Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study

Oliver Howes; Ilaria Bonoldi; Robert A. McCutcheon; Matilda Azis; Mathilde Antoniades; Matthijs G. Bossong; Gemma Modinos; Jesus Perez; James Stone; Barbara Santangelo; Mattia Veronese; Anthony A. Grace; Paul Allen; Philip McGuire

doi:10.1038/s41386-019-0541-2

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study

Oliver Howes, Ilaria Bonoldi, Robert A. McCutcheon, Matilda Azis, Mathilde Antoniades, Matthijs G. Bossong, Gemma Modinos, Jesus Perez, James Stone, Barbara Santangelo, Mattia Veronese, Anthony A. Grace, Paul Allen, Philip McGuire

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Abstract

Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampalglutamate concentrations.

© 2019, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

Original language	English
Pages (from-to)	641-648
Number of pages	8
Journal	NEUROPSYCHOPHARMACOLOGY
Volume	45
Issue number	4
DOIs	https://doi.org/10.1038/s41386-019-0541-2
Publication status	Published - 16 Mar 2020

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Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multimodal PET-magnetic resonance brain imaging studyFinal published version, 916 KBLicence: CC BY

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Howes, O., Bonoldi, I., McCutcheon, R. A., Azis, M., Antoniades, M., Bossong, M. G., Modinos, G., Perez, J., Stone, J., Santangelo, B., Veronese, M., Grace, A. A., Allen, P., & McGuire, P. (2020). Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study. NEUROPSYCHOPHARMACOLOGY, 45(4), 641-648. https://doi.org/10.1038/s41386-019-0541-2

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title = "Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study",

abstract = "Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampalglutamate concentrations.{\textcopyright} 2019, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/ ",

author = "Oliver Howes and Ilaria Bonoldi and McCutcheon, {Robert A.} and Matilda Azis and Mathilde Antoniades and Bossong, {Matthijs G.} and Gemma Modinos and Jesus Perez and James Stone and Barbara Santangelo and Mattia Veronese and Grace, {Anthony A.} and Paul Allen and Philip McGuire",

year = "2020",

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day = "16",

doi = "10.1038/s41386-019-0541-2",

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Howes, O, Bonoldi, I, McCutcheon, RA, Azis, M, Antoniades, M, Bossong, MG, Modinos, G, Perez, J, Stone, J, Santangelo, B, Veronese, M, Grace, AA, Allen, P & McGuire, P 2020, 'Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study', NEUROPSYCHOPHARMACOLOGY, vol. 45, no. 4, pp. 641-648. https://doi.org/10.1038/s41386-019-0541-2

Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study. / Howes, Oliver; Bonoldi, Ilaria; McCutcheon, Robert A. et al.
In: NEUROPSYCHOPHARMACOLOGY, Vol. 45, No. 4, 16.03.2020, p. 641-648.

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

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T1 - Glutamatergic and dopaminergic function and the relationship to outcome in people at clinical high risk of psychosis: a multi-modal PET-magnetic resonance brain imaging study

AU - Howes, Oliver

AU - Bonoldi, Ilaria

AU - McCutcheon, Robert A.

AU - Azis, Matilda

AU - Antoniades, Mathilde

AU - Bossong, Matthijs G.

AU - Modinos, Gemma

AU - Perez, Jesus

AU - Stone, James

AU - Santangelo, Barbara

AU - Veronese, Mattia

AU - Grace, Anthony A.

AU - Allen, Paul

AU - McGuire, Philip

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AB - Preclinical models of psychosis propose that hippocampal glutamatergic neuron hyperactivity drives increased striatal dopaminergic activity, which underlies the development of psychotic symptoms. The aim of this study was to examine the relationship between hippocampal glutamate and subcortical dopaminergic function in people at clinical high risk for psychosis, and to assess the association with the development of psychotic symptoms. 1H-MRS was used to measure hippocampal glutamate concentrations, and 18F-DOPA PET was used to measure dopamine synthesis capacity in 70 subjects (51 people at clinical high risk for psychosis and 19 healthy controls). Clinical assessments were undertaken at baseline and follow-up (median 15 months). Striatal dopamine synthesis capacity predicted the worsening of psychotic symptoms at follow-up (r = 0.35; p < 0.05), but not transition to a psychotic disorder (p = 0.22), and was not significantly related to hippocampal glutamate concentration (p = 0.13). There were no differences in either glutamate (p = 0.5) or dopamine (p = 0.5) measures in the total patient group relative to controls. Striatal dopamine synthesis capacity at presentation predicts the subsequent worsening of sub-clinical total and psychotic symptoms, consistent with a role for dopamine in the development of psychotic symptoms, but is not strongly linked to hippocampalglutamate concentrations.© 2019, The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/

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DO - 10.1038/s41386-019-0541-2

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