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The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study
Open accessAbstract
Background The pathophysiology of psychosis is incompletely understood. Disruption in cortical glutamatergic signalling causing aberrant striatal dopamine synthesis capacity is a proposed model for psychosis, but has not been tested in vivo. We therefore aimed to test the relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity, and psychotic symptoms. Methods In this cross-sectional multimodal imaging study, 28 individuals with first-episode psychosis and 20 healthy controls underwent 18 F-DOPA PET (measuring striatal dopamine synthesis capacity), and proton magnetic resonance spectroscopy (measuring anterior cingulate cortex glutamate concentrations). Participants were recruited from first-episode psychosis services in London, UK and were required to be in the first episode of a psychotic illness, with no previous illness or treatment episodes. Exclusion criteria for all participants were: history of substantial head trauma, dependence on illicit substances, medical comorbidity (other than minor illnesses), and contraindications to scanning (such as pregnancy). Symptoms were measured using the Positive and Negative Syndrome Scale. The primary endpoint was the relationship between anterior cingulate cortex glutamate concentrations and striatal dopamine synthesis capacity in individuals with their first episode of psychosis as shown by imaging, examined by linear regression. Linear regression was used to examine relationships between measures. Findings Glutamate concentrations showed a significant inverse relationship with striatal dopamine synthesis capacity in patients with psychosis ( R 2 =0·16, p=0·03, β −1·71 × 10 −4 , SE 0·76 × 10 −4 ). This relationship remained significant after the addition of age, gender, ethnicity, and medication status to the model (p=0·015). In healthy controls, there was no significant relationship between dopamine and glutamate measures ( R 2 =0·04, p=0·39). Positive and Negative Syndrome Scale positive psychotic symptoms were positively associated with striatal dopamine synthesis capacity ( R 2 =0·14, p=0·046, β 2546, SE 1217) and showed an inverse relationship with anterior cingulate glutamate concentrations ( R 2 =0·16, p=0·03, β −1·71 × 10 −4 , SE 7·63 × 10 −5 ). No relationships were seen with negative symptoms (positive symptoms, mean [SD] −18·4 (6·6) negative symptoms, mean [SD] −15·4 [6·1]). Interpretation These observations are consistent with the hypothesis that cortical glutamate dysfunction is related to subcortical dopamine synthesis capacity and psychosis. Although the precise mechanistic relationship between cortical glutamate and dopamine in vivo remains unclear, our findings support further studies to test the effect of modulating cortical glutamate in the treatment of psychosis. Funding Medical Research Council, Wellcome Trust, Biomedical Research Council, South London and Maudsley NHS Foundation Trust, JMAS Sim Fellowship, Royal College of Physicians (Edinburgh) (SJ).
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“It is widely accepted that dopaminergic dysregulation stands as one of the most supported hypotheses for the pathogenesis of SCZ and psychosis as a whole (Jauhar et al., 2018; McCutcheon et al., 2020).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as Jauhar et al., 2018
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“Glutamatergic projections from cortex in turn repress dopamine release from the VTA to limbic area with a top-down control manner (Jauhar et al., 2018).”
Huang, L.-C., Lin, S., Tseng, H., Chen, K. C., & Yang, Y. K. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110159 · Cited by 10
Monte Carlo study of metabolite correlations originating from spectral overlap
Hong, S., An, L., & Shen, J. (2022) · Journal of Magnetic Resonance · doi:10.1016/j.jmr.2022.107257 · Cited by 10
McCarty, P. J., Pines, A. R., Sussman, B. L., Wyckoff, S. N., Jensen, A., Bunch, R., Boerwinkle, V. L., & Frye, R. E. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11100969 · Cited by 10
“Current modalities with the capacity to detect alterations in neurotransmitters, such as positron emissions tomography (PET) and magnetic resonance spectroscopy (MRS), are limited in their spatial resolution and sensitivity to pertinent neurotransmitters, respectively [9].”
