Dopamine D 2 Receptor Occupancy Estimated From Plasma Concentrations of Four Different Antipsychotics and the Subjective Experience of Physical and Mental Well-Being in Schizophrenia Results From the Randomized NeSSy Trial Tanja Veselinović, MD,* Martin Scharpenberg, PhD,† Martin Heinze, MD,‡ Joachim Cordes, MD,§ Bernd Mühlbauer, MD,†|| Georg Juckel, MD, PhD,¶ Eckart Rüther, MD,# Michael Paulzen, MD,*** Ekkehard Haen, MD,†† Christoph Hiemke, PhD,‡‡ Jürgen Timm, PhD,† and Gerhard Gründer, MD,§§ on behalf of the NeSSy Study Group Abstract: Background: Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antido- paminergic effects of medication. Thus, it is important to capture the associ- ation between striatal dopamine D 2 receptor occupancy (D2-RO) and global subjective well-being. We examined this association using data from our multicenter, randomized, double-blind Neuroleptic Strategy Study (NeSSy). Methods: An innovative double randomization process was used for al- location of patients to the specific treatment groups. Plasma drug concen- trations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an explor- atory analysis of associations between eD2-RO and subjective well-being scores. One hundred two blood samples from 69 patients were available for the analysis. Because of the lack of a satisfactory occupancy model for quetiapine, only haloperidol, flupentixol, and olanzapine treatment groups were pooled, whereas aripiprazole data were analyzed separately, because of its partial agonistic properties. Results: In the pooled antagonist group, eD2-RO correlated negatively with the summarized well-being score. In a more detailed analysis, this as- sociation could be confirmed for all first-generation antipsychotic-treated patients, but not for the separate second-generation antipsychotic groups. In the aripiprazole group, higher eD2-RO was associated with impaired physical well-being, but had no association with mental well-being. Conclusions: Our results suggest that high plasma levels and conse- quently high occupancy at D 2 receptors are disadvantageous for subjective well-being, as distinct from the objective extrapyramidal side effects. To minimize patients' malaise, which disfavors adherence, implementation of therapeutic drug monitoring in the clinical routine may be useful. Key Words: antipsychotic, schizophrenia, subjective well-being (J Clin Psychopharmacol 2019;39: 550–560) B esides treatment resistance, poor medication adherence remains one of the major challenges in everyday clinical work with schizophrenia patients. 1 The underlying cause of poor adherence is often impaired well-being or dysphoria induced by antipsychotic drugs. 2–4 Negative subjective experience under antipsychotic treatment has been documented for both first- (FGA) and second-generation an- tipsychotics (SGA). 5,6 Although currently used antipsychotics affect various neurotransmitter systems, net antagonism at dopamine D 2 and D 3 receptors (hereafter collectively designated D 2 ) nonetheless re- mains an indispensable prerequisite for their antipsychotic effects, 6 which may be obtained at the expense of the patient's subjective well-being. 7–9 Indeed, results of several molecular neuroimaging stud- ies show increasing risk of negative subjective experience with greater D 2 blockade in schizophrenia patients treated with olanzapine, risper- idone, and haloperidol. 9–12 However, one of the main limitations of such studies is the relatively small sample size. 13 Further, previous studies included 1 or at most 2 different antipsychotic drugs, thus not affording comparisons between drugs or the possibility to general- ize across the broader classes of antipsychotic medications. Numerous molecular imaging studies have shown that the relationship between D 2 receptor occupancy (D2-RO) and the plasma drug level fits a one site occupancy model described by the hyperbolic approach to complete saturation, 14–18 suggesting that plasma antipsychotic levels could indeed be used to predict D2-RO. 19,20 Based on this model, Takeuchi and colleagues 13 ex- amined the relationship between subjective experience/drug atti- tude and the estimated D2-RO (eD2-RO), calculated relative to From the *Department of Psychiatry, Psychotherapy and Psychosomatics, Medi- cal Faculty, RWTH Aachen University, Aachen; †Competence Center for Clinical Trials—Biometry, University of Bremen, Bremen; ‡Department of Psychiatry and Psychotherapy, Brandenburg Medical School, Immanuel Klinik, Rüdersdorf; §Department of Psychiatry and Psychotherapy, Medical Faculty, Heinrich-Heine- University, Düsseldorf; ||Department of Pharmacology, Klinikum Bremen Mitte, Bremen; ¶Department of Psychiatry, LWL University Hospital, Ruhr University Bochum, Bochum; #Department of Psychiatry and Psychotherapy, University of Göttingen, Göttingen; **Alexianer Hospital Aachen; ††Clinical Pharmacology, Department of Psychiatry and Psychotherapy and Department of Pharmacology and Toxicology, University of Regensburg, Regensburg; ‡‡Department of Psychi- atry and Psychotherapy, University Medical Center of Mainz, Mainz; and §§Depart- ment of Molecular Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany. Received November 11, 2018; accepted after revision July 21, 2019. Reprints: Tanja Veselinović, MD, Department of Psychiatry, Psychotherapy and Psychosomatics, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany (e‐mail: tveselinovic@ukaachen.de). The study was funded by the German Federal Ministry of Education and Research, BMBF 01KG0907; ClinicalTrials.gov no. NCT01164059). Trial registration: German Clinical Trials Register DRKS00000304 http://www.drks.de/drks_web/navigate.do? navigationId=trial.HTML&TRIAL_ID=DRKS00000304. The NeSSy Study Group includes the following authors: Stefan Bleich, MD; Markus Borgmann, MD; Vasiliki Breunig-Lyriti, PhD; Constanze Schulz, PhD; Martin Brüne, MD; Peter Falkai, MD; Sandra Feyerabend; Christian Figge, MD; Helge Frieling; Wolfgang Gaebel, MD; Jürgen Gallinat, MD; Dmitri Handschuh; Jörg Heller, MD; Rainer Kirchhefer, MD; André Kirner, MD; Barbara Kowalenko, MD; Marion Lautenschlager, MD; Claus Wolff-Menzler, MD; Dieter Naber, MD; Katharina Prumbs; and Thomas Wobrock, MD. Supplemental digital content is available for this article. Direct URL citation appears in the printed text and is provided in the HTML and PDF versions of this article on the journal’s Web site (www.psychopharmacology.com). Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0271-0749 DOI: 10.1097/JCP.0000000000001131 ORIGINAL CONTRIBUTION 550 www.psychopharmacology.com Journal of Clinical Psychopharmacology • Volume 39, Number 6, November/December 2019 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.