf> (2002).

  44. Nemeroff, C. B. & Owens, M. J. Treatment of mood disorders. Nature Neurosci. 5, S1068–S1070 (2002).

    Article  CAS  Google Scholar 

  45. McEwen, B. S. Stress and hippocampal plasticity. Annu. Rev. Neurosci. 22, 105–122 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Lewin, R. Clinical trial for Parkinson's disease? Science 230, 527–528 (1985).

    Article  CAS  PubMed  Google Scholar 

  47. Shoulson, I. et al. Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Ann. Neurol. 51, 604–612 (2002).

    Article  CAS  PubMed  Google Scholar 

  48. Sivenius, J. et al. Selegiline treatment facilitates recovery after stroke. Neurorehabil. Neural Repair 15, 183–190 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. van der Hart, M. G. et al. Substance P receptor antagonist and clomipramine prevent stress-induced alterations in cerebral metabolites, cytogenesis in the dentate gyrus and hippocampal volume. Mol. Psychiatry 7, 933–941 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Duman, R. S., Malberg, J., Nakagawa, S. & D'Sa, C. Neuronal plasticity and survival in mood disorders. Biol. Psychiatry 48, 732–739 (2000).

    Article  CAS  PubMed  Google Scholar 

  51. Smith, M. A., Makino, S., Kvetnansky, R. & Post, R. M. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J. Neurosci. 15, 1768–1777 (1995).

    Article  CAS  PubMed  PubMed Central  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. 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  PubMed  Google Scholar 

  54. 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  PubMed  PubMed Central  Google Scholar 

  55. Malberg, J. E. & Duman, R. S. Cell proliferation in adult hippocampus is decreased by inescapable stress: reversal by fluoxetine treatment. Neuropsychopharmacology 28, 1562–1571 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  57. Licinio, J. & Wong, M. L. The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection. Mol. Psychiatry 4, 317–327 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Connor, T. J. & Leonard, B. E. Depression, stress and immunological activation: the role of cytokines in depressive disorders. Life Sci. 62, 583–606 (1998).

    Article  CAS  PubMed  Google Scholar 

  59. Berkenbosch, F., van Oers, J., del Rey, A., Tilders, F. & Besedovsky, H. Corticotropin-releasing factor-producing neurons in the rat activated by interleukin-1. Science 238, 524–536 (1987).

    Article  CAS  PubMed  Google Scholar 

  60. Sapolsky, R., Rivier, C., Yamamoto, G., Plotsky, P. & Vale, W. Interleukin-1 stimulates the secretion of hypothalamic corticotropin releasing factor. Science 238, 522–524 (1987).

    Article  CAS  PubMed  Google Scholar 

  61. Zorrilla, E. P. et al. The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain Behav. Immun. 15, 199–226 (2001).

    Article  CAS  PubMed  Google Scholar 

  62. Maes, M. et al. Higher α1-antitrypsin, haptoglobin, ceruloplasmin and lower retinol binding protein plasma levels during depression: further evidence for the existence of an inflammatory response during that illness. J. Affect. Disord. 24, 183–192 (1992).

    Article  CAS  PubMed  Google Scholar 

  63. Song, C., Dinan, T. & Leonard, B. E. Changes in immunoglobulin, complement and acute phase protein levels in the depressed patients and normal controls. J. Affect. Disord. 30, 283–288 (1994).

    Article  CAS  PubMed  Google Scholar 

  64. Connor, T. J., Kelly, J. P. & Leonard, B. E. Forced swim test-induced endocrine and immune changes in the rat: effect of subacute desipramine treatment. Pharmacol. Biochem. Behav. 59, 171–177 (1998).

    Article  CAS  PubMed  Google Scholar 

  65. Castanon, N., Leonard, B. E., Neveu, P. J. & Yirmiya, R. Effects of antidepressants on cytokine production and actions. Brain Behav. Immun. 16, 569–574 (2002).

    Article  CAS  PubMed  Google Scholar 

  66. Leonard, B. E. The immune system, depression and the action of antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry 25, 767–780 (2001).

    Article  CAS  PubMed  Google Scholar 

  67. Rott, R. et al. Detection of serum antibodies to Borna disease virus in patients with psychiatric disorders. Science 228, 755–756 (1985).

    Article  CAS  PubMed  Google Scholar 

  68. Bode, L., Zimmermann, W., Ferszt, R., Steinbach, F. & Ludwig, H. Borna disease virus genome transcribed and expressed in psychiatric patients. Nature Med. 1, 232–236 (1995).

    Article  CAS  PubMed  Google Scholar 

  69. Bode, L., Durrwald, R., Rantam, F. A., Ferszt, R. & Ludwig, H. First isolates of infectious human Borna disease virus from patients with mood disorders. Mol. Psychiatry 1, 200–212 (1996).

    CAS  PubMed  Google Scholar 

  70. Schwaninger, M., Schofl, C., Blume, R., Rossig, L. & Knepel, W. Inhibition by antidepressant drugs of cyclic AMP response element-binding protein/cyclic AMP response element-directed gene transcription. Mol. Pharmacol. 47, 1112–1118 (1995). Initial report on the involvement of CREB in antidepressant drug response. The lapse between treatment initiation and symptom relief suggested an action at the gene transcription level.

