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

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“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)”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“Cytokines have been implicated in the pathology of depression.”

• Also stated in: § Influence on Neurotransmitter Metabolism and Signaling · plain

  “Given that peripheral production of cytokines has been associated with depression (2, 81)”

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
• Not checked yetcites [81] Lichtblau, 2013, Cytokines as biomarkers in depressive disorder: current standing and prospects, Int Rev Psychiatry source

In the paper

“such positive results have not been obtained by all studies”

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

“Results of cytokine research which are partly contradicting and often difficult to interpret have also been obtained in post-traumatic stress disorder (PTSD) (34–36) and eating disorders (37).”

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 [35] Waheed, 2018, A systematic review of interleukin-1β in post-traumatic stress disorder: evidence from human and animal studies, J Interfer Cytokine Res. source
• Not checked yetcites [36] Passos, 2015, Inflammatory markers in post-traumatic stress disorder: a systematic review, meta-analysis, and meta-regression, Lancet Psychiatry source
• Not checked yetcites [37] Dalton, 2018, A meta-analysis of cytokine concentrations in eating disorders, J Psychiatr Res. source

In the paper

“Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α.”

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

“heterogeneity of the results between studies is large (2)”

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

“Thus, the discriminative power of cytokine concentrations between depressed and non-depressed people is likely weak.”

In the paper

“One cytokine can act on multiple cell types and have different effects on these cells (48).”

What the sources say

• Not checked yetcites [48] Tracey, 1994, Tumor necrosis factor: a pleiotropic cytokine and therapuetic target, Ann Rev Med. source

In the paper

“it is unknown which type of cells are most responsible for cytokine changes measured in the blood”

In the paper

“Thus, cytokine alterations seem extremely unspecific.”

In the paper

“they have also been shown to be altered in other psychiatric disorders.”

• Also stated in: § Cytokine Alterations in Patients With Psychiatric Disorders in General · plain

  “The aforementioned cytokine alterations in affective disorders are not specific to major depression or bipolar disorder.”

What the sources say

• 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

“Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α.”

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

“Treatment with certain antidepressants appears to decrease peripheral levels of IL-6, IL-10, and TNF-α.”

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

“nor have the main target cells or target tissues been identified”

In the paper

“However, the overlap of cytokine values between acutely depressed patients, remitted and recovered patients and healthy controls is considerable.”

In the paper

“the same cell can produce various cytokines.”

• Also stated in: § Cytokine Release · plain

  “Furthermore, one single cell can produce different cytokines. For example, TH2 cells can produce IL-3, IL-4, IL-5, IL-6, and IL-13 (47).”

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

“Cytokines also influence the synthesis of monoamines through disruption of tetrahydrobiopterin, an essential enzyme co-factor to hydroxylases involved in monoamine synthesis.”

What the sources say

• Not checked yetcites [89] Zhu, 2006, The Proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters, Neuropsychopharmacology source
• Not checked yetcites [90] Zhu, 2005, p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process, J Biol Chem. source
• Not checked yetcites [91] Zhu, 2010, Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters, Neuropsychopharmacology source
• Not checked yetcites [92] Morón, 2003, Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity, J Neurosci. source

In the paper

“Cytokines can also antagonize each other's effects.”

What the sources say

• 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

In the paper

“peripherally produced cytokines can influence the central nervous system (CNS)”

What the sources say

• Not checked yetcites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source
• Not checked yetcites [80] D'Mello, 2009, Cerebral microglia recruit monocytes into the brain in response to tumor necrosis factoralpha signaling during peripheral organ inflammation, J Neurosci. source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“Therefore, the currently available diagnostic systems may not be the ideal starting point for psychiatric cytokine research.”

In the paper

“Cytokines can decrease serotonin synthesis by activating the enzyme indoleamine 2,3 dioxygenase (IDO) which breaks down tryptophan, the amino acid precursor of serotonin, to kynurenin (KYN) instead of metabolizing tryptophan to serotonin.”

