Linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes: translational relevance for schizophrenia and antipsychotic treatment: a systematic review
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Evidence from clinical, preclinical, and post-mortem studies supports the inflammatory/immune hypothesis of schizophrenia pathogenesis. Less evident is the link between the inflammatory background and two well-recognized functional and structural findings of schizophrenia pathophysiology: the dopamine-glutamate aberrant interaction and the alteration of dendritic spines architecture, both believed to be the "quantal" elements of cortical-subcortical dysfunctional network. In this systematic review, we tried to capture the major findings linking inflammation, aberrant glutamate-dopamine interaction, and post-synaptic changes under a direct and inverse translational perspective, a paramount picture that at present is lacking. The inflammatory effects on dopaminergic function appear to be bidirectional: the inflammation influences dopamine release, and dopamine acts as a regulator of discrete inflammatory processes involved in schizophrenia such as dysregulated interleukin and kynurenine pathways. Furthermore, the link between inflammation and glutamate is strongly supported by clinical studies aimed at exploring overactive microglia in schizophrenia patients and maternal immune activation models, indicating impaired glutamate regulation and reduced N-methyl-D-aspartate receptor (NMDAR) function. In addition, an inflammatory/immune-induced alteration of post-synaptic density scaffold proteins, crucial for downstream NMDAR signaling and synaptic efficacy, has been demonstrated. According to these findings, a significant increase in plasma inflammatory markers has been found in schizophrenia patients compared to healthy controls, associated with reduced cortical integrity and functional connectivity, relevant to the cognitive deficit of schizophrenia. Finally, the link between altered inflammatory/immune responses raises relevant questions regarding potential new therapeutic strategies specifically for those forms of schizophrenia that are resistant to canonical antipsychotics or unresponsive to clozapine.
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The above neurophysiological mechanisms are likely highly interactive at multiple explanatory levels.
“The above neurophysiological mechanisms are also likely highly interactive at multiple explanatory levels; for example, dopamine can regulate inflammatory responses and vice versa, 105 and neuroendocrine stress systems and immune regulation may impact neuronal connectivity and brain function.”
From Towards an Integrative Account of Potential Mechanisms Mediating the Path From Sleep Dysfunction to Hallucinations (2025) · cites this paper as [105]
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Gallego, J. A., Blanco, E. A., Husain-Krautter, S., Fagen, E. M., Moreno-Merino, P., del Ojo-Jiménez, J. A., Ahmed, A. O., Rothstein, T. L., Lencz, T., & Malhotra, A. K. (2018) · Schizophrenia Research · doi:10.1016/j.schres.2018.07.019 · Cited by 107 · see citing works
Immune-inflammatory markers and psychosis risk: A systematic review and meta-analysis
Misiak, B., Bartoli, F., Carrà, G., Stańczykiewicz, B., Gładka, A., Frydecka, D., Samochowiec, J., Jarosz, K., Hadryś, T., & Miller, B. J. (2021) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2021.105200 · Cited by 107 · see citing works
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Parellada, E., & Gassó, P. (2021) · Translational Psychiatry · doi:10.1038/s41398-021-01385-9 · Cited by 106 · see citing works
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Immunological findings in psychotic syndromes: a tertiary care hospital's CSF sample of 180 patients
Endres, D., Perlov, E., Baumgärtner, A., Hottenrott, T., Dersch, R. S., Stich, O., & van Elst, L. T. (2015) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2015.00476 · Cited by 102 · see citing works
Regulation of innate and adaptive immune responses by the related cytokines IL-12, IL-23, and IL-27
Beadling, C., & Slifka, M. K. (2006) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-006-0002-6 · Cited by 100 · see citing works
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Flagged first, then by citations
Research works printed but not linked: 2
- [168]Li R Ma X Wang G Yang J Wang C Why sex differences in schizophrenia? J transl neuroscience 2016 1 1 37 42 PMC5688947 29152382
- [289]Müller N 2010 COX-2 inhibitors as antidepressants and antipsychotics: clinical evidence. Current opinion in investigational drugs (London, England: 2000) 11 (1):31–42 20047157
Cited by
Sorted by citations
De Simone, G., Mazza, B., Vellucci, L., Barone, A., Ciccarelli, M., & de Bartolomeis, A. (2023) · Antioxidants · doi:10.3390/antiox12040975 · Cited by 49 · see citing works
Self-citationLiu, Y., Ren, H., Zhang, Y., Deng, W., Ma, X., Zhao, L., Li, X., Sham, P., Wang, Q., & Li, T. (2024) · Psychological Medicine · doi:10.1017/s003329172400014x · Cited by 15 · see citing works
Brain structure in schizophrenia: what do we know and what next?
Lawrie, S. M. (2025) · The Lancet Psychiatry · doi:10.1016/s2215-0366(25)00172-5 · Cited by 7 · see citing works
Sheaves, B., Cropley, V. L., Moseley, P., Woodruff, P. W. R., Punton, G., Speth, C., Speth, J., Meerlo, P., & Brederoo, S. G. (2025) · Schizophrenia Bulletin · doi:10.1093/schbul/sbaf107 · Cited by 6 · see citing works
- Authors
- de Bartolomeis, A., Barone, A., Vellucci, L., Mazza, B., Austin, M. C., Iasevoli, F., & Ciccarelli, M.
- Affiliations
- Federico II University Hospital (IT)
- Idaho State University (US)
- Venue
- Molecular Neurobiology
- Published
- 2022-08-13
- Volume
- 59
- Issue
- 10
- Pages
- 6460-6501
- ISSN
- 0893-7648 (ISSN-L)
- 1559-1182
- PMC
- PMC9463235
- OpenAlex
- W4291237996
- Cited by
- 113
- References
- 325
- Citations by year
- 2026: 31 · 2025: 30 · 2024: 33 · 2023: 15 · 2022: 4
- FWCI
- 1.55
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Molecular Neurobiology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Università degli Studi di Napoli Federico II
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- schizophrenia, inflammation, dopamine-glutamate interaction, dendritic spines, postsynaptic density, NMDA receptor, microglia, maternal immune activation, kynurenine pathway, plasma inflammatory markers, functional connectivity, cognitive impairment, antipsychotic resistance, clozapine, translational research
- MeSH terms
- Dopamine, Humans, Inflammation, Schizophrenia, Antipsychotic Agents, Receptors, N-Methyl-D-Aspartate, Glutamic Acid
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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