Clinical Pharmacokinetics

, Volume 46, Issue 5, pp 359–388

Clinical Pharmacokinetics of Atypical Antipsychotics

A Critical Review of the Relationship Between Plasma Concentrations and Clinical Response
  • Massimo C. Mauri
  • Lucia S. Volonteri
  • Alessandro Colasanti
  • Alessio Fiorentini
  • Ilaria F. De Gaspari
  • Silvio R. Bareggi
Review Article


In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients’ quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of Clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics.

In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects.

Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods.

Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350–420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking.

The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form.

The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20–50 ng/mL has been found.

There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial.

Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100–400 ng/mL is proposed from non-systematic clinical experience.

There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.


  1. 1.
    Brodie BB. Displacement of one drug by another from carrier or receptor sites. Proc R Soc Med 1965; 58: 946–55PubMedGoogle Scholar
  2. 2.
    Buur-Rasmussen B, Brosen K. Cytochrome P450 and therapeutic drug monitoring with respect to Clozapine. Eur Neuropsychopharmacol 1999; 9: 453–9PubMedCrossRefGoogle Scholar
  3. 3.
    Prior TI, Chue PS, Tibbo P, et al. Drug metabolism and atypical antipsychotics. Eur Neuropsychopharmacol 1999; 9: 301–9PubMedCrossRefGoogle Scholar
  4. 4.
    Preskorn SH. Comments on the role of therapeutic drug monitoring for Clozapine. J Psychiatr Pract 2005; 11: 340–3PubMedCrossRefGoogle Scholar
  5. 5.
    Baumann P, Hiemke C, Ulrich S, et al. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry. Pharmacopsychiatry 2004; 37: 243–65PubMedCrossRefGoogle Scholar
  6. 6.
    Meltzer HY, Bastani B, Ramirez L, et al. Clozapine: new research on efficacy and mechanism of action. Eur Arch Psychiatry Neural Sci 1989; 238: 332–9CrossRefGoogle Scholar
  7. 7.
    Meltzer HY. The mechanism of action of clozapine in relation to its clinical advantages. In: Meltzer HY, editor. Novel antipsychotic drugs. New York: Raven Press Ltd, 1992: 1–13Google Scholar
  8. 8.
    Perry PJ, Miller DD, Arndt SV, et al. clozapine and norclozapine plasma concentrations and clinical response treatment-refractory schizophrenic patients. Am J Psychiatry 1991; 148: 231–5PubMedGoogle Scholar
  9. 9.
    Hasegawa M, Gutierrez-Esteinou R, Way L, et al. Relationship between clinical efficacy and clozapine concentration in plasma in schizophrenia: effect of smocking. J Clin Psychopharmacol 1993; 13: 383–90PubMedCrossRefGoogle Scholar
  10. 10.
    Potkin SG, Bera R, Gulasekaram B, et al. Plasma Clozapine concentrations predict clinical response in treatment-resistant schizophrenia. J Clin Psychiatry 1994; 55: 133–6PubMedGoogle Scholar
  11. 11.
    Kronig MH, Munne RA, Szymansky S, et al. Plasma Clozapine levels and clinical response for treatment-refractory schizophrenic patients. Am J Psychiatry 1995; 152: 179–82PubMedGoogle Scholar
  12. 12.
    Mauri MC, Volonteri LS, Fiorentini A, et al. Clinical outcome and plasma levels of clozapine and norclozapine in drugresistant schizophrenic patients. Schizophr Res 2004; 66: 197–8PubMedCrossRefGoogle Scholar
  13. 13.
    Freeman DJ, Oyewumi LK. Will routine therapeutic drug monitoring have a place in clozapine therapy? Clin Pharmacokinet 1997; 32: 95–100CrossRefGoogle Scholar
  14. 14.
    Khan AY, Preskorn SH. Examining concentration-dependence toxicity of Clozapine: role of therapeutic drug monitoring. J Psychiat Pract 2005; 11: 289–301CrossRefGoogle Scholar
  15. 15.
    Ackenheil VM, Brau H, Burkhart A, et al. Antipsychotic efficacy in relation to plasma levels of Clozapine. Arzneimttelforschung 1976; 26: 1156–8Google Scholar
  16. 16.
    Thorup M, Fog R. clozapine tretment of schizophrenic patients: plasma concentration and coagulation factors. Acta Psychiatr Scand 1977; 66: 123–6CrossRefGoogle Scholar
  17. 17.
    Brau VH, Burkhart A, Pacha W, et al. Relationships between effects and plasma levels of Clozapine. Arzneimttelforschung 1978; 28: 1300Google Scholar
  18. 18.
    Bell R, McLaren A, Galanos J, et al. The clinical use of plasma Clozapine levels. Aust N Z J Psychiatry 1998; 32: 567–74PubMedCrossRefGoogle Scholar
  19. 19.
    Volpicelli SA, Centorrino F, Puopolo PR, et al. Determination of Clozapine, norclozapine and clozapine-N-oxide in serum by liquid chromatography. Clin Chem 1993; 39: 1656–9PubMedGoogle Scholar
  20. 20.