BackgroundDemler, V. F., Sterner, E., Wilson, M., Zimmer, C., & Knolle, F. (2023) · Scientific Reports · doi:10.1038/s41598-023-39881-1 · Cited by 9
van Hooijdonk, C. V., van der Pluijm, M., Smith, C. L. C., Yaqub, M., van Velden, F. V., Horga, G., Wengler, K., Hoven, M., van Holst, R. V., de Haan, L., et al. (2023) · Neuroscience Applied · doi:10.1016/j.nsa.2023.101134 · Cited by 13
“Additionally, striatal DSC might fl uctuate more over time in patients compared to HC, as striatal DSC is associated with psychotic symptom severity in patients (Jauhar et al., 2017, 2018).”
InfluentialLiddle, P. F., & Sami, M. B. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.08.007 · Cited by 9
“Glutamate concentration in anterior cingulate cortex is inversely related to striatal dopamine synthesis capacity in patients with psychosis (76).”
BackgroundAnand, R., Turolla, A., Chinellato, G., Roy, A., & Hartman, R. D. (2024) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae061 · Cited by 9
Bojesen, K. B., Ambrosen, K. S., Sigvard, A. K., Nielsen, M. Ø., GJEDDE, A. H., Kumakura, Y., Jensen, L. T., Fuglø, D., Ebdrup, B. H., Rostrup, E., et al. (2025) · Molecular Psychiatry · doi:10.1038/s41380-025-03229-0 · Cited by 10
“This seemingly contrasts earlier fi ndings [15, 34], but the present data do in many ways differ from the data from Jauhar et al. First, all patients in the present study were strictly antipsychotic-naïve and within the schizophrenia spectrum and both medication status and diagnosis might in fl uence…”
InfluentialLopes, J. J., Carruthers, S. P., Meyer, D., Dean, B., & Rossell, S. L. (2024) · Australian & New Zealand Journal of Psychiatry · doi:10.1177/00048674241254216 · Cited by 9
“…did not provide participant means and standard deviations (Aoyama et al., 2011; Briend et al., 2020; Bustillo et al., 2014; Cadena et al., 2018; Chang et al., 2007; Gurler et al., 2021; Hugdahl et al., 2015; Jauhar et al., 2018; Rauchmann et al., 2020; Shakory et al., 2018; Théberge et al., 2003).”
BackgroundEtiopathogenic Models of Psychosis Spectrum Illnesses Must Resolve Four Key Features
Vinogradov, S., Hamid, A., & Redish, A. D. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.06.024 · Cited by 9
Halff, E. F., Natesan, S., Bonsall, D. R., Veronese, M., Garcia-Hidalgo, A., Kokkinou, M., Tang, S.-P., Riggall, L. J., Gunn, R. N., Irvine, E. E., et al. (2022) · Molecular Imaging · doi:10.1155/2022/4419221 · Cited by 10
“A major advantage of kinetic modelling using Patlak analysis is that outcome values correspond directly to those used in human [(18)F]-FDOPA PET imaging [10, 41].”
MethodSelf-citationXue, T., Sheng, J., Gao, H., Gu, Y., Dai, J., Yang, X., Peng, H., Gao, H., Lu, R., Shen, Y., et al. (2024) · Psychiatry and Clinical Neurosciences · doi:10.1111/pcn.13641 · Cited by 11
“71,72 Meditation may regulate dopamine release 73 and increase glutamate metabolism in the anterior cingulate cortex and left thalamus, 74,75 potentially linked to the reduction of hallucinations and delusions.”
