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

In the paper

“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.”

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [46] Perskidskii, 1992, Biological manifestations of the tumor necrosis factor effect and its role in the pathogenesis of various diseases, Arkhiv Patologii

In the paper

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

In the paper

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

What the sources say

• Not checked yetcites [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

In the paper

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

In the paper

“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.”

What the sources say

• Not checked yetcites [60] Lorentz, 2001, Regulation of human intestinal mast cells by stem cell factor and IL-4, Immunol Rev. source

In the paper

“Another typical phenomenon in cytokine signaling is synergy which is a strong combined effect of 2 cytokines when acting together”

What the sources say

• Not checked yetcites [47] Del Prete, 1992, Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy, Allergy source

In the paper

“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.”

In the paper

“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).”

What the sources say

• Not checked yetcites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [79] Tilg, 1996, Interferon-alpha and its effects on the cytokine cascade: a pro- and anti-inflammatory cytokine, Leukem Lymphoma source

In the paper

“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).”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [37] Dalton, 2018, A meta-analysis of cytokine concentrations in eating disorders, J Psychiatr Res. source
• Not checked yetcites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source
• Not checked yetcites [38] Goldsmith, 2016, A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression, Mol Psychiatry source

In the paper

“all of which have been found to be elevated in patients with major depression (99–101)”

What the sources say

• Not checked yetcites [99] Besedovsky, 1996, Immune-neuro-endocrine interactions: facts and hypotheses, Endocr Rev. source
• Not checked yetcites [100] Pariante, 2001, Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment, Biol Psychiatry source
• Not checked yetcites [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

In the paper

“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.”

In the paper

“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.”

What the sources say

• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source

In the paper

“Molecules produced by microbiota, e.g. LPS, can induce cytokine production (198), and lead to depressive symptoms (199).”

What the sources say

• Not checked yetcites [198] Bromberg, 2018, Gut microbiota-dependent modulation of innate immunity and lymph node remodeling affects cardiac allograft outcomes, JCI Insight source
• Not checked yetcites [199] Reichenberg, 2001, Cytokine-associated emotional and cognitive disturbances in humans, Arch Gen Psychiatry source

In the paper

“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.”

What the sources say

• Not checked yetcites [125] Himmerich, 2014, Prävention psychischer Erkrankungen am Beispiel der Depression
• Not checked yetcites [156] Rose-John, 2017, The role of IL-6 in host defence against infections: immunobiology and clinical implications, Nat Rev Rheumatol. source
• Not checked yetcites [157] Arango-Duque, 2014, Macrophage cytokines: involvement in immunity and infectious diseases, Front Immunol. source
• Not checked yetcites [158] Li, 2017, Innate lymphoid cell-derived cytokines in autoimmune diseases, J Autoimmun. source
• Not checked yetcites [159] Kuwabara, 2017, The Role of IL-17 and related cytokines in inflammatory autoimmune diseases, Mediator Inflamm. source
• Not checked yetcites [160] Igaz, 2000, Cytokines in diseases of the endocrine system, Cell Biol Int. source

In the paper

“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).”

What the sources say

• Not checked yetcites [133] Grudet, 2014, Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood, Psychoneuroendocrinology source
• Not checked yetcites [134] Amini, 2018, Postpartum depression and vitamin D: a systematic review, Crit Rev Food Sci Nutr. source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [148] Heberlein, 2014, TNF-α and IL-6 serum levels: neurobiological markers of alcohol consumption in alcohol-dependent patients?, Alcohol source
• Not checked yetcites [163] Thormann, 2013, Obesity and depression: an overview on the complex interactions of two diseases, Fortschr Neurol Psychiatr. source

In the paper

“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).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [119] Piliero, 2003, T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11, Blood source

In the paper

“Therefore, foods with a high ratio of ω3/ω6 fatty acids can dampen inflammatory processes and thus potentially prevent or ameliorate depressive symptoms (135).”

What the sources say

• Not checked yetcites [135] Husted, 2016, The importance of n-6/n-3 fatty acids ratio in the major depressive disorder source

In the paper

“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).”

What the sources say

• Not checked yetcites [136] Dinan, 2017, The microbiome-gut-brain axis in health and disease, Gastroenterol Clin North Am. source

In the paper

“Adipose tissue is known to accumulate and activate macrophages and lymphocytes which secrete inflammatory factors (186, 187).”

What the sources say

• Not checked yetcites [186] Bastard, 1999, Evidence for a link between adipose tissue interleukin-6 content and serum C-reactive protein concentrations in obese subjects, Circulation source
• Not checked yetcites [187] Wellen, 2003, Obesity-induced inflammatory changes in adipose tissue, J Clin Invest. source

In the paper

“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”

In the paper

“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).”

In the paper

“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).”

What the sources say

• Not checked yetcites [12] Isaacs, 1957, Virus interference. I. the interferon, Proc Royal Soc B Biol Sci. source
• Not checked yetcites [17] Hitchcock, 1960, Protection of mice against the lethal action of an encephalitis virus, BMJ source
• Not checked yetcites [18] Hitchcock, 1961, The production of interferon in brains of mice infected with an arthropod-borne virus, Virology source

In the paper

“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.”

What the sources say

• Not checked yetcites [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
• Not checked yetcites [54] Boraschi, 1985, Arachidonic acid metabolism in macrophages: regulation by interferons and interleukin 1, Int J Immunopharmacol. source
• Not checked yetcites [55] Munk, 1995, Functions of T-cell subsets and cytokines in mycobacterial infections, Eur Respir J Suppl.
• Not checked yetcites [47] Del Prete, 1992, Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy, Allergy source
• Not checked yetcites [56] Georas, 2005, T-helper cell type-2 regulation in allergic disease, Eur Respir J. source
• Not checked yetcites [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 yetcites [58] Kane, 2015, Refractory asthma - beyond step 5, the role of new and emerging adjuvant therapies, Chronic Respir Dis. source
• Not checked yetcites [59] Krumm, 2014, Structural biology of the IL-1 superfamily: key cytokines in the regulation of immune and inflammatory responses, Protein Sci. source

In the paper

“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).”

What the sources say

• Not checked yetcites [201] Kraus, 2002, Body weight, the tumor necrosis factor system, and leptin production during treatment with mirtazapine or venlafaxine, Pharmacopsychiatry source
• Not checked yetcites [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

In the paper

“The close relationship between inflammatory processes and psychiatric symptoms has been scientifically investigated since the 19th century (123).”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [65] Leonard, 2016, IL-21 Signaling in immunity, F1000Res. source
• Not checked yetcites [66] Alabbas, 2018, The role of IL-22 in the resolution of sterile and nonsterile inflammation, Clin Transl Immunol. source
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [207] Baumeister, 2016, Effects of psychotropic drugs on inflammation: consequence or mediator of therapeutic effects in psychiatric treatment?, Psychopharmacology source

In the paper

“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).”

What the sources say

• Not checked yetcites [10] Tracey, 1992, Tumor necrosis factor and regulation of metabolism in infection: role of systemic versus tissue levels, Exp Biol Med. source

In the paper

“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).”

What the sources say

• Not checked yetcites [206] Himmerich, 2005, Plasma levels of leptin and endogenous immune modulators during treatment with carbamazepine or lithium, Psychopharmacology source

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [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 yetcites [214] Himmerich, 2010, Regulatory T cells increased while IL-1β decreased during antidepressant therapy, J Psychiatr Res. source