    CAS  PubMed  Google Scholar 

  71. Sassone-Corsi, P. Transcription factors responsive to cAMP. Annu. Rev. Cell Dev. Biol. 11, 355–377 (1995).

    Article  CAS  PubMed  Google Scholar 

  72. Schulman, H. Protein phosphorylation in neuronal plasticity and gene expression. Curr. Opin. Neurobiol. 5, 375–381 (1995).

    Article  CAS  PubMed  Google Scholar 

  73. Bourtchuladze, R. et al. Deficient long-term memory in mice with a targeted mutation of the cAMP- responsive element-binding protein. Cell 79, 59–68 (1994).

    Article  CAS  PubMed  Google Scholar 

  74. Manier, D. H., Shelton, R. C. & Sulser, F. Noradrenergic antidepressants: does chronic treatment increase or decrease nuclear CREB-P? J. Neural Transm. 109, 91–99 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Nibuya, M., Nestler, E. J. & Duman, R. S. Chronic antidepressant administration increases the expression of cAMP response element binding protein (CREB) in rat hippocampus. J. Neurosci. 16, 2365–2372 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Newton, S. S. et al. Inhibition of cAMP response element-binding protein or dynorphin in the nucleus accumbens produces an antidepressant-like effect. J. Neurosci. 22, 10883–10890 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Shaywitz, A. J. & Greenberg, M. E. CREB: a stimulus-induced transcription factor activated by a diverse array of extracellular signals. Annu. Rev. Biochem. 68, 821–861 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. 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  PubMed  PubMed Central  Google Scholar 

  79. Borsook, D., Konradi, C., Falkowski, O., Comb, M. & Hyman, S. E. Molecular mechanisms of stress-induced proenkephalin gene regulation: CREB interacts with the proenkephalin gene in the mouse hypothalamus and is phosphorylated in response to hyperosmolar stress. Mol. Endocrinol. 8, 240–248 (1994).

    CAS  PubMed  Google Scholar 

  80. Cole, R. L., Konradi, C., Douglass, J. & Hyman, S. E. Neuronal adaptation to amphetamine and dopamine: molecular mechanisms of prodynorphin gene regulation in rat striatum. Neuron 14, 813–823 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Carlezon, W. A. Jr et al. Regulation of cocaine reward by CREB. Science 282, 2272–2275 (1998).

    Article  CAS  PubMed  Google Scholar 

  82. Pare, C. M., Rees, L. & Sainsbury, M. J. Differentiation of two genetically specific types of depression by the response to anti-depressants. Lancet 2, 1340–1343 (1962).

    Article  CAS  PubMed  Google Scholar 

  83. Licinio, J. & Wong, M. L. The pharmacogenomics of depression. Pharmacogenomics J. 1, 175–177 (2001).

    Article  CAS  PubMed  Google Scholar 

  84. Smeraldi, E. et al. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol. Psychiatry 3, 508–511 (1998). Reveals that genotyping the serotonin transporter regulatory region might be used as a tool to predict treatment response in depression.

    Article  CAS  PubMed  Google Scholar 

  85. Wong, M. L., Khatri, P., Licinio, J., Esposito, A. & Gold, P. W. Identification of hypothalamic transcripts upregulated by antidepressants. Biochem. Biophys. Res. Commun. 229, 275–279 (1996).

    Article  CAS  PubMed  Google Scholar 

  86. Landgrebe, J. et al. Molecular characterisation of antidepressant effects in the mouse brain using gene expression profiling. J. Psychiatr. Res. 36, 119–129 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Yamada, M. et al. Differential expression of VAMPs/synaptobrevin-2 after antidepressant and electroconvulsive treatment in rat frontal cortex. Pharmacogenomics J. 2, 377–382 (2003).

    Article  CAS  Google Scholar 

  88. Reti, I. M. & Baraban, J. M. Sustained increase in Narp protein expression following repeated electroconvulsive seizure. Neuropsychopharmacology 23, 439–443 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Johansson, I. M. et al. Chronic amitriptyline treatment induces hippocampal NGFI-A, glucocorticoid receptor and mineralocorticoid receptor mRNA expression in rats. Brain Res. Mol. Brain Res. 62, 92–95 (1998).

    Article  CAS  PubMed  Google Scholar 

  90. Torres, G., Horowitz, J. M., Laflamme, N. & Rivest, S. Fluoxetine induces the transcription of genes encoding c-fos, corticotropin-releasing factor and its type 1 receptor in rat brain. Neuroscience 87, 463–477 (1998).

    Article  CAS  PubMed  Google Scholar 

  91. Bjartmar, L. et al. Selective effects on NGFI-A, MR, GR and NGFI-B hippocampal mRNA expression after chronic treatment with different subclasses of antidepressants in the rat. Psychopharmacology (Berl) 151, 7–12 (2000).

