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Dopamine D2 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

Veselinović, Tanja MD*; Scharpenberg, Martin PhD; Heinze, Martin MD; Cordes, Joachim MD§; Mühlbauer, Bernd MD†,∥; Juckel, Georg MD, PhD; Rüther, Eckart MD#; Paulzen, Michael MD*,**; Haen, Ekkehard MD††; Hiemke, Christoph PhD‡‡; Timm, Jürgen PhD; Gründer, Gerhard MD§§ on behalf of the NeSSy Study Group

Journal of Clinical Psychopharmacology: November/December 2019 - Volume 39 - Issue 6 - p 550–560
doi: 10.1097/JCP.0000000000001131
Original Contributions
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Background Impaired subjective well-being in schizophrenia patients treated with antipsychotics has often been linked inter alia to the antidopaminergic effects of medication. Thus, it is important to capture the association between striatal dopamine D2 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 allocation of patients to the specific treatment groups. Plasma drug concentrations were measured after 6 and 24 weeks of treatment to obtain the estimated D2-RO (eD2-RO) relative to literature values. We made an exploratory 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 association 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 consequently high occupancy at D2 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.

From the *Department of Psychiatry, Psychotherapy and Psychosomatics, Medical 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 Psychiatry and Psychotherapy, University Medical Center of Mainz, Mainz

§§Department 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).

Online date: November 4, 2019

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