Role of Dopamine D2 Receptors for Antipsychotic Activity

  • Nathalie Ginovart
  • Shitij KapurEmail author
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 212)


This review summarizes the current state of knowledge regarding the proposed mechanisms by which antipsychotic agents reduce the symptoms of schizophrenia while giving rise to adverse side effects. The first part summarizes the contribution of neuroimaging studies to our understanding of the neurochemical substrates of schizophrenia, putting emphasis on direct evidence suggestive of a presynaptic rather than a postsynaptic dysregulation of dopaminergic neurotransmission in this disorder. The second part addresses the role of D2 and non-D2 receptor blockade in the treatment of schizophrenia and highlights a preponderant role of D2 receptors in the mechanism of antipsychotic action. Neuroimaging studies have defined a narrow, but optimal, therapeutic window of 65–78 % D2 receptor blockade within which most antipsychotics achieve optimal clinical efficacy with minimal side effects. Some antipsychotics though do not conform to that therapeutic window, notably clozapine. The reasons for its unexcelled clinical efficacy despite subthreshold levels of D2 blockade are unclear and current theories on clozapine’s mechanisms of action are discussed, including transiency of its D2 receptor blocking effects or preferential blockade of limbic D2 receptors. Evidence is also highlighted to consider the use of extended antipsychotic dosing to achieve transiency of D2 blockade as a way to optimize functional outcomes in patients. We also present some critical clinical considerations regarding the mechanisms linking dopamine disturbance to the expression of psychosis and its blockade to the progressive resolution of psychosis, keeping in perspective the speed and onset of antipsychotic action. Finally, we discuss potential novel therapeutic strategies for schizophrenia.


Schizophrenia Antipsychotic drugs Dopamine receptor D2 blockade PET imaging 


  1. Abi-Dargham A, Gil R, Krystal J, Baldwin RM, Seibyl JP, Bowers M, van Dyck CH, Charney DS, Innis RB, Laruelle M (1998) Increased striatal dopamine transmission in schizophrenia: confirmation in a second cohort. Am J Psychiatry 155:761–767PubMedGoogle Scholar
  2. Abi-Dargham A, Rodenhiser J, Printz D, Zea-Ponce Y, Gil R, Kegeles LS, Weiss R, Cooper TB, Mann JJ, Van Heertum RL, Gorman JM, Laruelle M (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A 97:8104–8109PubMedGoogle Scholar
  3. Abi-Dargham A, Mawlawi O, Lombardo I, Gil R, Martinez D, Huang Y, Hwang DR, Keilp J, Kochan L, Van Heertum R, Gorman JM, Laruelle M (2002) Prefrontal dopamine D1 receptors and working memory in schizophrenia. J Neurosci 22:3708–3719PubMedGoogle Scholar
  4. Agid O, Kapur S, Arenovich T, Zipursky RB (2003) Delayed-onset hypothesis of antipsychotic action: a hypothesis tested and rejected. Arch Gen Psychiatry 60:1228–1235PubMedGoogle Scholar
  5. Agid O, Seeman P, Kapur S (2006) The “delayed onset” of antipsychotic action–an idea whose time has come and gone. J Psychiatry Neurosci 31:93–100PubMedGoogle Scholar
  6. Agid O, Mamo D, Ginovart N, Vitcu I, Wilson AA, Zipursky RB, Kapur S (2007) Striatal vs extrastriatal dopamine D2 receptors in antipsychotic response–a double-blind PET study in schizophrenia. Neuropsychopharmacology 32:1209–1215PubMedGoogle Scholar
  7. Agid O, Kapur S, Warrington L, Loebel A, Siu C (2008) Early onset of antipsychotic response in the treatment of acutely agitated patients with psychotic disorders. Schizophr Res 102:241–248PubMedGoogle Scholar
  8. Arvanitis LA, Miller BG (1997) Multiple fixed doses of “seroquel” (quetiapine) in patients with acute exacerbation of schizophrenia: a comparison with haloperidol and placebo. The seroquel trial 13 study group. Biol Psychiatry 42:233–246PubMedGoogle Scholar
  9. Awad AG, Voruganti LN (2005) Neuroleptic dysphoria: revisiting the concept 50 years later. Acta Psychiatr Scand Suppl 111(427):6–13Google Scholar
  10. Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, Caillard V, Blin J, Huret JD, Loc’h C, Maziere B (1989) Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology (Berl) 99:463–472Google Scholar
  11. Berridge KC (2007) The debate over dopamine’s role in reward: the case for incentive salience. Psychopharmacology (Berl) 191:391–431Google Scholar
  12. Bertolino A, Breier A, Callicott JH, Adler C, Mattay VS, Shapiro M, Frank JA, Pickar D, Weinberger DR (2000) The relationship between dorsolateral prefrontal neuronal N-acetylaspartate and evoked release of striatal dopamine in schizophrenia. Neuropsychopharmacology 22:125–132PubMedGoogle Scholar
  13. Bigliani V, Mulligan RS, Acton PD, Ohlsen RI, Pike VW, Ell PJ, Gacinovic S, Kerwin RW, Pilowsky LS (2000) 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) 150:132–140Google Scholar
  14. Bose SK, Turkheimer FE, Howes OD, Mehta MA, Cunliffe R, Stokes PR, Grasby PM (2008) Classification of schizophrenic patients and healthy controls using [18F] fluorodopa PET imaging. Schizophr Res 106(2–3):148–155PubMedGoogle Scholar
  15. Breier A, Su TP, Saunders R, Carson RE, Kolachana BS, de Bartolomeis A, Weinberger DR, Weisenfeld N, Malhotra AK, Eckelman WC, Pickar D (1997) Schizophrenia is associated with elevated amphetamine-induced synaptic dopamine concentrations: evidence from a novel positron emission tomography method. Proc Natl Acad Sci U S A 94:2569–2574PubMedGoogle Scholar
  16. Bressan RA, Erlandsson K, Jones HM, Mulligan RS, Ell PJ, Pilowsky LS (2003) Optimizing limbic selective D2/D3 receptor occupancy by risperidone: a [123I]-epidepride SPET study. J Clin Psychopharmacol 23:5–14PubMedGoogle Scholar
