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Cited by 1,443Tryptophan and brain disordersStress Responses and CortisolTreatment of Major Depression

Peripheral cytokine and chemokine alterations in depression: a meta‐analysis of 82 studies

Open access
Köhler, C. A., Freitas, T. H., Maes, M., de Andrade, N. Q., Liu, C. S., Fernandes, B. S., Stubbs, B., Solmi, M. +6 more·2017·Acta Psychiatrica Scandinavica
DOI 10.1111/acps.12698
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Abstract

Objective: To conduct a systematic review and meta‐analysis of studies that measured cytokine and chemokine levels in individuals with major depressive disorder (MDD) compared to healthy controls (HC s). Method: The PubMed/MEDLINE, EMBASE, and PsycINFO databases were searched up until May 30, 2016. Effect sizes were estimated with random‐effects models. Result: Eighty‐two studies comprising 3212 participants with MDD and 2798 HC s met inclusion criteria. Peripheral levels of interleukin‐6 (IL‐6), tumor necrosis factor (TNF)‐alpha, IL‐10, the soluble IL‐2 receptor, C‐C chemokine ligand 2, IL‐13, IL‐18, IL‐12, the IL‐1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HC s, whereas interferon‐gamma levels were lower in MDD (Hedge's g = −0.477, P = 0.043). Levels of IL‐1β, IL‐2, IL‐4, IL‐8, the soluble IL‐6 receptor (sIL‐6R), IL‐5, CCL‐3, IL‐17, and transforming growth factor‐beta 1 were not significantly altered in individuals with MDD compared to HC s. Heterogeneity was large (I2: 51.6–97.7%), and sources of heterogeneity were explored (e.g., age, smoking status, and body mass index). Conclusion: Our results further characterize a cytokine/chemokine profile associated with MDD. Future studies are warranted to further elucidate sources of heterogeneity, as well as biosignature cytokines secreted by other immune cells.

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Crossref · 10.1111/acps.12698

Cites

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Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Peripheral interleukin-10 levels are elevated in individuals with major depressive disorder compared with healthy controls.

    “Levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs”
    • Also stated in: § Studies of IFN-γ · plain
      “IL-10 levels were investigated in 17 studies, and levels were significantly higher in the MDD group compared to HCs, with a small ES (g = 0.375, P = 0.045)”
    Quote in the paperSubstantial claim
  • Findingown data

    Peripheral tumor necrosis factor-alpha levels are elevated in individuals with major depressive disorder compared with healthy controls.

    “Levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs”
    • Also stated in: § Studies of TNF-α · plain
      “TNF-α was investigated across 42 studies, and levels were significantly higher in the MDD group compared to HCs, while there was evidence of small-study effects (g = 0.638; P < 0.001; Table 1 and Figure 2B)”
    Quote in the paperSubstantial claim
  • Findingown data

    Peripheral interleukin-6 levels are elevated in individuals with major depressive disorder compared with healthy controls.

    “Levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs”
    • Also stated in: § Studies of IL-6 · plain
      “Participants with MDD had higher concentrations compared to HCs (g = 0.621; P < 0.001; Table 1 and Figure 2A).”
    Quote in the paperSubstantial claim
  • Findingown data

    Peripheral C-C chemokine ligand 2 levels are elevated in individuals with major depressive disorder compared with healthy controls.

    “Levels of interleukin-6 (IL-6), tumor necrosis factor (TNF)-alpha, IL-10, the soluble IL-2 receptor, C-C chemokine ligand 2, IL-13, IL-18, IL-12, the IL-1 receptor antagonist, and the soluble TNF receptor 2 were elevated in patients with MDD compared to HCs”
    • Also stated in: § Studies of C-C chemokine ligand 2 (CCL-2) · plain
      “Levels of CCL-2 were significantly higher in participants with MDD compared to HCs with a large ES (g = 1.718;P=0.045)”
    Quote in the paperSubstantial claim
  • Findingown data

    Eighty-two studies with 3212 participants with major depressive disorder and 2798 healthy controls met the inclusion criteria.

