Skip to main content

Thank you for visiting 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.

The 'atypicality' of antipsychotics: a concept re-examined and re-defined


Recent clinical trials have raised questions over the perceived advantages of second-generation 'atypical' antipsychotics over those from the first generation. An atypical antipsychotic in its original sense is one that lacks extrapyramidal side effects. However, the addition of other clinical features to the original concept of atypicality, such as efficacy against negative and cognitive symptoms, seems to have become a feature of searches for novel antipsychotics in the past two decades. Although this approach has led to some therapeutic advances, we propose that it has also hampered antipsychotic drug research and that reframing the concept of atypicality could have a key role in making genuine breakthroughs in schizophrenia therapy.

This is a preview of subscription content

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Current and proposed classification of compounds for the treatment of schizophrenia.
Figure 2: Dopamine receptor binding profiles of three antipsychotic drugs illustrating putative mechanisms of low propensity for extrapyramidal side effects.


  1. 1

    Charpentier, P., Gailliot, P., Jacob, R., Gaudechon, J. & Buisson, P. Recherches sur les diméthylaminopropyl-N-phénothiazines substituées. C. R. Hebd. Seances Acad. Sci. 235, 59–60 (1952) (in French).

    CAS  Google Scholar 

  2. 2

    Delay, J., Deniker, P. & Harl, J. M. Utilisation thérapeutique psychiatrique d'une phénothiazine d'action centrale elective. Ann. Médico-Psychol. 110, 112–117 (1952) (in French).

    CAS  Google Scholar 

  3. 3

    Barsa, J. A. & Kline, N. S. Use of reserpine in disturbed psychotic patients. Am. J. Psychiatry 112, 684–690 (1956).

    CAS  Article  PubMed  Google Scholar 

  4. 4

    Sigwald, J., Bouttier, D., Raymond, C. & Pichot, C. Quartre cas de dyskinésie, facio-bucco-linguo-masticatrice à l'évolution prolongée secondaire à un treatment par les neuroleptiques. Rev. Neurol. (Paris) 100, 751–755 (1959) (in French).

    CAS  Google Scholar 

  5. 5

    Enss, H., Hartmann, K., Hippius, H. & Richter, H. E. Clinical experiences with a new piperazine derivative of phenothiazine in neuropsychiatry. Arch. Psychiatr. Nervenkr. Z. Gesamte Neurol. Psychiatr. 197, 534–550 (1958) (in German).

    CAS  Article  PubMed  Google Scholar 

  6. 6

    Bente, D., Engelmeier, M.-P., Heinrich, K., Hippius, H. & Schmitt, W. Klinische Untersuchungen über eine neue Gruppe tricyklischer Neuroleptika (Substanzen mit 7-gliedrigen heterocyclischen Zentralringen) 977–983 (V CINP Kongress, Washington, 1966) (in German).

  7. 7

    Angst, J. et al. Das klinische Wirkungsbild von Clozapin (Untersuchung mit dem AMP-System). Pharmacopsychiatry 4, 201–211 (1971) (in German).

    Article  Google Scholar 

  8. 8

    Stille, G. & Hippius, H. Kritische Stellungnahme zum Begriff der Neuroleptika (anhand von pharmakologischen und klinischen Befunden mit Clozapin). Pharmakopsychiatr. Neuropsychopharmakol. 4, 182–191 (1971) (in German).

    CAS  Article  Google Scholar 

  9. 9

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

    PubMed  Google Scholar 

  10. 10

    Kane, J., Honigfeld, G., Singer, J. & Meltzer, H. Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch. Gen. Psychiatry 45, 789–796 (1988).

    CAS  Article  PubMed  Google Scholar 

  11. 11

    Kinon, B. J. & Lieberman, J. A. Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Berl.) 124, 2–34 (1996).

    CAS  Article  Google Scholar 

  12. 12

    Remington, G. & Kapur, S. Atypical antipsychotics: are some more atypical than others? Psychopharmacology 148, 3–15 (2000).

    CAS  Article  PubMed  Google Scholar 

  13. 13

    Meltzer, H. Y. An atypical compound by any other name is still a.... Psychopharmacology 148, 16–19 (2000).

    CAS  Article  PubMed  Google Scholar 

  14. 14

    Gründer, G. & Benkert, O. Prolaction is not a core dimension of “atypicality”. Psychopharmacology 162, 93 (2002).