    Article  CAS  Google Scholar 

  92. Thome, J. et al. cAMP response element-mediated gene transcription is upregulated by chronic antidepressant treatment. J. Neurosci. 20, 4030–4036 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, J. et al. Regulation of δ FosB and FosB-like proteins by electroconvulsive seizure and cocaine treatments. Mol. Pharmacol. 48, 880–889 (1995).

    CAS  PubMed  Google Scholar 

  94. Wong, M. -L. et al. St. John's wort and imipramine-induced gene expression profiles identify cellular functions relevant to antidepressant action and novel pharmacogenetic candidates for the phenotype of antidepressant treatment response. Mol. Psychiatry 13 Jan 2004 (doi:10.1038/sj.mp.4001470). Highlights the involvement of the following cellular functions in antidepressant response in the hypothalamus: protein synthesis, scaffolding/ intracellular transport and mitochondrial function.

  95. Gunther, E. C., Stone, D. J., Gerwien, R. W., Bento, P. & Heyes, M. P. Prediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro. Proc. Natl Acad. Sci. USA 100, 9608–9613 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Agid, O. et al. Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia. Mol. Psychiatry 4, 163–172 (1999).

    Article  CAS  PubMed  Google Scholar 

  97. Maier, S. F. Learned helplessness and animal models of depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 8, 435–446 (1984).

    Article  CAS  PubMed  Google Scholar 

  98. Seligman, M. E. & Beagley, G. Learned helplessness in the rat. J. Comp. Physiol. Psychol. 88, 534–541 (1975).

    Article  CAS  PubMed  Google Scholar 

  99. Vollmayr, B. & Henn, F. A. Learned helplessness in the rat: improvements in validity and reliability. Brain Res. Brain Res. Protoc. 8, 1–7 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Porsolt, R. D., Bertin, A. & Jalfre, M. 'Behavioural despair' in rats and mice: strain differences and the effects of imipramine. Eur. J. Pharmacol. 51, 291–294 (1978).

    Article  CAS  PubMed  Google Scholar 

  101. West, A. P. Neurobehavioral studies of forced swimming: the role of learning and memory in the forced swim test. Prog. Neuropsychopharmacol. Biol. Psychiatry 14, 863–877 (1990).

    Article  CAS  PubMed  Google Scholar 

  102. Porsolt, R. D. et al. Use of the automated tail suspension test for the primary screening of psychotropic agents. Arch. Int. Pharmacodyn. Ther. 288, 11–30 (1987).

    CAS  PubMed  Google Scholar 

  103. Bai, F., Li, X., Clay, M., Lindstrom, T. & Skolnick, P. Intra- and interstrain differences in models of 'behavioral despair'. Pharmacol. Biochem. Behav. 70, 187–192 (2001).

    Article  CAS  PubMed  Google Scholar 

  104. Mayorga, A. J. & Lucki, I. Limitations on the use of the C57BL/6 mouse in the tail suspension test. Psychopharmacology (Berl) 155, 110–112 (2001).

    Article  CAS  Google Scholar 

  105. Shizgal, P. Toward a cellular analysis of intracranial self-stimulation: contributions of collision studies. Neurosci. Biobehav. Rev. 13, 81–90 (1989).

    Article  CAS  PubMed  Google Scholar 

  106. Matthews, K., Forbes, N. & Reid, I. C. Sucrose consumption as an hedonic measure following chronic unpredictable mild stress. Physiol. Behav. 57, 241–248 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Forbes, N. F., Stewart, C. A., Matthews, K. & Reid, I. C. Chronic mild stress and sucrose consumption: validity as a model of depression. Physiol. Behav. 60, 1481–1484 (1996).

    Article  CAS  PubMed  Google Scholar 

  108. Harris, R. B., Zhou, J., Youngblood, B. D., Smagin, G. N. & Ryan, D. H. Failure to change exploration or saccharin preference in rats exposed to chronic mild stress. Physiol. Behav. 63, 91–100 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. van der Kooy, D. in Methods of Assessing the Reinforcing Properties of Abused Drugs (ed. Bozarth, M. A.) 229–240 (Springer, New York, 1987).

    Book  Google Scholar 

  110. Kelly, J. P., Wrynn, A. S. & Leonard, B. E. The olfactory bulbectomized rat as a model of depression: an update. Pharmacol. Ther. 74, 299–316 (1997).

    Article  CAS  PubMed  Google Scholar 

  111. Hozumi, S. et al. Characteristics of changes in cholinergic function and impairment of learning and memory-related behavior induced by olfactory bulbectomy. Behav. Brain Res. 138, 9–15 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Katz, R. J., Roth, K. A. & Carroll, B. J. Acute and chronic stress effects on open field activity in the rat: implications for a model of depression. Neurosci. Biobehav. Rev. 5, 247–251 (1981).

    Article  CAS  PubMed  Google Scholar 

  113. Willner, P., Muscat, R. & Papp, M. Chronic mild stress-induced anhedonia: a realistic animal model of depression. Neurosci. Biobehav. Rev. 16, 525–534 (1992).