  17. Bristow LJ, Collinson N, Cook GP, Curtis N, Freedman SB, Kulagowski JJ, Leeson PD, Patel S, Ragan CI, Ridgill M, Saywell KL, Tricklebank MD (1997) L-745,870, a subtype selective dopamine D4 receptor antagonist, does not exhibit a neuroleptic-like profile in rodent behavioral tests. J Pharmacol Exp Ther 283:1256–1263PubMedGoogle Scholar
  18. Brown WD, Taylor MD, Roberts AD, Oakes TR, Schueller MJ, Holden JE, Malischke LM, DeJesus OT, Nickles RJ (1999) FluoroDOPA PET shows the nondopaminergic as well as dopaminergic destinations of levodopa. Neurology 53:1212–1218PubMedGoogle Scholar
  19. Buchanan RW, Breier A, Kirkpatrick B, Ball P, Carpenter WT Jr (1998) Positive and negative symptom response to clozapine in schizophrenic patients with and without the deficit syndrome. Am J Psychiatry 155:751–760PubMedGoogle Scholar
  20. Buchsbaum MS, Christian BT, Lehrer DS, Narayanan TK, Shi B, Mantil J, Kemether E, Oakes TR, Mukherjee J (2006) D2/D3 dopamine receptor binding with [F-18]fallypride in thalamus and cortex of patients with schizophrenia. Schizophr Res 85:232–244PubMedGoogle Scholar
  21. Burris KD, Molski TF, Xu C, Ryan E, Tottori K, Kikuchi T, Yocca FD, Molinoff PB (2002) Aripiprazole, a novel antipsychotic, is a high-affinity partial agonist at human dopamine D2 receptors. J Pharmacol Exp Ther 302:381–389PubMedGoogle Scholar
  22. Burt DR, Creese I, Snyder SH (1977) Antischizophrenic drugs: chronic treatment elevates dopamine receptor binding in brain. Science 196:326–328PubMedGoogle Scholar
  23. Carlsson A, Lindqvist M (1963) Effect of chlorpromazine or haloperidol on formation of 3-methoxytyramine and normetanephrine in mouse brain. Acta Pharmacol Toxicol 20:140–144Google Scholar
  24. Carlsson A, Lindqvist M, Magnusson T (1957) 3,4-dihydroxyphenylalanine and 5-hydroxytryptophan as reserpine antagonists. Nature 180:1200PubMedGoogle Scholar
  25. Carman J, Peuskens J, Vangeneugden A (1995) Risperidone in the treatment of negative symptoms of schizophrenia: a meta-analysis. Int Clin Psychopharmacol 10:207–213PubMedGoogle Scholar
  26. Catafau AM, Corripio I, Perez V, Martin JC, Schotte A, Carrio I, Alvarez E (2006) Dopamine D2 receptor occupancy by risperidone: implications for the timing and magnitude of clinical response. Psychiatry Res 148:175–183PubMedGoogle Scholar
  27. Catafau AM, Penengo MM, Nucci G, Bullich S, Corripio I, Parellada E, Garcia-Ribera C, Gomeni R, Merlo-Pich E (2008) Pharmacokinetics and time-course of D(2) receptor occupancy induced by atypical antipsychotics in stabilized schizophrenic patients. J Psychopharmacol 22:882–894PubMedGoogle Scholar
  28. Chiodo LA, Bunney BS (1983) Typical and atypical neuroleptics: differential effects of chronic administration on the activity of A9 and A10 midbrain dopaminergic neurons. J Neurosci 3:1607–1619PubMedGoogle Scholar
  29. Connell PH (1958) Amphetamine psychosis. Oxford University Press, LondonGoogle Scholar
  30. Copolov DL, Link CG, Kowalcyk B (2000) A multicentre, double-blind, randomized comparison of quetiapine (ICI 204,636, ‘seroquel’) and haloperidol in schizophrenia. Psychol Med 30:95–105PubMedGoogle Scholar
  31. Correll CU, Schenk EM (2008) Tardive dyskinesia and new antipsychotics. Curr Opin Psychiatry 21:151–156PubMedGoogle Scholar
  32. Correll CU, Malhotra AK, Kaushik S, McMeniman M, Kane JM (2003) Early prediction of antipsychotic response in schizophrenia. Am J Psychiatry 160:2063–2065PubMedGoogle Scholar
  33. Corrigan MH, Gallen CC, Bonura ML, Merchant KM (2004) Effectiveness of the selective D4 antagonist sonepiprazole in schizophrenia: a placebo-controlled trial. Biol Psychiatry 55:445–451PubMedGoogle Scholar
  34. Creese I, Burt DR, Snyder SH (1976) Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs. Science 192:481–483PubMedGoogle Scholar
  35. Dao-Castellana MH, Paillere-Martinot ML, Hantraye P, Attar-Levy D, Remy P, Crouzel C, Artiges E, Feline A, Syrota A, Martinot JL (1997) Presynaptic dopaminergic function in the striatum of schizophrenic patients. Schizophr Res 23:167–174PubMedGoogle Scholar
  36. Davis KL, Kahn RS, Ko G, Davidson M (1991) Dopamine in schizophrenia: a review and reconceptualization. Am J Psychiatry 148:1474–1486PubMedGoogle Scholar
  37. Davis JM, Chen N, Glick ID (2003) A meta-analysis of the efficacy of second-generation antipsychotics. Arch Gen Psychiatry 60:553–564PubMedGoogle Scholar
  38. Day JJ, Roitman MF, Wightman RM, Carelli RM (2007) Associative learning mediates dynamic shifts in dopamine signaling in the nucleus accumbens. Nat Neurosci 10:1020–1028PubMedGoogle Scholar
  39. Diaconescu AO, Jensen J, Wang H, Willeit M, Menon M, Kapur S, McIntosh AR (2011) Aberrant effective connectivity in schizophrenia patients during appetitive conditioning. Front Hum Neurosci 4:239. doi: 10.3389/fnhum.2010.00239Google Scholar
  40. Elkashef AM, Doudet D, Bryant T, Cohen RM, Li SH, Wyatt RJ (2000) 6-(18)F-DOPA PET study in patients with schizophrenia. Positron emission tomography. Psychiatry Res 100:1–11PubMedGoogle Scholar
  41. Farde L, Wiesel FA, Hall H, Halldin C, Stone-Elander S, Sedvall G (1987) No D2 receptor increase in PET study of schizophrenia. Arch Gen Psychiatry 44:671–672PubMedGoogle Scholar
  42. Farde L, Wiesel FA, Nordstrom AL, Sedvall G (1989) D1- and D2-dopamine receptor occupancy during treatment with conventional and atypical neuroleptics. Psychopharmacology (Berl) 99:S28–S31Google Scholar