BackgroundCombinations and Temporal Associations Among Precursor Symptoms Before a First Episode of Psychosis
Paquin, V., MALLA, A. K., Iyer, S. N., Lepage, M., Joober, R., & Shah, J. L. (2023) · Schizophrenia Bulletin · doi:10.1093/schbul/sbad152 · Cited by 8
Psychosis in Huntington's disease: a review and comparison with schizophrenia
Badenoch, J., Rickards, H. E., McCutcheon, R. A., & Nair, A. (2025) · Schizophrenia Research · doi:10.1016/j.schres.2025.07.012 · Cited by 7
Self-citationVariability and Magnitude of Brain Glutamate Levels in Schizophrenia: A Meta and Mega-Analysis
Merritt, K., McCutcheon, R. A., Aleman, A., Ashley, S. A., Beck, K., Block, W., Bloemen, O., Borgan, F., Boules, C., Bustillo, J., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.02.020 · Cited by 7
Self-citationvan Hooijdonk, C. F. M., Tse, D. H. Y., Roosenschoon, J., Ceccarini, J., Booij, J., van Amelsvoort, T., & Vingerhoets, C. (2022) · Genes · doi:10.3390/genes13091672 · Cited by 6
“to findings in patients with psychosis [31], we hypothesized that in 22q11DS, ACC glutamate concentration would be inversely correlated with striatal dopamine D2/3R availability.”
BackgroundResultInfluentialOliver, D., Davies, C., Zelaya, F. O., Selvaggi, P., Micheli, A. D., Catalán, A., Baldwin, H., Arribas, M., Modinos, G., Crossley, N. A., et al. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1092213 · Cited by 6
Self-citationTakado, Y., Takuwa, H., Sampei, K., Urushihata, T., Takahashi, M., Shimojo, M., Uchida, S., Nitta, N., Shibata, S., Nagashima, K., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.10.25.353888 · Cited by 6
Grimaldi, D. A., Patane’, A., Cattarinussi, G., & Sambataro, F. (2025) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2025.106179 · Cited by 4
“…based on preclinical findings, the second one supports a more generalized dysfunction within the striatum, based on a large number of in vivo studies reporting an earlier and more widespread dopaminergic dysfunction within the associative striatum (Conn et al., 2020; McCutcheon et al., 2018).”
Positron Emission Tomography Assessments of Phosphodiesterase 10A in Patients With Schizophrenia
Kubota, M., Takahata, K., Matsuoka, K., Sano, Y., Yamamoto, Y., Tagai, K., Tarumi, R., Suzuki, H., Kurose, S., Nakajima, S., et al. (2022) · Schizophrenia Bulletin · doi:10.1093/schbul/sbac181 · Cited by 4
Acute psychosis following baclofen overdose
Mostafa, K., Kelbrick, M., Mustafa, F., Willis, G., & Paduret, G. (2024) · Progress in Neurology and Psychiatry · doi:10.1002/pnp.837 · Cited by 3
“25 GABA-A receptors have been implicated in catatonia in psychosis.”
BackgroundArumuham, A., Nour, M. M., Veronese, M., Beck, K., Onwordi, E. C., Lythgoe, D. J., Jauhar, S., Rabiner, E. A., & Howes, O. D. (2024) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyae011 · Cited by 3
“The ACC, which is associated with several cognitive processes (Richard et al., 2004; Vincent et al., 2008), has been found to have alterations of the glutamate system in schizophrenia depending on illness progression (Jauhar et al., 2018).”
BackgroundSelf-citationPET and SPECT Imaging of the Central Dopamine System in Humans
Booij, J., van Wieringen, J., van de Giessen, E., Knol, R. J. J., & Finnema, S. J. (2020) · Springer eBooks · doi:10.1007/978-3-030-53176-8_11 · Cited by 3
Zarghami, T. S. (2023) · Brain Structure and Function · doi:10.1007/s00429-023-02697-w · Cited by 2
Sano, Y., Yamamoto, Y., Kubota, M., Moriguchi, S., Matsuoka, K., Kurose, S., Tagai, K., Endo, H., Yamagata, B., Suzuki, H., et al. (2024) · Translational Psychiatry · doi:10.1038/s41398-024-03107-3 · Cited by 2
“Our data justi fi es future clinical trials to investigate the ef fi cacy of PDE10A stimulators for reducing the recurrence rate of manic and depressive episodes in BD-I.”