    Article  CAS  PubMed  Google Scholar 

  114. Kokkinidis, L., Zacharko, R. M. & Anisman, H. Amphetamine withdrawal: a behavioral evaluation. Life Sci. 38, 1617–1623 (1986).

    Article  CAS  PubMed  Google Scholar 

  115. Anraku, T., Ikegaya, Y., Matsuki, N. & Nishiyama, N. Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test. Psychopharmacology (Berl) 157, 217–220 (2001).

    Article  CAS  Google Scholar 

  116. Cryan, J. F., Hoyer, D. & Markou, A. Withdrawal from chronic amphetamine induces depressive-like behavioral effects in rodents. Biol. Psychiatry 54, 49–58 (2003).

    Article  CAS  PubMed  Google Scholar 

  117. Matthews, K. & Robbins, T. W. Early experience as a determinant of adult behavioural responses to reward: the effects of repeated maternal separation in the rat. Neurosci. Biobehav. Rev. 27, 45–55 (2003).

    Article  PubMed  Google Scholar 

  118. Ladd, C. O., Owens, M. J. & Nemeroff, C. B. Persistent changes in corticotropin-releasing factor neuronal systems induced by maternal deprivation. Endocrinology 137, 1212–1218 (1996).

    Article  CAS  PubMed  Google Scholar 

  119. Pryce, C. R. & Feldon, J. Long-term neurobehavioural impact of the postnatal environment in rats: manipulations, effects and mediating mechanisms. Neurosci. Biobehav. Rev. 27, 57–71 (2003).

    Article  PubMed  Google Scholar 

  120. Vogel, G., Neill, D., Hagler, M. & Kors, D. A new animal model of endogenous depression: a summary of present findings. Neurosci. Biobehav. Rev. 14, 85–91 (1990).

    Article  CAS  PubMed  Google Scholar 

  121. Overstreet, D. H. The Flinders sensitive line rats: a genetic animal model of depression. Neurosci. Biobehav. Rev. 17, 51–68 (1993).

    Article  CAS  PubMed  Google Scholar 

  122. Overstreet, D. H. Behavioral characteristics of rat lines selected for differential hypothermic responses to cholinergic or serotonergic agonists. Behav. Genet. 32, 335–348 (2002).

    Article  PubMed  Google Scholar 

  123. Rezvani, A. H., Parsian, A. & Overstreet, D. H. The Fawn-Hooded (FH/Wjd) rat: a genetic animal model of comorbid depression and alcoholism. Psychiatr. Genet. 12, 1–16 (2002).

    Article  PubMed  Google Scholar 

  124. El Yacoubi, M. et al. Behavioral, neurochemical, and electrophysiological characterization of a genetic mouse model of depression. Proc. Natl Acad. Sci. USA 100, 6227–6232 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Vaugeois, J. M., Odievre, C., Loisel, L. & Costentin, J. A genetic mouse model of helplessness sensitive to imipramine. Eur. J. Pharmacol. 316, R1–R2 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Ramboz, S. et al. Serotonin receptor1A knockout: an animal model of anxiety-related disorder. Proc. Natl Acad. Sci. USA 95, 14476–14481 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Heisler, L. K. et al. Elevated anxiety and antidepressant-like responses in serotonin 5-HT1A receptor mutant mice. Proc. Natl Acad. Sci. USA 95, 15049–15054 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Parks, C. L., Robinson, P. S., Sibille, E., Shenk, T. & Toth, M. Increased anxiety of mice lacking the serotonin1A receptor. Proc. Natl Acad. Sci. USA 95, 10734–10739 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Boutrel, B., Monaca, C., Hen, R., Hamon, M. & Adrien, J. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice. J. Neurosci. 22, 4686–4692 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Mayorga, A. J. et al. Antidepressant-like behavioral effects in 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) receptor mutant mice. J. Pharmacol. Exp. Ther. 298, 1101–1107 (2001).

    CAS  PubMed  Google Scholar 

  131. Knobelman, D. A., Hen, R., Blendy, J. A. & Lucki, I. Regional patterns of compensation following genetic deletion of either 5-hydroxytryptamine(1A) or 5-hydroxytryptamine(1B) receptor in the mouse. J. Pharmacol. Exp. Ther. 298, 1092–1100 (2001).

    CAS  PubMed  Google Scholar 

  132. Knobelman, D. A., Hen, R. & Lucki, I. Genetic regulation of extracellular serotonin by 5-hydroxytryptamine(1A) and 5-hydroxytryptamine(1B) autoreceptors in different brain regions of the mouse. J. Pharmacol. Exp. Ther. 298, 1083–1091 (2001).

    CAS  PubMed  Google Scholar 

  133. De Groote, L., Olivier, B. & Westenberg, H. G. The effects of selective serotonin reuptake inhibitors on extracellular 5-HT levels in the hippocampus of 5-HT1B receptor knockout mice. Eur. J. Pharmacol. 439, 93–100 (2002).

    Article  CAS  PubMed  Google Scholar 

  134. Malagie, I. et al. Improved efficacy of fluoxetine in increasing hippocampal 5-hydroxytryptamine outflow in 5-HT1B receptor knock-out mice. Eur. J. Pharmacol. 443, 99–104 (2002).

