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.

  • Perspective
  • Published:

Another view of the history of antipsychotic drug discovery and development

Abstract

Chlorpromazine initiated effective pharmacotherapy for schizophrenia 60 years ago. This discovery initiated or stimulated key developments in the field of psychiatry. Nonetheless, advances in pharmacotherapy of schizophrenia have been modest. Psychosis remains the primary aspect of psychopathology addressed, and core pathologies such as cognition and negative symptom remain unmet therapeutic challenges. New clinical and basic neuroscience paradigms may guide the near future and provide a more heuristic construct for novel and innovative discovery.

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

Access options

Buy this article

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

Similar content being viewed by others

References

  1. Lopez-Munoz F, Alamo C, Cuenca E, Shen WW, Clervoy P, Rubio G . History of the discovery and clinical introduction of chlorpromazine. Ann Clin Psychiatry 2005; 17: 113–135.

    Article  Google Scholar 

  2. Sabbatini RME . The History of Shock Therapy in Psychiatry.

  3. Dawson DJC, Kernohan GA, Knox SJ . Reserpine in schizophrenia. Lancet 1958; 272: 589.

    Article  Google Scholar 

  4. Braslow JT . Mental Ills and Bodily Cures: Psychiatric Treatment in the First Half of the Twentieth Century. University of California Press, 1997.

    Google Scholar 

  5. Rees L, King GM . Cortisone in the treatment of schizophrenia. Br J Psychiatry 1952; 98: 401–403.

    CAS  Google Scholar 

  6. Rees L, King GM . Intensive cortisone therapy in schizophrenia. Br J Psychiatry 1956; 102: 155–159.

    CAS  Google Scholar 

  7. Lamb HR, Weinberger LE . The shift of psychiatric inpatient care from hospitals to jails and prisons. J Am Acad Psychiatry Law 2005; 33: 529–534.

    PubMed  Google Scholar 

  8. Delay J, Deniker P . Le traitement des psychoses par une methode neurolytique derivee de l'hibernotherapie. Congres des medecins alienistes et neurologistes, Luxembourg; July 1952.

  9. Kirkpatrick B, Fenton WS, Carpenter WT, Marder SR . The NIMH-MATRICS consensus statement on negative symptoms. Schizophr Bull 2006; 32: 214–219.

    Article  Google Scholar 

  10. Klein DF, Davis JM . Diagnosis and Drug Treatment of Psychiatric Disorders. Williams and Wilkins: Baltimore, 1969.

    Google Scholar 

  11. Healy D . The Creation of Psychopharmacology. Harvard University Press: Cambridge, MA, 2002.

    Book  Google Scholar 

  12. Thuillier J . Ten Years that Changed the Face of Mental Illness. English edition approved by David Healy; translated by Gordon Hickish Martin Dunitz: London Blackwell Science: Malden, MA 1999.

  13. Kraepelin E . Dementia Praecox and Paraphrenia. Krieger: New York, 1971 [First published, 1919].

    Google Scholar 

  14. Blueler E . Dementia Praecox or the Group of Schizophrenias. International Universities Press: New York, 1950 [First Published, 1911].

    Google Scholar 

  15. Rado S . Psychoanalysis of Behavior: The Collected Papers of Sandor Rado Vol 2. Grune and Stratton: New York, 1962.

    Google Scholar 

  16. Meehl PE . Primary and secondary hypohedonia. J Abnorm Psychol 2001; 110: 188–193.

    Article  CAS  Google Scholar 

  17. Strauss JS, Carpenter WT, Bartko JJ . The diagnosis and understanding of schizophrenia. Part III. Speculations on the processes that underlie schizophrenic symptoms and signs. Schizophr Bull 1974; 11: 61–69.

    Article  Google Scholar 

  18. Peralta V, Cuest MJ . How many and which are the psychopathological dimensions in schizophrenia? Issues influencing their ascertainment. Schizophr Res 2001; 49: 269–285.

    Article  CAS  Google Scholar 

  19. Davis JM . Overview: maintenance therapy in psychiatry: I. Schizophrenia. Am J Psychiatry 1975; 132: 1237–1245.

    Article  CAS  Google Scholar 

  20. May Philip RA . Treatment of Schizophrenia: A comparative study of five treatment methods 1st edn (Science House, New York, 1968).

