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.

  • Viewpoint
  • Published:

How can drug discovery for psychiatric disorders be improved?

Nature Reviews Drug Discovery volume 6, pages 189–201 (2007)Cite this article

Abstract

Psychiatric disorders such as depression, anxiety and schizophrenia are leading causes of disability worldwide, and have a huge societal impact. However, despite the clear need for better therapies, and major advances in the understanding of the molecular basis of these disorders in recent years, efforts to discover and develop new drugs for neuropsychiatric disorders, particularly those that might revolutionize disease treatment, have been relatively unsuccessful. A multidisciplinary approach will be crucial in addressing this problem, and in the first Advances in Neuroscience for Medical Innovation symposium, experts in multiple areas of neuroscience considered key questions in the field, in particular those related to the importance of neuronal plasticity. The discussions were used as a basis to propose steps that can be taken to improve the effectiveness of drug discovery for psychiatric disorders.

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: Convergence of signalling pathways on crucial 'nodes': implications for drug targets.
Figure 2: Enhancing cellular plasticity and resilience to treat severe mood disorders.
Figure 3: Brain-generated ensemble patterns in cortical structures.
Figure 4: Reversal of the suppressive effects of stress on neuronal plasticity in the hippocampus and prefrontal cortex by antidepressant treatment.
Figure 5: A proposed model regarding the interaction between stress, the limbic system, and the delayed onset of schizophrenia.
Figure 6: GABAA receptors and behaviour.
Figure 7: Converging evidence implicating the subgenual anterior cingulate region (Cg25) in major depression.

Similar content being viewed by others

References

  1. Manji, H. K., Gottesman, I .I. & Gould, T. D. Signal transduction and genes-to-behaviors pathways in psychiatric diseases. Sci. STKE 207, pe49 (2003).

    Google Scholar 

  2. Gould, T. D. & Gottesman, I. I. Psychiatric endophenotypes and the development of valid animal models. Genes Brain Behav. 5, 113–119 (2006).

    Article  CAS  Google Scholar 

  3. Diagnostic and Statistical Manual of Mental Disorders 4th Edition (American Psychiatric Association, 2000).

  4. Hasler, G., Gould, T. D., Drevets, W. C., Gottesman, I. I. & Manji, H. K. Toward constructing an endophenotype strategy for bipolar disorder. Biol. Psychiat. 60, 93–105 (2006).

    Article  Google Scholar 

  5. Charney, D. S. & Manji, H. K. Life stress, genes and depression: multiple pathways lead to increased risk and new opportunities for intervention. Sci. STKE re5 (2004).

  6. Einat, H. & Manji, H. K. Cellular plasticity cascades: genes-to-behavior pathways in animal models of bipolar disorder. Biol. Psychiat. 59, 1160–1171 (2006).

    Article  CAS  Google Scholar 

  7. Gould, T. D. & Manji, H. K. The molecular medicine revolution and psychiatry: bridging the gap between basic neuroscience research and clinical psychiatry. J. Clin. Psychiat. 65, 598–604 (2004).

    Article  Google Scholar 

  8. Berton, O. & Nestler, E. J. New approaches to antidepressant drug discovery: beyond monoamines. Nature Rev. Neurosci. 7, 137–151 (2006).

    Article  CAS  Google Scholar 

  9. Buzsaki, G. & Draguhn, A. Neuronal oscillations in cortical networks. Science 304, 1926–1929 (2004).

    Article  CAS  Google Scholar 

  10. Robbe, D. et al. Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nature Neurosci. 9, 1526–1533 (2006).

    Article  CAS  Google Scholar 

  11. Harris, K. D., Csicsvari, J., Hirase, H., Dragoi, G. & Buzsáki, G. Organization of cell assemblies in the hippocampus. Nature 424, 552–556 (2003).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. Grace, A. A. The depolarization block hypothesis of neuroleptic action: implications for the etiology and treatment of schizophrenia. J. Neural Transm. Suppl. 36, 91–131 (1992).

    CAS  PubMed  Google Scholar 

  14. Grace, A. A., Bunney, B. S., Moore, H. & Todd, C. L. Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci. 20, 31–37 (1997).

    Article  CAS  Google Scholar 

  15. Rauch, S. L., Shin, L. M. & Phelps, E. A. Neurocircuitry models of posttraumatic stress disorder and extinction: human neuroimaging research — past, present, and future. Biol. Psychiatry 60, 376–382 (2006).