What the sources say

• Not checked yetcites [87] Bonaccorso, 2002, Increased depressive ratings in patients with hepatitis c receiving interferon-α-based immunotherapy are related to interferon-α-induced changes in the serotonergic system, J Clin Psychopharmacol. source
• Not checked yetcites [88] Capuron, 2003, Interferon-alpha-induced changes in tryptophan metabolism. relationship to depression and paroxetine treatment, Biol Psychiatry source

In the paper

“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”

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
• Not checked yetcites [33] Schmidt, 2014, Cytokine levels in depressed and non-depressed subjects, and masking effects of obesity, J Psychiatr Res. source
• Not checked yetcites [61] Howren, 2009, Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis, Psychosomatic Med. source
• Not checked yetcites [62] Haase, 2015, Die Regulation des Immunsystems und immunprivilegierte Organe source
• Not checked yetcites [63] Breitbart, 2013, Depression, cytokines, and pancreatic cancer, Psycho Oncol. source

In the paper

“In bipolar disorder, Munkholm et al. (116) found significantly higher serum or plasma levels of TNF-α, its receptor soluble TNFR1 and IL-4.”

What the sources say

• Not checked yetcites [116] Munkholm, 2013, Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis, J Psychiatr Res. source

In the paper

“However, these cytokines have not been found to be elevated by all studies in patients with depression and bipolar patients (2, 116).”

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
• Not checked yetcites [116] Munkholm, 2013, Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis, J Psychiatr Res. source

In the paper

“The aforementioned cytokine alterations in affective disorders are not specific to major depression or bipolar disorder.”

In the paper

“Even though there is considerable evidence for an involvement of cytokines in the pathophysiology of many psychiatric disorders, the directionality of this relationship has not yet been elucidated with certainty.”

In the paper

“Nevertheless, cytokine changes might also be the consequence of a psychiatric disorder, for example they can be a consequence of treatment with psychopharmacological agents or of weight changes that appear during acute episodes of the disorder or during recovery (117).”

What the sources say

• Not checked yetcites [117] Himmerich, 2015, Weight gain and metabolic changes during treatment with antipsychotics and antidepressants, Endocr Metabol Immune Disorder Drug Targets source

In the paper

“Acute cytokine administration has been shown to increase corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and cortisol release”

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

“In contrast, chronic cytokine administration is associated with a flattening of the diurnal cortisol curve”

What the sources say

• Not checked yetcites [102] Sephton, 2000, Diurnal cortisol rhythm as a predictor of breast cancer survival, J Natl Cancer Inst. source
• Not checked yetcites [103] Matthews, 2006, Diurnal cortisol decline is related to coronary calcification: CARDIA study, Psychosomatic Med. source
• Not checked yetcites [104] Raison, 2010, Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior, Mol Psychiatry source

In the paper

“certain pro-inflammatory cytokines stimulate glutamate release by astrocytes.”

What the sources say

• Not checked yetcites [105] Hardingham, 2002, Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways, Nat Neurosci. source

In the paper

“which has been linked to adverse behavioral effects and poor outcomes in several illnesses such as cardiovascular disorders and cancer (102–104)”

What the sources say

• Not checked yetcites [102] Sephton, 2000, Diurnal cortisol rhythm as a predictor of breast cancer survival, J Natl Cancer Inst. source
• Not checked yetcites [103] Matthews, 2006, Diurnal cortisol decline is related to coronary calcification: CARDIA study, Psychosomatic Med. source
• Not checked yetcites [104] Raison, 2010, Interferon-alpha effects on diurnal hypothalamic-pituitary-adrenal axis activity: relationship with proinflammatory cytokines and behavior, Mol Psychiatry source

In the paper

“In bipolar disorder, Munkholm et al. (116) found significantly higher serum or plasma levels of TNF-α, its receptor soluble TNFR1 and IL-4.”

What the sources say

• Not checked yetcites [116] Munkholm, 2013, Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis, J Psychiatr Res. source

In the paper

“Cytokines can also affect neuroendocrine function by increasing hypothalamic-pituitary-adrenal (HPA) axis activity.”

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

“In bipolar disorder, Munkholm et al. (116) found significantly higher serum or plasma levels of TNF-α, its receptor soluble TNFR1 and IL-4.”

What the sources say

• Not checked yetcites [116] Munkholm, 2013, Cytokines in bipolar disorder vs. healthy control subjects: a systematic review and meta-analysis, J Psychiatr Res. source

In the paper

“However, evidence is increasing that inflammation and specifically cytokine signaling play a role in the pathophysiology of psychiatric disorders.”