    Palego L, Biondi L, Giannaccini G, et al. Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related veriables. Prog Neuropsychopharmacol Biol Psychiatry 2002; 26: 473–80PubMedCrossRefGoogle Scholar
  21. 21.
    Overall JE, Gorham DR. The Brief Psychiatric Rating Scale. Psychol Rep 1962; 10: 799–812CrossRefGoogle Scholar
  22. 22.
    Llorca PM, Lancon C, Disdier B, et al. Effectiveness of Clozapine in neuroleptic-resistent schizophrenia: clinical response and plasma concentrations. J Psychiatry Neurosci 2002; 27: 30–7PubMedGoogle Scholar
  23. 23.
    Kay SR, Fiszbein A, Opler LA. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophr Bull 1987; 13: 261–76PubMedCrossRefGoogle Scholar
  24. 24.
    Guy W. ECDEU assessment manual for psychopharmacology. DHEW publication no. 76-338. Bethesda (MD): US National Institute of Mental Health, 1976Google Scholar
  25. 25.
    Kane J, Honigfeld G, Singer J, et al. clozapine for the treatmentresistant schizophrenic: a double-blind comparison with clorpromazine. Arch Gen Psychiatry 1988; 45: 789–96PubMedCrossRefGoogle Scholar
  26. 26.
    Jann MW, Grimsley SR, Gray EC, et al. Pharmacokinetics and pharmacodynamics of Clozapine. Clin Pharmacokinetic 1993; 24: 161–76CrossRefGoogle Scholar
  27. 27.
    Choc MG, Lehr RG, Hsuan F, et al. Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res 1987 Oct; 4(5): 402–5PubMedCrossRefGoogle Scholar
  28. 28.
    Choc MG, Hsuan F, Honigfeld G, et al. Single- vs multiple-dose pharmacokinetics of clozapine in psychiatric patients. Pharm Res 1990 Apr; 7(4): 347–51PubMedCrossRefGoogle Scholar
  29. 29.
    Tugnait M, Hawes EM, Mc Kay G, et al. Characterization of the human hepatic cytochromes 450 involved in the in vitro oxidation of Clozapine. Chem Biol Interact 1999; 118: 171–89PubMedCrossRefGoogle Scholar
  30. 30.
    Centorrino F, Baldessarrini RJ, Kando JC, et al. clozapine and metabolites: concentrations in serum and clinical findings durino treatment of cronically psychotic patients. J Clin Psychopharmacol 1994; 14: 119–25PubMedCrossRefGoogle Scholar
  31. 31.
    Raggi MA, Mandrioli R, Sabbioni C, et al. Atypical antipsychotics: pharmaco-kinetics, theurapeutic drug monitoring and pharmacological interactions. Curr Med Chem 2004; 11: 279–96PubMedCrossRefGoogle Scholar
  32. 32.
    Jann MW, Liu HC, Wei FC, et al. Gender differences in plasma Clozapine leveld and its metabolites in schizophrenic patients. Hum Psychopharmacol 1997; 12: 489–95CrossRefGoogle Scholar
  33. 33.
    Kuoppamaki M, Syvalahti E, Hietala J. clozapine and N-desmethylclozapine are potent 5-HT1C receptor antagonists. Eur J Pharmacol 1993; 245: 179–82PubMedCrossRefGoogle Scholar
  34. 34.
    Olesen OV, Thomsen K, Jensen PN, et al. clozapine serum levels and side effects during steady state treatment of schizophrenic patients: a cross-sectional study. Psychopharmacology 1995; 117: 371–8PubMedCrossRefGoogle Scholar
  35. 35.
    Lane HY, Chang YC, Chang WH, et al. Effects of gender and age on plasma levels of clozapine and its metabolites: analyzed by critical statistics. J Clin Psychiatry 1999; 60: 36–40PubMedCrossRefGoogle Scholar
  36. 36.
    Cheng YF, Lundberg T, Bondesson U, et al. Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Psychopharmacol 1988; 34: 445–9Google Scholar
  37. 37.
    Haring C, Fleischhacker WW, Schett P, et al. Influence of patient-related variables on clozapine plasma levels. Am J Psychiatry 1990; 147: 1471–5PubMedGoogle Scholar
  38. 38.
    Ereshefsky L. Pharmacokinetics and drug interactions: update for new antipsychotics. J Clin Psychiatry 1996; 57 Suppl. 11: 12–25PubMedGoogle Scholar
  39. 39.
    Szymanski S, Lieberman J, Pollack S, et al. Gender differences in neuroleptic nonresponsive clozapine-treated schizophrenics. Biol Psychiatry 1996; 39: 249–54PubMedCrossRefGoogle Scholar
  40. 40.
    Fabrazzo M, Esposito G, Fusco R, et al. Effect of treatment duration on plasma levels of clozapine and N-desmethyl-clozapine in men and women. Psychopharmacology 1996; 124: 197–200PubMedCrossRefGoogle Scholar
  41. 41.
    Liu HC, Chang WH, Wei FC, et al. Monitoring of plasma Clozapine levels and its metabolites in refractory schizophrenic patients. Ther Drug Monit 1996; 18: 200–7PubMedCrossRefGoogle Scholar
  42. 42.
    Mauri MC, Volonteri LS, Dell’Osso B, et al. Predictors of clinical outcome in schizophrenic patients responding to Clozapine. J Clin Psychopharmacol 2003; 23: 1–5CrossRefGoogle Scholar
  43. 43.
    Andreasen NC. The Scale for the Assessment of Negative Symptoms (SANS). Iowa City (IA): University of Iowa Press, 1983Google Scholar
  44. 44.
    Andreasen NC. The Scale for the Assessment of Positive Symptoms (SAPS). Iowa City (IA): University of Iowa Press, 1984Google Scholar
  45. 45.