    Article  Google Scholar 

  16. McEwen, B. S. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54 (Suppl. 1), 20–23 (2005).

    Article  CAS  Google Scholar 

  17. Diamond, D. M., Campbell, A., Park, C. R. & Vouimba, R. M. Preclinical research on stress, memory, and the brain in the development of pharmacotherapy for depression. Eur. Neuropsychopharmacol. 14, S491–S495 (2004).

    Article  CAS  Google Scholar 

  18. Bonanno, G. et al. Chronic antidepressants reduce depolarization-evoked glutamate release and protein interactions favoring formation of SNARE complex in hippocampus. J. Neurosci. 25, 3270–3279 (2005).

    Article  CAS  Google Scholar 

  19. Grace, A. A. Gating of information flow within the limbic system and the pathophysiology of schizophrenia. Brain Res. Brain Res. Rev. 31, 330–341 (2000).

    Article  CAS  Google Scholar 

  20. Weinberger, D. R. & Lipska, B. K. Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground. Schizophr. Res. 16, 87–110 (1995).

    Article  CAS  Google Scholar 

  21. Moore, H., Ghajarnia, M. E., Jentsch, J. D., Geyer, M. A. & Grace, A. A. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol. Psychiat. 60, 253–264 (2006).

    Article  CAS  Google Scholar 

  22. Lipska, B. K. et al. Neonatal excitotoxic hippocampal damage in rats causes post-pubertal changes in prepulse inhibition of startle and its disruption by apomorphine. Psychopharmacology 122, 35–43 (1995).

    Article  CAS  Google Scholar 

  23. Thompson, J. L., Pogue-Geile, M. F. & Grace, A. A. Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr. Bull. 30, 875–900 (2004).

    Article  Google Scholar 

  24. Grace, A. A. in Neurodevelopment and Schizophrenia (eds Keshavan, M., Kennedy, J. L. & Murray, R. M.) 273–294 (Cambridge Univ. Press, 2004).

    Book  Google Scholar 

  25. Sugiyama, S., Dupas, S., Volovitch, M., Prochiantz, A. & Hensch, T. K. Endogenous Otx2 transfer into visual cortex specifies critical period plasticity. Ab. Soc. Neurosci. N25 A14 (2005).

  26. Prakash, N. & Wurst, W. Development of dopaminergic neurons in the mammalian brain. Cell. Mol. Life Sci. 63, 187–206 (2006).

    Article  CAS  Google Scholar 

  27. Joliot, A. & Prochiantz, A. Transduction peptides: from technology to physiology. Nature Cell Biol. 6, 189–196 (2004).

    Article  CAS  Google Scholar 

  28. Somogyi, P. et al. Salient features of synaptic organisation in the cerebral cortex. Brain Res. Rev. 26, 113–135 (1998).

    Article  CAS  Google Scholar 

  29. Cope, D. W. et al. Loss of zolpidem efficacy in the hippo-campus of mice with the GABAA receptor γ2 F771 point mutation. Eur. J. Neurosci. 21, 3002–3016 (2005).

    Article  CAS  Google Scholar 

  30. Rudolph, U. & Mohler, H. GABA-based therapeutic approaches: GABAA receptor subtype functions. Curr. Opinion Pharmacol. 6, 18–23 (2006).

    Article  CAS  Google Scholar 

  31. Whiting P. J. GABAA receptors: a viable target for novel anxiolytics? Curr. Opinion Pharmacol. 6, 24–29 (2006).

    Article  CAS  Google Scholar 

  32. Calabresi, P. et al. Dopamine and cAMP-regulated phosphoprotein 32 kDa controls both striatal long-term depression and long-term potentiation, opposing forms of synaptic plasticity. J. Neurosci. 20, 8443–8451 (2000).

    Article  CAS  Google Scholar 

  33. Greengard, P. The neurobiology of slow synaptic transmission. Science 294, 1024–1030 (2001).

    Article  CAS  Google Scholar 

  34. Svenningsson, P. et al. DARPP-32 — an integrator of neurotransmission in the striatum. Ann. Rev. Pharmacol. Toxicol. 44, 269–296 (2004).

    Article  CAS  Google Scholar 

  35. Svenningsson P. et al. Diverse psychotomimetics act through a common signaling pathway. Science 302, 1412–1415 (2003).