What the sources say

• Not checked yetcites [118] 2013, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis, Lancet source

In the paper

“There is considerable evidence that genetic risk factors for psychiatric disorders are closely related to cytokines or other functions of the immune system.”

What the sources say

• Not checked yetcites [118] 2013, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis, Lancet source

In the paper

“Moreover, pro-inflammatory cytokines can affect the release of neurotransmitters (93).”

What the sources say

• Not checked yetcites [93] Capuron, 2012, Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration, Arch General Psychiatry source

In the paper

“Glutamate can have a detrimental effect on neurogenesis by binding to extra-synaptic NMDA receptors, leading to a decrease in brain-derived neurotrophic factor (BDNF), which is pivotal for neurogenesis (105).”

What the sources say

• Not checked yetcites [105] Hardingham, 2002, Extrasynaptic NMDARs oppose synaptic NMDARs by triggering CREB shut-off and cell death pathways, Nat Neurosci. source

In the paper

“If we take a closer look at the raw data of specific studies, we see high variation in cytokine levels within groups of patients or healthy controls.”

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

“Positron emission tomography (PET) studies have revealed that the application of IFN-α leads to increases in basal ganglia glucose metabolism (109, 110).”

What the sources say

• Not checked yetcites [109] Juengling, 2000, Prefrontal cortical hypometabolism during low-dose interferon alpha treatment, Psychopharmacology source
• Not checked yetcites [110] Capuron, 2007, Basal ganglia hypermetabolism and symptoms of fatigue during interferon-α therapy, Neuropsychopharmacology source

In the paper

“depression and fatigue are the main side effects of treatment with IFN-α (111, 112).”

What the sources say

• Not checked yetcites [111] Brydon, 2008, Peripheral inflammation is associated with altered substantia nigra activity and psychomotor slowing in humans, Biol Psychiatry source
• Not checked yetcites [112] Majer, 2008, IFN-alpha-induced motor slowing is associated with increased depression and fatigue in patients with chronic hepatitis C, Brain Behav Immun. source

In the paper

“Furthermore, they can modulate serotonin signaling by increasing the expression and function of monoamine transporters which perform the re-uptake of synaptic serotonin (89–92).”

What the sources say

• Not checked yetcites [89] Zhu, 2006, The Proinflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha activate serotonin transporters, Neuropsychopharmacology source
• Not checked yetcites [90] Zhu, 2005, p38 MAPK activation elevates serotonin transport activity via a trafficking-independent, protein phosphatase 2A-dependent process, J Biol Chem. source
• Not checked yetcites [91] Zhu, 2010, Interleukin-1 receptor activation by systemic lipopolysaccharide induces behavioral despair linked to MAPK regulation of CNS serotonin transporters, Neuropsychopharmacology source
• Not checked yetcites [92] Morón, 2003, Mitogen-activated protein kinase regulates dopamine transporter surface expression and dopamine transport capacity, J Neurosci. source

In the paper

“IFN-α has also been implicated in increased ACC activation as evidenced by fMRI studies (113, 114)”

What the sources say

• Not checked yetcites [113] Harrison, 2009, Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity, Biol Psychiatry source
• Not checked yetcites [114] Capuron, 2005, Anterior cingulate activation and error processing during interferon-alpha treatment, Biol Psychiatry source

In the paper

“such ACC activation is associated with increased anxiety, arousal, obsessive-compulsive disorder and bipolar affective disorder (108).”

What the sources say

• Not checked yetcites [108] Eisenberger, 2004, Why rejection hurts: a common neural alarm system for physical and social pain, Trends Cogn Sci. source

In the paper

“For example, glutamate release by astrocytes has been shown to be affected by cytokines, potentially leading to excitotoxicity (94, 95).”

What the sources say

• Not checked yetcites [94] Ida, 2008, Cytokine-induced enhancement of calcium-dependent glutamate release from astrocytes mediated by nitric oxide, Neurosci Lett. source
• Not checked yetcites [95] Matute, 2006, Glutamate-mediated glial injury: Mechanisms and clinical importance, Glia source

In the paper

“Studies have shown that CNS inflammation caused by infection can lead to the development of psychiatric symptoms (121) or full-blown syndromes such as depressive or manic episodes (122).”