    Mauri MC, Rudelli R, Bravin S, et al. clozapine metabolism rate as a possible index of drug-induced granulocytopenia. Psychopharmacology 1998; 137: 341–4PubMedCrossRefGoogle Scholar
  46. 46.
    Dettling M, Sachse C, Brockmoller J, et al. Long-term therapeutic drug monitoring of clozapine and metabolites in psychiatric. Psychopharmacology (Berl) 2000; 152: 80–6CrossRefGoogle Scholar
  47. 47.
    Cooper TB. clozapine plasma level monitoring: current status. Psychiatr Quart 1996; 4: 297–311CrossRefGoogle Scholar
  48. 48.
    Spina E, Avenoso A, Facciolà G, et al. Relationship between plasma concentrations of clozapine and norclozapine and therapeutic response in patients with schizophrenia resistant to conventional neuroleptics. Psychopharmacology (Berl) 2000; 148: 83–9CrossRefGoogle Scholar
  49. 49.
    VanderZwaag C, McGee M, McEvoy JP, et al. Response of patients with treatment-refractory schizophrenia to clozapine within three serum level ranges. Am J Psychiatry 1996; 153: 1579–84PubMedGoogle Scholar
  50. 50.
    Kaladjian A, Bery B, Deturmeny E, et al. clozapine monitoring plasma or serum levels? Ther Drug Monit 1996; 21: 327–9CrossRefGoogle Scholar
  51. 51.
    Fabrazzo M, La Pia S, Monteleone P, et al. Is the time corse of Clozapine response correlated to the time course of clozapine plasma levels? A one-year prospective study in drug-resistant patients with schizophrenia. Neuropsychopharmacology 2002; 27: 1050–5PubMedCrossRefGoogle Scholar
  52. 52.
    Miller DD, Fleming F, Holman TL, et al. Plasma Clozapine concentrations as a predictor of clinical response: a follow-up study. J Clin Psychiatry 1994; 55: 117–21PubMedGoogle Scholar
  53. 53.
    Schulte P. What is an adequate trial with Clozapine? Therapeutic drug monitoring and time to response in treatment-refractory schizophrenia. Clin Pharmacokinet 2003; 42: 607–18PubMedCrossRefGoogle Scholar
  54. 54.
    Eap CB, Bender S, Jaquenoud SE, et al. Nonresponse to Clozapine and ultrarapid CYP1A2 activity: clinical data and analysis of CYP1A2 gene. J Clin Psychopharmacol. 2004; 24: 214–9PubMedCrossRefGoogle Scholar
  55. 55.
    Nordstrom AL, Farde L, Nyberg S, et al. D1, D2, and 5-HT2 receptor occupancy in relation to clozapine serum concentration: a PET study of schizophrenic patients. Am J Psychiatry 1995; 152: 1444–9PubMedGoogle Scholar
  56. 56.
    Seeman P, Van Tol HH. Deriving the therapeutic concentrations for clozapine and haloperidol: the apparent dissociation constant of a neuroleptic at the dopamine D2 or D4 receptor varies with the affinity of the competing radioligand. Eur J Pharmacol 1995 Oct 15; 291(2): 59–66PubMedCrossRefGoogle Scholar
  57. 57.
    Zhao AL, Zhao JP, Zhang YH, et al. Dopamine D4 receptor gene exon III polymorphism and interindividual variation in response to Clozapine. Int J Neurosci 2005 Nov; 115: 1539–47PubMedCrossRefGoogle Scholar
  58. 58.
    Rabinowitz J, Davidson M. Risperidone versus haloperidol in long-term hospitalized chronic patients in a double blind randomized trial: a post hoc analysis. Schizophr Res 2001; 50: 89–93PubMedCrossRefGoogle Scholar
  59. 59.
    Emsley RA. Risperidone in the treatment of first-episode psychotic patients: a double-blind multicenter study. Risperidone Working Group. Schizophr Bull 1999; 25: 721–9PubMedCrossRefGoogle Scholar
  60. 60.
    Peuskens J, Risperidone Study Group. Risperidone in the treatment of patients with chronic schizophrenia: a multi-national, multi-centre, double-blind, parallel-group study versus haloperidol. Br J Psychiatry 1995; 166: 712–26PubMedCrossRefGoogle Scholar
  61. 61.
    Jansen PAJ, Niemegeers CJE, Awouters F, et al. Pharmacology of risperidone (R 64 766), a new antipsychotics with serotonins2 and dopamine-D2 antagonistic properties. J Pharmacol Exp Ther 1988; 244: 685–93Google Scholar
  62. 62.
    Leysen JE, Gommeren W, Eens A, et al. Biochemical profile of risperidone, a new antipsychotic. J Pharmacol Exp Ther 1998; 247: 661–70Google Scholar
  63. 63.
    Ereshefsky L, Lacombe S. Pharmacological profile of risperidone. Can J Psychiatry 1993; 38 Suppl. 3: 80–8Google Scholar
  64. 64.
    Mannens G, Huang ML, Meuldermans W, et al. Absorption, metabolism, and excretion of risperidone in humans. Drug Metab Disp 1993; 21: 1134–41Google Scholar
  65. 65.
    Baldessarini RJ. Drugs and treatment of psychiatric disorders: psychosis and anxiety. In: Goodman LS, Gilman A, editors. The pharmacological basis of therapeutics. 9th ed. New York: McGraw-Hill, 1996: 399–430Google Scholar
  66. 66.
    Huang ML, Van Peer A, Woestenborghs R, et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257–68PubMedCrossRefGoogle Scholar
  67. 67.
