The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder

Woelfer, Marie; Kasties, Vanessa; Kahlfuss, Sascha; Walter, Martin

doi:10.1016/j.neuroscience.2018.03.034

Cited by 171Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder

Woelfer, Marie, Kasties, Vanessa, Kahlfuss, Sascha, Walter, Martin·2019·Neuroscience

DOI 10.1016/j.neuroscience.2018.03.034

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Abstract

Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points toward an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset. Next, we examine the regional specificity of neuroinflammation, which shows striking overlaps with neural patterns activated in atypical MDD. Furthermore, we outline how inflammation may translate to subtype-specific clinical features and we suggest how this could be used for diagnostic and treatment purposes. By providing a link back to a dysregulated immune system as a contributing factor to MDD subtypes, we explain how brain regions particularly affected by certain subtypes may regulate the cortisol circuitry.

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IFN-Alpha-Induced Cortical and Subcortical Glutamate Changes Assessed by Magnetic Resonance Spectroscopy
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The subtypes of major depression in a twin registry
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Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression?
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Abnormal Pituitary-Adrenal Responses to Corticotropin-Releasing Hormone in Patients with Seasonal Affective Disorder: Clinical and Pathophysiological Implications
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CD4+CD25+ Regulatory T Cell Depletion Modulates Anxiety and Depression-Like Behaviors in Mice
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Minocycline treatment ameliorates interferon-alpha- induced neurogenic defects and depression-like behaviors in mice
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The brain’s best friend: microglial neurotoxicity revisited
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Stress-evoked sterile inflammation, danger associated molecular patterns (DAMPs), microbial associated molecular patterns (MAMPs) and the inflammasome
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Selective increase of cerebrospinal fluid IL-6 during experimental systemic inflammation in humans: association with depressive symptoms
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A History of the Concept of Atypical Depression
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Understanding Fatigue in Major Depressive Disorder and Other Medical Disorders
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Glucose Metabolism in the Insula and Cingulate Is Affected by Systemic Inflammation in Humans
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CD4+ but not CD8+ T cells revert the impaired emotional behavior of immunocompromised RAG-1-deficient mice
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The menace of obesity to depression and anxiety prevalence
Fulton, S., Décarie-Spain, L., Fioramonti, X., Guiard, B., & Nakajima, S. (2022) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2021.10.005 · Cited by 441 · see citing works
“This form of depression has stronger links to peripheral [10,11] and central [12] inflammation.”
Background
Asymmetric organocatalysis: an enabling technology for medicinal chemistry
Han, B., He, X., Liu, Y., He, G., Peng, C. Y., & Li, J. (2021) · Chemical Society Reviews · doi:10.1039/d0cs00196a · Cited by 405 · see citing works
A Review for the Pharmacological Effect of Lycopene in Central Nervous System Disorders