What the sources say

• Not checked yetcites [121] Ramirez, 2005, Protection of rat primary hippocampal cultures from A beta cytotoxicity by pro-inflammatory molecules is mediated by astrocytes, Neurobiol Dis. source
• Not checked yetcites [122] Mufaddel, 2014, Psychiatric aspects of infectious diseases, Open J Psychiatry source

In the paper

“Important confounders include aging, body weight, smoking, excessive alcohol consumption, and medication (183).”

What the sources say

• Not checked yetcites [183] Dugue, 1996, Preanalytical factors and the measurement of cytokines in human subjects, Int J Clin Lab Res. source

In the paper

“The treatment of physical disorders, e.g., interferon-based or virostatic treatments for hepatitis C (167, 197), chemotherapy for the treatment of cancer (168), surgery (169) or transplantation (170), can lead to additional cytokine release.”

What the sources say

• Not checked yetcites [167] Winckler, 2018, Influence of the inflammatory response on treatment of hepatitis C with triple therapy, Rev Soc Bras Med Trop. source
• Not checked yetcites [197] Murakami, 2016, Depressive symptoms as a side effect of Interferon-alpha therapy induced by induction of indoleamine 2,3-dioxygenase 1, Sci Rep. source
• Not checked yetcites [168] Seruga, 2008, Cytokines and their relationship to the symptoms and outcome of cancer, Nat Rev Cancer source

In the paper

“Thus, the cytokine system seems to be involved in almost all possible predisposing or precipitating risk factors for depression that contribute to the presentation of the disorder.”

In the paper

“Several studies have shown that the elevated levels of inflammation may contribute to the prevalence of neuropsychiatric disorders in these populations (188–192).”

What the sources say

• Not checked yetcites [188] Capuron, 2008, Depressive symptoms and metabolic syndrome: is inflammation the underlying link?, Biol Psychiatry source
• Not checked yetcites [189] Sweat, 2008, C-reactive protein is linked to lower cognitive performance in overweight and obese women, Inflammation source
• Not checked yetcites [190] Yaffe, 2004, The metabolic syndrome, inflammation, and risk of cognitive decline, JAMA source
• Not checked yetcites [191] Godbout, 2009, Age and neuroinflammation: a lifetime of psychoneuroimmune consequences, Immunol Allergy Clin N Am. source
• Not checked yetcites [192] Layé, 2010, Polyunsaturated fatty acids, neuroinflammation and well being, Prostaglandins Leukot Essent Fatty Acids source

In the paper

“Smoking (193), excessive alcohol consumption (148), and drug abuse (149) have been associated with inflammatory changes in the immune system, as reflected by an increase of pro-inflammatory cytokines.”

What the sources say

• Not checked yetcites [193] Johannsen, 2013, Smoking and inflammation: evidence for a synergistic role in chronic disease, Periodontol 2000 source
• 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 [149] Moreira, Cocaine abuse and effects in the serum levels of cytokines IL-6 and IL-10, Drug Alcohol Depend. source

In the paper

“Genome-wide association studies (GWAS) have identified immune pathway genes that significantly contribute to the risk of psychiatric disorders (118).”

What the sources say

• Not checked yetcites [118] 2013, Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis, Lancet source

In the paper

“Also, psychopharmacological medication, specifically those agents which lead to weight gain, have been reported to activate cytokine production (117, 194).”

What the sources say

• Not checked yetcites [117] Himmerich, 2015, Weight gain and metabolic changes during treatment with antipsychotics and antidepressants, Endocr Metabol Immune Disorder Drug Targets source
• Not checked yetcites [194] Kluge, 2009, Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever, Psychoneuroendocrinology source

In the paper

“As growing white adipose tissue becomes infiltrated by macrophages, this fatty tissue could be a major source of pro-inflammatory cytokines in the context of increasing body weight during psychopharmacological treatment (195).”