    Article  PubMed  Google Scholar 

  15. 15

    Newcomer, J. W. Antipsychotic medications: metabolic and cardiovascular risk. J. Clin. Psychiatry 68 (Suppl. 4), 8–13 (2007).

    PubMed  Google Scholar 

  16. 16

    Davis, J. M., Chen, N. & Glick, I. D. A meta-analysis of the efficacy of second-generation antipsychotics. Arch. Gen. Psychiatry 60, 553–564 (2003).

    CAS  Article  PubMed  Google Scholar 

  17. 17

    Lieberman, J. A. et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N. Engl. J. Med. 353, 1209–1223 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18

    Jones, P. B. 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 63, 1079–1087 (2006).

    CAS  Article  PubMed  Google Scholar 

  19. 19

    Keefe, R. S. et al. Neurocognitive effects of antipsychotic medications in patients with chronic schizophrenia in the CATIE Trial. Arch. Gen. Psychiatry 64, 633–647 (2007).

    CAS  Article  PubMed  Google Scholar 

  20. 20

    Meltzer, H. Y., Matsubara, S. & Lee, J. C. The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol. Bull. 25, 390–392 (1989).

    CAS  PubMed  Google Scholar 

  21. 21

    Wadenberg, M. L., Wiker, C. & Svensson, T. H. Enhanced efficacy of both typical and atypical antipsychotic drugs by adjunctive α2 adrenoceptor blockade: experimental evidence. Int. J. Neuropsychopharmacol. 10, 191–202 (2007).

    CAS  Article  PubMed  Google Scholar 

  22. 22

    Pilowsky, L. S. et al. Limbic selectivity of clozapine. Lancet 350, 490–491 (1997).

    CAS  Article  PubMed  Google Scholar 

  23. 23

    Kapur, S. & Seeman, P. Does fast dissociation from the dopamine D2 receptor explain the action of atypical antipsychotics? A new hypothesis. Am. J. Psychiatry 158, 360–369 (2001).

    CAS  Article  PubMed  Google Scholar 

  24. 24

    Meltzer, H. Y., Li, Z., Kaneda, Y. & Ichikawa, J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog. Neuropsychopharmacol. Biol. Psychiatry 27, 1159–1172 (2003).

    CAS  Article  PubMed  Google Scholar 

  25. 25

    Farde, L. et al. Positron emission tomographic analysis of central D1 and D2 dopamine receptor occupancy in patients treated with classical neuroleptics and clozapine. Relation to extrapyramidal side effects. Arch. Gen. Psychiatry 49, 538–544 (1992).

    CAS  Article  PubMed  Google Scholar 

  26. 26

    Kapur, S., Zipursky, R., Jones, C., Remington, G. & Houle, S. Relationship between dopamine D2 occupancy, clinical response, and side effects: a double-blind study of first-episode schizophrenia. Am. J. Psychiatry 157, 514–520 (2000).

    CAS  Article  PubMed  Google Scholar 

  27. 27

    Kapur, S. et al. A positron emission tomography study of quetiapine in schizophrenia: a preliminary finding of an antipsychotic effect with only transiently high dopamine D2 receptor occupancy. Arch. Gen. Psychiatry 57, 553–559 (2000).

    CAS  Article  PubMed  Google Scholar 

  28. 28

    Gründer, G. et al. The striatal and extrastriatal D2/D3 receptor-binding profile of clozapine in patients with schizophrenia. Neuropsychopharmacology 31, 1027–1035 (2006).

    Article  PubMed  Google Scholar 

  29. 29

    Kessler, R. M. et al. Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31, 1991–2001 (2006).

    CAS  Article  PubMed  Google Scholar 

  30. 30

    Kapur, S., Zipursky, R. B. & Remington, G. Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am. J. Psychiatry 156, 286–293 (1999).

    CAS  PubMed  Google Scholar 

  31. 31

    Knable, M. B., Heinz, A., Raedler, T. & Weinberger, D. R. Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res. 75, 91–101 (1997).

    CAS  Article  PubMed  Google Scholar 

  32. 32

    Nyberg, S., Eriksson, B., Oxenstierna, G., Halldin, C. & Farde, L. Suggested minimal effective dose of risperidone based on PET-measured D2 and 5-HT2A receptor occupancy in schizophrenic patients. Am. J. Psychiatry 156, 869–875 (1999).