    Aravagiri M, Marder SR, Wirshing D, et al. Plasma concentrations of risperidone and its 9-hydroxy metabolite and their relationship to dose in schizophrenic patients: simultaneous determination by a high performance liquid chromatography with electrochemical detection. Pharmacopsychiatry 1998; 31: 102–9PubMedCrossRefGoogle Scholar
  68. 68.
    Aravagiri M, Marder SR, Nuechterlein KH, et al. Intra- and interindividual variations in steady-state plasma concentrations of risperidone and 9-hydroxyrisperidone in schizophrenic patients treated chronically with various doses of risperidone. Ther Drug Monit 2003; 25: 657–64PubMedCrossRefGoogle Scholar
  69. 69.
    Grant S, Fitton A. Risperidone. A review of its pharmacology and therapeutic potential in the treatment of schizophrenia. Drugs 1994; 48: 253–73PubMedCrossRefGoogle Scholar
  70. 70.
    Heykants J, Hunag ML, Mannens G, et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry 1994; 55 Suppl. 5: 13–7PubMedGoogle Scholar
  71. 71.
    Spina E, Avenoso A, Facciola G, et al. Relationship between plasma risperidone and 9-hydroxyrisperidone concentrations and clinical response in patients with schizophrenia. Psychopharmacology (Berl) 2001; 153: 238–43CrossRefGoogle Scholar
  72. 72.
    Olesen OV, Licht RW, Thomsen E, et al. Serum concentrations and side effects in psychiatric patients during risperidone therapy. Ther Drug Monit 1998; 20: 380–4PubMedCrossRefGoogle Scholar
  73. 73.
    Riedel M, Schwarz MJ, Strassing M, et al. Risperidone plasma levels, clinical response and side-effects. Eur Arch Psychiatry Clin Neurosci 2005; 255: 261–8PubMedCrossRefGoogle Scholar
  74. 74.
    Mauri MC, Laini V, Boscati L, et al. Long term treatment of chronic schizophrenia with risperidone: a study with plasma levels. Eur Psychiatry 2001; 16: 57–63PubMedCrossRefGoogle Scholar
  75. 75.
    Chen PS, Yang YK, Su SF, et al. Correlation between scores on Continuous Performance Test and plasma concentration for schizophrenic patients on risperidone. Psychiatry Clin Neurosci. 2004; 58: 168–72PubMedCrossRefGoogle Scholar
  76. 76.
    Yoshimura R, Ueda N, Nakamura J. Possible relationship between combined plasma concentrations of risperidone plus 9-hydroxyrisperidone and extrapyramidal symptoms. Neurop-sychobiology 2001; 44: 129–33CrossRefGoogle Scholar
  77. 77.
    Anderson C, Trae J, Ereshefsky L, et al. Risperidone clinical efficacy: role of the metabolite 9-OH-risperidone. Psychopharmacol Bull 1994; 30 Suppl. 1: 88Google Scholar
  78. 78.
    Bondolfi G, Dufour H, Patris M, et al. Risperidone versus Clozapine in treatment-resistant chronic schizophrenia: a randomized double-blind study. Am J Psychiatry 1998; 155: 499–504PubMedGoogle Scholar
  79. 79.
    Lee HS, Tan CH, Khoo YM, et al. Serum concentrations and clinical effects of risperidone in schizophrenic patients in Singapore: a preliminary report. Br J Clin Pharmacol 1999; 47: 460–1PubMedGoogle Scholar
  80. 80.
    Darby JK, Pasta DJ, Elfand L, et al. Risperidone dose and blood level variability: accumulation effects and interindividual and intraindividual variability in the nonresponder patient in the clinical practice setting. J Clin Psychopharmacol 1997; 17: 478–84PubMedCrossRefGoogle Scholar
  81. 81.
    Odou P, Levron JC, Luyckx M, et al. Risperidone drag monitoring. Clin Drag Invest 2000; 19: 283–92CrossRefGoogle Scholar
  82. 82.
    Lingjaerde O, Ahlfors UG, Bech P, et al. The UKU side effect rating scale: a new comprehensive rating scale for psychotropic drags and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand 1987 (Suppl.); 334: 1–100CrossRefGoogle Scholar
  83. 83.
    Simpson RM, Angus JSW. A rating scale for extrapiramidal side effects. Acta Psychiatr Scand 1970; 212: 11–9CrossRefGoogle Scholar
  84. 84.
    Jones SH, Thornicroft G, Coffey M, et al. A brief mental health outcome scale: reliability and validity of the Global Assessment of Functioning (GAF). Br J Psychiatry 1995 May; 166(5): 654–9PubMedCrossRefGoogle Scholar
  85. 85.
    Conners CK. The computerized continuous performance test. Psychopharmacol Bull 1985; 21: 891–2PubMedGoogle Scholar
  86. 86.
    Kelleher JP, Centorrino F, Albert MJ, et al. Advances in atypical antipsychotics for the treatment of schizophrenia: new formulations and new agents. CNS Drags 2002; 16: 249–61CrossRefGoogle Scholar
  87. 87.
    Kane JM, Eerdekens M, Lindenmayer JP, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003; 160: 1125–32PubMedCrossRefGoogle Scholar
  88. 88.
    Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol 2005; 15: 111–7PubMedCrossRefGoogle Scholar
  89. 89.
    Mannaert E, Vermeulen A, Remmerie B, et al. Pharmacokinetic profile of long-acting injectable risperidone at steady-state: comparison with oral administration. Encephale 2005; 31: 609–15PubMedCrossRefGoogle Scholar
  90. 90.
