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Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia

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Abstract

Augmentation with low-dose fluvoxamine (50–100 mg/day) to antipsychotic treatment may improve the negative symptoms in schizophrenic patients, but involves a risk of drug-drug interaction. We studied the effects of fluvoxamine on plasma concentrations of haloperidol and reduced haloperidol, and their clinical symptoms, in haloperidol treated patients. Twelve schizophrenic inpatients with prevailingly negative symptoms receiving haloperidol 6 mg/day were additionally treated with incremental doses of fluvoxamine for 6 weeks (25, 75 and 150 mg/day for 2 weeks each). Plasma drug concentrations were monitored together with clinical assessments before and after each phase of the three fluvoxamine doses. Geometric mean of haloperidol concentrations during coadministration of fluvoxamine 25, 75 and 150 mg/day were 120% (95%CI; 114–127%), 139% (95%CI; 130–149%), and 160% (95%CI; 142–178%) of those before fluvoxamine coadministration, respectively. We found positive correlations between increase in plasma haloperidol concentrations and plasma fluvoxamine concentrations. Scores in negative symptoms were significantly reduced after fluvoxamine coadministration, whereas no changes were observed in the other psychiatric symptoms or any subgrouped side effects. Therefore, this study indicates that fluvoxamine increases plasma haloperidol concentrations in a dose-dependent manner. However, relatively small elevations in haloperidol concentration did not lead to the development of extrapyramidal symptoms under the conditions of this study.

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References

  • Armstrong SC, Stephans JR (1997) Blood clozapine levels elevated by fluvoxamine: potential for side effects and lower clozapine dosage. J Clin Psychiatry 58:499

    CAS  PubMed  Google Scholar 

  • Bech P, Kastrup M, Rafaelsen OJ (1986) Mini-compendium of rating scales for states of anxiety depression mania schizophrenia with corresponding DSM-III syndromes. Acta Psychiatr Scand Suppl 326:1–37

    CAS  PubMed  Google Scholar 

  • Caccia S (2000) Biotransformation of post-clozapine antipsychotics: pharmacological implications. Clin Pharmacokinet 38:393–414

    Google Scholar 

  • Carrillo JA, Ramos SI, Herraiz AG, Llerena A, Agundez JA, Berecz R, Duran M, Benitez J (1999) Pharmacokinetic interaction of fluvoxamine and thioridazine in schizophrenic patients. J Clin Psychopharmacol 19:494–499

    Article  CAS  PubMed  Google Scholar 

  • Christensen M, Tybring G, Mihara K, Yasui-Furukori N, Carrillo JA, Ramos SI, Andersson K, Dahl ML, Bertilsson L (2002) Low daily 10-mg and 20-mg doses of fluvoxamine inhibit the metabolism of both caffeine (cytochrome P4501A2) and omeprazole (cytochrome P4502C19). Clin Pharmacol Ther 71:141–152

    Article  CAS  PubMed  Google Scholar 

  • Daniel DG, Randolph C, Jaskiw G, Handel S, Williams T, Abi-Dargham A, Shoaf S, Egan M, Elkashef A, Liboff S (1994) Coadministration of fluvoxamine increases serum concentrations of haloperidol. J Clin Psychopharmacol 14:340–343

    CAS  PubMed  Google Scholar 

  • de Jong J, Hoogenboom B, van Troostwijk LD, de Haan L (2001) Interaction of olanzapine with fluvoxamine. Psychopharmacology 155:219–220

    Article  PubMed  Google Scholar 

  • Fabrazzo M, La Pia S, Monteleone P, Mennella R, Esposito G, Pinto A, Maj M (2000) Fluvoxamine increases plasma and urinary levels of clozapine and its major metabolites in a time- and dose-dependent manner. J Clin Psychopharmacol 20:708–710

    Article  CAS  PubMed  Google Scholar 

  • Fang J, Baker GB, Silverstone PH, Coutts RT (1997) Involvement of CYP3A4 and CYP2D6 in the metabolism of haloperidol. Cell Mol Neurobiol 17:227–233

    CAS  PubMed  Google Scholar 

  • Fleishaker JC, Hulst LK (1994) A pharmacokinetic and pharmacodynamic evaluation of the combined administration of alprazolam and fluvoxamine. Eur J Clin Pharmacol 46:35–39

    CAS  PubMed  Google Scholar 

  • Heeringa M, Beurskens R, Schouten W, Verduijn MM (1999) Elevated plasma levels of clozapine after concomitant use of fluvoxamine. Pharm World Sci 21:243–244

