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Cited by 313Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

Cytokine Research in Depression: Principles, Challenges, and Open Questions

Open access
Himmerich, Hubertus, Patsalos, Olivia, Lichtblau, Nicole, Ibrahim, Mohammad A. A., Dalton, Bethan·2019·Frontiers in Psychiatry
DOI 10.3389/fpsyt.2019.00030PMC PMC6374304
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Abstract

2), pro-inflammatory or anti-inflammatory cytokines of patients with a depressive disorder to those of healthy controls. Additionally, multiple longitudinal studies have investigated cytokine levels during antidepressant treatment. According to the current literature, it seems that peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated and that interferon (IFN)-γ levels are lower in patients with depression compared to healthy controls. However, the overlap of cytokine values between acutely depressed patients, remitted and recovered patients and healthy controls is considerable. Thus, the discriminative power of cytokine concentrations between depressed and non-depressed people is likely weak. Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α. However, weight gain-inducing psychopharmacological substances, such as the antidepressant mirtazapine, have been reported to potentially increase the production of pro-inflammatory cytokines. Even though cytokines are often discussed as biomarkers for depression, they have also been shown to be altered in other psychiatric disorders. Moreover, many environmental, social, psychological, biological, and medical factors are also associated with cytokine changes. Thus, cytokine alterations seem extremely unspecific. The interpretation of the results of these studies remains a challenge because it is unknown which type of cells are most responsible for cytokine changes measured in the blood nor have the main target cells or target tissues been identified. The same cytokine can be produced by multiple cell types, and the same cell can produce various cytokines. Additionally, redundancy, synergy, antagonism, and signaling cascades of cytokine signaling must be considered. Cytokines might not be associated with the diagnosis of depression according to the currently used diagnostic manuals, but rather with specific subtypes of depression, or with depressive symptoms across different psychiatric diagnoses. Therefore, the currently available diagnostic systems may not be the ideal starting point for psychiatric cytokine research.

Verified 2026-10-06 · 2 references not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review explains cytokine biology and critically assesses cytokine research in depression, concluding that peripheral cytokine alterations are statistically associated with depression but too overlapping and unspecific to serve as individual biomarkers. It argues that current diagnostic categories may be a poor starting point for psychiatric cytokine research.

Key findings

  • Meta-analytic evidence cited by the review indicates that patients with depression have elevated serum/plasma IL-6, IL-10, IL-12, IL-13, and TNF-α, and lower IFN-γ, compared with healthy controls; however, cytokine values overlap considerably between depressed, remitted/recovered, and healthy individuals.
  • A cited meta-analysis of 45 longitudinal studies and more than 1,500 patients found that antidepressant treatment overall decreases peripheral IL-6, IL-10, and TNF-α, but the review notes that reductions in peripheral inflammation were not shown to be associated with antidepressant treatment response.
  • Cytokine alterations are not specific to depression: elevated TNF-α has also been found in PTSD, anorexia nervosa, and acute relapse of schizophrenia, and many environmental, social, psychological, biological, and medical factors are associated with cytokine changes.
  • In one cited study, mean TNF-α serum concentrations were 50.35 ± 78.01 pg/ml in depressed patients versus 33.80 ± 46.17 pg/ml in healthy controls, illustrating substantial within-group variation and overlapping ranges despite significant group differences.

Methods

  • Narrative review; the authors did not apply strict selection criteria, instead selecting articles based on how comprehensive, innovative, clearly written, and informative they were for in-depth understanding and critical debate.
  • Included original research, reviews, book chapters, and case reports; for the section on cytokine alterations in depression and other psychiatric disorders, they strictly included only the latest meta-analysis on cytokine levels for each diagnosis in the text and Table 2.
  • The review synthesizes literature on cytokine biology, immune-brain signaling, cytokine alterations in depression and other psychiatric disorders, risk factors, confounders, and antidepressant/psychotherapy effects.