  43. Farde L, Nordstrom AL, Wiesel FA, Pauli S, Halldin C, Sedvall G (1992) 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 49:538–544PubMedGoogle Scholar
  44. Gardner EL, Seeger TF (1983) Neurobehavioral evidence for mesolimbic specificity of action by clozapine: studies using electrical intracranial self-stimulation. Biol Psychiatry 18:1357–1362PubMedGoogle Scholar
  45. Gefvert O, Bergström M, Långström B, Lundberg T, Lindström L, Yates R (1998) Time course of central nervous dopamine-D2 and 5-HT2 receptor blockade and plasma drug concentrations after discontinuation of quetiapine (seroquel) in patients with schizophrenia. Psychopharmacology (Berl) 135:119–126Google Scholar
  46. Ginovart N (2005) Imaging the dopamine system with in vivo [11C]raclopride displacement studies: understanding the true mechanism. Mol Imaging Biol 7:45–52PubMedGoogle Scholar
  47. Ginovart N, Wilson AA, Hussey D, Houle S, Kapur S (2009) D2-receptor upregulation is dependent upon temporal course of D2-occupancy: a longitudinal [11C]-raclopride PET study in cats. Neuropsychopharmacology 34:662–671PubMedGoogle Scholar
  48. Glenthoj BY, Mackeprang T, Svarer C, Rasmussen H, Pinborg LH, Friberg L, Baare W, Hemmingsen R, Videbaek C (2006) Frontal dopamine D(2/3) receptor binding in drug-naive first-episode schizophrenic patients correlates with positive psychotic symptoms and gender. Biol Psychiatry 60:621–629PubMedGoogle Scholar
  49. Goldberg SC (1985) Negative and deficit symptoms in schizophrenia do respond to neuroleptics. Schizophr Bull 11:453–456PubMedGoogle Scholar
  50. Goldstein JM (1999) Quetiapine fumarate (seroquel): a new atypical antipsychotic. Drugs Today (Barc) 35:193–210Google Scholar
  51. Goldstein JM (2000) The new generation of antipsychotic drugs: how atypical are they? Int J Neuropsychopharmacol 3:339–349PubMedGoogle Scholar
  52. Goldstein JM, Litwin LC, Sutton EB, Malick JB (1993) Seroquel: electrophysiological profile of a potential atypical antipsychotic. Psychopharmacology (Berl) 112:293–298Google Scholar
  53. Grace AA (1991) Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia. Neuroscience 41:1–24PubMedGoogle Scholar
  54. Grace AA, Bunney BS, Moore H, Todd CL (1997) Dopamine-cell depolarization block as a model for the therapeutic actions of antipsychotic drugs. Trends Neurosci 20:31–37PubMedGoogle Scholar
  55. Graff-Guerrero A, Mamo D, Shammi CM, Mizrahi R, Marcon H, Barsoum P, Rusjan P, Houle S, Wilson AA, Kapur S (2009a) The effect of antipsychotics on the high-affinity state of D2 and D3 receptors: a positron emission tomography study with [11C]-(+)-PHNO. Arch Gen Psychiatry 66:606–615PubMedGoogle Scholar
  56. Graff-Guerrero A, Mizrahi R, Agid O, Marcon H, Barsoum P, Rusjan P, Wilson AA, Zipursky R, Kapur S (2009b) The dopamine D2 receptors in high-affinity state and D3 receptors in schizophrenia: a clinical [11C]-(+)-PHNO PET study. Neuropsychopharmacology 34:1078–1086PubMedGoogle Scholar
  57. Gross G, Drescher K (2012) The role of dopamine D3 receptors for antipsychotic activity and cognitive functions. In: Gross G, Geyer M (eds) Handbook of Experimental Pharmacology, vol 213. Current Antipsychotics. Springer, HeidelbergGoogle Scholar
  58. Gründer G, Fellows C, Janouschek H, Veselinovic T, Boy C, Brocheler A, Kirschbaum KM, Hellmann S, Spreckelmeyer KM, Hiemke C, Rosch F, Schaefer WM, Vernaleken I (2008) Brain and plasma pharmacokinetics of aripiprazole in patients with schizophrenia: an [18F]fallypride PET study. Am J Psychiatry 165(8):988–995PubMedGoogle Scholar
  59. Hand TH, Hu XT, Wang RY (1987) Differential effects of acute clozapine and haloperidol on the activity of ventral tegmental (A10) and nigrostriatal (A9) dopamine neurons. Brain Res 415:257–269PubMedGoogle Scholar
  60. Haro JM, Salvador-Carulla L (2006) The SOHO (schizophrenia outpatient health outcome) study: implications for the treatment of schizophrenia. CNS Drugs 20:293–301PubMedGoogle Scholar
  61. Haro JM, Novick D, Suarez D, Roca M (2009) Antipsychotic treatment discontinuation in previously untreated patients with schizophrenia: 36-month results from the SOHO study. J Psychiatr Res 43(3):265–273PubMedGoogle Scholar
  62. Hellewell JS (1999) Treatment-resistant schizophrenia: reviewing the options and identifying the way forward. J Clin Psychiatry 60(Suppl 23):14–19PubMedGoogle Scholar
  63. Hertel P (2006) Comparing sertindole to other new generation antipsychotics on preferential dopamine output in limbic versus striatal projection regions: mechanism of action. Synapse 60:543–552PubMedGoogle Scholar
  64. Hietala J, Syvalahti E, Vuorio K, Nagren K, Lehikoinen P, Ruotsalainen U, Rakkolainen V, Lehtinen V, Wegelius U (1994) Striatal D2 dopamine receptor characteristics in neuroleptic-naive schizophrenic patients studied with positron emission tomography. Arch Gen Psychiatry 51:116–123PubMedGoogle Scholar
  65. Hietala J, Syvalahti E, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M, Solin O, Kuoppamaki M, Kirvela O, Ruotsalainen U et al (1995) Presynaptic dopamine function in striatum of neuroleptic-naive schizophrenic patients. Lancet 346:1130–1131PubMedGoogle Scholar
  66. Hietala J, Syvalahti E, Vilkman H, Vuorio K, Rakkolainen V, Bergman J, Haaparanta M, Solin O, Kuoppamaki M, Eronen E, Ruotsalainen U, Salokangas RK (1999) Depressive symptoms and presynaptic dopamine function in neuroleptic-naive schizophrenia. Schizophr Res 35:41–50PubMedGoogle Scholar
  67. Howes OD, Kapur S (2009) The dopamine hypothesis of schizophrenia: version III–the final common pathway. Schizophr Bull 35:549–562PubMedGoogle Scholar