    Eerdekens M, Van Hove I, Remmerie B, et al. Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia. Schizophr Res 2004 Sep 1; 70: 91–100PubMedCrossRefGoogle Scholar
  91. 91.
    Nesvag R, Hendset M, Refsum H, et al. Serum concentrations of risperidone and 9-OH risperidone following intramuscular injection of long-acting risperidone compared with oral risperidone medication. Acta Psychiatr Scand 2006; 114: 21–6PubMedCrossRefGoogle Scholar
  92. 92.
    Castberg I, Spigset O. Serum concentrations of risperidone and 9-hydroxyrisperidone after administration of the long-acting injectable form of risperidone: evidence from a routine therapeutic drug monitoring service. Ther Drug Monit 2005; 27: 103–6PubMedCrossRefGoogle Scholar
  93. 93.
    Gefvert O, Eriksson B, Persson P, et al. Pharmacokinetics and D2 receptor occupancy of long-acting injectable risperidone (Risperdal Consta) in patients with schizophrenia. Int J Neuropsychopharmacol 2005; 8: 27–36PubMedCrossRefGoogle Scholar
  94. 94.
    Marder SR, Meibach R. Risperidone in the treatment of schizophrenia. Am J Psychiatry 1994; 151: 825–35PubMedGoogle Scholar
  95. 95.
    McCormack PL, Wiseman LR. Olanzapine: a review of its use in the management of bipolar disorder. Drags 2004; 64: 2709–26CrossRefGoogle Scholar
  96. 96.
    Lieberman JA, Tollefson G, Tohen M, et al. Comparative efficacy and safety of atypical and conventional antipsychotic drags in first-episode psychosis: a randomized, double-blind trial of olanzapine versus haloperidol. Am J Psychiatry 2003; 160: 1396–404PubMedCrossRefGoogle Scholar
  97. 97.
    Lambert M, Haro JM, Novick D, et al. Olanzapine vs. other antipsychotics in actual out-patient settings: six months tolerability results from the European Schizophrenia Out-patient Health Outcomes Study. Acta Psychiatr Scand 2005; 111: 232–43PubMedCrossRefGoogle Scholar
  98. 98.
    Duggan L, Fenton M, Rathbone J, et al. Olanzapine for schizophrenia. Cochrane Database Syst Rev 2005; (18): CD001359Google Scholar
  99. 99.
    Bymaster F, Perry KW, Nelson DL, et al. Olanzapine: a basic science update. Br J Psychiatry 1999; 37: 36–40Google Scholar
  100. 100.
    Callaghan JT, Bergstrom RF, Ptak LR, et al. Olanzapine: pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37: 177–93PubMedCrossRefGoogle Scholar
  101. 101.
    Kassahun K, Mattiuz E, Nyhart E Jr, et al. Disposition and biotransformation of the antipsychotic agent olanzapine in humans. Drag Metab Dispos 1997; 25: 81–93Google Scholar
  102. 102.
    Kelly DL, Conley RR, Tamminga CA. Differential olanzapine plasma concentrations by sex in a fixed-dose study. Schizophr Res 1999; 40: 101–4PubMedCrossRefGoogle Scholar
  103. 103.
    Dusci LJ, Peter Hackett L, Fellows LM, et al. Determination of olanzapine in plasma by high-performance liquid chromatography using ultraviolet absorbance detection. J Chromatogr B Analyt Technol Biomed Life Sci 2002; 773: 191–7PubMedCrossRefGoogle Scholar
  104. 104.
    Perry PJ, Lund BC, Sanger T, et al. Olanzapine plasma concentrations and clinical response: acute phase results of the North American Olanzapine Trial. J Clin Psychopharmacol 2001; 21: 14–20PubMedCrossRefGoogle Scholar
  105. 105.
    Gex-Fabry M, Balant-Gorgia AE, Balant LP. Therapeutic drug monitoring of olanzapine: the combined effect of age, gender, smoking, and comedication. Ther Drag Monit 2003; 25: 46–53CrossRefGoogle Scholar
  106. 106.
    Bergemann N, Frick A, Parzer P, et al. Olanzapine plasma concentration, average daily dose, and interaction with comedication in schizophrenic patients. Pharmacopsychiatry 2004a; 37: 63–8PubMedCrossRefGoogle Scholar
  107. 107.
    Mauri MC, Steinhilber CPC, Marino R, et al. Clinical outcome and olanzapine plasma levels in acute schizophrenia. Eur Psychiatry 2005; 20: 55–60PubMedCrossRefGoogle Scholar
  108. 108.
    Aravagiri M, Ames D, Wirshing WC, et al. Plasma level monitoring of olanzapine in patients with schizophrenia: determination by high-performance liquid chromatography with electrochemical detection. Ther Drag Monit 1997; 19: 307–13CrossRefGoogle Scholar
  109. 109.
    Olesen OV, Linnet K. Olanzapine serum concentrations in psychiatric patients given standard doses: the influence of comedication. Ther Drug Monit 1999; 21: 87–90PubMedCrossRefGoogle Scholar
  110. 110.
    Lane HY, Guo SC, Hwang TJ, et al. Effects of olanzapine plasma concentrations on depressive symptoms in schizophrenia: a pilot study. J Clin Psychopharmacol 2002; 22: 530–2PubMedCrossRefGoogle Scholar
  111. 111.
    Skogh E, Reis M, Dahl ML, et al. Therapeutic drag monitoring data on olanzapine and its N-demethyl metabolite in the naturalistic clinical setting. Ther Drag Monit 2002; 24: 518–26CrossRefGoogle Scholar
  112. 112.
