Dopamine and glutamate in schizophrenia: biology, symptoms and treatment
Open accessAbstract
Glutamate and dopamine systems play distinct roles in terms of neuronal signalling, yet both have been proposed to contribute significantly to the pathophysiology of schizophrenia. In this paper we assess research that has implicated both systems in the aetiology of this disorder. We examine evidence from post‐mortem, preclinical, pharmacological and in vivo neuroimaging studies. Pharmacological and preclinical studies implicate both systems, and in vivo imaging of the dopamine system has consistently identified elevated striatal dopamine synthesis and release capacity in schizophrenia. Imaging of the glutamate system and other aspects of research on the dopamine system have produced less consistent findings, potentially due to methodological limitations and the heterogeneity of the disorder. Converging evidence indicates that genetic and environmental risk factors for schizophrenia underlie disruption of glutamatergic and dopaminergic function. However, while genetic influences may directly underlie glutamatergic dysfunction, few genetic risk variants directly implicate the dopamine system, indicating that aberrant dopamine signalling is likely to be predominantly due to other factors. We discuss the neural circuits through which the two systems interact, and how their disruption may cause psychotic symptoms. We also discuss mechanisms through which existing treatments operate, and how recent research has highlighted opportunities for the development of novel pharmacological therapies. Finally, we consider outstanding questions for the field, including what remains unknown regarding the nature of glutamate and dopamine function in schizophrenia, and what needs to be achieved to make progress in developing new treatments.
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Different biological pathways have been implicated in the aetio-pathogenesis across multiple mental disorders, including serotonin, dopamine, GABA/glutamatergic, inflammation, oxidative stress, synaptic plasticity/neurogenesis, and the HPA axis.
“Different biological pathways have been implicated in the aetio-pathogenesis across multiple mental disorders. Some of these are pathways related to neurotransmission such as serotonin (Provenzi, Giorda, Beri, & Montirosso, 2016), dopamine or GABA/glutamatergic processes (McCutcheon, Krystal, & Howes, 2020); while others pathways involve inflammation (Cullen et al., 2019), oxidative stress (Steul”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as McCutcheon, Krystal, & Howes, 2020
Alterations in glutamatergic and GABAergic pathways, which can lead to either excitatory/inhibitory imbalance, have been reported to play a role in the etiopathogenesis of psychotic disorders and ASD.
“Alterations in glutamatergic and GABAergic pathways, which can lead to either excitatory/inhibitory imbalance, have been reported to play a role in the etiopathogenesis of psychotic disorders (McCutcheon et al., 2020) and ASD (Marotta et al., 2020).”
From Can epigenetics shine a light on the biological pathways underlying major mental disorders? (2022) · cites this paper as McCutcheon et al., 2020
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.
“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 McCutcheon et al., 2020
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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).”
BackgroundCullen, A. E., Fisher, H. L., Gullet, N., Fraser, E. R., Roberts, R. E., Zahid, U., To, M., Yap, N. H., Zunszain, P. A., Pariante, C. M., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2021.08.009 · Cited by 27 · see citing works
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- Authors
- McCutcheon, R. A., Krystal, J. H., & Howes, O. D.
- Affiliations
- King's College London (GB)
- Yale University (US)
- Venue
- World Psychiatry
- Publisher
- Wiley
- Published
- 2020-01-10
- Volume
- 19
- Issue
- 1
- Pages
- 15-33
- ISSN
- 1723-8617 (ISSN-L)
- 2051-5545
- PMC
- PMC6953551
- OpenAlex
- W2999889141
- Cited by
- 612
- References
- 34
- Citations by year
- 2026: 83 · 2025: 116 · 2024: 121 · 2023: 97 · 2022: 99 · 2021: 67 · 2020: 27 · 2019: 2
- FWCI
- 52.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- World Psychiatry (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Funders
- Wellcome Trust (200102/Z/15/Z)
- National Institute for Health and Care Research
- National Institutes of Health (UL1TR001863)
- Medical Research Council (MR/L022176/1, MR/N026063/1, MR/N027078/1)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- schizophrenia, dopamine, glutamate, glutamatergic dysfunction, dopaminergic dysfunction, striatal dopamine synthesis, dopamine release, genetic risk factors, environmental risk factors, neural circuits, psychotic symptoms, antipsychotic mechanism of action, neuroimaging
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