What the sources say

• Not checked yetcites [195] Berthold-Losleben, The TNF-alpha system: functional aspects in depression, narcolepsy and psychopharmacology, Curr Neuropharmacol. source

In the paper

“ω6 fatty acids, in contrast, promote the production of these pro-inflammatory cytokines.”

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

“A risk factor like acute or chronic stress could, for example, lead to an increased production of pro-inflammatory cytokines (115, 138–140)”

What the sources say

• Not checked yetcites [115] Himmerich, 2013, Stress-induced cytokine changes in rats, Eur Cytokine Network source
• Not checked yetcites [138] Rohleder, 2014, Stimulation of systemic low-grade inflammation by psychosocial stress, Psychosomatic Med. source
• Not checked yetcites [139] Menard, 2017, Social stress induces neurovascular pathology promoting depression, Nat Neurosci. source
• Not checked yetcites [140] Levine, 2015, Childhood and later life stressors and increased inflammatory gene expression at older ages, Soc Sci Med. source

In the paper

“Table 3 provides evidence from the scientific literature that all of these risk factors for depression have been shown or suggested to be associated with alterations in cytokine production or cytokine signaling.”

In the paper

“Normal aging is marked by chronic low-level inflammation characterized by over-expression of circulating pro-inflammatory factors (184, 185).”

What the sources say

• Not checked yetcites [184] Fagiolo, 1992, Increased cytokine production by peripheral blood mononuclear cells from healthy elderly people, Ann N Y Acad Sci. source
• Not checked yetcites [185] Fagiolo, 1993, Increased cytokine production in mononuclear cells of healthy elderly people, Eur J Immunol. source

In the paper

“and these cytokines could then enter the brain (31) and lead to changes in neurotransmitter systems involved in the development of depression, such as the serotonin system (82, 83, 85, 86, 182).”

What the sources say

• Not checked yetcites [31] Capuron, 2011, Immune system to brain signaling: neuropsychopharmacological implications, Pharmacol Ther. source
• Not checked yetcites [82] Dunn, 1995, Cytokine effects on CNS biogenic amines, Neuroimmunomodulation source
• Not checked yetcites [83] Dunn, 1999, Effects of cytokines on cerebral neurotransmission. Comparison with the effects of stress, Adv Exp Med Biol. source

In the paper

“Another example of how food can influence the immune system is the anti-inflammatory effect of ω3 fatty acids, which can reduce the production of IL-1β, IL-6, and TNF-α.”

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

“Chronic inflammation with increased circulating levels of cytokines is also characteristic of obesity (162, 186, 187).”

What the sources say

• Not checked yetcites [162] Schmidt, 2015, Inflammatory cytokines in general and central obesity and modulating effects of physical activity, PLoS ONE source
• 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

“Thus, the mentioned group effects may not be relevant on an individual level.”

In the paper

“For example, patients with schizophrenia can also suffer from depressive symptoms (212).”

What the sources say

• Not checked yetcites [212] Lyngstad, 2018, Consequences of persistent depression and apathy in first-episode psychosis — A one-year follow-up study, Comprehen Psychiatry source

In the paper

“Moreover, a number of environmental, social, psychological and medical factors (see Table 3) are also associated with cytokine changes.”

In the paper

“What in vitro studies clearly show, however, is that antidepressants (69), antipsychotics (208) and mood stabilizers (209) have a direct influence on cytokine production within the blood.”

What the sources say

• Not checked yetcites [69] Munzer, 2013, Impact of antidepressants on cytokine production of depressed patients in vitro, Toxins source
• Not checked yetcites [208] Himmerich, 2011, Impact of antipsychotics on cytokine production in-vitro, J Psychiatr Res. source
• Not checked yetcites [209] Himmerich, 2013, Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro, J Psychiatr Res. source

In the paper

“Therefore, cytokines may currently not be considered as specific biomarkers for depression.”

In the paper

“However, attempts to try cytokine blockers in people with depression did not show striking success (218).”

What the sources say

• Not checked yetcites [218] Schmidt, 2014, The TNF-alpha inhibitor etanercept as monotherapy in treatment-resistant depression - report of two cases, Psychiatr Danub.

In the paper

“Among antipsychotics, it has been shown that those with the highest risk of weight gain, for example clozapine and olanzapine (117), lead to a significant increase in pro-inflammatory cytokine levels in the blood (194).”