    Fellows L, Ahmad, Castle DJ, et al. Investigation of target plasma concentration-effect relationships for olanzapine in schizophrenia. Ther Drug Monit 2003; 25: 682–9PubMedCrossRefGoogle Scholar
  113. 113.
    Wright P, Lindborg SR, Birkett M, et al. Intramuscular olanzapine and intramuscular haloperidol in acute schizophrenia: antipsychotic efficacy and extrapyramidal safety during the first 24 hours of treatment. Can J Psychiatry 2003; 48: 716–21PubMedGoogle Scholar
  114. 114.
    Lindborg SR, Beasley CM, Alaka K, et al. Effects of intramuscular olanzapine vs. haloperidol and placebo on QTc intervals in acutely agitated patients. Psychiatry Res 2003 15; 119: 113–23PubMedCrossRefGoogle Scholar
  115. 115.
    Breier A, Meehan K, Birkett M, et al. A double-blind, placebocontrolled dose-response comparison of intramuscular olanzapine and haloperidol in the treatment of acute agitation in schizophrenia. Arch Gen Psychiatry 2002; 59: 441–8PubMedCrossRefGoogle Scholar
  116. 116.
    Perry PJ, Sanger T, Beasley C. Olanzapine plasma concentrations and clinical response in acutely ill schizophrenic patients. J Clin Psychopharmacol 1997; 17: 472–7PubMedCrossRefGoogle Scholar
  117. 117.
    Asberg M, Montgomery S, Perris C, et al. A comprehensive psychopathological rating scale. Acta Psychiatr Scand 1978; S271: 24–8Google Scholar
  118. 118.
    Hamilton M. 1960. A rating scale for depression. J Neurol Neurosurg Psychiatry 23: 56–62PubMedCrossRefGoogle Scholar
  119. 119.
    Kapur S, Zipursky RB, Remington G, et al. 5-HT2 and D2 receptor occupancy of olanzapine in schizophrenia: a PET investigation. Am J Psychiatry 1998; 155: 921–8PubMedGoogle Scholar
  120. 120.
    Attarbaschi T, Sacher J, Geiss-Granadia T, et al. Striatal D(2) receptor occupancy in bipolar patients treated with olanzapine. Eur Neuropsychopharmacol 2007; 17: 102–7PubMedCrossRefGoogle Scholar
  121. 121.
    Peuskens J, Link CG. A comparison of quetiapine and chlorpromazine in the treatment of schizophrenia. Acta Psychiatr Scand 1997; 96: 265–73PubMedCrossRefGoogle Scholar
  122. 122.
    Small JG, Hirsch SRM, Arvanitis LA, et al. Quetiapine in patients with schizophrenia: a high- and low-dose double blind comparison with placebo. Arch Gen Psych 1997; 54: 549–57CrossRefGoogle Scholar
  123. 123.
    DeVane CL, Nemeroff CB. Clinical pharmacokinetics of quetiapine: an atypical antipsychotic. Clin Pharmacokinet 2001; 40: 509–22PubMedCrossRefGoogle Scholar
  124. 124.
    Mauri MC, Fiorentini A, Volonteri LS, et al. Quetiapine in acute psychosis and personality disorders during hospitalization: assessment of a therapeutic range. Eur Neuropsychopharmacol 2004; 14(S3): 283–4Google Scholar
  125. 125.
    Davis PC, Wong J, Gevfert O. Analysis and pharmacokinetics of quetiapine and two metabolites in human plasma using reversed-phase HPLC with ultraviolet and electrochemical detection. J Pharm Biomed Analysis 1999; 20: 271–82CrossRefGoogle Scholar
  126. 126.
    Kapur S, Zipursky R, Jones C, et al. A positron emission tomography study of quetiapine in schizophrenia. Arch Gen Psychiatry 2000; 57: 553–9PubMedCrossRefGoogle Scholar
  127. 127.
    Caccia S. Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 2000; 38: 393–414PubMedCrossRefGoogle Scholar
  128. 128.
    Grimm SW, Stams KR, Bui K. In vitro prediction of potential metabolic drug interaction for Seroquel. Schizophr Res 1997; 24: 198CrossRefGoogle Scholar
  129. 129.
    Gunasekara NS, Spencer CM. Quetiapine: a review of its use in schizophrenia. CNS Drugs 1998; 9: 325–40CrossRefGoogle Scholar
  130. 130.
    Grimm SW, Richtand NM, Winter HR, et al. Effects of cytochrome P450 3A modulators ketoconazole and carbamazepine on quetiapine pharmacokinetics. Br J Pharmacol 2006; 61: 58–69CrossRefGoogle Scholar
  131. 131.
    Thyrum PT, Fabre LF, Wong YWJ. Multiple dose pharmacokinetics of ICI 204,636 in schizophrenic men and women [abstract]. Psychopharmacol Bull 1996; 32(3): 525Google Scholar
  132. 132.
    Sotaniemi EA, Arranto AJ, Pelkonen O, et al. Age and cytochrome P450-linked drug metabolism in humans: an analysis of 226 subjects with equal histopathologic conditions. Clin Pharmacol Ther 1997; 61: 331–9PubMedCrossRefGoogle Scholar
  133. 133.
    Fabre JR, Arvanitis L, Pultz J, et al. ICI 204,636, a novel atypical antipsychotic: early indication of safety and efficacy in patients with chronic and subchronic schizophrenia. Clin Ther 1995; 17: 366–78PubMedCrossRefGoogle Scholar
  134. 134.
    Gefvert O, Bergstrom M, Langstrom B, et al. Time course of central nervous dopamine D2 and 5HT2 receptor blockade and plasma drug concentration after discontinuation of quetiapine (Seroquel) in patients with schizophrenia. Psychopharmacology 1998; 135: 119–26PubMedCrossRefGoogle Scholar
  135. 135.