  68. Howes OD, Montgomery AJ, Asselin MC, Murray RM, Valli I, Tabraham P, Bramon-Bosch E, Valmaggia L, Johns L, Broome M, McGuire PK, Grasby PM (2009) Elevated striatal dopamine function linked to prodromal signs of schizophrenia. Arch Gen Psychiatry 66:13–20PubMedGoogle Scholar
  69. Ito H, Arakawa R, Takahashi H, Takano H, Okumura M, Otsuka T, Ikoma Y, Shidahara M, Suhara T (2009) No regional difference in dopamine D2 receptor occupancy by the second-generation antipsychotic drug risperidone in humans: a positron emission tomography study. Int J Neuropsychopharmacol 12(5):667–675PubMedGoogle Scholar
  70. Jauss M, Schroder J, Pantel J, Bachmann S, Gerdsen I, Mundt C (1998) Severe akathisia during olanzapine treatment of acute schizophrenia. Pharmacopsychiatry 31:146–148PubMedGoogle Scholar
  71. Jensen J, Willeit M, Zipursky RB, Savina I, Smith AJ, Menon M, Crawley AP, Kapur S (2008) The formation of abnormal associations in schizophrenia: neural and behavioral evidence. Neuropsychopharmacology 33:473–479PubMedGoogle Scholar
  72. Jones PB, Barnes TR, Davies L, Dunn G, Lloyd H, Hayhurst KP, Murray RM, Markwick A, Lewis SW (2006) 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 63:1079–1087PubMedGoogle Scholar
  73. Kane J, Honigfeld G, Singer J, Meltzer H (1988) Clozapine for the treatment-resistant schizophrenic. A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789–796PubMedGoogle Scholar
  74. Kane JM, Carson WH, Saha AR, McQuade RD, Ingenito GG, Zimbroff DL, Ali MW (2002) Efficacy and safety of aripiprazole and haloperidol versus placebo in patients with schizophrenia and schizoaffective disorder. J Clin Psychiatry 63:763–771PubMedGoogle Scholar
  75. Kapur S (2003) Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160:13–23PubMedGoogle Scholar
  76. Kapur S, Mamo D (2003) Half a century of antipsychotics and still a central role for dopamine D2 receptors. Prog Neuropsychopharmacol Biol Psychiatry 27:1081–1090PubMedGoogle Scholar
  77. Kapur S, Remington G (2001a) Atypical antipsychotics: new directions and new challenges in the treatment of schizophrenia. Annu Rev Med 52:503–517PubMedGoogle Scholar
  78. Kapur S, Remington G (2001b) Dopamine D(2) receptors and their role in atypical antipsychotic action: still necessary and may even be sufficient. Biol Psychiatry 50:873–883PubMedGoogle Scholar
  79. Kapur S, Zipursky R, Remington G, Jones C, McKay G, Houle S (1997) PET evidence that loxapine is an equipotent blocker of 5-HT2 and D2 receptors: implications for the therapeutics of schizophrenia. Am J Psychiatry 154:1525–1529PubMedGoogle Scholar
  80. Kapur S, Zipursky RB, Remington G, Jones C, DaSilva J, Wilson AA, Houle S (1998) 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 155:921–928PubMedGoogle Scholar
  81. Kapur S, Zipursky RB, Remington G (1999) Clinical and theoretical implications of 5-HT2 and D2 receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 156:286–293PubMedGoogle Scholar
  82. Kapur S, Zipursky R, Jones C, Remington G, Houle S (2000a) Relationship between dopamine D(2) occupancy, clinical response, and side effects: a double-blind PET study of first-episode schizophrenia. Am J Psychiatry 157:514–520PubMedGoogle Scholar
  83. Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P (2000b) 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 57:553–559PubMedGoogle Scholar
  84. Kapur S, Langlois X, Vinken P, Megens AA, De Coster R, Andrews JS (2002) The differential effects of atypical antipsychotics on prolactin elevation are explained by their differential blood-brain disposition: a pharmacological analysis in rats. J Pharmacol Exp Ther 302:1129–1134PubMedGoogle Scholar
  85. Kapur S, Mizrahi R, Li M (2005) From dopamine to salience to psychosis–linking biology, pharmacology and phenomenology of psychosis. Schizophr Res 79:59–68PubMedGoogle Scholar
  86. Karlsson P, Farde L, Halldin C, Sedvall G (2002) PET study of D(1) dopamine receptor binding in neuroleptic-naive patients with schizophrenia. Am J Psychiatry 159:761–767PubMedGoogle Scholar
  87. Kegeles LS, Slifstein M, Frankle WG, Xu X, Hackett E, Bae SA, Gonzales R, Kim JH, Alvarez B, Gil R, Laruelle M, Abi-Dargham A (2008) Dose-occupancy study of striatal and extrastriatal dopamine D2 receptors by aripiprazole in schizophrenia with PET and [18F]fallypride. Neuropsychopharmacology 33:3111–3125PubMedGoogle Scholar
  88. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2005) Occupancy of striatal and extrastriatal dopamine D2/D3 receptors by olanzapine and haloperidol. Neuropsychopharmacology 30:2283–2289PubMedGoogle Scholar
  89. Kessler RM, Ansari MS, Riccardi P, Li R, Jayathilake K, Dawant B, Meltzer HY (2006) Occupancy of striatal and extrastriatal dopamine D2 receptors by clozapine and quetiapine. Neuropsychopharmacology 31:1991–2001PubMedGoogle Scholar
  90. Kessler RM, Woodward ND, Riccardi P, Li R, Ansari MS, Anderson S, Dawant B, Zald D, Meltzer HY (2009) Dopamine D2 receptor levels in striatum, thalamus, substantia nigra, limbic regions, and cortex in schizophrenic subjects. Biol Psychiatry 65:1024–1031PubMedGoogle Scholar
  91. Kestler LP, Walker E, Vega EM (2001) Dopamine receptors in the brains of schizophrenia patients: a meta-analysis of the findings. Behav Pharmacol 12:355–371PubMedGoogle Scholar
  92. Kinon BJ, Chen L, Ascher-Svanum H, Stauffer VL, Kollack-Walker S, Sniadecki JL, Kane JM (2008) Predicting response to atypical antipsychotics based on early response in the treatment of schizophrenia. Schizophr Res 102:230–240PubMedGoogle Scholar