What the sources say

• Not checked yetcites [117] Himmerich, 2015, Weight gain and metabolic changes during treatment with antipsychotics and antidepressants, Endocr Metabol Immune Disorder Drug Targets source
• Not checked yetcites [194] Kluge, 2009, Effects of clozapine and olanzapine on cytokine systems are closely linked to weight gain and drug-induced fever, Psychoneuroendocrinology source

In the paper

“Regarding changes of cytokine levels during antidepressant treatment, the aforementioned recent meta-analysis of Köhler et al. (2) did not provide evidence that reductions in peripheral inflammation are associated with antidepressant treatment response.”

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

“For example, TNF-α can be produced 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

“For example, Del Grande da Silva et al. (211) reported a clinical study showing that successful brief psychodynamic psychotherapy leads to a reduction of pro-inflammatory cytokine serum levels.”

What the sources say

• Not checked yetcites [211] Del Grande da Silva, 2016, Pro-inflammatory cytokines and psychotherapy in depression: Results from a randomized clinical trial, J Psychiatric Res. source

In the paper

“Animal experiments have shown that cytokine blockers like TNF-α blockers can be effective in the treatment of depression-like behavior (217).”

What the sources say

• Not checked yetcites [217] Krügel, 2013, Antidepressant effects of TNF-α blockade in an animal model of depression, J Psychiatr Res. source

In the paper

“At this point, we would like to mention that there are only few studies available that measured cytokine concentrations in the cerebrospinal fluid [e.g., (216)], 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.”

What the sources say

• Not checked yetcites [216] Kern, 2014, Higher CSF interleukin-6 and CSF interleukin-8 in current depression in older women. Results from a population-based sample, Brain Behav Immun. source

In the paper

“However, the SSRI citalopram increased the production of IL-1β, IL-6, and TNF-α in another in vitro study (69).”

What the sources say

• Not checked yetcites [69] Munzer, 2013, Impact of antidepressants on cytokine production of depressed patients in vitro, Toxins source

In the paper

“For example, Jha et al. (210) found that higher baseline levels of IL-17 were associated with greater symptomatic reduction in depressed patients treated with a bupropion-SSRI combination.”

What the sources say

• Not checked yetcites [210] Jha, 2017, Interleukin 17 selectively predicts better outcomes with bupropion-SSRI combination: Novel T cell biomarker for antidepressant medication selection, Brain Behav Immun. source

In the paper

“There is currently not enough scientific literature available to draw firm conclusions about the influence of certain antidepressants on plasma or serum levels of cytokines in vivo.”

In the paper

“However, a recent meta-analysis which included data derived from 45 longitudinal studies and more than 1,500 patients found that antidepressant treatment, overall, decreases peripheral levels of IL-6, IL-10, and TNF-α (2).”

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

“Additionally, the described effects of antidepressants on certain cytokines may be a mere pharmacological effect of these medications on immune cells that is not necessarily related to the depressive syndrome, as it has been shown that antidepressants (69), antipsychotics (208), and mood stabilizers (209) influence cytokine production directly.”

What the sources say

• Not checked yetcites [69] Munzer, 2013, Impact of antidepressants on cytokine production of depressed patients in vitro, Toxins source
• Not checked yetcites [208] Himmerich, 2011, Impact of antipsychotics on cytokine production in-vitro, J Psychiatr Res. source
• Not checked yetcites [209] Himmerich, 2013, Impact of mood stabilizers and antiepileptic drugs on cytokine production in-vitro, J Psychiatr Res. source

In the paper

“During the 1970s it became clear that immune cells are not the only cells that release cytokines (19).”

What the sources say

• Not checked yetcites [19] Cohen, 1974, Similarities of T cell function in cell-mediated immunity and antibody production, Cell Immunol. source

In the paper

“In contrast, however, Gupta et al. (203) found that successful treatment with mirtazapine led to a decrease in serum TNF-α levels.”

What the sources say

• Not checked yetcites [203] Gupta, 2016, Effect of mirtazapine treatment on serum levels of brain-derived neurotrophic factor and tumor necrosis factor-a in patients of major depressive disorder with severe depression, Pharmacology source