    Gefvert O, Lundberg T, Wieselgren I, et al. D2 and 5HT2a receptor occupancy of different doses of quetiapine in schizophrenia: a PET study. Eur Neuropsychopharmacol 2001; 11: 105–10PubMedCrossRefGoogle Scholar
  136. 136.
    Carriere P, Bonhomme D, Lemperiere T. Amisulpride has a superior risk/benefit profile to haloperidol in schizophrenia: results of a multicentre, double-blind study. Amisulpride Study Group. Eur Psychiatry 2000; 15: 321–9PubMedCrossRefGoogle Scholar
  137. 137.
    Perrault G, Depoortere R, Morel E, et al. Psychopharmacological profile of amisulpride: an antipsychotic drug with presynaptic D2/D3 dopamine receptor antagonist activity and limbic selectivity. J Pharmacol Exp Ther 1997; 280: 73–82PubMedGoogle Scholar
  138. 138.
    Kopecek M, Bares M, Svarc J, et al. Hyperprolactinemia after low dose of amisulpride. Neuro Endocrinol Lett 2004; 25: 419–22PubMedGoogle Scholar
  139. 139.
    Rosenzweig P, Canal M, Patat A, et al. A review of the pharmacokinetics, tolerability and pharmacodynamics of amisulpride in healthy volunteers. Hum Psychopharmacol 2002; 17: 1–13PubMedCrossRefGoogle Scholar
  140. 140.
    Dufour A, Desanti C. Pharmacokinetics and metabolism of amisulpride. Ann Psychiatry 1988; 3: 298–305Google Scholar
  141. 141.
    Bergemann N, Kopitz J, Kress KR, et al. Plasma amisulpride levels in schizophrenia or schizoaffective disorder. Eur Neuropsychopharmacol 2004; 14: 245–50PubMedCrossRefGoogle Scholar
  142. 142.
    Caley CF, Cooper CK. Ziprasidone: the fifth atypical antipsychotic. Ann Pharmacotherap 2002; 36: 839–51CrossRefGoogle Scholar
  143. 143.
    Gunasekara NS, Spencer CM, Keating GM. Spotlight on ziprasidone in schizophrenia and schizoaffective disorder. CNS drugs 2002; 16: 645–52PubMedCrossRefGoogle Scholar
  144. 144.
    Schmidt AW, Lebel LA, Howard Jr HR, et al. Ziprasidone: a novel antipsychotic agent with a unique human receptor binding profile. Eur J Pharmacol 2001 Aug 17; 425(3): 197–201PubMedCrossRefGoogle Scholar
  145. 145.
    Miceli JJ, Wilner KD, Hansen RA, et al. Single- and multipledose pharmaco-kinetics of ziprasidone under non-fasting conditions in healthy male volunteers. Br J Clin Pharmacol 2000; 49 Suppl. 1: 5–13Google Scholar
  146. 146.
    Wilner KD, Tensfeldt TG, Baris B, et al. Single- and multipledose pharmacokinetics of ziprasidone in healthy young and elderly volunteers. Br J Clin Pharmacol 2000; 49 Suppl. 1: 15–20Google Scholar
  147. 147.
    Stimmel GL, Gutierrez MA, Lee V. Ziprasidone: an atypical antipsychotic drug for the treatment of schizophrenia. Clin Therap 2002; 24: 21–37CrossRefGoogle Scholar
  148. 148.
    Beedham C, Miceli JJ, Obach RS. Ziprasidone metabolism, aldehyde oxidase, and clinical implications. J Clin Psychopharmacol 2003; 23: 229–32PubMedGoogle Scholar
  149. 149.
    Prakash C, Kamel A, Gummerus J. Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions. Drug Metab Disp 1997; 25: 863–72Google Scholar
  150. 150.
    Preskorn SH. Pharmacokinetics and therapeutics of acute intramuscular ziprasidone. Clin Pharmacokinet 2005; 44: 1117–33PubMedCrossRefGoogle Scholar
  151. 151.
    Miceli JJ, Wilner KD, Swan SK, et al. Pharmacokinetics, safety, and tolerability of intramuscular ziprasidone in healthy volunteers. J Clin Pharmacol. 2005; 45(6): 620–30PubMedCrossRefGoogle Scholar
  152. 152.
    Wilner KD, Demattos SB, Anziano RJ, et al. Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers. Br J Clin Pharmacol 2000; 49 Suppl. 1: 43–7Google Scholar
  153. 153.
    Mamo D, Kapur S, Shammi CM, et al. A PET study of dopamine D2 and serotonin 5-HT2 receptor occupancy in patients with schizophrenia treated with therapeutic doses of ziprasidone. Am J Psychiatry 2004; 161: 818–25PubMedCrossRefGoogle Scholar
  154. 154.
    Suckow RF, Fein M, Correli CU, et al. Determination of plasma ziprasidone using liquid chromatography with fluorescence detection. J Cromatography 2004; 799: 201–8CrossRefGoogle Scholar
  155. 155.
    Daniel DG, Zimbroff D1, Potkin SG, et al. Ziprasidone 80 mg/ day and 160 mg/day in the acute exacerbation of schizophrenia and schizoaffective disorder: a 6-week placebo-controlled trial. Ziprasidone Study Group. Neuropsychopharmacology 1999; 20: 491–505PubMedCrossRefGoogle Scholar
  156. 156.
    Goff DC, Posever T, Herz L, et al. An exploratory haloperidolcontrolled dose-finding study of ziprasidone in hospitalized patients with schizophrenia or schizoaffective disorder. J Clin Psychopharmacol 1998; 18: 296–304PubMedCrossRefGoogle Scholar
  157. 157.
    Winans E. Aripiprazole. Am J Health Syst Pharm 2003; 60: 2437–45PubMedGoogle Scholar
  158. 158.
    Yokoi F, Grander G, Biziere K, 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 2002; 27: 248–59PubMedCrossRefGoogle Scholar