Limitations

  • Stated: the review is narrative and did not use strict selection criteria; cytokine research shows conflicting results and high variance; it is often unclear which cells produce measured cytokines or which target cells/tissues are involved; cytokine alterations are extremely unspecific; current diagnostic systems may not be ideal for psychiatric cytokine research; few studies have measured cytokines in cerebrospinal fluid; and there is not enough literature to draw firm conclusions about the influence of certain antidepressants on peripheral cytokine levels in vivo.
  • Evident from the text: as a narrative review, it lacks a systematic search strategy, formal quality appraisal, and quantitative synthesis, so its conclusions depend on selected literature and cited meta-analyses rather than a reproducible systematic review process.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/fpsyt.2019.00030

Cites

226 of 228 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 212 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Peripheral levels of interleukin-6 are elevated in patients with depression compared to healthy controls.

    “peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated”
    • Also stated in: § Cytokine Alterations in Patients With Affective Disorders · plain
      “patients with depression have elevated serum or plasma concentrations of IL-6, IL-10, IL-12, IL-13, IL-18, TNF-α, and its receptor soluble TNFR2 compared to healthy controls”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

      Not checked in the free run.

    • cites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source

      Not checked in the free run.

    • cites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source

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    • cites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

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  • Premisecitation

    Peripheral levels of tumor necrosis factor-alpha are elevated in patients with depression compared to healthy controls.

    “peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated”
    • Also stated in: § Cytokine Alterations in Patients With Affective Disorders · plain
      “patients with depression have elevated serum or plasma concentrations of IL-6, IL-10, IL-12, IL-13, IL-18, TNF-α, and its receptor soluble TNFR2 compared to healthy controls”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

      Not checked in the free run.

    • cites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source

      Not checked in the free run.

    • cites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source

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    • cites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

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  • Premisecitation

    Interferon-gamma levels are lower in patients with depression than in healthy controls.

    “interferon (IFN)-γ levels are lower in patients with depression compared to healthy controls”
    • Also stated in: § Cytokine Alterations in Patients With Affective Disorders · plain
      “whereas IFN-γ levels are lower in patients with depression than healthy controls (2, 33, 61–63)”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

      Not checked in the free run.

    • cites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source

      Not checked in the free run.

    • cites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source

      Not checked in the free run.

    • cites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

      Not checked in the free run.

  • Premisecitation

    Peripheral levels of interleukin-12 are elevated in patients with depression compared to healthy controls.

    “peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated”
    • Also stated in: § Cytokine Alterations in Patients With Affective Disorders · plain
      “patients with depression have elevated serum or plasma concentrations of IL-6, IL-10, IL-12, IL-13, IL-18, TNF-α, and its receptor soluble TNFR2 compared to healthy controls”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

      Not checked in the free run.

    • cites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source

      Not checked in the free run.

    • cites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source

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    • cites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

      Not checked in the free run.

  • Premisecitation

    Peripheral levels of interleukin-10 are elevated in patients with depression compared to healthy controls.

    “peripheral levels of interleukin (IL)-6, IL-10, IL-12, IL-13, and tumor necrosis factor (TNF)-α are elevated”
    • Also stated in: § Cytokine Alterations in Patients With Affective Disorders · plain
      “patients with depression have elevated serum or plasma concentrations of IL-6, IL-10, IL-12, IL-13, IL-18, TNF-α, and its receptor soluble TNFR2 compared to healthy controls”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

      Not checked in the free run.

    • cites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source

      Not checked in the free run.

    • cites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source

      Not checked in the free run.

    • cites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

      Not checked in the free run.

  • May combine two claims. 30
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisereasoning

    The categories TH1, TH2, pro-inflammatory, and anti-inflammatory are neither distinct nor generally accepted categories for the classification of cytokines.

    “Even though these categories are often referred to in the psychoimmunological literature, these are neither distinct nor generally accepted categories for the classification of cytokines.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Cytokines might not be associated with the diagnosis of depression according to currently used diagnostic manuals, but rather with specific subtypes of depression, or with depressive symptoms across different psychiatric diagnoses.

    “Cytokines might not be associated with the diagnosis of depression according to the currently used diagnostic manuals, but rather with specific subtypes of depression, or with depressive symptoms across different psychiatric diagnoses.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The same cytokine can be produced by multiple cell types.