    “Eighty-two studies comprising 3212 participants with MDD and 2798 HCs met inclusion criteria.”
    • Also stated in: § Study Selection · plain
      “Finally, 82 original studies met inclusion criteria, which provided data from 6010 participants (3212 participants with MDD and 2798 HCs).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 37
  • May combine two claims. 32
  • The quote only partly states this claim. 2

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    Findingown data

    Twenty immune mediators were assayed in at least three studies and were therefore meta-analyzed.

    “Twenty mediators were assayed in at least 3 studies and were thus metaanalyzed.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Most included studies (81; 98.8%) reported either the assay manufacturer or the coefficient of variation.

    “most studies (k=81; 98.8%) reported either the manufacturer of the assay or provided values of the coefficient of variation (CV) of the test.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Most included studies did not report illness duration (56; 68.3%); the remaining studies reported a mean illness duration of 2.97 years with a standard deviation of 6.15 years.

    “most studies did not provide information on illness duration (k=56; 68.3%); the remaining studies included MDD participants with illness duration of 2.97 ± 6.15 (mean ± SD) years.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Most included studies (65; 79.3%) provided medication status, and 3 studies (3.7%) included only treatment-naive participants with major depressive disorder.

    “most studies (k=65; 79.3%) provided data regarding medication status, whereas 3 (3.7%)included only treatment-naïve (i.e., never treated with antidepressants) participants with MDD.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    In 43 included studies (52.4%), participants with major depressive disorder and healthy controls were age- and gender-matched.

    “in 43 studies (52.4%) participants with MDD and HCs were age-and gender-matched”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Interleukin-6 heterogeneity was smaller in serum and whole blood samples than in plasma, and ELISA measurement was associated with higher heterogeneity than other assay types.

    “Subgroup analyses showed that heterogeneity was smaller in studies that measured IL-6 in serum and whole blood samples compared to plasma, while results suggest that the measurement of IL-6 with ELISA is associated with higher heterogeneity compared to other types of assay.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Methodological quality scores of included studies ranged from 1 to 6, with a median of 4.

    “The methodological quality scores of each study varied from 1 to 6 (median: 4)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingown data

    Cumulative meta-analysis for interleukin-10 indicated that the effect size was not consistent over time.

    “the cumulative meta-analysis indicates that the ES has not been consistent over time (Figure S29).”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Findingown data

    Sensitivity analysis for interleukin-10 showed that excluding 11 of 17 studies one at a time rendered the effect size non-significant.

    “Sensitivity analyses showed that the exclusion of 11 of 17 studies one-at-a-time rendered the ES estimate nonsignificant (Figure S18).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Mean body mass index of the healthy control group, publication year, sample size, and mean age of the major depressive disorder and healthy control groups emerged as potential sources of heterogeneity for interferon-gamma.

    “Mean BMI of the HC group, publication year, sample size, and mean age of the MDD and HC groups emerged as potential sources of heterogeneity in meta-regression analyses (Table S3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Soluble interleukin-2 receptor heterogeneity was lower in studies measuring plasma compared with serum and in studies where major depressive disorder and healthy control groups were not age- and gender-matched.

    “Subgroup analyses suggested that heterogeneity was lower in studies that measured sIL2 in plasma (compared to serum) as well as in studies in which MDD and HC groups were not age and gender-matched (Table S4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was evidence of small-study effects for interferon-gamma, but adjustment for publication bias did not change the effect size.

    “There was evidence of small-study effects, but adjustment for publication bias did not change the ES (g = -0.452;Table 1 and Figure 3A).”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Findingown data

    Heterogeneity for interleukin-10 was large, with an I2 of 89.2%.

    “Heterogeneity was large (I 2 = 89.2%)”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The tumor necrosis factor-alpha meta-analysis included 42 studies.

    “TNF-α was investigated across 42 studies”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Interleukin-1 beta heterogeneity was lower in studies measuring whole blood and in studies using stimulated leucocytes.

