Dosing Regimens of Olanzapine and Risperidone

Dosing Regimens of Olanzapine and Risperidone

Original Research Article

Significant dissociation of brain and plasma kinetics with antipsychotics

J Tauscher^1,2,4, C Jones¹, G Remington^2,3, R B Zipursky^2,3 and S Kapur^1,2,3

¹Schizophrenia-PET Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada

²Schizophrenia and Continuing Care Program, Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada

³Department of Psychiatry, University of Toronto, Toronto, Canada

⁴Department of General Psychiatry, University of Vienna, Vienna, Austria

Correspondence to: J Tauscher, MD, Dept of General Psychiatry, University of Vienna, Währinger Gürtel 18-20, A-1050 Vienna, Austria. E-mail: johannes.tauscher@akh-wien.ac.at

Abstract

Current dosing regimens of psychotropic drugs are based on plasma kinetic considerations, although it is unclear whether plasma levels faithfully reflect brain kinetics of drugs.^1,2 To examine this, we compared the kinetics of plasma levels of two widely used antipsychotics, olanzapine and risperidone, vs the time course of their effects in the brain. We used positron emission tomography (PET) and [¹¹C]-labeled ligands to quantify striatal and extra-striatal dopamine-2 (D₂), and cortical serotonin-2A (5-HT_2A) receptor occupancy in healthy subjects after a single dose, and in patients chronically treated for psychosis. We found a significant dissociation of brain and plasma kinetics. Mean plasma elimination half-lives of single doses of olanzapine and risperidone were 24.2 and 10.3 h, respectively, whereas it took on average 75.2 h with olanzapine, and 66.6 h with risperidone to decline to 50% of their peak striatal D₂ receptor occupancy. We found similar discrepancies between the time course of plasma levels and extra-striatal D₂ as well as 5-HT_2A receptor occupancy.

Our results question the current reliance on plasma kinetics as the main basis for dosing regimens of antipsychotics. Studies of brain kinetics may provide a sounder basis for determining dosing schedules of psychotropic medications.

Molecular Psychiatry (2002) 7, 317-321. DOI: 10.1038/sj/mp/4001009

References

1 Farde L, Wiesel FA, Halldin C, Sedvall G. Central D2-dopamine receptor occupancy in schizophrenic patients treated with antipsychotic drugs. Arch Gen Psychiatry 1988; 45: 71-76. MEDLINE

2 Gifford AN, Gatley SJ, Volkow ND. Evaluation of the importance of rebinding to receptors in slowing the approach to equilibrium of high-affinity PET and SPECT radiotracers. Synapse 1998; 28: 167-175. Article MEDLINE

3 Seeman P, Lee T, Chau-Wong M, Wong K. Antipsychotic drug doses and neuroleptic/dopamine receptors. Nature 1976; 261: 717-719. MEDLINE

4 Seeman P, Tallerico T, Corbett R, Van Tol HH, Kamboj RK. Role of dopamine D2, D4 and serotonin(2A) receptors in antipsychotic and anticataleptic action. J Psychopharmacol 1997; 11: 15-17. MEDLINE

5 Schotte A, Janssen PF, Gommeren W, Luyten WH, Van Gompel P, Lesage AS et al. Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding. Psychopharmacol (Berl) 1996; 124: 57-73.

6 Nyberg S, Farde L, Halldin C. A PET study of 5-HT2 and D2 dopa-mine receptor occupancy induced by olanzapine in healthy subjects. Neuropsychopharmacology 1997; 16: 1-7. Article MEDLINE

7 Kapur S, Zipursky RB, Remington G. Clinical and theoretical implications of 5-HT₂ and D₂ receptor occupancy of clozapine, risperidone, and olanzapine in schizophrenia. Am J Psychiatry 1999; 156: 286-293. MEDLINE

8 Baron JC, Martinot JL, Cambon H, Boulenger JP, Poirier MF, Caillard V et al. Striatal dopamine receptor occupancy during and following withdrawal from neuroleptic treatment: correlative evaluation by positron emission tomography and plasma prolactin levels. Psychopharmacology 1989; 99: 463-472. MEDLINE

9 Nyberg S, Farde L, Halldin C. Delayed normalization of central D2 dopamine receptor availability after discontinuation of haloperidol decanoate. Preliminary findings. Arch Gen Psychiatry 1997; 54: 953-958. MEDLINE

10 Farde L, Suhara T, Nyberg S, Karlsson P, Nakashima Y, Hietala J et al. A PET-study of [¹¹C]FLB 457 binding to extrastriatal D₂-dopamine receptors in healthy subjects and antipsychotic drug-treated patients. Psychopharmacol (Berl) 1997; 133: 396-404.

11 Callaghan JT, Bergstrom RF, Ptak LR, Beasley CM. Olanzapine. Pharmacokinetic and pharmacodynamic profile. Clin Pharmacokinet 1999; 37: 177-193. MEDLINE

12 Heykants J, Huang ML, Mannens G, Meuldermans W, Snoeck E, Van Beijsterveldt L et al. The pharmacokinetics of risperidone in humans: a summary. J Clin Psychiatry 1994; 55 Suppl: 13-17. MEDLINE

13 Huang ML, Van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen AA et al. Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects. Clin Pharmacol Ther 1993; 54: 257-268. MEDLINE

14 Borison RL, Diamond B, Pathiraja A, Meibach RC. Pharmacokinetics of risperidone in chronic schizophrenic patients. Psychopharmacol Bull 1994; 30: 193-197. MEDLINE

15 Meltzer HY, Matsubara S, Lee JC. Classification of typical and atypical antipsychotic drugs on the basis of dopamine D-1, D-2 and serotonin2 pKi values. J Pharmacol Exp Ther 1989; 251: 238-246. MEDLINE

16 Aravagiri M, Teper Y, Marder SR. Pharmacokinetics and tissue distribution of olanzapine in rats. Biopharm Drug Dispos 1999; 20: 369-377. Article MEDLINE

17 Kapur S, Zipursky R, Jones C, Shammi CS, Remington G, Seeman P. 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 2000; 57: 553-559. MEDLINE

18 Nyberg S, Farde L, Halldin C, Dahl ML, Bertilsson L. D₂ dopamine receptor occupancy during low-dose treatment with haloperidol decanoate. Am J Psychiatry 1995; 152: 173-178. MEDLINE

19 Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K. The UKU side effect rating scale. A new comprehensive rating scale for psychotropic drugs and a cross-sectional study of side effects in neuroleptic-treated patients. Acta Psychiatr Scand Suppl 1987; 334: 1-100. MEDLINE

20 Lammertsma AA, Hume SP. Simplified reference tissue model for PET receptor studies. Neuroimage 1996; 4: 153-158. Article MEDLINE

21 Berna M, Shugert R, Mullen J. Determination of olanzapine in human plasma and serum by liquid chromatography/tandem mass spectrometry. J Mass Spectrom 1998; 33: 1003-1008. Article MEDLINE

22 Woestenborghs R, Lorreyne W, Van Rompaey F, Heykants J. Determination of risperidone and 9-hydroxyrisperidone in plasma, urine and animal tissues by high-performance liquid chromatography. J Chromatogr 1992; 583: 223-230. MEDLINE

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