  159. 159.
    McGavin JK, Goa KL. Aripiprazole. CNS Drags 2002; 16: 779–88CrossRefGoogle Scholar
  160. 160.
    Mallikaarjun S, Salazar DE, Bramer SL. Pharmacokinetics, tolerability, and safety of aripiprazole following multiple oral dosing in normal healthy volunteers. J Clin Pharmacol 2004; 44: 179–87PubMedCrossRefGoogle Scholar
  161. 161.
    DeLeon A, Patel NC, Crismon ML. Aripiprazole: a comprehensive review of its pharmacology, clinical efficacy, and tolerability. Clin Ther 2004 May; 26: 649–66PubMedCrossRefGoogle Scholar
  162. 162.
    Citrome L, Josiassen R, Bark N, et al. Pharmacokinetics of aripiprazole and concomitant lithium and Valproate. J Clin Pharmacol 2005; 45: 89–93PubMedCrossRefGoogle Scholar
  163. 163.
    Sanchez C, Amt J, Dragsted N. Neurochemical and in vivo pharmacological profile of sertindole, a limbic selective neuroleptic compound. Drug Dev Res 1992; 22: 239–50CrossRefGoogle Scholar
  164. 164.
    Hyttel J, Nielsen JB, Nowak G. The acute effect of sertindole on brain 5HT2, D2 and al receptors (ex vivo radioreceptor binding studies). J Neural Transm Gen Sect 1992; 89: 61–9PubMedCrossRefGoogle Scholar
  165. 165.
    Perquin L, Steinert T. A review of the efficacy, tolerability and safety of sertindole in clinical trials. CNS Drags 2004; 18 Suppl. 2: 19–30CrossRefGoogle Scholar
  166. 166.
    Van Kammen DP, Targum SD, McEvoy JP, et al. A randomized, controlled, dose ranging trial of sertindole in patients with schizophrenia. Psychopharmacology (Berl) 1996; 124: 168–75CrossRefGoogle Scholar
  167. 167.
    Kasper S, Tauscher J, Küfferle, et al. Sertindole and dopamine D2 receptor occupancy in comparison to risperidone, clozapine and haloperidol: a 123I-IBZM SPECT study. Psychopharmacology (Berl) 1998; 136: 367–73CrossRefGoogle Scholar
  168. 168.
    Wilton LV, Heeley EL, Pickering RM, et al. Comparative study of mortality rates and cardiac dysrhythmias in post-marketing surveillance studies of sertindole and two other atypical antipsychotic drags, risperidone and olanzapine. J Psychopharmacol 2001; 15: 120–6PubMedCrossRefGoogle Scholar
  169. 169.
    Wong SL, Linnen P, Mack R, et al. Effect of food, antiacid, and dosage form on the pharmacokinetics and relative bioavailability of sertindole in healthy volunteers. Biopharm Drug Dispos 1997; 18: 533–41PubMedCrossRefGoogle Scholar
  170. 170.
    Wong SL, Granneman GR. Modeling of sertindole pharmacokinetic disposition in healthy volunteers in short term doseescalation studies. J Pharm Sci 1998; 87: 1629–31PubMedCrossRefGoogle Scholar
  171. 171.
    Wong SL, Locke C, Staser J, et al. Lack of multiple dosing effects of sertindole on the pharmacokinetics of alprazolam in healthy volunteers. Psychopharmacology (Berl) 1998; 135: 236–41CrossRefGoogle Scholar
  172. 172.
    Sakamoto K, Nakamura Y, Aikoh S, et al. Metabolism of sertindole: identification of the metabolites in the rat and dog, and species comparison of liver microsomal metabolism. Xenobiotica 1995; 25: 1327–43PubMedCrossRefGoogle Scholar
  173. 173.
    Wong SL, Menacherry S, Mulford D, et al. Pharmacokinetics of sertindole and dehydrosertindole in volunteers with normal or impaired renal function. Eur J Pharmacol 1997; 52: 223–7CrossRefGoogle Scholar
  174. 174.
    Wong SL, Cao G, Mack RJ, et al. Pharmacokinetics of sertindole in healthy young and elderly male and female subjects. Clin Pharmacol Ther 1997; 62(2): 157–64PubMedCrossRefGoogle Scholar
  175. 175.
    Drici MD, Wang WX, Liu XK, et al. Prolongation of QT interval in isolated feline hearts by antipsychotic drugs. J Clin Psychopharmacol 1998; 18: 477–81PubMedCrossRefGoogle Scholar
  176. 176.
    Zimbroff DL, Kane JM, Tamminga CA, et al. Controlled, doseresponse study of sertindole and haloperidol in the treatment of schizophrenia. Am J Psychiatry 1997; 154: 782PubMedGoogle Scholar
  177. 177.
    Canal-Raffin M, Déridet E, Titier K, et al. Simplified ultraviolet liquid Chromatographic method for determination of sertindole, dehydrosertindole and norsertindole, in human plasma. J Chromatogr B 2005; 814: 61–7CrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2007

Authors and Affiliations

  • Massimo C. Mauri
    • 1
  • Lucia S. Volonteri
    • 1
  • Alessandro Colasanti
    • 1
  • Alessio Fiorentini
    • 1
  • Ilaria F. De Gaspari
    • 1
  • Silvio R. Bareggi
    • 2
  1. 1.Department of Internal Medicine, Clinical PsychiatryUniversity of Milan, IRCCS Ospedale Maggiore PoliclinicoMilanItaly
  2. 2.Department of Pharmacology, School of MedicineUniversity of MilanMilanItaly
  3. 3.Clinical Psychiatry, Clinical Neuropsychopharmacology UnitUniversity of Milan, IRCCS Fondazione IRCCS Ospedale Maggiore PoliclinicoMilanItaly

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