    “subgroup analyses suggest that heterogeneity is lower in studies that measured this immune mediator in whole blood (compared to studies which assayed IL-1β in serum or plasma) and in studies that used stimulated leucocytes (Table S4).”
    Quote in the paperNot a substantial claim

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    Findingown data

    There was evidence of small-study effects for CCL-2, but the effect size was not altered after adjustment for publication bias.

    “There was evidence of smallstudy effects (Table 1).However, the ES was not altered after adjustment for publication bias.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    There was evidence of small-study effects for tumor necrosis factor-alpha, but the effect size was unchanged after adjustment for publication bias.

    “while there was evidence of small-study effects (g = 0.638; P < 0.001; Table 1 and Figure 2B); the ES was unaltered after adjustment for publication bias (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Heterogeneity for interleukin-18 was large, with an I2 of 95.3%, and no evidence of small-study effects was observed.

    “Heterogeneity was large (I 2 = 95.3%), and no evidence of small-study effects was observed (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Heterogeneity for interleukin-12 was large, with an I2 of 92.9%, and no evidence of small-study effects was observed.

    “The heterogeneity was large (I 2 = 92.9%),and no evidence of small-study effects was observed (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Heterogeneity for interleukin-13 was large, with an I2 of 96.0%, but could not be reliably explored because only six studies were included.

    “The heterogeneity was large (I 2 = 96.0%)but could not be reliably explored due to the limited number of included studies (k=6).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    sTNFR2 levels were higher in individuals with MDD than in healthy controls, with a large effect size (g = 1.173, P = 0.003) based on three studies.

    “Three studies indicate that sTNFR2 levels are higher in individuals with MDD compared to HCs with a large ES (g = 1.173;P=0.003), but high heterogeneity (I 2 = 83.2%)(Table 1; Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Peripheral IL-1Ra levels were higher in the MDD group than in healthy controls, with a Hedges' g of 0.449 and P = 0.016.

    “Peripheral levels of IL-1Ra were higher in the MDD group compared to HCs (g= 0.449; P=0.016) (Table 1; Figure 4D).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    IL-6 was the most extensively investigated cytokine in this meta-analysis, with a consistent moderate effect size in cumulative meta-analysis.

    “It is worthy to note that IL-6 was cytokine more extensively investigated in this meta-analysis, with a consistent moderate ES observed in cumulative meta-analysis.”
    Quote in the paperNot a substantial claim

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    Findingown data

    The IFN-γ effect size was small and sensitivity analyses pointed to significant outliers.

    “However, the ES was small and sensitivity analyses pointed to significant outliers.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The methodological quality of included studies varied, and this factor emerged as a significant moderator of differences in TNF-α levels between participants with MDD and healthy controls.

    “Finally, the methodological quality of included studies has varied, and in our exploratory meta-regression analyses this factor emerged as a significant moderator of differences in TNF-α levels between participants with MDD and HCs.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    This meta-analysis indicates that several cytokines and CCL-2 are elevated in MDD.

    “In conclusion, this meta-analysis indicates that several cytokines and CCL-2 are elevated in MDD.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    A low-grade inflammatory response, including increased granulocytes and monocytes, elevated acute phase reactants, inflammatory cytokines, and possibly chemokines, has been demonstrated in individuals with major depressive disorder compared with healthy controls.

    “A low-grade inflammatory response characterized by increased numbers of granulocytes and monocytes (1), as well as elevated levels of acute phase reactants (for example, Creactive protein and haptoglobin) (5,6), inflammatory cytokines (7), and possibly chemokines (8) have been demonstrated in groups of individuals with MDD compared to healthy controls (HCs).”
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    Premisecitation

    Cytokines may cross the blood-brain barrier, and certain cytokines such as interleukin-1 beta may signal the brain through afferent nerves like the vagus.

    “evidence indicates that cytokines may cross the blood-brain barrier, while certain cytokines (e.g., IL-1β) may convey signals to the brain via afferent nerves like the vagus (2,4).”
    Quote in the paperSubstantial claim0 of 2 sources checked
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    Premisecitation

    A prior meta-analysis of 24 studies found that peripheral tumor necrosis factor-alpha and interleukin-6 levels are significantly elevated in individuals with major depressive disorder compared with healthy controls.