  93. Kinon BJ, Chen L, Ascher-Svanum H, Stauffer VL, Kollack-Walker S, Zhou W, Kapur S, Kane JM (2011) Early response to antipsychotic drug therapy as a clinical marker of subsequent response in the treatment of schizophrenia. Neuropsychopharmacology 35(2):581–590. doi: 10.1038/npp. 2009.164Google Scholar
  94. Knable MB, Heinz A, Raedler T, Weinberger DR (1997) Extrapyramidal side effects with risperidone and haloperidol at comparable D2 receptor occupancy levels. Psychiatry Res 75:91–101PubMedGoogle Scholar
  95. Kramer MS, Last B, Getson A, Reines SA (1997) The effects of a selective D4 dopamine receptor antagonist (L-745,870) in acutely psychotic inpatients with schizophrenia. D4 dopamine antagonist group. Arch Gen Psychiatry 54:567–572PubMedGoogle Scholar
  96. Kuhar MJ, Joyce AR (2001) Slow onset of CNS drugs: can changes in protein concentration account for the delay? Trends Pharmacol Sci 22:450–456PubMedGoogle Scholar
  97. Kumakura Y, Cumming P, Vernaleken I, Buchholz HG, Siessmeier T, Heinz A, Kienast T, Bartenstein P, Gründer G (2007) Elevated [18 F]fluorodopamine turnover in brain of patients with schizophrenia: an [18 F]fluorodopa/positron emission tomography study. J Neurosci 27:8080–8087PubMedGoogle Scholar
  98. Lambert M, Schimmelmann BG, Karow A, Naber D (2003) Subjective well-being and initial dysphoric reaction under antipsychotic drugs - concepts, measurement and clinical relevance. Pharmacopsychiatry 36(Suppl 3):S181–S190PubMedGoogle Scholar
  99. Lambert M, Schimmelmann BG, Schacht A, Suarez D, Haro JM, Novick D, Wagner T, Wehmeier PM, Huber CG, Hundemer HP, Dittmann RW, Naber D (2011) Differential 3-year effects of first- versus second-generation antipsychotics on subjective well-being in schizophrenia using marginal structural models. J Clin Psychopharmacol 31:226–230PubMedGoogle Scholar
  100. Lane RF, Blaha CD, Rivet JM (1988) Selective inhibition of mesolimbic dopamine release following chronic administration of clozapine: involvement of alpha 1-noradrenergic receptors demonstrated by in vivo voltammetry. Brain Res 460:398–401PubMedGoogle Scholar
  101. Laruelle M (1998) Imaging dopamine transmission in schizophrenia. A review and meta-analysis. Q J Nucl Med 42:211–221PubMedGoogle Scholar
  102. Laruelle M (2000) Imaging synaptic neurotransmission with in vivo binding competition techniques: a critical review. J Cereb Blood Flow Metab 20:423–451PubMedGoogle Scholar
  103. Laruelle M, Abi-Dargham A, van Dyck CH, Gil R, D’Souza CD, Erdos J, McCance E, Rosenblatt W, Fingado C, Zoghbi SS, Baldwin RM, Seibyl JP, Krystal JH, Charney DS, Innis RB (1996) Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects. Proc Natl Acad Sci U S A 93:9235–9240PubMedGoogle Scholar
  104. Lee T, Seeman P, Tourtellotte WW, Farley IJ, Hornykeiwicz O (1978) Binding of 3H-neuroleptics and 3H-apomorphine in schizophrenic brains. Nature 274:897–900PubMedGoogle Scholar
  105. Lemmens P, Brecher M, Van Baelen B (1999) A combined analysis of double-blind studies with risperidone vs. Placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms. Acta Psychiatr Scand 99:160–170PubMedGoogle Scholar
  106. Leucht S, Pitschel-Walz G, Abraham D, Kissling W (1999) Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials. Schizophr Res 35:51–68PubMedGoogle Scholar
  107. Leucht S, Busch R, Hamann J, Kissling W, Kane JM (2005) Early-onset hypothesis of antipsychotic drug action: a hypothesis tested, confirmed and extended. Biol Psychiatry 57:1543–1549PubMedGoogle Scholar
  108. Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM (2009) Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis. Lancet 373:31–41PubMedGoogle Scholar
  109. Levant B (1997) The D3 dopamine receptor: neurobiology and potential clinical relevance. Pharmacol Rev 49:231–252PubMedGoogle Scholar
  110. Lewander T (1994) Neuroleptics and the neuroleptic-induced deficit syndrome. Acta Psychiatr Scand Suppl 380:8–13PubMedGoogle Scholar
  111. Lieberman JA, Kane JM, Johns CA (1989) Clozapine: guidelines for clinical management. J Clin Psychiatry 50:329–338PubMedGoogle Scholar
  112. Lieberman JA, Stroup TS, McEvoy JP, Swartz MS, Rosenheck RA, Perkins DO, Keefe RS, Davis SM, Davis CE, Lebowitz BD, Severe J, Hsiao JK (2005) Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 353:1209–1223PubMedGoogle Scholar
  113. Lindstrom LH, Gefvert O, Hagberg G, Lundberg T, Bergstrom M, Hartvig P, Langstrom B (1999) Increased dopamine synthesis rate in medial prefrontal cortex and striatum in schizophrenia indicated by L-(beta-11C) DOPA and PET. Biol Psychiatry 46:681–688PubMedGoogle Scholar
  114. Ljungberg T, Ungerstedt U (1985) A rapid and simple behavioural screening method for simultaneous assessment of limbic and striatal blocking effects of neuroleptic drugs. Pharmacol Biochem Behav 23:479–485PubMedGoogle Scholar
  115. Lomena F, Catafau AM, Parellada E, Bernardo M, Font M, Gutierrez F, Pavia J (2004) Striatal dopamine D2 receptor density in neuroleptic-naive and in neuroleptic-free schizophrenic patients: an 123I-IBZM-SPECT study. Psychopharmacology (Berl) 172:165–169Google Scholar
  116. Luft B, Taylor D (2006) A review of atypical antipsychotic drugs versus conventional medication in schizophrenia. Expert Opin Pharmacother 7:1739–1748PubMedGoogle Scholar
  117. Mamo D, Graff A, Mizrahi R, Shammi CM, Romeyer F, Kapur S (2007) Differential effects of aripiprazole on D(2), 5-HT(2), and 5-HT(1A) receptor occupancy in patients with schizophrenia: a triple tracer PET study. Am J Psychiatry 164:1411–1417PubMedGoogle Scholar
  118. Marder SR (2005) Subjective experiences on antipsychotic medications: synthesis and conclusions. Acta Psychiatr Scand Suppl 111(427):43–46Google Scholar