    “The same cytokine can be produced by multiple cell types.”
    • Also stated in: § Cytokine Release · plain
      “The same cytokine can be produced by multiple cell types. For instance, TNF-α is released by white blood cells, the endothelium, fat cells and other cells (46).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Perskidskii, 1992, Biological manifestations of the tumor necrosis factor effect and its role in the pathogenesis of various diseases, Arkhiv Patologii

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    Study design and conductreasoning

    This review did not apply strict selection criteria for the inclusion of articles.

    “This is a narrative review; therefore, we did not apply strict selection criteria for the inclusion of certain articles.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytokine signaling shows redundancy, because two or more cytokines can have a similar function.

    “Cytokine signaling shows redundancy, because two or more cytokines can have a similar function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Bruserud, 1992, IL2- and IL4-dependent proliferation of T-cell clones derived early after allogeneic bone marrow transplantation: Studies of patients with chronic myelogenous leukaemia, Eur J Haematol. source

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  • May combine two claims.

    Interpretationnone given

    Cytokine research in psychiatry faces difficulties such as conflicting results and high variance of cytokine values within samples.

    “Cytokine research in psychiatry faces several difficulties, such as conflicting results and high variance of cytokine values within samples.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Cytokine cascades play a significant role in cytokine signaling.

    “Additionally, cytokine cascades play a significant role in cytokine signaling which means that an activation of one cytokine produced by one cell type induces cytokine production by other cell types.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Lorentz, 2001, Regulation of human intestinal mast cells by stem cell factor and IL-4, Immunol Rev. source

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    Premisecitation

    Cytokine signaling shows synergy, a strong combined effect of two cytokines when acting together.

    “Another typical phenomenon in cytokine signaling is synergy which is a strong combined effect of 2 cytokines when acting together”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Del Prete, 1992, Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy, Allergy source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    For the section on cytokine alterations, the review strictly included only the latest meta-analysis on cytokine levels for each diagnosis in the text and Table 2.

    “Regarding the section on cytokine alterations in depression and other psychiatric disorders, we strictly included only the latest meta-analysis on cytokine levels for each diagnosis in the text and in Table 2.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductcitation

    Most studies measure serum or plasma cytokine levels, but it has often been discussed whether these results reflect the situation in the brain.

    “Most of the studies measure serum or plasma cytokine levels, but it has often been discussed whether these results reflect the situation in the brain (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source

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    Premisecitation

    Cytokines can have different effects on different cells and thus may have pro- but also anti-inflammatory properties.

    “One must also take into account that cytokines can have different effects on different cells and thus may have pro- but also anti-inflammatory properties.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [78] de Waal Malefyt, 1993, Effects of IL-13 on phenotype, cytokine production, and cytotoxic function of human monocytes. Comparison with IL-4 and modulation by IFN-gamma or IL-10, J Immunol. source

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    • cites [79] Tilg, 1996, Interferon-alpha and its effects on the cytokine cascade: a pro- and anti-inflammatory cytokine, Leukem Lymphoma source

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    Premisecitation

    Elevated levels of tumor necrosis factor-alpha have also been found in PTSD studies, in patients with anorexia nervosa and in patients with acute relapse of schizophrenia.

    “For example, elevated levels of TNF-α have also been found in PTSD studies (34), in patients with anorexia nervosa (37) and in patients with acute relapse of schizophrenia (31, 38).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [34] Hussein, 2017, A systematic review of tumor necoris factor-α in post-traumatic stress disorder: evidence from human and animal studies, Psychiatr Danub. source

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    • cites [37] Dalton, 2018, A meta-analysis of cytokine concentrations in eating disorders, J Psychiatr Res. source

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    • cites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source

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    • cites [38] Goldsmith, 2016, A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression, Mol Psychiatry source

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    Premisecitation

    Corticotropin-releasing hormone, adrenocorticotropic hormone, and cortisol have been found to be elevated in patients with major depression.

