Antidepressant therapies inhibit inflammation and microglial M1-polarization
Abstract
Macrophages and their counterparts in the central nervous system, the microglia, detect and subsequently clear microbial pathogens and injured tissue. These phagocytic cells alter and adapt their phenotype depending on their prime activity, i.e., whether they participate in acute defence against pathogenic organisms ('M1'-phenotype) or in clearing damaged tissues and performing repair activities ('M2'-phenotype). Stimulation of pattern recognition receptors by viruses (vaccines), bacterial membrane components (e.g., LPS), alcohol, or long-chain saturated fatty acids promotes M1-polarization. Vaccine or LPS administration to healthy human subjects can result in sickness symptoms and low mood. Alcohol abuse and abdominal obesity are recognized as risk factors for depression. In the M1-polarized form, microglia and macrophages generate reactive oxygen and nitrogen radicals to eradicate microbial pathogens. Inadvertently, also tetrahydrobiopterin (BH4) may become oxidized. This is an irreversible reaction that generates neopterin, a recognized biomarker for depression. BH4 is a critical cofactor for the synthesis of dopamine, noradrenaline, and serotonin, and its loss could explain some of the symptoms of depression. Based on these aspects, the suppression of M1-polarization would limit the inadvertent catabolism of BH4. In the current review, we evaluate the evidence that antidepressant treatments (monoamine reuptake inhibitors, PDE4 inhibitors, lithium, valproate, agomelatine, tianeptine, electroconvulsive shock, and vagus nerve stimulation) inhibit LPS-induced microglia/macrophage M1-polarization. Consequently, we propose that supplementation with BH4 could limit the reduction in central monoamine synthesis and might represent an effective treatment for depressed mood.
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Suppression of microglia and astrocyte reactivity is implicated in the response to antidepressant therapies.
“Consistently, suppression of microglia [80] and astrocyte [81] reactivity is implicated in the response to antidepressant therapies.”
From The menace of obesity to depression and anxiety prevalence (2022) · cites this paper as [80]
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Peripheral cytokine and chemokine alterations in depression: a meta‐analysis of 82 studies
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- Authors
- Kalkman, H. O., & Feuerbach, D.
- Affiliations
- Novartis Institutes for BioMedical Research (CH)
- Corresponding author
- Kalkman, Hans O.
- Venue
- Pharmacology & Therapeutics
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 163
- Pages
- 82-93
- ISSN
- 0163-7258 (ISSN-L)
- OpenAlex
- W2339641321
- Semantic Scholar
- af6eac8dc2429b5d773109dd9d983af827f3749c
- Cited by
- 212
- References
- 204
- Citations by year
- 2026: 7 · 2025: 31 · 2024: 20 · 2023: 35 · 2022: 31 · 2021: 31 · 2020: 20 · 2019: 16 · 2018: 7 · 2017: 14
- FWCI
- 0.75
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Pharmacology & Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- antidepressants, microglial M1 polarization, neuroinflammation, tetrahydrobiopterin, neopterin, lipopolysaccharide, macrophages, depression, monoamine synthesis, BH4 supplementation, phosphodiesterase-4 inhibitors, lithium, valproic acid, agomelatine, tianeptine, electroconvulsive therapy, vagus nerve stimulation, monoamine reuptake inhibitors
- MeSH terms
- Animals, Antidepressive Agents, Biopterins, Depression, Electroconvulsive Therapy, Humans, Inflammation, Lipopolysaccharides, Macrophages, Phenotype, Risk Factors, Stress, Psychological, Signal Transduction, Biomarkers, Microglia
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.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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