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Clinical response in a risperidone-medicated naturalistic sample: patients’ characteristics and dose-dependent pharmacokinetic patterns

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Abstract

The purpose of this study was to disentangle an association between plasma concentrations of risperidone (RIS), its active metabolite 9-hydroxyrisperidone (9-OH-RIS) and the active moiety, AM (RIS + 9-OH-RIS), and clinical response in a naturalistic sample. Plasma concentrations of RIS, 9-OH-RIS and AM in patients out of a therapeutic drug monitoring (TDM) database were compared between responders (n = 64) and non-responders (n = 526) using the Clinical Global Impressions (CGI) Scale. Daily dosage of risperidone did not differ between responders and non-responders. Differences for active moiety plasma levels between the two groups did not reach statistical significance. However, responders showed lower plasma concentrations of the parent compound RIS as well as lower metabolic ratios RIS/9-OH-RIS than non-responders (p = 0.017 and p = 0.034). These differences did not remain after controlling for age and baseline symptoms. Furthermore, the cohort was split into two subgroups based on the daily dosage: patients under high (≥6 mg/day) (R H, n = 187) and patients under lower dosages (<6 mg) (R L, n = 403) of risperidone. Differences between responders and non-responders after controlling for demographic and clinical characteristics remained only for plasma concentrations of active moiety in the lower-dose medicated groups; non-responders showed higher active moiety plasma concentrations than responders. Understanding the mechanisms involved and factors associated with the clinical response in patients medicated with antipsychotics is of great interest. Our data imply that clinical response to an antipsychotic treatment cannot be attributed to a single pharmacokinetic pattern. It seems to be rather a complex patchwork of influencing factors such as demographic and clinical characteristics as well as the metabolizer status as surrogate of CYP activity. It seems that the ratio between RIS and 9-OH-RIS may play a crucial role in mediating the clinical effect.

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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 an 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 maintains together with his colleague A. Haas the KONBEST software and its data mining platform (Haas & Köstlbacher GbR, Regensburg/Germany).

The 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 and medical doctors: 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, M. Schwarz; M. Dobmeier, M. Wittmann, M. Vogel, M. Böhme, K. Wenzel-Seifert, B. Plattner, P. Holter, R. Böhm, R. Knorr.

Furthermore, the authors thank Dr. S. Lammertz and Mr. Nikos Perpinias for their expertise in translating numbers into intriguing figures.

Authors’ contributions

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

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Authors and Affiliations

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

    Michael Paulzen, Gerhard Gründer & Georgios Schoretsanitis

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

    Ekkehard Haen & Benedikt Stegmann

  3. Department of Psychiatry, Psychosomatics and Psychotherapy, University Hospital of Würzburg, Würzburg, Germany

    Stefan Unterecker

  4. University Hospital of Psychiatry, Bern, Switzerland

    Georgios Schoretsanitis

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

    Christoph Hiemke

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  1. Michael Paulzen
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Correspondence to Michael Paulzen.

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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 managing director of AGATE, a nonprofit 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 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, Ind, 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 Trommsdorf (Aachen, Germany). He has received grant support from Boehringer Ingelheim and Roche. He is co-founder of Pharma Image GmbH (Düsseldorf, Germany) and Brainfoods UG (Selfkant, Germany). He reports no conflict of interest with this publication. 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. The research study did not receive funds or support from any source.

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Paulzen, M., Haen, E., Stegmann, B. et al. Clinical response in a risperidone-medicated naturalistic sample: patients’ characteristics and dose-dependent pharmacokinetic patterns. Eur Arch Psychiatry Clin Neurosci 267, 325–333 (2017). https://doi.org/10.1007/s00406-016-0736-z

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