  119. McCormick PN, Kapur S, Graff-Guerrero A, Raymond R, Nobrega JN, Wilson AA (2011) The antipsychotics olanzapine, risperidone, clozapine, and haloperidol are D2-selective ex vivo but not in vitro. Neuropsychopharmacology 35(8):1826–1835. doi: 10.1038/npp. 2010.50Google Scholar
  120. McGowan S, Lawrence AD, Sales T, Quested D, Grasby P (2004) Presynaptic dopaminergic dysfunction in schizophrenia: a positron emission tomographic [18F]fluorodopa study. Arch Gen Psychiatry 61:134–142PubMedGoogle Scholar
  121. Meltzer HY (2004) What’s atypical about atypical antipsychotic drugs? Curr Opin Pharmacol 4:53–57PubMedGoogle Scholar
  122. Meltzer HY, Matsubara S, Lee JC (1989) The ratios of serotonin2 and dopamine2 affinities differentiate atypical and typical antipsychotic drugs. Psychopharmacol Bull 25:390–392PubMedGoogle Scholar
  123. Meltzer HY, Li Z, Kaneda Y, Ichikawa J (2003) Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 27:1159–1172PubMedGoogle Scholar
  124. Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (2002) Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia. Nat Neurosci 5:267–271PubMedGoogle Scholar
  125. Moghaddam B, Bunney BS (1990) Acute effects of typical and atypical antipsychotic drugs on the release of dopamine from prefrontal cortex, nucleus accumbens, and striatum of the rat: an in vivo microdialysis study. J Neurochem 54:1755–1760PubMedGoogle Scholar
  126. Möller HJ, Riedel M, Jager M, Wickelmaier F, Maier W, Kuhn KU, Buchkremer G, Heuser I, Klosterkötter J, Gastpar M, Braus DF, Schlosser R, Schneider F, Ohmann C, Riesbeck M, Gaebel W (2008) Short-term treatment with risperidone or haloperidol in first-episode schizophrenia: 8-week results of a randomized controlled trial within the German research network on schizophrenia. Int J Neuropsychopharmacol 11:985–997PubMedGoogle Scholar
  127. Morken G, Widen JH, Grawe RW (2008) Non-adherence to antipsychotic medication, relapse and rehospitalisation in recent-onset schizophrenia. BMC Psychiatry 8:32PubMedGoogle Scholar
  128. Murray GK, Corlett PR, Clark L, Pessiglione M, Blackwell AD, Honey G, Jones PB, Bullmore ET, Robbins TW, Fletcher PC (2008) Substantia nigra/ventral tegmental reward prediction error disruption in psychosis. Mol Psychiatry 13(239):267–276Google Scholar
  129. Naber D, Karow A, Lambert M (2005) Subjective well-being under the neuroleptic treatment and its relevance for compliance. Acta Psychiatr Scand Suppl 111(427):29–34Google Scholar
  130. Newcomer JW (2005) Second-generation (atypical) antipsychotics and metabolic effects: a comprehensive literature review. CNS Drugs 19(Suppl 1):1–93PubMedGoogle Scholar
  131. Nordstrom AL, Farde L, Halldin C (1992) Time course of D2-dopamine receptor occupancy examined by PET after single oral doses of haloperidol. Psychopharmacology (Berl) 106:433–438Google Scholar
  132. Nordstrom AL, Farde L, Eriksson L, Halldin C (1995) No elevated D2 dopamine receptors in neuroleptic-naive schizophrenic patients revealed by positron emission tomography and [11C]N-methylspiperone. Psychiatry Res 61:67–83PubMedGoogle Scholar
  133. Nordstrom AL, Nyberg S, Olsson H, Farde L (1998) Positron emission tomography finding of a high striatal D2 receptor occupancy in olanzapine-treated patients. Arch Gen Psychiatry 55:283–284PubMedGoogle Scholar
  134. Nozaki S, Kato M, Takano H, Ito H, Takahashi H, Arakawa R, Okumura M, Fujimura Y, Matsumoto R, Ota M, Takano A, Otsuka A, Yasuno F, Okubo Y, Kashima H, Suhara T (2009) Regional dopamine synthesis in patients with schizophrenia using L-[beta-11C]DOPA PET. Schizophr Res 108:78–84PubMedGoogle Scholar
  135. Nyberg S, Olsson H, Nilsson U, Maehlum E, Halldin C, Farde L (2002) Low striatal and extra-striatal D2 receptor occupancy during treatment with the atypical antipsychotic sertindole. Psychopharmacology (Berl) 162:37–41Google Scholar
  136. O’Connor SE, Brown RA (1982) The pharmacology of sulpiride—a dopamine receptor antagonist. Gen Pharmacol 13:185–193PubMedGoogle Scholar
  137. Oakley NR, Hayes AG, Sheehan MJ (1991) Effect of typical and atypical neuroleptics on the behavioural consequences of activation by muscimol of mesolimbic and nigro-striatal dopaminergic pathways in the rat. Psychopharmacology (Berl) 105:204–208Google Scholar
  138. Owen F, Cross AJ, Waddington JL, Poulter M, Gamble SJ, Crow TJ (1980) Dopamine-mediated behaviour and 3H-spiperone binding to striatal membranes in rats after nine months haloperidol administration. Life Sci 26:55–59PubMedGoogle Scholar
  139. Pae CU, Kim JJ, Lee CU, Lee SJ, Lee C, Patkar AA, Masand PS, Paik IH (2007) Rapid versus conventional initiation of quetiapine in the treatment of schizophrenia: a randomized, parallel-group trial. J Clin Psychiatry 68:399–405PubMedGoogle Scholar
  140. Patil ST, Zhang L, Martenyi F, Lowe SL, Jackson KA, Andreev BV, Avedisova AS, Bardenstein LM, Gurovich IY, Morozova MA, Mosolov SN, Neznanov NG, Reznik AM, Smulevich AB, Tochilov VA, Johnson BG, Monn JA, Schoepp DD (2007) Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nat Med 13:1102–1107PubMedGoogle Scholar
  141. Perala J, Suvisaari J, Saarni SI, Kuoppasalmi K, Isometsa E, Pirkola S, Partonen T, Tuulio-Henriksson A, Hintikka J, Kieseppa T, Harkanen T, Koskinen S, Lonnqvist J (2007) Lifetime prevalence of psychotic and bipolar I disorders in a general population. Arch Gen Psychiatry 64:19–28PubMedGoogle Scholar
  142. Pilowsky LS, Costa DC, Ell PJ, Verhoeff NP, Murray RM, Kerwin RW (1994) D2 dopamine receptor binding in the basal ganglia of antipsychotic-free schizophrenic patients. An 123I-IBZM single photon emission computerised tomography study. Br J Psychiatry 164:16–26PubMedGoogle Scholar