    Article  CAS  PubMed  Google Scholar 

  135. Holmes, A., Yang, R. J., Murphy, D. L. & Crawley, J. N. Evaluation of antidepressant-related behavioral responses in mice lacking the serotonin transporter. Neuropsychopharmacology 27, 914–923 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Li, Q. et al. Reduction of 5-hydroxytryptamine (5-HT1A)-mediated temperature and neuroendocrine responses and 5-HT1A binding sites in 5-HT transporter knockout mice. J. Pharmacol. Exp. Ther. 291, 999–1007 (1999).

    CAS  PubMed  Google Scholar 

  137. Gobbi, G., Murphy, D. L., Lesch, K. & Blier, P. Modifications of the serotonergic system in mice lacking serotonin transporters: an in vivo electrophysiological study. J. Pharmacol. Exp. Ther. 296, 987–995 (2001).

    CAS  PubMed  Google Scholar 

  138. Mannoury la Cour, C. et al. Functional consequences of 5-HT transporter gene disruption on 5-HT1A receptor-mediated regulation of dorsal raphe and hippocampal cell activity. J. Neurosci. 21, 2178–2185 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Cryan, J. F. et al. Use of dopamine-β-hydroxylase-deficient mice to determine the role of norepinephrine in the mechanism of action of antidepressant drugs. J. Pharmacol. Exp. Ther. 298, 651–657 (2001).

    CAS  PubMed  Google Scholar 

  140. Schramm, N. L., McDonald, M. P. & Limbird, L. E. The α2A-adrenergic receptor plays a protective role in mouse behavioral models of depression and anxiety. J. Neurosci. 21, 4875–4882 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sallinen, J. et al. Genetic alteration of the α2-adrenoceptor subtype c in mice affects the development of behavioral despair and stress-induced increases in plasma corticosterone levels. Mol. Psychiatry 4, 443–452 (1999).

    Article  CAS  PubMed  Google Scholar 

  142. Haller, J. et al. Behavioral responses to social stress in noradrenaline transporter knockout mice: effects on social behavior and depression. Brain Res. Bull. 58, 279–284 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Evrard, A. et al. Altered regulation of the 5-HT system in the brain of MAO-A knock-out mice. Eur J. Neurosci. 15, 841–851 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. 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  PubMed  PubMed Central  Google Scholar 

  145. Grimsby, J. et al. Increased stress response and beta-phenylethylamine in MAOB-deficient mice. Nature Genet. 17, 206–210 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Filliol, D. et al. Mice deficient for delta- and mu-opioid receptors exhibit opposing alterations of emotional responses. Nature Genet. 25, 195–200 (2000).

    Article  CAS  PubMed  Google Scholar 

  147. Stork, O. et al. Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65. Brain Res. 865, 45–58 (2000).

    Article  CAS  PubMed  Google Scholar 

  148. Schuler, V. et al. Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABA(B) responses in mice lacking GABA(B(1)). Neuron 31, 47–58 (2001).

    Article  CAS  PubMed  Google Scholar 

  149. Miyamoto, Y. et al. Lower sensitivity to stress and altered monoaminergic neuronal function in mice lacking the NMDA receptor epsilon 4 subunit. J. Neurosci. 22, 2335–2342 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cryan, J. F. et al. Antidepressant and anxiolytic-like effects in mice lacking the group III metabotropic glutamate receptor mGluR7. Eur J. Neurosci. 17, 2409–2417 (2003).

    Article  PubMed  Google Scholar 

  151. Rupniak, N. M. et al. Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs. Behav. Pharmacol. 12, 497–508 (2001).

    Article  CAS  PubMed  Google Scholar 

  152. Santarelli, L., Gobbi, G., Blier, P. & Hen, R. Behavioral and physiologic effects of genetic or pharmacologic inactivation of the substance P receptor (NK1). J. Clin. Psychiatry 63 (Suppl. 11), 11–17 (2002).

    CAS  PubMed  Google Scholar 

  153. Froger, N. et al. 5-hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization. J. Neurosci. 21, 8188–8197 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Bilkei-Gorzo, A., Racz, I., Michel, K. & Zimmer, A. Diminished anxiety- and depression-related behaviors in mice with selective deletion of the Tac1 gene. J. Neurosci. 22, 10046–10052 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Montkowski, A. et al. Long-term antidepressant treatment reduces behavioural deficits in transgenic mice with impaired glucocorticoid receptor function. J. Neuroendocrinol. 7, 841–845 (1995).

    Article  CAS  PubMed  Google Scholar 

  156. Groenink, L. et al. HPA axis dysregulation in mice overexpressing corticotropin releasing hormone. Biol. Psychiatry 51, 875–881 (2002).

    Article  CAS  PubMed  Google Scholar 

  157. van Gaalen, M. M., Stenzel-Poore, M. P., Holsboer, F. & Steckler, T. Effects of transgenic overproduction of CRH on anxiety-like behaviour. Eur J. Neurosci. 15, 2007–2015 (2002).