    Article  CAS  PubMed  Google Scholar 

  • Hiemke C, Peled A, Jabarin M, Hadjez J, Weigmann H, Hartter S, Modai I, Ritsner M, Silver H (2002) Fluvoxamine augmentation of olanzapine in chronic schizophrenia: pharmacokinetic interactions and clinical effects. J Clin Psychopharmacol 22:502–506

    Article  CAS  PubMed  Google Scholar 

  • Hikida K, Inoue Y, Miyazaki T, Kojima N, Ohkura Y (1989) Determination of bromperidol in serum by automated column-switching high-performance liquid chromatography. J Chromatogr 495:227–234

    CAS  Google Scholar 

  • Kudo S, Odomi M (1998) Involvement of human cytochrome P450 3A4 in reduced haloperidol oxidation. Eur J Clin Pharmacol 54:253–259

    Article  CAS  PubMed  Google Scholar 

  • Lindenmayer JP, Bernstein-Hyman R, Grochowski S, Bark N (1995) Psychopathology of schizophrenia: initial validation of a 5-factor model. Psychopathology 28:22–31

    CAS  PubMed  Google Scholar 

  • Lingjaerde O, Ahlfors UG, Bech P, Dencker SJ, Elgen K (1987) 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 334:1–100

    CAS  PubMed  Google Scholar 

  • Markowitz JS, Gill HS, Lavia M, Brewerton TD, DeVane CL (1996) Fluvoxamine-clozapine dose-dependent interaction. Can J Psychiatry 41:670–671

    CAS  PubMed  Google Scholar 

  • Santamaria B, Perez M, Montero D, Madurga M, de Abajo FJ (2002) Use of antipsychotic agents in Spain through 1985–2000. Eur Psychiatry 17:471–476

    Article  PubMed  Google Scholar 

  • Silver H (2001) Fluvoxamine as an adjunctive agent in schizophrenia. CNS Drug Rev 7:283–304

    CAS  PubMed  Google Scholar 

  • Silver H, Barash I, Aharon N, Kaplan A, Poyurovsky M (2000) Fluvoxamine augmentation of antipsychotics improves negative symptoms in psychotic chronic schizophrenic patients: a placebo-controlled study. Int Clin Psychopharmacol 15:257–261

    CAS  PubMed  Google Scholar 

  • Tsang MW, Shader RI, Greenblatt DJ (1994) Metabolism of haloperidol: clinical implications and unanswered questions. J Clin Psychopharmacol 14:159–162

    CAS  PubMed  Google Scholar 

  • Van Putten T, Marder SR, Mintz J, Poland RE (1992) Haloperidol plasma levels and clinical response: a therapeutic window relationship. Am J Psychiatry 149:500–505

    PubMed  Google Scholar 

  • von Bahr C, Ursing C, Yasui N, Tybring G, Bertilsson L, Rojdmark S (2000) Fluvoxamine but not citalopram increases serum melatonin in healthy subjects—an indication that cytochrome P450 CYP1A2 and CYP2C19 hydroxylate melatonin. Eur J Clin Pharmacol 56:123–127

    Google Scholar 

  • von Moltke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI (1995) Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 15:125–131

    Google Scholar 

  • Weigmann H, Gerek S, Zeisig A, Muller M, Hartter S, Hiemke C (2001) Fluvoxamine but not sertraline inhibits the metabolism of olanzapine: evidence from a therapeutic drug monitoring service. Ther Drug Monit 23:410–413

    Article  CAS  PubMed  Google Scholar 

  • Yasui N, Otani K, Kaneko S, Ohkubo T, Osanai T, Sugawara K, Chiba K, Ishizaki T (1996) A kinetic and dynamic study of oral alprazolam with and without erythromycin in humans: in vivo evidence for the involvement of CYP3A4 in alprazolam metabolism Clin Pharmacol Ther 59:514–519

    Google Scholar 

  • Yasui N, Kondo T, Otani K, Furukori H, Mihara K, Suzuki A, Kaneko S, Inoue Y (1999) Effects of itraconazole on the steady-state plasma concentrations of haloperidol and its reduced metabolite in schizophrenic patients: in vivo evidence of the involvement of CYP3A4 for haloperidol metabolism. J Clin Psychopharmacol 19:149–154

    Article  CAS  PubMed  Google Scholar 

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Acknowledgement

This study was supported by a grand from the Hirosaki Research Institute for Neurosciences.

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Correspondence to Norio Yasui-Furukori.

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Yasui-Furukori, N., Kondo, T., Mihara, K. et al. Fluvoxamine dose-dependent interaction with haloperidol and the effects on negative symptoms in schizophrenia. Psychopharmacology 171, 223–227 (2004). https://doi.org/10.1007/s00213-003-1567-y

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  • DOI: https://doi.org/10.1007/s00213-003-1567-y

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