    “all of which have been found to be elevated in patients with major depression (99–101)”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [99] Besedovsky, 1996, Immune-neuro-endocrine interactions: facts and hypotheses, Endocr Rev. source

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    • cites [100] Pariante, 2001, Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment, Biol Psychiatry source

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    • cites [101] Pace, 2007, Cytokine-effects on glucocorticoid receptor function: Relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression, Brain Behav Immun. source

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    Interpretationcitation

    Despite the significant difference between the means of both groups, depressed participants and healthy controls did not have distinct TNF-alpha levels, but rather overlapping ranges of TNF-alpha levels.

    “This range indicates that, despite the significant difference between the means of both groups, depressed participants and healthy controls did not have distinct TNF-α levels, but rather overlapping ranges of TNF-α levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In Schmidt et al., mean TNF-alpha serum concentrations of depressed patients were 50.35 pg/ml with a standard deviation of 78.01 pg/ml, whereas mean TNF-alpha levels of healthy controls were 33.80 ± 46.17 pg/ml.

    “For example, in a paper published by Schmidt et al. (33), mean TNF-α serum concentrations of depressed patients were 50.35 pg/ml with a standard deviation of 78.01 pg/ml, whereas mean TNF-α levels of healthy controls were 33.80 ± 46.17 pg/ml.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

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  • May combine two claims.

    Premisecitation

    Molecules produced by microbiota, such as LPS, can induce cytokine production and lead to depressive symptoms.

    “Molecules produced by microbiota, e.g. LPS, can induce cytokine production (198), and lead to depressive symptoms (199).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [198] Bromberg, 2018, Gut microbiota-dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomes, JCI Insight source

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    • cites [199] Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans, Arch Gen Psychiatry source

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    Premisecitation

    Many physical disorders have been reported to increase the risk for developing a depressive disorder and to activate the production of pro-inflammatory cytokines.

    “Many physical disorders have been reported to increase the risk for developing a depressive disorder (125) and to activate the production of pro-inflammatory cytokines.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [125] Himmerich, 2014, Prävention psychischer Erkrankungen am Beispiel der Depression

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    • cites [156] Rose-John, 2017, The role of IL-6 in host defence against infections: immunobiology and clinical implications, Nat Rev Rheumatol. source

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    • cites [157] Arango-Duque, 2014, Macrophage cytokines: involvement in immunity and infectious diseases, Front Immunol. source

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    • cites [158] Li, 2017, Innate lymphoid cell-derived cytokines in autoimmune diseases, J Autoimmun. source

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    • cites [159] Kuwabara, 2017, The Role of IL-17 and related cytokines in inflammatory autoimmune diseases, Mediator Inflamm. source

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    • cites [160] Igaz, 2000, Cytokines in diseases of the endocrine system, Cell Biol Int. source

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    Premisecitation

    Vitamin D deficiency has been shown to increase pro-inflammatory cytokine production and to lead to depressive symptoms.

    “Vitamin deficiency, e.g., vitamin D deficiency, has also been shown to increase pro-inflammatory cytokine production and to lead to depressive symptoms (133, 134).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [133] Grudet, 2014, Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood, Psychoneuroendocrinology source

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    • cites [134] Amini, 2018, Postpartum depression and vitamin D: a systematic review, Crit Rev Food Sci Nutr. source

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    Premisecitation

    In the Whitehall II cohort study, inflammatory markers (CRP and IL-6) measured in British civil workers predicted symptoms of depression at follow-up, but symptoms of depression did not predict the inflammatory markers.

    “The results of the Whitehall II cohort study in which British civil workers were monitored for CRP, IL-6 and cognitive symptoms of depression from 1991 to 2004 (baseline and follow-up) suggest that the inflammatory markers measured predicted symptoms of depression at follow-up, but not the other way around (120).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [120] Gimeno, 2008, Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study, Psychological Med. source

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    Premisecitation

    Alcohol misuse and obesity are not only confounding factors, but also risk factors for the development of depression.

    “One has to keep in mind, however, that alcohol misuse (148), obesity (163) are not only confounding factors, but also risk factors for the development of depression.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [148] Heberlein, 2014, TNF-α and IL-6 serum levels: neurobiological markers of alcohol consumption in alcohol-dependent patients?, Alcohol source

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    • cites [163] Thormann, 2013, Obesity and depression: an overview on the complex interactions of two diseases, Fortschr Neurol Psychiatr. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The observation that inflammatory diseases can lead to psychiatric disorders such as depression is not recent; a meta-analytic scientific approach to such observations was published by Emil Kraepelin in 1881 and 1882.