    Article  CAS  Google Scholar 

  36. Valjent, E. et al. Regulation of a protein phosphatase cascade allows convergent dopamine and glutamate signals to activate ERK in the striatum. Proc. Natl Acad. Sci. USA 102, 491–496 (2005).

    Article  CAS  Google Scholar 

  37. Valjent, E. et al. Plasticity-associated gene Krox24/Zif268 is required for long-lasting behavioral effects of cocaine. J. Neurosci. 26, 4956–4960 (2006).

    Article  CAS  Google Scholar 

  38. Valjent, E. et al. Inhibition of ERK pathway or protein synthesis during reexposure to drugs of abuse erases previously learned place preference. Proc. Natl Acad. Sci. USA 103, 2932–2937 (2006).

    Article  CAS  Google Scholar 

  39. Schenk, J. F. Safety of strong, static magnetic fields. J. Magn. Reson. Imaging 12, 2–19, (2000).

    Article  Google Scholar 

  40. Thieben, M. J. et al. The distribution of structural neuropathology in pre-clinical Huntington's disease. Brain 125, 1815–1828 (2002).

    Article  CAS  Google Scholar 

  41. Draganski, B. et al. Neuroplasticity: changes in grey matter induced by training. Nature 427, 311–312 (2004).

    Article  CAS  Google Scholar 

  42. Lee, L. et al. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308–5318, (2003).

    Article  CAS  Google Scholar 

  43. Loubinoux, I. et al. A single dose of the serotonin neurotransmission agonist paroxetine enhances motor output: double-blind, placebo-controlled, fMRI study in healthy subjects. Neuroimage 15, 26–36, (2002).

    Article  Google Scholar 

  44. Giedd, J. N., Shaw, P., Wallace, G., Gogtay, N. & Lenroot, R. L. in Developmental Neuroscience Vol 2. 2nd edn (eds Cicchetti, D. & Cohen, D. J.) 127–196 (John Wiley & Sons, 2006).

    Google Scholar 

  45. Shaw, P. et al. Intellectual ability and cortical development in children and adolescents. Nature 440, 676–679 (2006).

    Article  CAS  Google Scholar 

  46. Seckl J. R. & Meaney M. J. Glucocorticoid “programming” and PTSD risk. Ann. NY Acad. Sci. 1071, 351–378 (2006).

    Article  CAS  Google Scholar 

  47. Olney, J. W. & Farber, N. B. Glutamate receptor dysfunction and schizophrenia. Arch. Gen. Psychiatry 52, 998–1007 (1995).

    Article  CAS  Google Scholar 

  48. Angrist, B. M. & Gershon, S. The phenomenology of experimentally induced amphetamine psychosis — preliminary observations. Biol. Psychiatry 2, 95–107 (1970).

    CAS  PubMed  Google Scholar 

  49. Carlsson, A. & Lindqvist, M. Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol. Toxicol. 20, 140–144 (1963).

    Article  CAS  Google Scholar 

  50. Creese, I., Burt, D. R. & Snyder, S. H. Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192, 481–483 (1976).

    Article  CAS  Google Scholar 

  51. Flagstad, P. et al. Disruption of neurogenesis at gestational day 17 in the rat causes behavioral changes relevant to positive and negative schizophrenia symptoms and alters amphetamine-induced dopamine release in the nucleus accumbens. Neuropsychopharmacology 29, 2052–2064 (2004).

    Article  CAS  Google Scholar 

  52. Gourevitch, R., Rocher, C., Le Pen, G., Krebs, M. O. & Jay, T. M. Working memory deficits in adult rats after prenatal disruption of neurogenesis. Behav. Pharmacol. 15, 287–292 (2004).

    Article  CAS  Google Scholar 

  53. Grace, A. A. and Moore, H. in Origins and Development of Schizophrenia: Advances in Experimental Psychopathology (eds Lenzenweger, M. F. & Dworkin, R.H.) 123–157 (American Psychological Association Press, Washington DC, 1998).

    Book  Google Scholar 

  54. Tsoory, M. & Richter-Levin, G. Learning under stress in the adult rat is differentially affected by or stress. Int. J. Neuropsychopharmacol. 2, 1–16 (2005).

    Google Scholar 

  55. Avital, A. & Richter-Levin, G. Exposure to juvenile stress exacerbates the behavioural consequences of exposure to stress in the adult rat. Int. J. Neuropsychopharmacol. 8, 163–173 (2005).