    CAS  Article  PubMed  Google Scholar 

  33. 33

    Bigliani, V. et al. Striatal and temporal cortical D2/D3 receptor occupancy by olanzapine and sertindole in vivo: a [123I]epidepride single photon emission tomography (SPET) study. Psychopharmacology (Berl.) 150, 132–140 (2000).

    CAS  Article  Google Scholar 

  34. 34

    Bressan, R. A. et al. Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J. Clin. Psychopharmacol. 23, 5–14 (2003).

    CAS  Article  PubMed  Google Scholar 

  35. 35

    Xiberas, X. et al. Extrastriatal and striatal D2 dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br. J. Psychiatry 179, 503–508 (2001).

    CAS  Article  PubMed  Google Scholar 

  36. 36

    Talvik, M. et al. No support for regional selectivity in clozapine-treated patients: a PET study with [11C]raclopride and [11C]FLB 457. Am. J. Psychiatry 158, 926–930 (2001).

    CAS  Article  PubMed  Google Scholar 

  37. 37

    Vernaleken, I. et al. High striatal occupancy of D2-like dopamine receptors by amisulpride in the brain of patients with schizophrenia. Int. J. Neuropsychopharmacol. 7, 421–430 (2004).

    CAS  Article  PubMed  Google Scholar 

  38. 38

    Uchida, H. et al. Monthly administration of long-acting injectable risperidone and striatal dopamine D2 receptor occupancy for the management of schizophrenia. J. Clin. Psychiatry 69, 1281–1286 (2008).

    CAS  Article  PubMed  Google Scholar 

  39. 39

    Carlsson, A. & Carlsson, M. L. A dopaminergic deficit hypothesis of schizophrenia: the path to discovery. Dialogues Clin. Neurosci. 8, 137–142 (2006).

    PubMed  PubMed Central  Google Scholar 

  40. 40

    Carlsson, A. & Carlsson, M. L. Adaptive properties and heterogeneity of dopamine D2 receptors — pharmacological implications. Brain Res. Rev. 58, 374–378 (2008).

    CAS  Article  PubMed  Google Scholar 

  41. 41

    Sesack, S. R., Hawrylak, V. A., Matus, C., Guido, M. A. & Levey, A. I. Dopamine axon varicosities in the prelimbic division of the rat prefrontal cortex exhibit sparse immunoreactivity for the dopamine transporter. J. Neurosci. 18, 2697–2708 (1998).

    CAS  Article  PubMed  Google Scholar 

  42. 42

    Lewis, D. A. et al. Dopamine transporter immunoreactivity in monkey cerebral cortex: regional, laminar, and ultrastructural localization. J. Comp. Neurol. 432, 119–136 (2001).

    CAS  Article  PubMed  Google Scholar 

  43. 43

    Gründer, G. et al. Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18F]fallypride PET study. Am. J. Psychiatry 165, 988–995 (2008).

    Article  PubMed  Google Scholar 

  44. 44

    Yokoi, F. et al. Dopamine D2 and D3 receptor occupancy in normal humans treated with the antipsychotic drug aripiprazole (OPC 14597): a study using positron emission tomography and [11C]raclopride. Neuropsychopharmacology 27, 248–259 (2002).

    CAS  Article  PubMed  Google Scholar 

  45. 45

    Gründer, G., Carlsson, A. & Wong, D. F. Mechanism of new antipsychotic medications: occupancy is not just antagonism. Arch. Gen. Psychiatry 60, 974–977 (2003).

    Article  PubMed  Google Scholar 

  46. 46

    Saha, A. R. et al. Safety and tolerability of aripiprazole at doses higher than 30 mg. Int. J. Neuropsychopharmacol. 5 (Suppl. 1), 185 (2002).

    Google Scholar 

  47. 47

    Wetzel, H. et al. Amisulpride versus flupentixol in schizophrenia with predominantly positive symptomatology – a double-blind controlled study comparing a selective D2-like antagonist to a mixed D1-/D2-like antagonist. The Amisulpride Study Group. Psychopharmacology 137, 223–232 (1998).