  143. Pilowsky LS, Mulligan RS, Acton PD, Ell PJ, Costa DC, Kerwin RW (1997) Limbic selectivity of clozapine. Lancet 350:490–491PubMedGoogle Scholar
  144. Reith J, Benkelfat C, Sherwin A, Yasuhara Y, Kuwabara H, Andermann F, Bachneff S, Cumming P, Diksic M, Dyve SE, Etienne P, Evans AC, Lal S, Shevell M, Savard G, Wong DF, Chouinard G, Gjedde A (1994) Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc Natl Acad Sci U S A 91:11651–11654PubMedGoogle Scholar
  145. Remington G, Seeman P, Shammi C, Mann S, Kapur S (2005) “Extended” antipsychotic dosing: rationale and pilot data. J Clin Psychopharmacol 25:611–613PubMedGoogle Scholar
  146. Remington G, Seeman P, Feingold A, Mann S, Shammi C, Kapur S (2011) “Extended” antipsychotic dosing in the maintenance treatment of schizophrenia: a double-blind, placebo-controlled trial. J Clin Psychiatry 72(8):1042–1048. doi: 10.4088/JCP.09m05866yelPubMedGoogle Scholar
  147. Robinson D, Woerner MG, Alvir JM, Bilder R, Goldman R, Geisler S, Koreen A, Sheitman B, Chakos M, Mayerhoff D, Lieberman JA (1999) Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder. Arch Gen Psychiatry 56:241–247PubMedGoogle Scholar
  148. Robinson DG, Woerner MG, Alvir JM, Bilder RM, Hinrichsen GA, Lieberman JA (2002) Predictors of medication discontinuation by patients with first-episode schizophrenia and schizoaffective disorder. Schizophr Res 57:209–219PubMedGoogle Scholar
  149. Rosenheck RA, Leslie DL, Sindelar J, Miller EA, Lin H, Stroup TS, McEvoy J, Davis SM, Keefe RS, Swartz M, Perkins DO, Hsiao JK, Lieberman J (2006) Cost-effectiveness of second-generation antipsychotics and perphenazine in a randomized trial of treatment for chronic schizophrenia. Am J Psychiatry 163:2080–2089PubMedGoogle Scholar
  150. Roth BL, Tandra S, Burgess LH, Sibley DR, Meltzer HY (1995) D4 dopamine receptor binding affinity does not distinguish between typical and atypical antipsychotic drugs. Psychopharmacology (Berl) 120:365–368Google Scholar
  151. Samaha AN, Seeman P, Stewart J, Rajabi H, Kapur S (2007) “Breakthrough” dopamine supersensitivity during ongoing antipsychotic treatment leads to treatment failure over time. J Neurosci 27:2979–2986PubMedGoogle Scholar
  152. Samaha AN, Reckless GE, Seeman P, Diwan M, Nobrega JN, Kapur S (2008) Less is more: antipsychotic drug effects are greater with transient rather than continuous delivery. Biol Psychiatry 64:145–152PubMedGoogle Scholar
  153. Schoemaker H, Claustre Y, Fage D, Rouquier L, Chergui K, Curet O, Oblin A, Gonon F, Carter C, Benavides J, Scatton B (1997) Neurochemical characteristics of amisulpride, an atypical dopamine D2/D3 receptor antagonist with both presynaptic and limbic selectivity. J Pharmacol Exp Ther 280:83–97PubMedGoogle Scholar
  154. Schooler NR (1994) Deficit symptoms in schizophrenia: negative symptoms versus neuroleptic-induced deficits. Acta Psychiatr Scand Suppl 380:21–26PubMedGoogle Scholar
  155. Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS, De Loore K, Leysen JE (1996) Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacology (Berl) 124:57–73Google Scholar
  156. Schultz W (2006) Behavioral theories and the neurophysiology of reward. Annu Rev Psychol 57:87–115PubMedGoogle Scholar
  157. Seeman P (1987) Dopamine receptors and the dopamine hypothesis of schizophrenia. Synapse 1:133–152PubMedGoogle Scholar
  158. Seeman P (2002) Atypical antipsychotics: mechanism of action. Can J Psychiatry 47:27–38PubMedGoogle Scholar
  159. Seeman P, Lee T (1975) Antipsychotic drugs: direct correlation between clinical potency and presynaptic action on dopamine neurons. Science 188:1217–1219PubMedGoogle Scholar
  160. Seeman P, Ulpian C, Bergeron C, Riederer P, Jellinger K, Gabriel E, Reynolds GP, Tourtellotte WW (1984) Bimodal distribution of dopamine receptor densities in brains of schizophrenics. Science 225:728–731PubMedGoogle Scholar
  161. Seeman P, Weinshenker D, Quirion R, Srivastava LK, Bhardwaj SK, Grandy DK, Premont RT, Sotnikova TD, Boksa P, El-Ghundi M, O’Dowd BF, George SR, Perreault ML, Mannisto PT, Robinson S, Palmiter RD, Tallerico T (2005) Dopamine supersensitivity correlates with D2high states, implying many paths to psychosis. Proc Natl Acad Sci U S A 102:3513–3518PubMedGoogle Scholar
  162. Skarsfeldt T (1988) Differential effects after repeated treatment with haloperidol, clozapine, thioridazine and tefludazine on SNC and VTA dopamine neurones in rats. Life Sci 42:1037–1044PubMedGoogle Scholar
  163. Skarsfeldt T, Perregaard J (1990) Sertindole, a new neuroleptic with extreme selectivity on A10 versus A9 dopamine neurones in the rat. Eur J Pharmacol 182:613–614PubMedGoogle Scholar
  164. Small JG, Kolar MC, Kellams JJ (2004) Quetiapine in schizophrenia: onset of action within the first week of treatment. Curr Med Res Opin 20:1017–1023PubMedGoogle Scholar
  165. Stanniland C, Taylor D (2000) Tolerability of atypical antipsychotics. Drug Saf 22:195–214PubMedGoogle Scholar
  166. Stephenson CM, Bigliani V, Jones HM, Mulligan RS, Acton PD, Visvikis D, Ell PJ, Kerwin RW, Pilowsky LS (2000) Striatal and extra-striatal D(2)/D(3) dopamine receptor occupancy by quetiapine in vivo. [(123)I]-epidepride single photon emission tomography (SPET) study. Br J Psychiatry 177:408–415PubMedGoogle Scholar
  167. Stockton ME, Rasmussen K (1996) Electrophysiological effects of olanzapine, a novel atypical antipsychotic, on A9 and A10 dopamine neurons. Neuropsychopharmacology 14:97–105PubMedGoogle Scholar