    Article  PubMed  Google Scholar 

  158. Bale, T. L. & Vale, W. W. Increased depression-like behaviors in corticotropin-releasing factor receptor-2-deficient mice: sexually dichotomous responses. J. Neurosci. 23, 5295–5301 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Holmes, A., Yang, R. J. & Crawley, J. N. Evaluation of an anxiety-related phenotype in galanin overexpressing transgenic mice. J. Mol. Neurosci. 18, 151–165 (2002).

    Article  CAS  PubMed  Google Scholar 

  160. Yamada, K. et al. Neurobehavioral alterations in mice with a targeted deletion of the tumor necrosis factor-α gene: implications for emotional behavior. J. Neuroimmunol. 111, 131–138 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Calapai, G. et al. Interleukin-6 involvement in antidepressant action of Hypericum perforatum. Pharmacopsychiatry 34 (Suppl. 1), S8–S10 (2001).

    Article  CAS  PubMed  Google Scholar 

  162. Svenningsson, P. et al. Involvement of striatal and extrastriatal DARPP-32 in biochemical and behavioral effects of fluoxetine (Prozac). Proc. Natl Acad. Sci. USA 99, 3182–3187 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Zhang, H. T. et al. Antidepressant-like profile and reduced sensitivity to rolipram in mice deficient in the PDE4D phosphodiesterase enzyme. Neuropsychopharmacology 27, 587–595 (2002).

    CAS  PubMed  Google Scholar 

  164. Cao, B. J. & Li, Y. Reduced anxiety- and depression-like behaviors in Emx1 homozygous mutant mice. Brain Res 937, 32–40 (2002).

    Article  CAS  PubMed  Google Scholar 

  165. 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  PubMed  PubMed Central  Google Scholar 

  166. Rahman, Z. et al. RGS9 modulates dopamine signaling in the basal ganglia. Neuron 38, 941–952 (2003).

    Article  CAS  PubMed  Google Scholar 

  167. El Yacoubi, M., Ledent, C., Parmentier, M., Costentin, J. & Vaugeois, J. M. Adenosine A2A receptor knockout mice are partially protected against drug-induced catalepsy. Neuroreport 12, 983–986 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Drago, J., McColl, C. D., Horne, M. K., Finkelstein, D. I. & Ross, S. A. Neuronal nicotinic receptors: insights gained from gene knockout and knockin mutant mice. Cell. Mol. Life Sci. 60, 1267–1280 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Martin, M., Ledent, C., Parmentier, M., Maldonado, R. & Valverde, O. Involvement of CB1 cannabinoid receptors in emotional behaviour. Psychopharmacology (Berl) 159, 379–387 (2002).

    Article  CAS  Google Scholar 

  170. Gavioli, E. C. et al. Blockade of nociceptin/orphanin FQ-NOP receptor signalling produces antidepressant-like effects: pharmacological and genetic evidences from the mouse forced swimming test. Eur J. Neurosci. 17, 1987–1990 (2003).

    Article  CAS  PubMed  Google Scholar 

  171. Tschenett, A. et al. Reduced anxiety and improved stress coping ability in mice lacking NPY-Y2 receptors. Eur J. Neurosci. 18, 143–148 (2003).

    Article  PubMed  Google Scholar 

  172. Holmes, A. et al. Behavioral characterization of dopamine D5 receptor null mutant mice. Behav. Neurosci. 115, 1129–1144 (2001).

    Article  CAS  PubMed  Google Scholar 

  173. Okuyama, S., Sakagawa, T., Sugiyama, F., Fukamizu, A. & Murakami, K. Reduction of depressive-like behavior in mice lacking angiotensinogen. Neurosci. Lett. 261, 167–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  174. Stork, O. et al. Recovery of emotional behaviour in neural cell adhesion molecule (NCAM) null mutant mice through transgenic expression of NCAM180. Eur J. Neurosci. 12, 3291–3306 (2000).

    Article  CAS  PubMed  Google Scholar 

  175. Cheeta, S., Ruigt, G., van Proosdij, J. & Willner, P. Changes in sleep architecture following chronic mild stress. Biol. Psychiatry 41, 419–427 (1997).

    Article  CAS  PubMed  Google Scholar 

  176. Nonogaki, K., Abdallah, L., Goulding, E. H., Bonasera, S. J. & Tecott, L. H. Hyperactivity and reduced energy cost of physical activity in serotonin 5-HT2C receptor mutant mice. Diabetes 52, 315–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  177. Ballard, T. M. et al. Severe impairment of NMDA receptor function in mice carrying targeted point mutations in the glycine binding site results in drug-resistant nonhabituating hyperactivity. J. Neurosci. 22, 6713–6723 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Haller, J. & Bakos, N. Stress-induced social avoidance: a new model of stress-induced anxiety? Physiol. Behav. 77, 327–332 (2002).

    Article  CAS  PubMed  Google Scholar 

  179. Dixon, A. K., Huber, C. & Lowe, D. A. Clozapine promotes approach-oriented behavior in male mice. J. Clin. Psychiatry 55 (Suppl. B), 4–7 (1994).