    Google Scholar 

  21. Carpenter WT, Schooler NR, Kane JM . The rationale and ethics of medication-free research in schizophrenia. Arch Gen Psychiatry 1997; 54: 401–407.

    Article  Google Scholar 

  22. Carpenter WT . The risk of medication-free research. Schizophr Bull 1997; 23: 11–18.

    Article  Google Scholar 

  23. Carpenter WT, Appelbaum PS, Levine RJ . The declaration of Helsinki and clinical trials: a focus on placebo-controlled trials in schizophrenia. Am J Psychiatry 2003; 160: 356–362.

    Article  Google Scholar 

  24. Leucht S, Tardy M, Komossa K, Heres S, Kissling W, Salanti G et al. Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: a systematic review and meta-analysis. Lancet 2012; 379: 2063–2071.

    Article  CAS  Google Scholar 

  25. Dixon LB, Dickerson F, Bellack AS, Bennett M, Dickinson D, Goldberg RW et al. The 2009 schizophrenia PORT psychosocial treatment recommendations and summary statements. Schizophr Bull 2010; 36: 48–70.

    Article  Google Scholar 

  26. Buchanan RW, Kreyenbuhl J, Kelly DL, Noel JM, Boggs DL, Fischer BA et al. The 2009 schizophrenia PORT psychopharmacological treatment recommendations and summary statements. Schizophr Bull 2010; 36: 71–93.

    Article  Google Scholar 

  27. Kreyenbuhl J, Buchanan RW, Dickerson FB, Dixon LB . The Schizophrenia Patient Outcomes Research Team (PORT): updated treatment recommendations 2009. Schizophr Bull 2010; 36: 94–103.

    Article  Google Scholar 

  28. Carlsson A, Lindqvist M . Effect of chlorpromazine or haloperidol on formation of 3methoxytramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 1963; 20: 140–144.

    CAS  Google Scholar 

  29. Creese I, Burt DR, Snyder SH . Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 1976; 192: 481–483.

    Article  CAS  Google Scholar 

  30. Seeman P, Lee T . Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 1975; 188: 1217–1219.

    Article  CAS  Google Scholar 

  31. Kapur S, Zipursky R, Jones C, Remington G, Houle S . Relationship between dopamine D2 occupancy, clinical response, and side effects: A Double-Blind PET Study of First-Episode Schizophrenia. Am J Psychiatry 2000; 157: 514–520.

    Article  CAS  Google Scholar 

  32. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A et al. Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci USA 1997; 94: 2569–2574.

    Article  CAS  Google Scholar 

  33. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J et al. Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci USA 1996; 93: 9235–9240.

    Article  CAS  Google Scholar 

  34. Smith A, Li M, Becker S, Kapur S . Dopamine, prediction error and associative learning: a model-based account. Network 2006; 17: 61–84.

    Article  Google Scholar 

  35. Cade JFJ . Lithium salts in the treatment of psychotic excitement. Med J Aust 1949; 2: 349–352.

    CAS  Google Scholar 

  36. Kane JM . The use of depot neuroleptics: clinical experience in the United States. J Clin Psychiatry 1984; 45 (5 Pt 2): 5–12.

    CAS  PubMed  Google Scholar 

  37. Hippius H . A historical perspective of clozapine. J Clin Psychiatry 1999; 60 (Suppl 12): 22–23.

    PubMed  Google Scholar 

  38. Kane J, Honigfeld G, Singer J, Meltzer H . Clozapine for the treatment-resistant schizophrenic. A double-blind comparision with chlorpromazine. Arch Gen Psychiatry 1988; 45: 789–796.

    Article  CAS  Google Scholar 

  39. Breier A, Buchanan RW, Kirkpatrick B, Davis OR, Irish D, Summerfelt A et al. Effects of clozapine on positive and negative symptoms in outpatients with schizophrenia. Am J Psychiatry 1994; 151: 20–26.

    Article  CAS  Google Scholar 

  40. Meltzer HY, Alphs L, Green AI, Altamura AC, Anand R, Bertoldi A et al. International Suicide Prevention Trial Study Group. Clozapine treatment for suicidality in schizophrenia: International Suicide Prevention Trial (InterSePT). Arch Gen Psychiatry 2003; 60: 82–91, Erratum in: Arch Gen Psychiatry.2003;60(7):735.