MethodGlutamate-dopamine matters in psychosis
Hernaus, D., & van Amelsvoort, T. (2018) · The Lancet Psychiatry · doi:10.1016/s2215-0366(18)30299-2 · Cited by 2
Dopamine and Response to Antipsychotic Medication
Ntephe, C., & Demjaha, A. (2020) · Springer eBooks · doi:10.1007/978-3-030-57231-0_14 · Cited by 2
Kokkinou, M., Irvine, E. E., Bonsall, D. R., Natesan, S., Wells, L. A., Smith, M., Glegola, J. A., Paul, E. J., Tossell, K., Veronese, M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/748665 · Cited by 2
Self-citationZahid, U., Osugo, M., Selvaggi, P., Lythgoe, D. J., Fortunato, C., Diederen, K. M. J., Kiemes, A., Wall, M. B., Whitehurst, T., Onwordi, E. C., et al. (2025) · The British Journal of Psychiatry · doi:10.1192/bjp.2025.10319 · Cited by 1
“These findings align with some human imaging studies showing an inverse relationship between cortical glutamate concentrations and striatal dopamine synthesis capacity in psychosis, 34 although this was not replicated by another study.”
Self-citationNeuropharmacological targets for schizophrenia treatment: An update
de Lima, C. A. C., Barbosa, M. E. O., de Souza-Júnior, F. J. C., Farias, S. V., Fontes-Júnior, E. A., & Maia, C. D. S. F. (2025) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2025.111580 · Cited by 1
Hamati, R., Kanaa, N., Chidiac, B., Guimond, S., Cassidy, C., & Tuominen, L. J. (2026) · Schizophrenia · doi:10.1038/s41537-026-00731-4 · Cited by 1
“Moreover, dopamine releasing drugs induce psychosis 23 , dopamine blocking drugs attenuate psychosis 24 and dopamine synthesis capacity correlates with positive symptoms in psychotic illness 25,26 .”
18F-fluorodeoxyglucose PET in Major Psychiatric Disorders
Ferrando, R., & Coutinho, A. M. (2026) · PET Clinics · doi:10.1016/j.cpet.2026.05.007 · Cited by 1
Limongi, R., Mackinley, M., Dempster, K., KHAN, A. R., Gati, J. S., & Palaniyappan, L. K. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.02.07.939470 · Cited by 1
Metadata
- Authors
- Jauhar, S., McCutcheon, R., Borgan, F., Veronese, M., Nour, M., Pepper, F., Rogdaki, M., Stone, J., Egerton, A., Turkheimer, F., McGuire, P., & Howes, O. D.
- Affiliations
- King's College London (GB)
- Corresponding author
- Howes, Oliver D
- ORCID
- Venue
- The Lancet Psychiatry
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 5
- Issue
- 10
- Pages
- 816-823
- ISSN
- 2215-0366 (ISSN-L)
- PMC
- PMC6162342
- OpenAlex
- W2889742508
- Cited by
- 114
- References
- 35
- Citations by year
- 2026: 4 · 2025: 9 · 2024: 14 · 2023: 15 · 2022: 21 · 2021: 14 · 2020: 21 · 2019: 15 · 2018: 1
- FWCI
- 10.03
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Lancet Psychiatry (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Portal (King's College London) (submittedVersion, cc-by)
- Padua Research Archive (University of Padova) (submittedVersion)
- Funders
- Wellcome Trust (200102/Z/15/Z)
- National Institute for Health and Care Research (ACF-2016-17-005)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced MRI Techniques and Applications
- Keywords
- first-episode psychosis, anterior cingulate cortex, glutamatergic signalling, dopamine-glutamate interaction, 18F-DOPA PET, 1H NMR, positive psychotic symptoms, negative symptoms, psychosis pathophysiology, multimodal neuroimaging
- MeSH terms
- Adult, Corpus Striatum, Cross-Sectional Studies, Dihydroxyphenylalanine, Dopamine, Female, Humans, London, Magnetic Resonance Imaging, Male, Magnetic Resonance Spectroscopy, Psychiatric Status Rating Scales, Psychotic Disorders, Glutamic Acid
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