    “However, it must be mentioned that the observation that inflammatory diseases can lead to psychiatric disorders, such as depression, is not an achievement of recent decades of research: a meta-analytic scientific approach to such observations had already been published by Emil Kraepelin in 1881 and 1882 (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Steinberg, 2013, Emil Kraepelin's habilitation and his thesis: a pioneer work for modern systematic reviews, psychoimmunological research and categories of psychiatric diseases, World J Biol Psychiatry source

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    Premisecitation

    Psychiatrically relevant genes include those in the human leukocyte antigen gene complex or rare copy number variants important for immune function.

    “Psychiatrically relevant genes include, for example, those in the human leukocyte antigen (HLA) gene complex or rare copy number variants important for immune function (119).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [119] Piliero, 2003, T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11, Blood source

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  • May combine two claims.

    Interpretationreasoning

    Foods with a high ratio of ω3/ω6 fatty acids can dampen inflammatory processes and thus potentially prevent or ameliorate depressive symptoms.

    “Therefore, foods with a high ratio of ω3/ω6 fatty acids can dampen inflammatory processes and thus potentially prevent or ameliorate depressive symptoms (135).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Husted, 2016, The importance of n-6/n-3 fatty acids ratio in the major depressive disorder source

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    Premisecitation

    Gut microbes can produce certain neurotransmitters and influence the central neurochemistry of the brain and thus human behavior.

    “Gut microbes have, for example, been found to be capable of producing certain neurotransmitters and of influencing the central neurochemistry of the brain and thus human behavior (136).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [136] Dinan, 2017, The microbiome-gut-brain axis in health and disease, Gastroenterol Clin North Am. source

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    Premisecitation

    Adipose tissue accumulates and activates macrophages and lymphocytes which secrete inflammatory factors.

    “Adipose tissue is known to accumulate and activate macrophages and lymphocytes which secrete inflammatory factors (186, 187).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [186] Bastard, 1999, Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects, Circulation source

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    • cites [187] Wellen, 2003, Obesity-induced inflammatory changes in adipose tissue, J Clin Invest. source

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  • May combine two claims.

    Interpretationreasoning

    The meta-analytic results compare means of groups, and there is huge overlap of the distributions of cytokine levels of depressed patients and healthy controls.

    “However, one has to take into account that these are results comparing means of groups. There is huge overlap of the distributions of cytokine levels of depressed patients and healthy controls”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    Cytokine levels are not only elevated in depression, but also in other psychiatric disorders.

    “This might be a reason for limited specificity of cytokines as biomarkers for a certain psychiatric diagnosis, because the mentioned cytokine levels are not only elevated in depression, but also in other psychiatric disorders (see Table 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    After the discovery of IFN-α, it became clear that this cytokine can influence immunological processes in the brain even when peripherally administered and can be produced by cells within the brain.

    “Shortly after the discovery of the first cytokine, IFN-α (12), it became clear that this cytokine was able to influence immunological processes in the brain even when peripherally administered (17, 18) and that it can be produced by cells within the brain (18).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [12] Isaacs, 1957, Virus interference. I. the interferon, Proc Royal Soc B Biol Sci. source

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    • cites [17] Hitchcock, 1960, Protection of mice against the lethal action of an encephalitis virus, BMJ source

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    • cites [18] Hitchcock, 1961, The production of interferon in brains of mice infected with an arthropod-borne virus, Virology source

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    Premisecitation

    Cytokine signaling often shows redundancy, synergy, antagonistic effects, or signaling cascades.

    “As cytokine signaling often shows redundancy (53–55), synergy (47), antagonistic effects (56–59) or signaling cascades (60), it seems advisable to take all cytokines that work together or against each other into account and thus measure a whole range instead of a single cytokine.”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [53] Bruserud, 1992, IL2- and IL4-dependent proliferation of T-cell clones derived early after allogeneic bone marrow transplantation: Studies of patients with chronic myelogenous leukaemia, Eur J Haematol. source

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    • cites [54] Boraschi, 1985, Arachidonic acid metabolism in macrophages: regulation by interferons and interleukin 1, Int J Immunopharmacol. source

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    • cites [55] Munk, 1995, Functions of T-cell subsets and cytokines in mycobacterial infections, Eur Respir J Suppl.