    PubMed  Google Scholar 

  180. Dunn, A. L. & Crnic, L. S. Repeated injections of interferon-α A/D in Balb/c mice: behavioral effects. Brain Behav. Immun. 7, 104–111 (1993).

    Article  CAS  PubMed  Google Scholar 

  181. Grippo, A. J., Beltz, T. G. & Johnson, A. K. Behavioral and cardiovascular changes in the chronic mild stress model of depression. Physiol. Behav. 78, 703–710 (2003).

    Article  CAS  PubMed  Google Scholar 

  182. van Gaalen, M. M., Stenzel-Poore, M., Holsboer, F. & Steckler, T. Reduced attention in mice overproducing corticotropin-releasing hormone. Behav. Brain Res. 142, 69–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  183. Contarino, A. et al. Reduced anxiety-like and cognitive performance in mice lacking the corticotropin-releasing factor receptor 1. Brain Res. 835, 1–9 (1999).

    Article  CAS  PubMed  Google Scholar 

  184. Estape, N. & Steckler, T. Cholinergic blockade impairs performance in operant DNMTP in two inbred strains of mice. Pharmacol. Biochem. Behav. 72, 319–334 (2002).

    Article  CAS  PubMed  Google Scholar 

  185. Maccari, S. et al. Prenatal stress and long-term consequences: implications of glucocorticoid hormones. Neurosci. Biobehav. Rev. 27, 119–127 (2003).

    Article  CAS  PubMed  Google Scholar 

  186. Mitchell, P. J. & Redfern, P. H. Potentiation of the time-dependent, antidepressant-induced changes in the agonistic behaviour of resident rats by the 5-HT1A receptor antagonist, WAY-100635. Behav. Pharmacol. 8, 585–606 (1997).

    Article  CAS  PubMed  Google Scholar 

  187. Dunn, A. J. & Swiergiel, A. H. The reductions in sweetened milk intake induced by interleukin-1 and endotoxin are not prevented by chronic antidepressant treatment. Neuroimmunomodulation 9, 163–169 (2001).

    Article  CAS  PubMed  Google Scholar 

  188. Benedetti, F. et al. Influence of a functional polymorphism within the promoter of the serotonin transporter gene on the effects of total sleep deprivation in bipolar depression. Am. J. Psychiatry 156, 1450–1452 (1999).

    CAS  PubMed  Google Scholar 

  189. Kim, D. K. et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 11, 215–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  190. Pollock, B. G. et al. Allelic variation in the serotonin transporter promoter affects onset of paroxetine treatment response in late-life depression. Neuropsychopharmacology 23, 587–590 (2000).

    Article  CAS  PubMed  Google Scholar 

  191. Zanardi, R., Benedetti, F., Di Bella, D., Catalano, M. & Smeraldi, E. Efficacy of paroxetine in depression is influenced by a functional polymorphism within the promoter of the serotonin transporter gene. J. Clin. Psychopharmacol. 20, 105–107 (2000).

    Article  CAS  PubMed  Google Scholar 

  192. Zill, P. et al. Evidence for an association between a G-protein β3-gene variant with depression and response to antidepressant treatment. Neuroreport 11, 1893–1897 (2000).

    Article  CAS  PubMed  Google Scholar 

  193. Mundo, E., Walker, M., Cate, T., Macciardi, F. & Kennedy, J. L. The role of serotonin transporter protein gene in antidepressant-induced mania in bipolar disorder: preliminary findings. Arch. Gen. Psychiatry 58, 539–544 (2001).

    Article  CAS  PubMed  Google Scholar 

  194. Serretti, A. et al. Influence of tryptophan hydroxylase and serotonin transporter genes on fluvoxamine antidepressant activity. Mol. Psychiatry 6, 586–592 (2001).

    Article  CAS  PubMed  Google Scholar 

  195. Zanardi, R. et al. Factors affecting fluvoxamine antidepressant activity: influence of pindolol and 5-HTTLPR in delusional and nondelusional depression. Biol. Psychiatry 50, 323–330 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Baghai, T. C. et al. Possible influence of the insertion/deletion polymorphism in the angiotensin I-converting enzyme gene on therapeutic outcome in affective disorders. Mol. Psychiatry 6, 258–259 (2001).

    Article  CAS  PubMed  Google Scholar 

  197. Serretti, A. et al. Tyrosine hydroxylase gene associated with depressive symptomatology in mood disorder. Am. J. Med. Genet. 81, 127–130 (1998).

    Article  CAS  PubMed  Google Scholar 

  198. Serretti, A. et al. No association between dopamine D(2) and D(4) receptor gene variants and antidepressant activity of two selective serotonin reuptake inhibitors. Psychiatry Res. 104, 195–203 (2001).

    Article  CAS  PubMed  Google Scholar 

  199. Cusin, C. et al. Influence of monoamine oxidase A and serotonin receptor 2A polymorphisms in SSRI antidepressant activity. Int. J. Neuropsychopharmacol. 5, 27–35 (2002).