    Article  Google Scholar 

  56. Cohen, H. et al. Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder. Neuropsychopharmacology 29, 1962–1970 (2004).

    Article  Google Scholar 

  57. Antman, E. H. et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction; a report of ACC/AHA task force on practice guidelines. J. Am. Coll. Cardiol. 44, E1–E211 (2004).

    Article  Google Scholar 

  58. Fitzgerald, P. B. et al. A randomized, controlled trial of sequential bilateral repetitive transcranial magnetic stimulation for treatment-resistant depression. Am. J. Psychiatry 163, 88–94 (2006).

    Article  Google Scholar 

  59. Nahas, Z et al. Two-year outcome of vagus nerve stimulation (VNS) for treatment of major depressive episodes. J. Clin. Psychiatry 66, 1097–1104 (2005).

    Article  Google Scholar 

  60. Mayberg, H. S. et al. Deep brain stimulation for treatment resistant depression. Neuron 45, 651–660 (2005).

    Article  CAS  Google Scholar 

  61. Mayberg, H. S. Modulating dysfunctional limbic-cortical circuits in depression: towards development of brain-based algorithms for diagnosis and optimised treatment. Br. Med. Bull. 65, 193–207 (2003).

    Article  Google Scholar 

  62. Bertolino, A. et al. Interaction of COMT (Val(108/158)Met) genotype and olanzapine treatment on prefrontal cortical function in patients with schizophrenia. Am. J. Psychiatry 161, 1798–1805 (2004).

    Article  Google Scholar 

  63. Weickert, T. W. et al. Catechol-O-methyltransferase val108/158met genotype predicts working memory response to antipsychotic medications. Biol. Psychiatry 56, 677–682 (2004).

    Article  CAS  Google Scholar 

  64. Grace, A. A. Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41, 1–24 (1991).

    Article  CAS  Google Scholar 

  65. Liddle, P. F., Friston, K. J., Frith, C. D. & Frachowiak, R. S. J., Cerebral blood flow and mental processes in schizophrenia. J. R. Soc. Med. 85, 224–227 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. O'Donnell, P. & Grace, A. A. in Review of Psychiatry Vol 18: Schizophrenia in a Molecular Age. Ed. Tamminga, C. A. 109–140 (American Psychiatric Press, Washington DC, 1999).

    Google Scholar 

  67. Gould, T. & Manji, H. K. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology 30, 1223–1237 (2005).

    Article  CAS  Google Scholar 

  68. Diamond, D. M. et al. Influence of predator stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis. Hippocampus 16, 571–576 (2006).

    Article  Google Scholar 

  69. Spedding, M., Jay, T., Costa e Silva. J. & Perret, L. A pathophysiological paradigm for the therapy of psychiatric disease. Nature Rev. Drug Discov. 4, 467–476 (2005).

    Article  CAS  Google Scholar 

  70. Mayberg, H. S. et al. Reciprocal limbic-cortical function and negative converging PET findings in depression and normal sadness. Am. J. Psychiatry 156, 675–682 (1999).

    CAS  PubMed  Google Scholar 

  71. Mayberg, H. S. et al. The functional neuroanatomy of the placebo effect. Am. J. Psychiatry 159, 728–737 (2002).

    Article  Google Scholar 

  72. George, M. S. et al. Prefrontal repetitive transcranial magnetic stimulation (rTMS) reduces relative perfusion locally and remotely. Hum. Psychopharmacol. Clin. Exp. 14, 161–170 (1999).

    Article  Google Scholar 

  73. Nobler, M. S. et al. Decreased regional brain metabolism after ECT. Am. J. Psychiatry 158, 305–308 (2001).

    Article  CAS  Google Scholar 

  74. Talbot, P. S. & Cooper, S. J. Anterior cingulate and subgenual prefrontal blood flow changes following tryptophan depletion in healthy males. Neuropsychopharmacology 31,1757–1767 (2006).

    Article  CAS  Google Scholar 

  75. Pezawas, L. et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nature Neurosci. 8, 828–834 (2005).

    Article  CAS  Google Scholar 

  76. Ongur, D., Drevet, W. C. & Price, J. L. Glial reduction in the subgenual prefrontal cortex in mood disorders. Proc. Natl Acad. Sci. USA 95,13290–13295 (1998).

    Article  CAS  Google Scholar 

  77. Somogyi, P. & Klausberger, T. Defined types of cortical interneurone structure space and spike timing in the hippocampus. J. Physiol. 562, 9–26 (2005).

