Kynurenine pathway in schizophrenia: pathophysiological and therapeutic aspects
Abstract
The disturbance of the dopaminergic neurotransmission is a key-feature in the neurobiology of schizophrenia. The interaction between the dopaminergic and the glutamatergic neurotransmission, however, attracted more notice to the glutamatergic system. Recent research focussed on factors influencing the glutamatergic neurotransmission. A pro-inflammatory immune state influences the glutamatergic neurotransmission indirectly by its effects on the tryptophan/kynurenine metabolism. The immune response in schizophrenia seems to be associated with the activation of the enzyme indoleamine 2,3-dioxygenase (IDO) and imbalance in the tryptophan/kynurenine metabolism resulting in increased production of kynurenic acid in the brain. This is associated with an imbalance in the glutamatergic neurotransmission, leading to an NMDA antagonism in schizophrenia. The immunological effects of antipsychotics reverse partly the immune imbalance and the unphysiologically enhanced production of the kynurenic acid. These immunological and neurochemical imbalances result in a chronic pro-inflammatory state in association with increased prostaglandin E₂ (PGE₂) production, increased cyclo-oxygenase-2 (COX-2) expression and increased pro-inflammatory cytokines production and NMDA receptor hypofunctioning. Substances acting directly on the kynurenine metabolism are still in very early stages of development, anti-inflammatory drugs acting indirectly on this metabolism are discussed as therapeutic or preventive agents in schizophrenia. Most of the existing data are related to COX-2 inhibitors, which have been tested in animal experiments and in clinical trials, pointing to favourable effects in schizophrenia.
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Inflammatory processes cause increased production of kynurenic acid, an endogenous NMDAR antagonist, through dysregulation of tryptophan/kynurenine metabolism.
“Moreover, inflammatory processes cause increased production of kynurenic acid, an endogenous NMDAR antagonist, via dysregulation of tryptophan/kynurenine metabolism (Muller et al., 2011).”
From Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A “central hub” in schizophrenia pathophysiology? (2016) · cites this paper as Muller et al., 2011
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Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations.
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Self-citationThe role of inflammation in schizophrenia
Müller, N., Weidinger, E., Leitner, B., & Schwarz, M. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00372 · Cited by 469 · see citing works
“A predominant type 2 immune response inhibits the enzyme indoleamine 2,3-dioxygenase (IDO), resulting in an increased production of kynurenic acid in schizophrenia and in NMDA receptor antagonism (Müller and Schwarz, 2007; Müller et al., 2011).”
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“Microglia over-activation also leads to elevated production of quinolinic acid (QUIN) and 3-hydroxykynurenine (3-OHKY), both of which have potent neurotoxic properties too (Müller et al., 2011; Wonodi and Schwarcz, 2010).”
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“Moreover, inflammatory processes cause increased production of kynurenic acid, an endogenous NMDAR antagonist, via dysregulation of tryptophan/kynurenine metabolism (Muller et al., 2011).”
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“A via da QUIN está alterada em grande número de doenças neuropsiquiátricas, e a produção de mediadores inflamatórios, como as citocinas e quimiocinas, é capaz de aumentar a atividade da enzima indoleamina-2,3-dioxigenase (IDO) (20,24,29), que é fundamental para o metabolismo do TRP e a sua conversão em QUIN nos difere…”
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Barone, A., Vellucci, L., Ciccarelli, M., Matrone, M., Simone, G. D., Iannotta, F., Iasevoli, F., & de Bartolomeis, A. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178598 · Cited by 6 · see citing works
“But KP is mechanistically attractive because it links immune activation to glutamatergic tone and redox biology [158,163–165].”
Neuroinflammation. Contemporary anti-inflammatory treatment approaches
Al-Amin, M. M., & Reza, H. M. (2014) · Neurosciences · doi:10.17712/1658-3183.2066 · Cited by 6 · see citing works
Pinto, A. V. L. (2014) · Journal of Alzheimer’s Disease & Parkinsonism · doi:10.4172/2161-0460.1000132 · Cited by 6 · see citing works
“From a pathological point of view, schizophrenia could be due to a neuroinflammation processes, mostly by alterations of the kynurenic acid (a tryptophan metabolite) pathway [75,76].”
BackgroundKrämer, P., & Bressan, P. (2021) · doi:10.31234/osf.io/pja8w · Cited by 6 · see citing works
Arolt, V., & Ambrée, O. (2013) · Modern trends in psychiatry · doi:10.1159/000343972 · Cited by 4 · see citing works
Inflammation and Immunity in Schizophrenia
Müller, N. (2021) · Springer eBooks · doi:10.1007/978-3-030-71229-7_14 · Cited by 4 · see citing works
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Social Isolation Rearing and Sensorimotor Gating in Rat Models of Relevance to Schizophrenia
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“Altered inflammatory status in PTSD is further indicated by changes in the cytokine IL6 and the cytokine-stimulated transcript for indoleamine 2,3-dioxygenase 1 (IDO), which diverts tryptophan into kynurenine (rather than 5-HT), with implications for cytotoxicity and altered glutamatergic signaling([55,56]).”
BackgroundReview of Experimental Models of Schizophrenia
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Contemporary anti-inflammatory treatment approaches
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- Authors
- Muller, N., Myint, A.-M., & J. Schwarz, M.
- ORCID
- Myint, Aye-Mu
- Venue
- Current Pharmaceutical Design
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2011-01-01
- Volume
- 17
- Issue
- 2
- Pages
- 130-136
- ISSN
- 1381-6128 (ISSN-L)
- OpenAlex
- W2171832535
- Cited by
- 94
- References
- 0
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 5 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 6 · 2018: 2 · 2017: 6 · 2016: 8 · 2015: 11 · 2014: 13 · 2013: 8 · 2012: 11
- FWCI
- 3.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Pharmaceutical Design (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- kynurenine pathway, schizophrenia, tryptophan metabolism, indoleamine 2,3-dioxygenase, kynurenic acid, glutamatergic neurotransmission, NMDA receptor hypofunction, proinflammatory state, antipsychotic drugs, COX-2 inhibitors, prostaglandin E2, inflammatory cytokines, dopamine signaling, anti-inflammatory agents
- MeSH terms
- Animals, Anti-Inflammatory Agents, Humans, Inflammation, Kynurenic Acid, Kynurenine, Synaptic Transmission, Schizophrenia, Antipsychotic Agents, Tryptophan, Receptors, N-Methyl-D-Aspartate, Indoleamine-Pyrrole 2,3,-Dioxygenase, Mice, Rats, Molecular Targeted Therapy
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