    Article  CAS  PubMed  Google Scholar 

  200. Roberts, R. L., Joyce, P. R., Mulder, R. T., Begg, E. J. & Kennedy, M. A. A common P-glycoprotein polymorphism is associated with nortriptyline-induced postural hypotension in patients treated for major depression. Pharmacogenomics J. 2, 191–196 (2002).

    Article  CAS  PubMed  Google Scholar 

  201. Murphy, G. M., Jr, Kremer, C., Rodrigues, H. E. & Schatzberg, A. F. Pharmacogenetics of antidepressant medication intolerance. Am. J. Psychiatry 160, 1830–1835 (2003).

    Article  PubMed  Google Scholar 

  202. Lerer, B. & Macciardi, F. Pharmacogenetics of antidepressant and mood-stabilizing drugs: a review of candidate-gene studies and future research directions. Int. J. Neuropsychopharmacol. 5, 255–275 (2002).

    Article  CAS  PubMed  Google Scholar 

  203. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (American Psychiatric Association, Washington, DC, 1994).

  204. Wong, M. -L. & Licinio, J. Research and treatment approaches to depression. Nature Rev. Neurosci. 2, 343–351 (2001).

    Article  CAS  Google Scholar 

  205. Willner, P. & Mitchell, P. J. The validity of animal models of predisposition to depression. Behav. Pharmacol. 13, 169–188 (2002).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors are supported by National Institutes of Health grants and by awards from the Dana Foundation, National Alliance for Research on Schizophrenia and Depression, and Amgen. We are grateful to W. Potter and C. Austin for their insightful comments.

Author information

Authors and Affiliations

  1. Interdepartmental Clinical Pharmacology Center, Center for Pharmacogenomics, Neuropsychiatric Institute and David Geffen School of Medicine at UCLA, 695 Charles Young Drive South, Los Angeles, 90095-1761, California, USA

    Ma-Li Wong & Julio Licinio

Authors
  1. Ma-Li Wong
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julio Licinio
    View author publications

    You can also search for this author in PubMed Google Scholar

Ethics declarations

Competing interests

J.L. has consulted with Celera Diagnostics, Seryx and Perlegen Sciences. M.-L.W. and J.L. are co-inventors of a provisional US patent entitled 'Novel aspects of antidepressant action'.

Supplementary information

Related links

Related links

DATABASES

LocusLink

BDNF

CREB

CRH

CRHR1

monoamine oxidase B

substance P

Online Mendelian Inheritance in Man

Parkinson's disease

FURTHER INFORMATION

Encyclopedia of Life Sciences

Affective disorders

mood disorders

nervous and immune system interactions

Array Express

Gene Expression Omnibus

Nobel Prize in Medicine or Physiology 1970

Nobel Prize in Medicine or Physiology 2000

Glossary

MONOAMINE HYPOTHESIS OF DEPRESSION

Proposes that depression results from a central deficiency of monoaminergic function.

BRDU-LABELLED CELL NUMBER

5-bromo-2′-deoxyuridine (BrdU) labelling permits the identification of cells undergoing proliferation.

ELECTROCONVULSIVE SEIZURES

Seizures induced by external electrical stimulation of the brain. This technique has been used to model electroconvulsive therapy (ECT), a highly effective, albeit invasive, treatment for depression.

BASIC DOMAIN/LEUCINE-ZIPPER MOTIFS

These bind any eight-base-pair regulatory palindromic DNA sequence (cAMP-responsive elements).

TAIL-SUSPENSION TEST

A test procedure for antidepressants in which a mouse is suspended by the tail from a lever and its movements are recorded. The six-minute duration of the test is divided into periods of agitation and immobility.

DIFFERENTIAL DISPLAY

Systematic amplification of 3′ terminal portions of mRNAs and resolution of those fragments on a DNA sequencing gel. One method uses anchored primers to bind the 5′ boundary of poly-A tails for reverse transcription, followed by PCR amplification with random sequence upstream primers, and permits comparisons of mRNA subpopulations.

SERIAL ANALYSIS OF GENE EXPRESSION

A method for analysing gene expression in a comprehensive manner. The method requires the identification of short (10–17 bp) sequence tags with sufficient information to uniquely identify a transcript. Sequence tags can be linked together to form long serial molecules that can be cloned and sequenced. Quantitation of the number of times a particular tag is observed provides the expression level of the corresponding transcript.

COMPLEMENTARY DNA MICROARRAYS

A practical and inexpensive method to quantify the expression of thousands of genes in parallel. Known and unknown DNA samples are matched according to base-pairing rules in an automated process aimed at identifying the unknowns. Microarray sample spot sizes are less than 200 microns in diameter, and are created by high-speed robotics on glass (or nylon) substrates. The method permits high-throughput gene expression and gene discovery studies.

HYPERICUM

The plant Hypericum perforatum, also known as St. John's Wort, extracts of which are used in the treatment of mild to moderate depression in some countries.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wong, ML., Licinio, J. From monoamines to genomic targets: a paradigm shift for drug discovery in depression. Nat Rev Drug Discov 3, 136–151 (2004). https://doi.org/10.1038/nrd1303

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1303

This article is cited by

Search

Advanced search

Quick links

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