    Article  CAS  Google Scholar 

  78. Ohyama, A. et al. Regulation of exocytosis through Ca2 /ATP-dependent binding of autophosphorylated Ca2 /calmodulin-activated protein kinase II to syntaxin1A. J. Neurosci. 22, 3342–3351 (2002).

    Article  CAS  Google Scholar 

Download references

Author information

Author notes

  1. Emmanuel Canet: IDRS, 11 Rue des Moulineaux, 92150 Suresnes, France.

  2. Graham Collingridge: Department of Anatomy, Medical School, University of Bristol, University Walk, Bristol, BS8 1TD, UK.

  3. André Delacourte: 75 Rue Gambetta, 59045 Falmes Thumesnil, France.

  4. Ray Dolan: Wellcome Department of Imaging Neuroscience, Institute of Neurology, 12 Queen Square, London, WC1N 3BG, UK.

  5. Philippe Fossati: Service de Psychiatrie d'Adultes, Hôpital Pitié Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France.

  6. Therese Jay: INSERM E0117, 2 Ter Rue d'Alésia, 75014 Paris, France.

  7. Jean-Pierre Lepine: Hôpital Fernand Widal, Psychiatrie Adultes (CS), 200 Faubourg St Denis, 75475 Paris Cedex 10, France.

  8. Pierre Lestage: IDRS, 11 Rue des Moulineaux, 92150 Suresnes, France.

  9. Bernard Marchand: IRIS, 6 Place des Pléiades, 92415 Courbevoie, France.

  10. Mark J. Millan: IDRS, 11 Rue des Moulineaux, 92150 Suresnes, France.

  11. Laurent Perret: IRIS, 6 Place des Pléiades, 92415 Courbevoie, France.

  12. Léon Tremblay: Neurologie et Thérapeutique expérimentale, INSERM U 289, Hôpital Pitié Salpêtrière, 47 Boulevard de l'Hôpital, 75013 Paris, France.

  13. Stéphane Vandenabeele: IDRS, 11 Rue des Moulineaux, 92150 Suresnes, France.

Authors and Affiliations

  1. Yves Agid: Physiologie and Pathogénie des Maladies Neurodégénératives, INSERM U 289, Hôpital Salpêtrière, 47 Boulevard de l'Hôpital, 75651 Paris Cedex 13, France.,

    Yves Agid

  2. György Buzsáki: Center for Molecular and Behavioural Neuroscience, Rutgers University, 197 University Avenue, Newark, New Jersey 07102, USA.,

    György Buzsáki

  3. David M. Diamond: Medical Research Division, Departments of Psychology and Pharmacology, Veterans Hospital and University of South Florida, 4202 East Fowler Avenue (PCD 4118G) Tampa, Florida 33620-8200, USA.,

    David M. Diamond

  4. Richard Frackowiak: Wellcome Department of Imaging Neuroscience, Institute of Neurology, 12 Queen Square, London, WC1N 3BG, UK.,

    Richard Frackowiak

  5. Jay Giedd: Department of Health and Human Services, National Institute of Mental Health, National Institutes of Health (NIMH/NIH), Room 4C110, 10 Center Drive, MSC 1367, Bethesda, Maryland 20892, USA.,

    Jay Giedd

  6. Jean-Antoine Girault: INSERM U 536, Institut du Fer à Moulin, 17 Rue du Fer à Moulin, 75005 Paris, France.,

    Jean-Antoine Girault

  7. Department of Neuroscience, Anthony Grace: University of Pittsburgh, 458 Crawford Hall, Pittsburgh, Pennsylvania 15260, USA.,

    Anthony Grace

  8. Division of Pathology and Neuroscience, Jeremy J. Lambert: Neurosciences Institute, University of Dundee, Ninewells Hospital and Medical School, Dundee, DD1 9SY, UK.,

    Jeremy J. Lambert

  9. Husseini Manji: Mood and Anxiety Disorders Program, DIRP/NIMH/NIH, Building 15K, Room 102, 15K Northdrive Bethesda, Maryland 20892 2670, USA.,

    Husseini Manji

  10. Helen Mayberg: Emory University School of Medicine, 101 Woodruff Circle, WMB 4-313, Atlanta, Georgia 30322, USA.,

    Helen Mayberg

  11. Center of Neuropharmacology-Department of Pharmacological Sciences, Maurizio Popoli: University of Milan, Via Balzaretti 9, 20133 Milano, Italy.,

