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The association between N-methyl-d-aspartate receptor availability and glutamate levels: A multi-modal PET-MR brain imaging study in first-episode psychosis and healthy controls

Research output: Contribution to journalArticlepeer-review

Original languageEnglish
Pages (from-to)1051-1060
Number of pages10
JournalJournal of psychopharmacology (Oxford, England)
Volume36
Issue number9
Early online date19 Sep 2022
DOIs
Accepted/In press17 Apr 2022
E-pub ahead of print19 Sep 2022
PublishedSep 2022

Bibliographical note

Funding Information: We are grateful to Martin J Fisher for the development of [18F]GE179 and the Radiopharmaceutical Unit, Wolfson Brain Imaging Centre, University of Cambridge for its manufacture. The author(s) disclosed receipt of the following financial support for the research, authorship and/or publication of this article: K.B. has received funding from the Royal College of Psychiatrists, Rosetrees Trust and Stoneygate Trust. M.V. is funded by the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust and King’s College London, and by the Wellcome Trust Digital Award 215747/Z/19/Z. C.J.M. was supported by the Medical Research Council MR/N013042/1 and subsequently by the Wellcome Trust/Engineering and Physical Sciences Research Council (EPSRC) Centre for Medical Engineering WT 203148/Z/16/Z and the Engineering and Physical Sciences Research Council Centre for Doctoral Training in Medical Imaging EP/L015226/1. J.D.’s work was supported by the Wellcome/EPSRC Centre for Medical Engineering WT 203148/Z/16/Z. R.A.M. received funding from NIHR. N.S. was funded by a grant from the Medical Research Council, MR/K022733/1 (awarded to F.T.). T.P.’s work is supported by the NIHR and Maudsley Charity. T.S.’s work was funded by departmental funding Wellcome-EPSRC, Grant/Award Number: WT 203148/Z/16/Z. F.T. has received MRC funding MR/K022733/1. A.H. is funded by King’s College London. O.D.H. has received funding from the Medical Research Council-UK no. MC_U120097115, Maudsley Charity no. 66, Brain and Behavior Research Foundation, and Wellcome Trust no. 094849/Z/10/Z grants to O.D.H. and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The School of Biomedical Engineering and Imaging Sciences is supported by the Wellcome EPSRC Centre for Medical Engineering at King’s College London (WT 203148/Z/16/Z) and the Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust. This research was funded in whole, or in part, by the Wellcome Trust 094849/Z/10/Z. Development of [18F]GE179 was funded by an MRC PET Neuroscience programme grant (Training and Novel Probes Programme in PET Neurochemistry - MR/K02308X/1). For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed are those of the author(s) and not necessarily those of H Lundbeck A/s, the NHS/NIHR or the Department of Health. Funding Information: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: K.B., A.A., B.S., J.D., N.S., T.S., F.T. and D.L. have no conflicts of interest. M.V. has received consulting honoraria from GSK. C.J.M. has received fees from GE Healthcare Ltd but neither he nor any of his family have ever been employed by the organisation; nor does he or any of his family have holdings/a financial stake in GE Healthcare Ltd. S.K. received travel expenses for a scientific meeting from Autifony Ltd. R.A.M. has received honoraria for lectures from Otsuka and is an investigator on research funded by Neurocrine. T.P. has participated in educational speaker meetings organised by Lundbeck, Otsuka, Sunovion, Schwabe Pharma and Recordati. R.N. is an employee of Siemens Healthcare. In the last 3 years, J.S. has been PI on research studies sponsored by Takeda and Protexin. He has received an honorarium from Janssen for attending an advisory board meeting. S.J. has received honoraria for educational talks given for Sunovian. Kings College London has received honoraria for educational talks S.J. has given for Lundbeck. S.J. is Co PI on a drug trial for Alkermes. F.B. became an employee at COMPASS Pathways plc after completion of this work. This work is unrelated to COMPASS Pathways plc. A.H. has received honoraria or consultation fees from Imperial Innovations and is a shareholder in Imperial Innovations, and has participated in educational speaker meetings organised by Siemens. O.D.H. is a part-time employee of H Lundbeck A/s (obtained post after completion of this project) and has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Jansenn, Lundbeck, Neurocrine, Otsuka, Sunovion, Rand, Recordati, Roche and Viatris/Mylan. Neither O.D.H. nor his family have holdings/a financial stake in any pharmaceutical company. O.D.H. has a patent for the use of dopaminergic imaging. Publisher Copyright: © The Author(s) 2022.

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Abstract

Background: Evidence from post-mortem studies and in vivo imaging studies suggests there may be reduced N-methyl-d-aspartate receptor (NMDAR) levels in the hippocampus in patients with schizophrenia. Other studies have reported increased glutamate in striatum in schizophrenia patients. It has been hypothesised that NMDAR hypofunction leads to the disinhibition of glutamatergic signalling; however, this has not been tested in vivo. Methods: In this study, we investigated the relationship between hippocampal NMDAR and striatal glutamate using simultaneous positron emission tomography-magnetic resonance (PET-MR) imaging. We recruited 40 volunteers to this cross-sectional study; 21 patients with schizophrenia, all in their first episode of illness, and 19 healthy controls. We measured hippocampal NMDAR availability using the PET ligand [ 18F]GE179. This was indexed relative to whole brain as the distribution volume ratio (DVR). Striatal glutamatergic indices (glutamate and Glx) were acquired simultaneously, using combined PET-MR proton magnetic resonance spectroscopy ( 1H-MRS). Results: A total of 33 individuals (15 healthy controls, 18 patients) were included in the analyses (mean (SD) age of controls, 27.31 (4.68) years; mean (SD) age of patients, 24.75 (4.33), 27 male and 6 female). We found an inverse relationship between hippocampal DVR and striatal glutamate levels in people with first-episode psychosis (rho = −0.74, p < 0.001) but not in healthy controls (rho = −0.22, p = 0.44). Conclusion: This study show that lower relative NMDAR availability in the hippocampus may drive increased striatal glutamate levels in patients with schizophrenia. Further work is required to determine whether these findings may yield new targets for drug development in schizophrenia.

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