    CAS  Article  PubMed  Google Scholar 

  48. 48

    Roth, B. L., Sheffler, D. J. & Kroeze, W. K. Magic shotguns versus magic bullets: selectively non-selective drugs for mood disorders and schizophrenia. Nature Rev. Drug Discov. 3, 353–359 (2004).

    CAS  Article  Google Scholar 

  49. 49

    Seeman, P., Lee, T., Chau-Wong, M. & Wong, K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 261, 717–719 (1976).

    CAS  Article  PubMed  Google Scholar 

  50. 50

    Spooren, W., Riemer, C., Meltzer, H. NK3 receptor antagonists: the next generation of antipsychotics? Nature Rev. Drug Discov. 4, 967–975 (2005).

    CAS  Article  Google Scholar 

  51. 51

    Meltzer, H. Y., Arvanitis, L., Bauer, D. & Rein, W. Placebo-controlled evaluation of four novel compounds for the treatment of schizophrenia and schizoaffective disorder. Am. J. Psychiatry 161, 975–984 (2004).

    Article  PubMed  Google Scholar 

  52. 52

    Moghaddam, B. Stress activation of glutamate neurotransmission in the prefrontal cortex: implications for dopamine-associated psychiatric disorders. Biol. Psychiatry 51, 775–787 (2002).

    CAS  Article  PubMed  Google Scholar 

  53. 53

    Rorick-Kehn, L. M. et al. In vivo pharmacological characterization of the structurally novel, potent, selective mGlu2/3 receptor agonist LY4040439 in animal models of psychiatric disorders. Psychopharmacology 193, 121–136 (2007).

    CAS  Article  PubMed  Google Scholar 

  54. 54

    Patil, S. T. et al. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized Phase 2 clinical trial. Nature Med. 13, 1102–1107 (2007).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  55. 55

    Lane, H. Y., Chang, Y. C., Liu, Y. C., Chiu, C. C. & Tsai, G. E. Sarcosine or D-serine add-on treatment for acute exacerbation of schizophrenia: a randomized, double-blind, placebo-controlled study. Arch. Gen. Psychiatry 62, 1196–1204 (2005).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56

    Lane, H. Y. et al. Glycine transporter I inhibitor, N-methylglycine (sarcosine), added to clozapine for the treatment of schizophrenia. Biol. Psychiatry 60, 645–649 (2006).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  57. 57

    Leucht, S. et al. Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373, 31–41 (2009).

    CAS  Article  PubMed  Google Scholar 

  58. 58

    Freyhan, F. A. Course and outcome of schizophrenia. Am. J. Psychiatry 112, 161–169 (1955).

    CAS  Article  PubMed  Google Scholar 

  59. 59

    Green, M. F. et al. Approaching a consensus cognitive battery for clinical trials in schizophrenia: the NIMH-MATRICS conference to select cognitive domains and test criteria. Biol. Psychiatry 56, 301–307 (2004).

    Article  PubMed  Google Scholar 

  60. 60

    Carter, C. S. et al. Identifying cognitive mechanisms targeted for treatment development in schizophrenia: an overview of the first meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia Initiative. Biol. Psychiatry 64, 4–10 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  61. 61

    Freedman, R. et al. Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am. J. Psychiatry 165, 1040–1047 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  62. 62

    Lewis, D. A. et al. Subunit-selective modulation of GABA type A receptor neurotransmission and cognition in schizophrenia. Am. J. Psychiatry 165, 1585–1593 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

Download references


This work was partly supported by the German Research Council (DFG), GR1399/4–1 and 4–2.

Author information



Corresponding author

Correspondence to Gerhard Gründer.

Ethics declarations

Competing interests

Gründer has served as a consultant for AstraZeneca, Bristol-Myers Squibb, Johnson & Johnson, Otsuka and Pfizer. He has also served on the speakers' bureau of AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Janssen Cilag, Otsuka, Pfizer, Servier and Wyeth. He has received grant support from Alkermes, Bristol-Myers Squibb, Johnson & Johnson and Pfizer.

Hippius has served as a consultant for Eli Lilly.

Related links

Related links


Gerhard Gründer's homepage

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gründer, G., Hippius, H. & Carlsson, A. The 'atypicality' of antipsychotics: a concept re-examined and re-defined. Nat Rev Drug Discov 8, 197–202 (2009).

Download citation


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