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Pharmacokinetic patterns of risperidone-associated adverse drug reactions

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

The aim of the study was to investigate a correlation between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety (AM) (RIS + 9-OH-RIS), and adverse drug reactions (ADRs) in a naturalistic sample.

Methods

Plasma concentrations of RIS, 9-OH-RIS, and AM in patients out of a therapeutic drug monitoring (TDM) database complaining ADRs were categorized according to the Udvalg for Kliniske Undersogelser side effect rating scales (UKU) (n = 97) and compared to patients without ADRs (n = 398).

Results

Patients in the ADR group received a significantly lower daily dosage of risperidone (trimmed mean 3.64 mg/day) than patients without ADRs (4.40 mg/day). No differences were found for active moiety plasma concentrations between the groups (p = 0.454). Differences were detected only in the case of dose-adjusted plasma concentration values (concentration-by-dose, C/D) for 9-OH-RIS, being higher in patients reporting ADRs (4.78 ng/mL/mg) than in patients without ADRs (4.3 ng/mL/mg) (p = 0.037 for Mann-Whitney U test). Note that differences for non-adjusted 9-OH-RIS plasma levels between groups failed to reach significance (p = 0.697).

Conclusions

Our findings are consistent with previous data supporting a prominent role of 9-hydroxyrisperidone, but not of risperidone with regard to ADRs. When studying the various subgroups of reported ADRs separately, the size of these subsamples offers some plausible limitations by reducing the power of the analysis.

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Acknowledgments

The authors wish to express their gratitude to the number of people who contributed with excellent professional technical as well as pharmacological competence to build up the KONBEST database with 50,049 clinical pharmacological comments as of February 2, 2016 (ranked among the professional groups in historical order):

- A. Köstlbacher created the KONBEST software in his Ph.D. thesis based on the idea of E. Haen, C. Greiner, and D. Melchner along the workflow in the clinical pharmacological laboratory at the Department of Psychiatry and Psychotherapy of the University of Regensburg. He, together with his colleague A. Haas, currently maintains the KONBEST software and its data mining platform (Haas & Köstlbacher GbR, Regensburg, Germany).

- The following lab technicians performed the quantitative analysis: D. Melchner, T. Jahner, S. Beck, A. Dörfelt, U. Holzinger, and F. Pfaff-Haimerl.

- The clinical pharmacological comments to drug concentrations were composed by licensed pharmacists (C. Greiner, W. Bader, R. Köber, A. Hader, R. Brandl, M. Onuoha, N. Ben Omar, K. Schmid, A. Köppl, M. Silva, B. Fay, S. Unholzer, C. Rothammer, S. Böhr, F. Ridders, D. Braun, and M. Schwarz) and medical doctors (M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, and R. Knorr).

The research study did not receive funds or support from any source.

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Authors and Affiliations

  1. Department of Psychiatry, Psychotherapy and Psychosomatics and JARA–Translational Brain Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Georgios Schoretsanitis, Gerhard Gründer, Sarah E. Lammertz & Michael Paulzen

  2. University Hospital of Psychiatry, Bern, Switzerland

    Georgios Schoretsanitis & Sebastian Walther

  3. Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and Toxicology, University of Regensburg, Regensburg, Germany

    Benedikt Stegmann & Ekkehard Haen

  4. Department of Psychiatry and Psychotherapy and Institute of Clinical Chemistry and Laboratory Medicine, University Medical Center of Mainz, Mainz, Germany

    Christoph Hiemke

  5. Faculty of Health, Medicine and Life Sciences, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

    Koen R. J. Schruers

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  1. Georgios Schoretsanitis
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Correspondence to Georgios Schoretsanitis.

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Conflict of interest

Ekkehard Haen received speaker’s or consultancy fees from the following pharmaceutical companies: Servier, Novartis, and Janssen-Cilag. He is the managing director of AGATE, a non-profit working group to improve drug safety and efficacy in the treatment of psychiatric diseases. He reports no conflict of interest with this publication. Christoph Hiemke has received speaker’s or consultancy fees from the following pharmaceutical companies: Astra Zeneca, Janssen-Cilag, Pfizer, Lilly, and Servier. He is the managing director of the Psiac GmbH which provides an Internet-based drug–drug interaction program for psychopharmacotherapy. He reports no conflict of interest with this publication. Gerhard Gründer has served as a consultant for Boehringer Ingelheim (Ingelheim, Germany), Cheplapharm (Greifswald, Germany), Eli Lilly (Indianapolis, IN, USA), Lundbeck (Copenhagen, Denmark), Ono Pharmaceuticals (Osaka, Japan), Roche (Basel, Switzerland), Servier (Paris, France), and Takeda (Osaka, Japan). He has served on the speakers’ bureau of Eli Lilly, Gedeon Richter (Budapest, Hungary), Janssen-Cilag (Neuss, Germany), Lundbeck, Roche, Servier, and Trommsdorff (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is a co-founder of PharmaImage GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). Georgios Schoretsanitis received grant from the bequest “in memory of Maria Zaoussi,” State Scholarships Foundation, Greece, for clinical research in Psychiatry for the academic year 2015–2016. All other authors declare no conflicts of interest as well.

Contributions of the authors

GS, MP, GG, CH, EH, BS, KRJS, and SW participated in the research design. GS, MP, and SEL performed the data analysis. GS, MP, GG, CH, EH, BS, KRJS, SEL, and SW wrote or contributed to the writing of the manuscript.

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Schoretsanitis, G., Stegmann, B., Hiemke, C. et al. Pharmacokinetic patterns of risperidone-associated adverse drug reactions. Eur J Clin Pharmacol 72, 1091–1098 (2016). https://doi.org/10.1007/s00228-016-2085-2

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