Download PDF
Pharmacopsychiatry 2002; 35(2): 50-56
DOI: 10.1055/s-2002-25026
Original Paper
© Georg Thieme Verlag Stuttgart · New York

The Effect of Fluoxetine on the Pharmacokinetics and Safety of Risperidone in Psychotic Patients

G.  Bondolfi1, 2 , C.  B.  Eap1 , G.  Bertschy2 , D.  Zullino1 , A.  Vermeulen3 , P.  Baumann1
  • 1Département universitaire de psychiatrie adulte, Site de Cery, Prilly-Lausanne, Switzerland
  • 2Département de psychiatrie, Hôpitaux Universitaires de Genève, Geneva, Switzerland
  • 3Janssen Research Foundation, Beerse, Belgium
Further Information

Publication History

3. 1. 2001

29. 6. 2001

Publication Date:
12 April 2002 (online)

Also available at
    Permissions and Reprints

In this open, 30-day trial, the pharmacokinetics, safety and tolerability of a combination therapy of risperidone (4 or 6 mg/day) and fluoxetine (20 mg/day from day 6) were evaluated in 11 psychotic inpatients. CYP2D6 genotyping revealed that 3 and 8 patients were poor metabolizers (PMs) and extensive metabolizers (EMs) of debrisoquine, respectively. The mean (± SD) AUC of risperidone increased from 83.1 ± 46.8 ng.h/ml and 398.3 ± 33.2 ng.h/ml (monotherapy) to 345.1 ± 158.0 ng.h/ml (p < 0.05) and 514.0 ± 144.2 ng.h/ml (p < 0.001) when coadministered with fluoxetine in EMs and PMs, respectively. The AUC of the active moiety (risperidone plus 9-hydroxy-risperidone) increased from 470.0 ± 170.0 ng.h/ml to 663.0 ± 243.3 ng.h/ml (p < 0.05) and from 576.3 ± 19.6 ng.h/ml to 788.0 ± 89.1 ng.h/ml (ns) in EMs and PMs, respectively. In EMs, the AUC of 9-hydroxy-risperidone remained similar (monotherapy vs. combination therapy: 386.8 ± 153.0 ng.h/ml vs. 317.7 ± 125.2 ng.h/ml, ns), whereas it increased in PMs (178.3 ± 23.5 ng.h/ml vs. 274.0 ± 55.1 ng.h/ml (p < 0.05)). Ten of the 11 patients showed a clinical improvement (reduction of 20 % or more in total PANSS score and 70 % on the mean MADRS score compared to baseline). The severity and incidence of extrapyramidal symptoms and adverse events did not significantly increase when fluoxetine was added.

