Disrupted Relationship between Blood Glucose Levels and Dopamine D <sub>2/3</sub> Receptor Availability in Patients with First-Episode Schizophrenia. A Case-Control PET-Imaging Study

Abstract

Introduction: An elemental function of brain dopamine is to coordinate cognitive and motor resources for successful exploitation of environmental energy sources. Dopamine transmission, goal-directed behaviour, and glucose homeostasis are altered in schizophrenia patients prior to and after initiation of pharmacological treatment. Thus, we investigated the relationship between blood glucose levels and brain dopamine signalling in drug-naive patients with first-episode psychosis. Methods: We quantified blood glucose levels and binding of the D 3 preferring dopamine D 2/3 receptor agonist radioligand (+)-[11C]-PHNO in 15 medication-naive patients and 27 healthy volunteers employing positron emission tomography. Results: Whole-brain voxel-wise linear model analysis identified two clusters of significant interaction between blood glucose levels and diagnosis on (+)-[11C]-PHNO binding-potential values. One cluster was located in the ventral striatum and pallidum, the other one in the right ventral tegmental area. We observed positive correlations between blood glucose levels and binding-potential values in healthy volunteers but negative correlations in patients with first episode psychosis. Interpretation: Extracellular dopamine levels are a major determinant of (+)-[11C]-PHNO binding in the brain. In line with the concept that increased dopamine signalling occurs when goal-directed behaviour is needed for restoring energy supply, our data indicate that in healthy volunteers, extracellular dopamine levels are low, when blood glucose levels are high and vice-versa. This relationship is reversed in patients with first-episode psychosis, possibly reflecting a pathogenic alteration underlying two seemingly unrelated aspects of the illness: dysfunctional dopamine signalling and glucose homeostasis. Trial Registration: Clinical Trial Registry:EUDRACT 2010-019586-29 Funding: Vienna Science and Technology Fund; Austrian Science Fund; Medical Scientific Fund of the Mayor of the City of Vienna Declaration of Interests: Without relevance to this work, M. Willeit declares to having received speaker honoraria and consulting fees from Janssen-Cilag Pharma GmbH, Austria. Without relevance to this work, W. Wadsak declares to having received speaker honoraria from GE Healthcare, research grants from Ipsen Pharma, Eckert-Ziegler AG, Scintomics and ITG. WW is a part time eployee ofCBmed Ltd (Center for Biomarker Research in Medicine, Graz, Austria). and is a member of advisory boards of Amgen, Chieri and Sanofi-Aventis. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, Siemens Healthineers. R. Lanzenberger received travel grants and/or conference speaker honoraria within the last three years from Bruker BioSpin MR, Heel, and support from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. S. Kasper received grants/research support, consulting fees and/or honoraria within the last three years from Angelini, AOP Orphan Pharmaceuticals AG, Celegne GmbH, Eli Lilly, Janssen-Cilag Pharma GmbH,KRKA-Pharma, Lundbeck A/S, Mundipharma, Neuraxpharm, Pfizer, Sanofi,Schwabe, Servier, Shire, Sumitomo Dainippon Pharma Co. Ltd. and Takeda. U. Sauerzopf, A. Weidenauer, I. Dajic, M. Bauer, L. Bartova, B. Meyer, L. Nics, C. Philippe, S. Pfaff, V. Pichler, M. Mitterhauser, L. Pezawas and N. Praschak-Rieder have no conflict of interest to declare Ethics Approval Statement: This study was approved by the Ethics-Committee of the Medical University of Vienna and Austrian federal regulatory authorities. All subjects signed an informed consent form.