    Article  CAS  Google Scholar 

  41. Spivak B, Mester R, Wittenberg N, Maman Z, Weizman A . Reduction of aggressiveness and impulsiveness during clozapine treatment in chronic neuroleptic-resistant schizophrenic patients. Clin Neuropharmacol 1997; 20: 442–446.

    Article  CAS  Google Scholar 

  42. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO et al. Clinical antipsychotic trials of intervention effectiveness (CATIE) investigators. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005; 353: 1209–1223.

    Article  CAS  Google Scholar 

  43. Leucht S, Komossa K et al. A meta-analysis of head-to-head comparisons of second-generation antipsychotics in the treatment of schizophrenia. Am J Psychiatry 2009; 166: 152–163.

    Article  Google Scholar 

  44. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP et al. Randomized controlled trial of the effect on quality of life of second – vs first-generation antipsychotic drugs in schizophrenia: cost utility of the latest antipsychotic drugs in Schizophrenia Study (CUtLASS 1). Arch Gen Psychiatry 2006; 63: 1079–1087.

    Article  CAS  Google Scholar 

  45. Davies LM, Lewis S, Jones PB, Barnes TR, Gaughran F, Hayhurst K et alCUtLASS team. Cost-effectiveness of first- v. second-generation antipsychotic drugs: results from a randomized controlled trial in schizophrenia responding poorly to previous therapy. Br J Psychiatry 2007; 191: 14–22.

    Article  CAS  Google Scholar 

  46. Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L et al. Double-blind comparison of first-and second- generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study. Am J Psychiatry 2008; 165: 1420–1431.

    Article  Google Scholar 

  47. Scolnick E . Program to improve cognitive functioning in patients with schizophrenia: reflections. Schizophr Res 2004; 72: 75–77.

    Article  Google Scholar 

  48. Carpenter WT . Clinical constructs and therapeutic discovery. Schizophr Res 2004; 72: 69–73.

    Article  Google Scholar 

  49. Carpenter WT, Koenig JI . The evolution of drug development in schizophrenia: past issues and future opportunities. Neuropsychopharmacology 2008; 33: 2061–2079.

    Article  CAS  Google Scholar 

  50. Bergen SE, Petryshen TL . Genome-wide association studies of schizophrenia: does bigger lead to better results? Curr Opin Psychiatry 2012; 25: 76–82.

    Article  Google Scholar 

  51. Allardyce J, Gaebel W, Zielasek J, van Os J . Deconstructing Psychosis Conference February 2006: the validity of schizophrenia and alternative approaches to the classification of psychosis. Schizophr Bull 2007; 33: 863–867.

    Article  Google Scholar 

  52. Buchanan RW, Davis M, Goff D, Green MF, Keefe RS, Leon AC et al. A summary of the FDA-NIMH-MATRICS workshop on clinical trial design for neurocognitive drugs for schizophrenia. Schizophr Bull 2005; 31: 5–19.

    Article  Google Scholar 

  53. Marder SR, Daniel DG, Alphs L, Awad AG, Keefe RS . Methodological issues in negative symptom trials. Schizophr Bull 2011; 37: 250–254.

    Article  Google Scholar 

  54. Cuthbert BN, Insel TR . Toward new approaches to psychotic disorders: The NIMH. Res Domain Criteria Project Schizophr Bull 2010; 36: 1061–1062.

    Article  Google Scholar 

  55. Insel T, Cuthbert B, Garvey M, Heinssen R, Pine DS, Quinn K et al. Research Domain Criteria (RDoC): toward a new classification framework for research on mental disorders. Am J Psychiatry 2010; 167: 748–751.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to W T Carpenter Jr.

Ethics declarations

Competing interests

During the past 12 months, Dr Carpenter has attended an advisory board meeting (Shire, 2011; Genentech, 2012) or conference call (Astra Zeneca, 2011) relating to psychopharmacology of schizophrenia. Dr Davis has no conflict of interest to report.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Carpenter, W., Davis, J. Another view of the history of antipsychotic drug discovery and development. Mol Psychiatry 17, 1168–1173 (2012). https://doi.org/10.1038/mp.2012.121

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/mp.2012.121

Keywords

This article is cited by

Search

Quick links