    Maurizio Popoli

  12. Alain Prochiantz: Ecole Normale Supérieure, CNRS UMR 8542, 46 Rue d'Ulm, Paris 75005, France.,

    Alain Prochiantz

  13. Gal Richter-Levin: Brain and Behaviour Research Center, University of Haifa, Haifa 31905, Israel.,

    Gal Richter-Levin

  14. Department of Pharmacology, Peter Somogyi: MRC Anatomical Neuropharmacology Unit, University of Oxford, Mansfield Road, Oxford, OX1 3TH, UK.,

    Peter Somogyi

  15. Michael Spedding: IDRS, 11 Rue des Moulineaux, 92150 Suresnes, France.,

    Michael Spedding

  16. Per Svenningsson: Karolinska Institute, Section of Molecular Neuropharmacology, Nanna Svartz Väg 2-4, 171 77 Stockholm, Sweden.,

    Per Svenningsson

  17. Daniel Weinberger: Clinical Brain Disorder Branch, NIH/NIMH 900 Rockville Pike, Building 10, Room 4S237B, Bethesda, Maryland 20892, USA.,

    Daniel Weinberger

Authors
  1. Yves Agid
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. György Buzsáki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David M. Diamond
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Frackowiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jay Giedd
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jean-Antoine Girault
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Anthony Grace
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jeremy J. Lambert
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Husseini Manji
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Helen Mayberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Maurizio Popoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Alain Prochiantz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Gal Richter-Levin
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Peter Somogyi
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Michael Spedding
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Per Svenningsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Daniel Weinberger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Spedding.

Ethics declarations

Competing interests

David Diamond has received funding from Institute de Recherches Servier. Helen Mayberg is a consultant for Advanced Neuromodulation System (ANS), has intellectual property licensed to ANS, and has served on the scientific advisory committee for Cyberonics. Michael Spedding is deputy director of research at Institute de Recherches Servier.

Supplementary information

Supplementary information S1 (figure)

Hypothesis on the molecular/functional changes induced by antidepressants in synaptic terminals. (PDF 307 kb)

Supplementary information S2 (figure)

Basic layout of a cor tical circuit in the hippocampus. (PDF 144 kb)

Supplementary information S3 (figure)

Role of the ERK pathway in striatal neurons in response to drugs of abuse. (PDF 160 kb)

Related links

Related links

DATABASES

OMIM

attention deficit hyperactivity disorder (ADHD)

bipolar disorder

Cushing disease

Parkinson's disease

obsessive compulsive disorder (OCD)

schizophrenia

FURTHER INFORMATION

Statistical Parametric Mapping (SPM)

Glossary

Deep brain stimulation

Continuous therapeutic electric stimulation of subcortical areas at high frequencies (130 Hz) using chronically implanted electrodes.

Neuronal plasticity

The capacity of the nervous system to modify its organization. Such changes can occur as a consequence of many events, including the normal development and maturation of the organism, the acquisition of new skills ('learning') in immature and mature organisms, and after damage to the nervous system.

Long-term potentiation (LTP)

The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.

Long-term depression (LTD)

An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

T1- weighted structural brain scans

MRI scans can be acquired with various types of contrast. T1-weighted images are weighted according to the so-called spin-lattice relaxation time (T1) of the protons that give rise to the MRI signals; such images provide good contrast between grey and white matter.

Transcranial magnetic stimulation (TMS)

A technique that is used to induce a transient interruption of normal activity in a relatively restricted area of the brain. It is based on the generation of a strong magnetic field near the area of interest, which, if changed rapidly enough, will induce an electric field that is sufficient to stimulate neurons

Vagus nerve stimulation

Vagus nerve stimulation uses a commercially available device for treating both refractory seizure disorders and treatment-resistant depression. The procedure involves the surgical implantation of a small pacemaker-like device into the left chest wall with a wire running under the skin leading to coils wrapped around the left vagus nerve. The device delivers continual electrical pulses, in 30 seconds-on and

Rights and permissions

Reprints and permissions

About this article

Cite this article

Agid, Y., Buzsáki, G., Diamond, D. et al. How can drug discovery for psychiatric disorders be improved?. Nat Rev Drug Discov 6, 189–201 (2007). https://doi.org/10.1038/nrd2217

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2217

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