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    • cites [47] Del Prete, 1992, Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy, Allergy source

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    • cites [56] Georas, 2005, T-helper cell type-2 regulation in allergic disease, Eur Respir J. source

      Not checked in the free run.

    • cites [57] Ito, 2005, TSLP-activated dendritic cells induce an inflammatory T helper type 2 cell response through OX40 ligand, J Exp Med. source

      Not checked in the free run.

    • cites [58] Kane, 2015, Refractory asthma - beyond step 5, the role of new and emerging adjuvant therapies, Chronic Respir Dis. source

      Not checked in the free run.

    • cites [59] Krumm, 2014, Structural biology of the IL-1 superfamily: key cytokines in the regulation of immune and inflammatory responses, Protein Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mirtazapine induced a significant increase in plasma levels of TNF-α and both soluble TNF receptors, whereas venlafaxine did not significantly alter plasma levels of TNF-α or soluble TNF receptors.

    “Whereas, mirtazapine induced a significant increase in the plasma levels of TNF-α and both soluble TNF receptors, venlafaxine did not alter plasma levels of TNF-α, or soluble TNF receptors significantly (201).”
    • Also stated in: § The Influence of Antidepressants on Cytokine Production · plain
      “These findings that mirtazapine increases circulating TNF-α levels were supported by Kast et al. (202).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [201] Kraus, 2002, Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine, Pharmacopsychiatry source

      Not checked in the free run.

    • cites [202] Kast, 2003, Anti- and pro-inflammatory considerations in antidepressant use during medical illness: bupropion lowers and mirtazapine increases circulating tumor necrosis factor-alpha levels, General Hosp Psychiatry source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The close relationship between inflammatory processes and psychiatric symptoms has been scientifically investigated since the 19th century.

    “The close relationship between inflammatory processes and psychiatric symptoms has been scientifically investigated since the 19th century (123).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Steinberg, 2013, Emil Kraepelin's habilitation and his thesis: a pioneer work for modern systematic reviews, psychoimmunological research and categories of psychiatric diseases, World J Biol Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Many immunologically important cytokines, such as IL-21 and IL-22, have not been extensively researched in psychiatric samples yet, although preliminary studies have revealed promising results.

    “There are many immunologically important cytokines like IL-21 (65) and IL-22 (66) which have not been extensively researched in psychiatric samples yet, even though the first preliminary studies have revealed promising results (67, 69).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [65] Leonard, 2016, IL-21 Signaling in immunity, F1000Res. source

      Not checked in the free run.

    • cites [66] Alabbas, 2018, The role of IL-22 in the resolution of sterile and nonsterile inflammation, Clin Transl Immunol. source

      Not checked in the free run.

    • cites [67] Juncal-Ruiz, 2018, Comparison of the anti-inflammatory effect of aripiprazole and risperidone in 75 drug-naïve first episode psychosis individuals: A 3 months randomized study, Schizophr Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro literature suggests that some antidepressants, such as clomipramine and fluoxetine, decrease IL-6, IFN-γ, and TNF-α, while others like mirtazapine and venlafaxine tend to increase their levels.

    “The in vitro literature on antidepressants suggest that some antidepressants, such as clomipramine and fluoxetine, decrease IL-6, IFN-γ, and TNF-α, whilst others like mirtazapine and venlafaxine tend to increase their levels (207).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [207] Baumeister, 2016, Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?, Psychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    When a specific cytokine like TNF-α is measured in serum or plasma, it is unclear from which cells or organ it is derived and where it will exert its effect, because one cytokine can have different effects on different cell types.

    “Therefore, if we measure a specific cytokine like TNF-α in the serum or plasma, it is unclear from which cells or which organ it is derived and where this cytokine will exert its effect, as one cytokine can have different effects on different cell types (10).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Tracey, 1992, Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels, Exp Biol Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mood stabilizers such as lithium and carbamazepine have been shown to lead to weight gain as well as an increase in pro-inflammatory cytokine levels.