  168. Strange PG (2001) Antipsychotic drugs: importance of dopamine receptors for mechanisms of therapeutic actions and side effects. Pharmacol Rev 53:119–133PubMedGoogle Scholar
  169. Suhara T, Okubo Y, Yasuno F, Sudo Y, Inoue M, Ichimiya T, Nakashima Y, Nakayama K, Tanada S, Suzuki K, Halldin C, Farde L (2002) Decreased dopamine D2 receptor binding in the anterior cingulate cortex in schizophrenia. Arch Gen Psychiatry 59:25–30PubMedGoogle Scholar
  170. Talvik M, Nordstrom AL, Nyberg S, Olsson H, Halldin C, Farde L (2001) No support for regional selectivity in clozapine-treated patients: a PET study with [(11)C]raclopride and [(11)C]FLB 457. Am J Psychiatry 158:926–930PubMedGoogle Scholar
  171. Talvik M, Nordstrom AL, Olsson H, Halldin C, Farde L (2003) Decreased thalamic D2/D3 receptor binding in drug-naive patients with schizophrenia: a PET study with [11C]FLB 457. Int J Neuropsychopharmacol 6:361–370PubMedGoogle Scholar
  172. Talvik M, Nordstrom AL, Okubo Y, Olsson H, Borg J, Halldin C, Farde L (2006) Dopamine D2 receptor binding in drug-naive patients with schizophrenia examined with raclopride-C11 and positron emission tomography. Psychiatry Res 148:165–173PubMedGoogle Scholar
  173. Tamminga CA (2002) Partial dopamine agonists in the treatment of psychosis. J Neural Transm 109:411–420PubMedGoogle Scholar
  174. Tarsy D, Baldessarini RJ (1977) The pathophysiologic basis of tardive dyskinesia. Biol Psychiatry 12:431–450PubMedGoogle Scholar
  175. Tauscher J, Jones C, Remington G, Zipursky RB, Kapur S (2002) Significant dissociation of brain and plasma kinetics with antipsychotics. Mol Psychiatry 7:317–321PubMedGoogle Scholar
  176. Tauscher-Wisniewski S, Kapur S, Tauscher J, Jones C, Daskalakis ZJ, Papatheodorou G, Epstein I, Christensen BK, Zipursky RB (2002) Quetiapine: an effective antipsychotic in first-episode schizophrenia despite only transiently high dopamine-2 receptor blockade. J Clin Psychiatry 63:992–997PubMedGoogle Scholar
  177. Tort AB, Souza DO, Lara DR (2005) On the simulation of the time-course of dopamine D2 receptor occupancy from the pharmacokinetics of antipsychotics. Int J Neuropsychopharmacol 8:137–139PubMedGoogle Scholar
  178. Trichard C, Paillere-Martinot ML, Attar-Levy D, Recassens C, Monnet F, Martinot JL (1998) Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients. Am J Psychiatry 155:505–508PubMedGoogle Scholar
  179. Tsuang M (2000) Schizophrenia: genes and environment. Biol Psychiatry 47:210–220PubMedGoogle Scholar
  180. Tune LE, Wong DF, Pearlson G, Strauss M, Young T, Shaya EK, Dannals RF, Wilson AA, Ravert HT, Sapp J et al (1993) Dopamine D2 receptor density estimates in schizophrenia: a positron emission tomography study with 11C-N-methylspiperone. Psychiatry Res 49:219–237PubMedGoogle Scholar
  181. Turrone P, Remington G, Kapur S, Nobrega JN (2003) Differential effects of within-day continuous vs. Transient dopamine D2 receptor occupancy in the development of vacuous chewing movements (VCMs) in rats. Neuropsychopharmacology 28:1433–1439PubMedGoogle Scholar
  182. van Rossum JM (1966) The significance of dopamine-receptor blockade for the mechanism of action of neuroleptic drugs. Arch Int Pharmacodyn Ther 160:492–494PubMedGoogle Scholar
  183. Van Tol HH, Bunzow JR, Guan HC, Sunahara RK, Seeman P, Niznik HB, Civelli O (1991) Cloning of the gene for a human dopamine D4 receptor with high affinity for the antipsychotic clozapine. Nature 350:610–614PubMedGoogle Scholar
  184. Vernaleken I, Janouschek H, Raptis M, Hellmann S, Veselinovic T, Brocheler A, Boy C, Cumming P, Hiemke C, Rosch F, Schafer WM, Gründer G (2011) Dopamine D2/3 receptor occupancy by quetiapine in striatal and extrastriatal areas. Int J Neuropsychopharmacol 13(7):951–960. doi: 10.1017/S1461145710000374Google Scholar
  185. Voruganti L, Awad AG (2004) Neuroleptic dysphoria: towards a new synthesis. Psychopharmacology (Berl) 171:121–132Google Scholar
  186. Walker E, Kestler L, Bollini A, Hochman KM (2004) Schizophrenia: etiology and course. Annu Rev Psychol 55:401–430PubMedGoogle Scholar
  187. White FJ, Wang RY (1983) Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons. Science 221:1054–1057PubMedGoogle Scholar
  188. Wong DF, Wagner HN Jr, Tune LE, Dannals RF, Pearlson GD, Links JM, Tamminga CA, Broussolle EP, Ravert HT, Wilson AA, Toung JK, Malat J, Williams JA, O’Tuama LA, Snyder SH, Kuhar MJ, Gjedde A (1986) Positron emission tomography reveals elevated D2 dopamine receptors in drug-naive schizophrenics. Science 234:1558–1563PubMedGoogle Scholar
  189. Xiberas X, Martinot JL, Mallet L, Artiges E, Loc HC, Maziere B, Paillere-Martinot ML (2001) Extrastriatal and striatal D(2) dopamine receptor blockade with haloperidol or new antipsychotic drugs in patients with schizophrenia. Br J Psychiatry 179:503–508PubMedGoogle Scholar
  190. Yang YK, Yu L, Yeh TL, Chiu NT, Chen PS, Lee IH (2004) Associated alterations of striatal dopamine D2/D3 receptor and transporter binding in drug-naive patients with schizophrenia: a dual-isotope SPECT study. Am J Psychiatry 161:1496–1498PubMedGoogle Scholar
  191. Youngren KD, Inglis FM, Pivirotto PJ, Jedema HP, Bradberry CW, Goldman-Rakic PS, Roth RH, Moghaddam B (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20:403–412PubMedGoogle Scholar
  192. Zakzanis KK, Hansen KT (1998) Dopamine D2 densities and the schizophrenic brain. Schizophr Res 32:201–206PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Psychiatry, Unité de NeuroimagerieUniversity of Geneva, Hôpital Belle IdéeGenevaSwitzerland
  2. 2.Department of Psychological MedicineInstitute of Psychiatry, King’s College LondonLondonUK

Personalised recommendations