References

  • 1 Amchin J, Zarycranski W, Taylor K P, Albano D, Klockowski P M. Effect of venlafaxine on the pharmacokinetics of risperidone.  J Clin Pharmacol. 1999;  39 297-309
    PubMedGoogle Scholar
  • 2 Aravagiri M, Marder S R, Wirshing D, Wirshing W C. 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;  31 102-109
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Ball S E, Ahern D, Scatina J, Kao J. Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2.  Br J Clin Pharmacol. 1997;  43 619-626
    CrossrefPubMedGoogle Scholar
  • 4 Baumann P. Pharmacokinetic-pharmacodynamic relationship of the selective serotonin reuptake inhibitors.  Clin Pharmacokinet. 1996;  31 444-469
    CrossrefPubMedGoogle Scholar
  • 5 Bondolfi G, Dufour H, Patris M, May J P, Billeter U, Eap C B,. et al . Risperidone versus clozapine in treatment-resistant chronic schizophrenia: a randomised double-blind study. The Risperidone Study Group.  Am J Psychiatry. 1998;  155 499-504
    PubMedGoogle Scholar
  • 6 Bork J A, Rogers T, Wedlund P J, de Leon J. A pilot study on risperidone metabolism: the role of cytochromes P450 2D6 and 3A.  J Clin Psychiatry. 1999;  60 469-476
    CrossrefPubMedGoogle Scholar
  • 7 Brosen K. Drug-metabolizing enzymes and therapeutic drug monitoring in psychiatry.  Ther Drug Monit. 1996;  18 393-396
    CrossrefPubMedGoogle Scholar
  • 8 Brøsen K. The pharmacogenetics of the selective serotonin reuptake inhibitors.  Clin Investig. 1993;  71 1002-1009
    PubMedGoogle Scholar
  • 9 Chouinard G, Ross-Chouinard A, Annabel L, Jones B. The Extrapyramidal symptom rating scale.  Can J Neurol Sci. 1980;  7 233
    PubMedGoogle Scholar
  • 10 Ciraulo D A, Shader R I. Fluoxetine drug-drug interaction: I. Antidepressants and antipsychotics.  J Clin Psychopharmacol. 1990;  10 48-50
    PubMedGoogle Scholar
  • 11 Darby J K, Pasta D J, Elfand L, Dabiri L, Clark L, Herbert J. 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;  17 478-484
    CrossrefPubMedGoogle Scholar
  • 12 Fang J, Bourin M, Baker G B. Metabolism of risperidone to 9-hydroxyrisperidone by human cytochromes P450 2D6 and 3A4.  Naunyn Schmiedebergs Arch Pharmacol. 1999;  359 147-151
    PubMedGoogle Scholar
  • 13 Goff D C, Brotman A W, Waites M, McCormick S. Trial of fluoxetine added to neuroleptics for treatment-resistant schizophrenic patients.  Am J Psychiatry. 1990;  147 492-494
    PubMedGoogle Scholar
  • 14 Goff D C, Midha K K, Brotmann A W, Waites M, Baldessarini R J. Elevation of plasma concentrations of haloperidol after the addition of fluoxetine.  Am J Psychiatry. 1991;  148 790-792
    PubMedGoogle Scholar
  • 15 Griese E U, Zanger U M, Brudermanns U, Gaedigk A, Mikus G, Morike K ,. et al . Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population.  Pharmacogenetics. 1998;  8 15-26
    PubMedGoogle Scholar
  • 16 Heim M, Meyer U A. Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification.  Lancet. 1990;  336 529-532
    CrossrefPubMedGoogle Scholar
  • 17 Heykants J, Huang M L, 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 5) 13-17
    PubMedGoogle Scholar
  • 18 Holliday S M, Benfield P. Venlafaxine: a review of its pharmacology and therapeutic potential in depression.  Drugs. 1995;  49 280-294
    CrossrefPubMedGoogle Scholar
  • 19 Huang M L, Van Peer A, Woestenborghs R, De Coster R, Heykants J, Jansen A A. et al . Pharmacokinetics of the novel antipsychotic agent risperidone and the prolactin response in healthy subjects.  Clin Pharmacol Ther. 1993;  54 257-268
    PubMedGoogle Scholar
  • 20 Kay S R, Fiszbein A, Opler L A. The positive and negative syndrome scale (PANSS) for schizophrenia.  Schizophr Bull. 1987;  13 261-276
    CrossrefPubMedGoogle Scholar
  • 21 Kobayashi K, Yamamoto T, Chiba K, Tani M, Ishizaki T, Kuroiwa Y. The effects of selective serotonin reuptake inhibitors and their metabolites on S-mephenytoin 4’-hydroxylase activity in human liver microsomes.  Br J Clin Pharmacol. 1995;  40 481-485
    PubMedGoogle Scholar
  • 22 Lammers C H, Deuschle M, Weigmann H, Hartter S, Hiemke C, Heese C. et al . Coadministration of clozapine and fluvoxamine in psychotic patients: clinical experience.  Pharmacopsychiatry. 1999;  32 76-77
    PubMedGoogle Scholar
  • 23 Lee H S, Tan C H, Khoo Y M, Chee K T, Wong K E, Chong S A. et al . Serum concentrations and clinical effects of risperidone in schizophrenic patients in Singapore-a preliminary report [letter].  Br J Clin Pharmacol. 1999;  47 460-461