    “Some of these mood stabilizers, for example lithium and carbamazepine, have also been shown to lead to weight gain as well as an increase in pro-inflammatory cytokine levels (206).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [206] Himmerich, 2005, Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium, Psychopharmacology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Meta-analytic research shows that peripheral levels of IL-6, IL-10, IL-12, IL-13, and TNF-α are significantly elevated and IFN-γ plasma concentrations are significantly lower in patients with depression compared to healthy controls.

    “As peripheral levels of IL-6, IL-10, IL-12, IL13, and TNF-α have been shown to be significantly elevated and IFN-γ plasma concentrations significantly lower in patients with depression compared to healthy controls in meta-analytic research (2), one could think that cytokines qualify as a biomarker of depression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Köhler, 2017, Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis, Mol Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes in specific cytokine-producing immune cells like Treg cells have been reported in depression and during antidepressant therapy.

    “Cytokine levels are often researched and interpreted in isolation from their origin in terms of the specific cell type and the particular tissue they are originating from, even though changes in specific cytokine-producing immune cells like Treg cells have been reported in depression (213) and during antidepressant therapy (214).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [213] Li, 2010, Altered expression of CD4+CD25+ regulatory T cells and its 5-HT1a receptor in patients with major depression disorder, J Affect Disord. source

      Not checked in the free run.

    • cites [214] Himmerich, 2010, Regulatory T cells increased while IL-1β decreased during antidepressant therapy, J Psychiatr Res. source

      Not checked in the free run.

37 of 37

  • The paper relies on this without support.

    Both the obese and the elderly exhibit behavioral symptoms such as depression and cognitive dysfunction at an increased rate compared to the general population.

    “Both the obese and the elderly exhibit behavioral symptoms such as depression and cognitive dysfunction at an increased rate compared to the general population.”

  • The paper relies on this without support.

    People with depression exhibit heterogeneous sets of symptoms.

    “People with depression exhibit heterogeneous sets of symptoms.”

  • The authors state this as an assumption.

    Cytokine concentrations in the cerebrospinal fluid might better reflect cytokine signaling in the brain than cytokine levels in the serum or plasma.

    “even though one would assume that cytokine concentrations in the cerebrospinal fluid might better reflect cytokine signaling in the brain than cytokine levels in the serum or plasma.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Cites

Flagged first, then by citations

1 of the 229 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Himmerich, 2014, Prävention psychischer Erkrankungen am Beispiel der Depression, 166
  2. Weschenfelder, 2012, The influence of cytokines on wakefulness regulation: clinical relevance, mechanisms and methodological problems, Psychiatr Danub., 24, 112

Cited by

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Related

Authors
Himmerich, H., Patsalos, O., Lichtblau, N., Ibrahim, M. A. A., & Dalton, B.
Affiliations
  • King's College London (GB)
  • Maidstone and Tunbridge Wells NHS Trust (GB)
  • Kings Health Partners (GB)
Corresponding author
Himmerich, Hubertus
ORCID
Venue
Frontiers in Psychiatry
Publisher
Frontiers Media SA
Published
2019-02-07
Volume
10
Pages
30-30
ISSN
1664-0640 (ISSN-L)
DOI
10.3389/fpsyt.2019.00030
PMC
PMC6374304
OpenAlex
W2912456649
Cited by
313
References
229
Citations by year
2026: 15 · 2025: 30 · 2024: 42 · 2023: 85 · 2022: 45 · 2021: 52 · 2020: 35 · 2019: 8 · 2018: 1
FWCI
2.16
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Psychiatry (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Portal (King's College London) (submittedVersion, cc-by)
Funders
  • South London and Maudsley NHS Foundation Trust
  • King's College London
  • Institute of Psychiatry, Psychology and Neuroscience, King’s College London
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
depression, cytokines, inflammatory cytokines, anti-inflammatory cytokines, interleukin-6, IL-10, TNF-α, interferon-gamma, antidepressant treatment, mirtazapine, weight gain, biomarkers, cytokine signaling, depression subtypes

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