Chen, D., Huang, C., & Chen, Z. (2019) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2018.12.151 · Cited by 206 · see citing works
Neural networks and the anti-inflammatory effect of transcutaneous auricular vagus nerve stimulation in depression
Liu, C.-H., Yang, M.-H., Zhang, G.-Z., Wang, X.-X., Li, B., Li, M., Woelfer, M., Walter, M., & Wang, L. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01732-5 · Cited by 210 · see citing works
Vagus nerve stimulation in brain diseases: Therapeutic applications and biological mechanisms
Wang, Y., Zhan, G., Cai, Z., Jiao, B., Zhao, Y., Li, S., & Luo, A. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.04.018 · Cited by 207 · see citing works
How inflammation affects the brain in depression: a review of functional and structural MRI studies
Han, K.-M., & Ham, B.-J. (2021) · Journal of Clinical Neurology · doi:10.3988/jcn.2021.17.4.503 · Cited by 187 · see citing works
Role of inflammation in depression relapse
Liu, C., Zhang, G., Li, B., Li, M., Woelfer, M., Walter, M., & Wang, L. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1475-7 · Cited by 166 · see citing works
Immuno-metabolic depression: from concept to implementation
Penninx, B. W. J. H., Lamers, F., Jansen, R., Berk, M., Khandaker, G. M., Picker, L. D., & Milaneschi, Y. (2024) · The Lancet Regional Health - Europe · doi:10.1016/j.lanepe.2024.101166 · Cited by 126 · see citing works
The role of monoamine oxidase enzymes in the pathophysiology of neurological disorders
Jones, D. N., & Raghanti, M. A. (2021) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2021.101957 · Cited by 116 · see citing works
Shared pathways for neuroprogression and somatoprogression in neuropsychiatric disorders
Morris, G., Puri, B. K., Walker, A. J., Maes, M. H. J., Carvalho, A. F., Bortolasci, C. C., Walder, K. R., & Berk, M. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.09.025 · Cited by 112 · see citing works
Alleviation of depression by glucagon-like peptide 1 through the regulation of Neuroinflammation, neurotransmitters, neurogenesis, and synaptic function
Kim, Y.-K., Kim, O. Y., & Song, J. (2020) · Frontiers in Pharmacology · doi:10.3389/fphar.2020.01270 · Cited by 109 · see citing works
(+)-Sesamin attenuates chronic unpredictable mild stress-induced depressive-like behaviors and memory deficits via suppression of neuroinflammation
Zhao, Y., Wang, Q., Jia, M., Fu, S., Pan, J., Chu, C., Liu, X., Liu, X., & Liu, Z. (2018) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2018.10.006 · Cited by 109 · see citing works
Neutrophil-to-Lymphocyte Ratio, Platelet-to-Lymphocyte Ratio, and Monocyte-to-Lymphocyte Ratio in Depression: An Updated Systematic Review and Meta-Analysis
Cheng, Y., Wang, Y., Wang, X., Jiang, Z., Zhu, L., & Fang, S. (2022) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2022.893097 · Cited by 110 · see citing works
Dysregulation of the gut-brain-skin axis and key overlapping inflammatory and immune mechanisms of psoriasis and depression
Wang, X., Li, Y., Wu, L., Xiao, S., Ji, Y., Tan, Y., Jiang, C., & Zhang, G. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.111065 · Cited by 95 · see citing works
Effects of Neurological Disorders on Bone Health
Kelly, R. R., Sidles, S. J., & LaRue, A. C. (2020) · Frontiers in Psychology · doi:10.3389/fpsyg.2020.612366 · Cited by 91 · see citing works
Neuroimaging insights into the link between depression and Insomnia: A systematic review
Bagherzadeh‐Azbari, S., Khazaie, H., Zarei, M., Spiegelhalder, K., Walter, M., Leerssen, J., Someren, E. J. W. V., Sepehry, A. A., & Tahmasian, M. (2019) · Journal of Affective Disorders · doi:10.1016/j.jad.2019.07.089 · Cited by 87 · see citing works
Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder
Zhan, Y., Zhou, Y., Zheng, W., Liu, W., Wang, C., Lan, X., Deng, X., Xu, Y., Zhang, B., & Ning, Y. (2020) · Translational Psychiatry · doi:10.1038/s41398-020-00933-z · Cited by 81 · see citing works
Review of microbiota gut brain axis and innate immunity in inflammatory and infective diseases
Yuan, C., He, Y., Xie, K., Feng, L., Gao, S., & Cai, L. (2023) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2023.1282431 · Cited by 82 · see citing works
Galectin-3: Roles in Neurodevelopment, Neuroinflammation, and Behavior
Srejovic, I. M., Selaković, D., Jovicic, N. U., Jakovljevic, V. L., Lukić, M. L., & Rosic, G. L. (2020) · Biomolecules · doi:10.3390/biom10050798 · Cited by 77 · see citing works
Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice
Xu, X., Xiao, X., Yan, Y., & Zhang, T. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.02.026 · Cited by 74 · see citing works
Neuroinflammation and microglia/macrophage phenotype modulate the molecular background of post-stroke depression: A literature review
Nagy, E. E., Frigy, A., Sz�sz, J., & Horv�th, E. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8933 · Cited by 73 · see citing works
CUMS and dexamethasone induce depression‐like phenotypes in mice by differentially altering gut microbiota and triggering macroglia activation
Wu, J., Li, J., Chhetri, G., Muhammad, U., Chen, Y., Li, X., Chen, J., & Wang, Z. (2021) · General Psychiatry · doi:10.1136/gpsych-2021-100529 · Cited by 69 · see citing works
Neuroinflammation, Gut-Brain Axis and Depression
Evrensel, A., Ünsalver, B. Ö., & Ceylan, M. E. (2019) · Psychiatry Investigation · doi:10.30773/pi.2019.08.09 · Cited by 71 · see citing works
Effects of sulforaphane in the central nervous system
Huang, C., Wu, J., Chen, D., Jin, J., Wu, Y. H., & Chen, Z. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.03.010 · Cited by 71 · see citing works
Linking atypical depression and insulin resistance-related disorders via low-grade chronic inflammation: Integrating the phenotypic, molecular and neuroanatomical dimensions
Sen, Z. D., Danyeli, L. V., Woelfer, M., Lamers, F., Wagner, G., Sobanski, T., & Walter, M. (2021) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.12.020 · Cited by 65 · see citing works
Self-citation
Tolerance-inducing effect and properties of innate immune stimulation on chronic stress-induced behavioral abnormalities in mice
Gu, Y., Ye, T., Tan, P., Tong, L., Jian-lin, J., Gu, Y., Shen, Z., Shen, X., Lu, X., & Huang, C. (2020) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2020.11.002 · Cited by 59 · see citing works
Hyper-inflammation of astrocytes in patients of major depressive disorder: Evidence from serum astrocyte-derived extracellular vesicles
Xie, X., Lai, W., Xu, S., Forti, M. D., Zhang, J., Chen, M., Yao, L., Wang, P., Hao, K., & Rong, H. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.12.014 · Cited by 60 · see citing works
miR-124 ameliorates depressive-like behavior by targeting STAT3 to regulate microglial activation
Lou, D., Wang, J., & Wang, X. (2019) · Molecular and Cellular Probes · doi:10.1016/j.mcp.2019.101470 · Cited by 58 · see citing works
Sigma-1 receptor: A potential target for the development of antidepressants
Wang, Y., Xia, C., Jia, H., He, J., Lian, W., Yan, Y., Wang, W., Zhang, W., & Xu, J. (2022) · Neurochemistry International · doi:10.1016/j.neuint.2022.105390 · Cited by 57 · see citing works
Extracellular Vesicles in Mental Disorders: A State-of-art Review
Kong, L., Zhang, D., Huang, S., Lai, J., Lü, L., Zhang, J., & Hu, S. (2023) · International Journal of Biological Sciences · doi:10.7150/ijbs.79666 · Cited by 57 · see citing works
Anti-inflammatory medications for the treatment of mental disorders: A scoping review
Fitton, R., Sweetman, J., Heseltine-Carp, W., & van der Feltz-Cornelis, C. (2022) · Brain, Behavior, & Immunity - Health · doi:10.1016/j.bbih.2022.100518 · Cited by 53 · see citing works
