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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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“41-43 However, the result of no differences in regional CB1R availabilities between female FEP and HC suggests that midbrain dopamine dysregulation driven primarily by cortical ECS dysregulation is not by itself a sufficient etiological model for the emergence of positive symptoms.”
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“However, the effect varied between subgroups, and a limitation of MRS in this context is that MRS-derived glutamate reflects both intra-and extra-synaptic pools, thereby limiting specificity (Jauhar et al., 2018).”
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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