The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment

Sameer Jauhar; Robert A. McCutcheon; Mattia Veronese; Faith Borgan; Matthew Nour; Maria Rogdaki; Fiona Pepper; James M. Stone; Alice Egerton; George Vamvakas; Federico Turkheimer; Philip K. McGuire; Oliver D. Howes

doi:10.1038/s41398-023-02479-2

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment

Sameer Jauhar^*, Robert A. McCutcheon, Mattia Veronese, Faith Borgan, Matthew Nour, Maria Rogdaki, Fiona Pepper, James M. Stone, Alice Egerton, George Vamvakas, Federico Turkheimer, Philip K. McGuire, Oliver D. Howes

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Ki^cer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks’ naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Ki^cer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Ki^cer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

Original language	English
Article number	184
Journal	Translational psychiatry
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41398-023-02479-2
Publication status	Published - Dec 2023

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Jauhar, S., McCutcheon, R. A., Veronese, M., Borgan, F., Nour, M., Rogdaki, M., Pepper, F., Stone, J. M., Egerton, A., Vamvakas, G., Turkheimer, F., McGuire, P. K., & Howes, O. D. (2023). The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment. Translational psychiatry, 13(1), Article 184. https://doi.org/10.1038/s41398-023-02479-2

@article{79d7553d9f954cdd8d2605c7c817235e,

title = "The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment",

abstract = "The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks{\textquoteright} naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.",

author = "Sameer Jauhar and McCutcheon, {Robert A.} and Mattia Veronese and Faith Borgan and Matthew Nour and Maria Rogdaki and Fiona Pepper and Stone, {James M.} and Alice Egerton and George Vamvakas and Federico Turkheimer and McGuire, {Philip K.} and Howes, {Oliver D.}",

note = "Funding Information: SJ, JMS, AE, FT, PM and ODH are supported by the National Institute for Health Research Biomedical Research Centre at South London, Maudsley National Health Service Foundation Trust, King{\textquoteright}s College London, and SJ by a JMAS (John, Margaret, Alfred, and Stewart) Sim Fellowship from the Royal College of Physicians, Edinburgh. MV is supported by MIUR, Italian Ministry for Education, under the initiatives “Departments of Excellence” (Law 232/2016) and by Wellcome Trust Digital Award (no. 215747/Z/19/Z). RM{\textquoteright}s work is funded by a Wellcome Trust Clinical Research Career Development (224625/Z/21/Z). FB became an employee at COMPASS Pathways plc after the completion of this work. This work is unrelated to COMPASS Pathways plc. For the purpose of open access, this paper has been published under the creative common licence (CC-BY). This study was funded by Medical Research Council-UK (MC_U120097115; MR/W005557/1 and MR/V013734/1), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH and the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King{\textquoteright}s College London. The views expressed are those of the author(s) and not necessarily those of the NHS/NIHR or the Department of Health. SJ has received honoraria for educational lectures given for Boehringer Ingelheim, Janssen, Sunovion, and King{\textquoteright}s College London has received honoraria for lectures SJ has given for Lundbeck. RM has received speaker consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and is director of a company that hosts psychotropic prescribing decision tools. MV hold a patent application for the use of dopamine imaging as a prognostic tool in mental health (WO2021111116). FB reports no biomedical, financial interests or potential conflicts of interest. MN reports no biomedical, financial interests or potential conflicts of interest. MR reports no biomedical, financial interests or potential conflicts of interest. FP reports no biomedical, financial interests or potential conflicts of interest. In the last 3 years, JMS has been principal investigator or sub-investigator on studies sponsored by Takeda, Janssen, and Lundbeck Plc. AE reports no biomedical, financial interests or potential conflicts of interest. GV reports no biomedical, financial interests or potential conflicts of interest. FT reports no biomedical, financial interests or potential conflicts of interest. PKM reports no biomedical, financial interests or potential conflicts of interest. ODH is a part-time employee and stock holder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the use of dopaminergic imaging. Funding Information: The authors would like to thank all the patients and their family members who facilitated this research, as well as Drs Paul Morrison and Nikola Rahamann, the Early Intervention teams in South London and Maudsley NHS Foundation Trust (COAST, STEP, LEO and LEIS) and CNWL who facilitated recruitment to the study. Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41398-023-02479-2",

language = "English",

volume = "13",

journal = "Translational psychiatry",

issn = "2158-3188",

publisher = "Nature Publishing Group",

number = "1",

}

Jauhar, S, McCutcheon, RA, Veronese, M , Borgan, F, Nour, M, Rogdaki, M, Pepper, F, Stone, JM, Egerton, A, Vamvakas, G, Turkheimer, F, McGuire, PK & Howes, OD 2023, 'The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment', Translational psychiatry, vol. 13, no. 1, 184. https://doi.org/10.1038/s41398-023-02479-2

TY - JOUR

T1 - The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment

AU - Jauhar, Sameer

AU - McCutcheon, Robert A.