Mast cell‑mediated neuroinflammation may have a role in attention deficit hyperactivity disorder (Review)
Song, Y., Lu, M., Yuan, H., Chen, T., & Han, X. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.8789 · Cited by 52 · see citing works
Serum FAM19A5 levels: A novel biomarker for neuroinflammation and neurodegeneration in major depressive disorder
Han, K.-M., Tae, W.-S., Kim, A., Kang, Y., Kang, W., Kang, J., Kim, Y.-K., Kim, B., Seong, J. Y., & Ham, B.-J. (2020) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2020.03.021 · Cited by 50 · see citing works
Investigating the Potential Mechanisms and Therapeutic Targets of Inflammatory Cytokines in Post-stroke Depression
Zhang, Y., Yang, Y., Li, H., Feng, Q., Ge, W., & Xu, X. (2023) · Molecular Neurobiology · doi:10.1007/s12035-023-03563-w · Cited by 54 · see citing works
The hippocampus in stress susceptibility and resilience: Reviewing molecular and functional markers
Larosa, A., & Wong, T. P. (2022) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2022.110601 · Cited by 47 · see citing works
Identification of suicidality in patients with major depressive disorder via dynamic functional network connectivity signatures and machine learning
Xu, M., Zhang, X., Li, Y., Chen, S., Zhang, Y., Zhou, Z., Lin, S., Dong, T., Hou, G., & Qiu, Y. (2022) · Translational Psychiatry · doi:10.1038/s41398-022-02147-x · Cited by 46 · see citing works
Decreased Risk of Anxiety in Diabetic Patients Receiving Glucagon-like Peptide-1 Receptor Agonist: A Nationwide, Population-Based Cohort Study
Tsai, W.-H., Sung, F., Chiu, L., Shih, Y., Tsai, M.-C., & Wu, S. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.765446 · Cited by 47 · see citing works
Neuro-immune interactions: Exploring the anti-inflammatory role of the vagus nerve.
Liu, L., Lou, S., Fu, D., Ji, P.-F., Xia, P., Shuang, S., Dong, W., Yuan, X.-Y., Wang, J., Xie, K., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114941 · Cited by 45 · see citing works
Lipopolysaccharide-binding protein expression is increased by stress and inhibits monoamine synthesis to promote depressive symptoms
Fang, M., Li, Y., Liao, Z., Gan, W., Cao, Q., Li, Y., Duan, Y., Han, Y., Deng, X., Wu, F., et al. (2023) · Immunity · doi:10.1016/j.immuni.2023.02.002 · Cited by 40 · see citing works
Microbiome and immuno-metabolic dysregulation in patients with major depressive disorder with atypical clinical presentation
Refisch, A., Şen, Z. D., Klassert, T. E., Busch, A., Besteher, B., Danyeli, L. V., Helbing, D. L., Schulze‐Späte, U., Stallmach, A., Bauer, M. W., et al. (2023) · Neuropharmacology · doi:10.1016/j.neuropharm.2023.109568 · Cited by 30 · see citing works
Occipital gamma-aminobutyric acid and glutamate-glutamine alterations in major depressive disorder: An mrs study and meta-analysis
Truong, V., Cheng, P. Z., Lee, H., Lane, T. J., Hsu, T., & Duncan, N. W. (2020) · Psychiatry Research Neuroimaging · doi:10.1016/j.pscychresns.2020.111238 · Cited by 31 · see citing works
Synaptic effects of IL-1β and CRF in the central amygdala after protracted alcohol abstinence in male rhesus macaques
Patel, R. R., Varodayan, F. P., Herman, M. A., Jiménez, V., Agnore, R., Gao, L., Bajo, M., Carlson, V. C. C., Walter, N. A. R., Fei, S. S., et al. (2021) · Neuropsychopharmacology · doi:10.1038/s41386-021-01231-y · Cited by 30 · see citing works
Combined serum IL-6, C-reactive protein, and cortisol may distinguish patients with anhedonia in major depressive disorder
Li, Y., Yue, Y., Chen, S., Jiang, W., Xu, Z., Chen, G., Zhu, Z., Tan, L., & Yuan, Y. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2022.935031 · Cited by 29 · see citing works
Antidepressive properties of macrophage-colony stimulating factor in a mouse model of depression induced by chronic unpredictable stress