    PubMedGoogle Scholar
  • 24 Lemmens P, Brecher M, Van Baelen B. A combined analysis of double-blind studies with risperidone vs. Placebo and other antipsychotic agents: factors associated with extrapyramidal symptoms.  Acta Psychiatr Scand. 1999;  99 160-170
    PubMedGoogle Scholar
  • 25 Lindstrom E, von Knorring L. Changes in single symptoms and separate factors of the schizophrenic syndrome after treatment with risperidone or haloperidol.  Pharmacopsychiatry. 1994;  27 108-113
    PubMedGoogle Scholar
  • 26 Lingjaerde O, Ahlfors U G, Bech P, Dencker S J, Elgen K. The UKU side effects rating scale.  Acta Psychiatr Scand. 1987;  76 (Suppl 334) 81-94
    PubMedGoogle Scholar
  • 27 Montgomery S A, Asberg M. A new depression scale designed to be sensitive to change.  Br J Psychiatry. 1979;  134 382-389
    CrossrefPubMedGoogle Scholar
  • 28 Nyberg S, Dahl M L, Halldin C. A PET study of D2 and 5-HT2 receptor occupancy induced by risperidone in poor metabolisers of debrisoquin and risperidone.  Psychopharmacology. 1995;  119 345-348
    PubMedGoogle Scholar
  • 29 O’Connor M, Silver H. Adding risperidone to selective serotonin reuptake inhibitor improves chronic depression.  J Clin Psychopharmacol. 1998;  18 89-91
    CrossrefPubMedGoogle Scholar
  • 30 Olesen O V, Linnet K. Simplified high-performance liquid chromatographic method for determination of risperidone and 9-hydroxyrisperidone in serum from patients comedicated with other psychotropic drugs.  J Chromatogr B Biomed Appl. 1997;  698 209-216
    PubMedGoogle Scholar
  • 31 Ostroff R B, Nelson J C. Risperidone augmentation of selective serotonin reuptake inhibitors in major depression.  J Clin Psychiatry. 1999;  60 256-259
    CrossrefPubMedGoogle Scholar
  • 32 Otton S V, Wu D, Joffe R T, Cheung S W, Sellers E M. Inhibition by fluoxetine of cytochrome P450 2D6 activity.  Clin Pharmacol Ther. 1993;  53 401-409
    CrossrefPubMedGoogle Scholar
  • 33 Pelkonen O, Maenpaa J, Taavitsainen P, Rautio A, Raunio H. Inhibition and induction of human cytochrome P450 (CYP) enzymes.  Xenobiotica. 1998;  28 1203-1253
    CrossrefPubMedGoogle Scholar
  • 34 Remington G, Kapur S, Zipursky R. The relationship between risperidone plasma levels and dopamine D2 occupancy: a positron emission tomographic study [letter].  J Clin Psychopharmacol. 1998;  18 82-83
    CrossrefPubMedGoogle Scholar
  • 35 Saxena S, Wang D, Bystritsky A, Baxter L R Jr. Risperidone augmentation of SRI treatment for refractory obsessive-compulsive disorder.  J Clin Psychiatry. 1996;  57 303-306
    PubMedGoogle Scholar
  • 36 Scordo M G, Spina E, Facciola G, Avenoso A, Johansson I, Dahl M L. Cytochrome P450 2D6 genotype and steady state plasma levels of risperidone and 9-hydroxyrisperidone.  Psychopharmacology. 1999;  147 300-305
    CrossrefPubMedGoogle Scholar
  • 37 Sommers D K, Snyman J R, van Wyk M, Blom M W, Huang M L, Levron J C. Lack of effect of amitriptyline on risperidone pharmacokinetics in schizophrenic patients.  Int Clin Psychopharmacol. 1997;  12 141-145
    PubMedGoogle Scholar
  • 38 Stevens J C, Wrighton S A. Interaction of the enantiomers of fluoxetine and norfluoxetine with human liver cytochromes P450.  J Pharmacol Exp Ther. 1993;  266 964-971
    PubMedGoogle Scholar
  • 39 Szegedi A, Anghelescu I, Wiesner J, Schlegel S, Weigmann H, Hartter S,. et al . Addition of low-dose fluvoxamine to low-dose clozapine monotherapy in schizophrenia: drug monitoring and tolerability data from a prospective clinical trial.  Pharmacotherapy. 1999;  32 148-153
    PubMedGoogle Scholar
  • 40 Vandel S, Bertschy G, Baumann P, Bouquet S, Bonin B, Francois T, . et al . Fluvoxamine and fluoxetine: interaction studies with amitriptyline, clomipramine and neuroleptics in phenotyped patients.  Pharmacol Res. 1995;  31 347-353
    PubMedGoogle Scholar
  • 41 Woestenborghs R, Geuens I, Lenoir H, Janssen C, Heykants J. In E. Reid and I.D. Wilson Methodological surveys in Biochemistry and analysis, Royal Society of Chemistry. Cambridge; 1990 20: 241-246
    Google Scholar
  • 42 Zullino D, Bondolfi G, Baumann P. The serotonin paradox: negative symptoms and SSRI augmentation.  Int J Psychiatry Clin Pract. 1998;  2 19-26
    PubMedGoogle Scholar

G. Bondolfi, M.D. 

Département de psychiatrie
Hôpitaux Universitaires de Genève

Boulevard de St. Georges 16-18

CH- 1205 Geneva/Switzerland

Phone: +41 (22) 327 75 55, +41 (22) 344 40 74 (Home)

Fax: +41 (22) 327 75 99

Email: guido.bondolfi@hcuge.ch