AU - Veronese, Mattia

AU - Borgan, Faith

AU - Nour, Matthew

AU - Rogdaki, Maria

AU - Pepper, Fiona

AU - Stone, James M.

AU - Egerton, Alice

AU - Vamvakas, George

AU - Turkheimer, Federico

AU - McGuire, Philip K.

AU - Howes, Oliver D.

N1 - Funding Information: SJ, JMS, AE, FT, PM and ODH are supported by the National Institute for Health Research Biomedical Research Centre at South London, Maudsley National Health Service Foundation Trust, King’s College London, and SJ by a JMAS (John, Margaret, Alfred, and Stewart) Sim Fellowship from the Royal College of Physicians, Edinburgh. MV is supported by MIUR, Italian Ministry for Education, under the initiatives “Departments of Excellence” (Law 232/2016) and by Wellcome Trust Digital Award (no. 215747/Z/19/Z). RM’s work is funded by a Wellcome Trust Clinical Research Career Development (224625/Z/21/Z). FB became an employee at COMPASS Pathways plc after the completion of this work. This work is unrelated to COMPASS Pathways plc. For the purpose of open access, this paper has been published under the creative common licence (CC-BY). This study was funded by Medical Research Council-UK (MC_U120097115; MR/W005557/1 and MR/V013734/1), and Wellcome Trust (no. 094849/Z/10/Z) grants to ODH 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 views expressed are those of the author(s) and not necessarily those of the NHS/NIHR or the Department of Health. SJ has received honoraria for educational lectures given for Boehringer Ingelheim, Janssen, Sunovion, and King’s College London has received honoraria for lectures SJ has given for Lundbeck. RM has received speaker consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and is director of a company that hosts psychotropic prescribing decision tools. MV hold a patent application for the use of dopamine imaging as a prognostic tool in mental health (WO2021111116). FB reports no biomedical, financial interests or potential conflicts of interest. MN reports no biomedical, financial interests or potential conflicts of interest. MR reports no biomedical, financial interests or potential conflicts of interest. FP reports no biomedical, financial interests or potential conflicts of interest. In the last 3 years, JMS has been principal investigator or sub-investigator on studies sponsored by Takeda, Janssen, and Lundbeck Plc. AE reports no biomedical, financial interests or potential conflicts of interest. GV reports no biomedical, financial interests or potential conflicts of interest. FT reports no biomedical, financial interests or potential conflicts of interest. PKM reports no biomedical, financial interests or potential conflicts of interest. ODH is a part-time employee and stock holder of Lundbeck A/s. He has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Heptares, Global Medical Education, Invicro, Janssen, Lundbeck, Neurocrine, Otsuka, Sunovion, Recordati, Roche and Viatris/ Mylan. ODH has a patent for the use of dopaminergic imaging. Funding Information: The authors would like to thank all the patients and their family members who facilitated this research, as well as Drs Paul Morrison and Nikola Rahamann, the Early Intervention teams in South London and Maudsley NHS Foundation Trust (COAST, STEP, LEO and LEIS) and CNWL who facilitated recruitment to the study. Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks’ naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

AB - The neuromodulator dopamine and excitatory neurotransmitter glutamate have both been implicated in the pathogenesis of psychosis, and dopamine antagonists remain the predominant treatment for psychotic disorders. To date no study has measured the effect of antipsychotics on both of these indices together, in the same population of people with psychosis. Striatal dopamine synthesis capacity (Kicer) and anterior cingulate glutamate were measured using 18F-DOPA positron emission tomography and proton magnetic resonance spectroscopy respectively, before and after at least 5 weeks’ naturalistic antipsychotic treatment in people with first episode psychosis (n = 18) and matched healthy controls (n = 20). The relationship between both measures at baseline and follow-up, and the change in this relationship was analyzed using a mixed linear model. Neither anterior cingulate glutamate concentrations (p = 0.75) nor striatal Kicer (p = 0.79) showed significant change following antipsychotic treatment. The change in relationship between whole striatal Kicer and anterior cingulate glutamate, however, was statistically significant (p = 0.017). This was reflected in a significant difference in relationship between both measures for patients and controls at baseline (t = 2.1, p = 0.04), that was not present at follow-up (t = 0.06, p = 0.96). Although we did not find any effect of antipsychotic treatment on absolute measures of dopamine synthesis capacity and anterior cingulate glutamate, the relationship between anterior cingluate glutamate and striatal dopamine synthesis capacity did change, suggesting that antipsychotic treatment affects the relationship between glutamate and dopamine.

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U2 - 10.1038/s41398-023-02479-2

DO - 10.1038/s41398-023-02479-2

M3 - Article

C2 - 37253720

AN - SCOPUS:85160613959

SN - 2158-3188

VL - 13

JO - Translational psychiatry

JF - Translational psychiatry

IS - 1

M1 - 184

ER -

The relationship between striatal dopamine and anterior cingulate glutamate in first episode psychosis changes with antipsychotic treatment

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