Ye, T., Wang, D., Cai, Z., Tong, L., Chen, Z., Lu, J., Lu, X., Huang, C., & Yuan, X. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108132 · Cited by 28 · see citing works
Ligands and Receptors of the TNF Superfamily Are Decreased in Major Depression and during Early Antidepressant Therapy
Schmidt, F. M., Koch, J., Nowak, C., Holdt, L. M., Teupser, D., Hegerl, U., & Himmerich, H. (2019) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2019.09.010 · Cited by 27 · see citing works
Weight changes in adults with major depressive disorder: A systematic review and meta-analysis of prospective studies
Treviño‐Alvarez, A. M., Sánchez-Ruiz, J. A., Barrera, F. J., Rodríguez-Bautista, M., Romo‐Nava, F., McElroy, S. L., & Barboza, A. B. C. (2023) · Journal of Affective Disorders · doi:10.1016/j.jad.2023.03.050 · Cited by 27 · see citing works
Connectomics-based resting-state functional network alterations predict suicidality in major depressive disorder
Wáng, Q., He, C., Wang, Z., Fan, D., Zhang, Z., Xie, C., Yan, C., Chen, X., Li, L., Castellanos, F. X., et al. (2023) · Translational Psychiatry · doi:10.1038/s41398-023-02655-4 · Cited by 26 · see citing works
Increased ratio of mature BDNF to precursor-BDNF in patients with major depressive disorder with severe anhedonia
Wu, C., Lü, J., Lu, S., Huang, M., & Xu, Y. (2020) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2020.05.010 · Cited by 25 · see citing works
Brain tissue properties link cardio-vascular risk factors, mood and cognitive performance in the CoLaus|PsyCoLaus epidemiological cohort
Trofimova, O., Loued‐Khenissi, L., Domenicantonio, G. D., Lutti, A., Kliegel, M., Stringhini, S., Marques-Vidal, P. M., Vollenweider, P., Waeber, G., Preisig, M., et al. (2021) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2021.02.002 · Cited by 24 · see citing works
Metabolomics dissection of depression heterogeneity and related cardiometabolic risk
Alshehri, T., Mook‐Kanamori, D. O., van Dijk, K. W., Dinga, R., Penninx, B. W. J. H., Rosendaal, F. R., le Cessie, S., & Milaneschi, Y. (2021) · Psychological Medicine · doi:10.1017/s0033291721001471 · Cited by 25 · see citing works
Liver and inflammatory biomarker relationships to depression symptoms in healthy older adults
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Authors: Woelfer, M., Kasties, V., Kahlfuss, S., & Walter, M.
Affiliations: New Jersey Institute of Technology (US)
University of Tübingen (DE)
New York University (US)
Center for Behavioral Brain Sciences (DE)
Corresponding author: Walter, Martin
ORCID: Woelfer, Marie
Kasties, Vanessa
Kahlfuss, Sascha
Walter, Martin
Venue: Neuroscience
Publisher: Elsevier BV
Published: 2019-04
Volume: 403
Pages: 93-110
ISSN: 0306-4522 (ISSN-L)
DOI: 10.1016/j.neuroscience.2018.03.034
OpenAlex: W2795176873
Cited by: 171
References: 260
Citations by year: 2026: 13 · 2025: 24 · 2024: 26 · 2023: 19 · 2022: 24 · 2021: 27 · 2020: 22 · 2019: 14 · 2018: 2
FWCI: 1.42
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neuroscience (publishedVersion)
PubMed (publishedVersion)
Funders: Deutsche Forschungsgemeinschaft (SFB779-A06, KA 4514/1-1)
Otto-von-Guericke-University
Topics: Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords: major depressive disorder, depression subtypes, neuroinflammation, atypical depression, endogenous depression, monoaminergic neurotransmission, glutamatergic neurotransmission, immune dysregulation
MeSH terms: Animals, Brain, Depressive Disorder, Major, Major Depressive Disorder, Humans, Inflammation, Models, Biological

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The role of depressive subtypes within the neuroinflammation hypothesis of major depressive disorder

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