    “A meta-analysis which included twenty-four studies provided evidence that peripheral levels of tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6) are significantly elevated in individuals with MDD compared to healthy controls (HCs) (7).”
    Quote in the paperSubstantial claim0 of 1 sources checked
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    Premisecitation

    Some cytokines and chemokines are predominantly pro-inflammatory, others are mainly anti-inflammatory, and some have been implicated in neuroplasticity mechanisms.

    “some cytokines/chemokines are predominantly pro-inflammatory, whereas others are mainly anti-inflammatory, and some of these immune mediators have been increasingly implicated in neuroplasticity mechanisms (17,18).”
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    Premisecitation

    Preclinical research indicates that pro-inflammatory cytokines may promote depressive-like behaviors, while TNF-alpha and IL-6 receptor knockout mice show resilience to stress-induced depressive-like behaviors.

    “preclinical research indicating that pro-inflammatory cytokines may promote depressive-like behaviors, whereas TNF-α and IL-6 receptor knockout mice exhibit resilience to stress-induced depressive-like behaviors (9)(10)(11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites (9)(10)(11)

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    Premisecitation

    Melancholic depression is associated with elevated hypothalamic-pituitary-adrenal axis activity.

    “melancholic depression is associated with elevated HPA axis activity (15,16)”
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    Premisecitation

    A recent meta-analysis estimated that approximately 25% of patients with chronic hepatitis C develop depression after treatment with interferon-alpha.

    “a recent meta-analysis estimates that ~ 25% of patients with chronic hepatitis C develop depression after treatment with the proinflammatory cytokine interferon-α (IFN-α) (12).”
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    Study design and conductown data

    For statistically significant effect sizes, sensitivity analyses excluded each study one at a time to check whether a single study changed the significance or direction of the effect.

    “For statistically significant ES estimates we performed sensitivity analyses in which we excluded each study from analyses to verify whether a single study turned results non-significant or otherwise changed the direction of the ES.”
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    Study design and conductown data

    Cumulative meta-analysis was performed for significant effect sizes with at least 10 datasets.

    “In addition, cumulative meta-analysis was performed for significant ES with at least 10 datasets.”
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    Study design and conductcitation

    The fail-safe N was used to determine how many additional studies would be needed to make a significant effect size non-significant.

    “the fail-safe N (i.e. the file drawer statistic) was used to determine how many additional studies would be necessary to turn a significant ES non-significant (32).”
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    Study design and conductnone given

    An a priori defined but unpublished protocol was followed.

    “An a priori defined yet unpublished protocol was followed.”
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    Study design and conductcitation

    Effect sizes were pooled using random-effects models according to the DerSimonian and Laird method.

    “Effect sizes were estimated with random-effects models.”
    • Also stated in: § Statistical analysis · plain
      “we pooled ES using a random-effects model according to the DerSimonian and Laird method (28).”
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    Study design and conductcitation

    Publication bias was assessed by inspecting funnel plot asymmetry and calculating Egger's regression test.

    “To assess publication bias, we inspected a funnel plot graph for asymmetry, and calculated the Egger's regression test for funnel plot asymmetry (30).”
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    Study design and conductcitation

    The trim-and-fill procedure was used to estimate effect sizes adjusted for publication bias.

    “The trim-and-fill procedure was used to estimate the ES adjusting for publication bias (31)”
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    Study design and conductcitation

    Meta-regression analyses were conducted only when at least 10 studies provided a moderator, because fewer datasets may yield spurious results.

    “Meta-regression analyses were conducted only when at least 10 studies provided moderator; this decision was made a piori because with fewer datasets this analytic tool may provide spurious results (33).”
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    Study design and conductnone given

    Literature search, title and abstract screening, final eligibility decisions after full-text review, and data extraction were performed independently by two investigators.

    “The literature search, title/abstract screening, final decision on eligibility after full-text-review, and data extraction were independently performed by two investigators.”
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    Study design and conductcitation

    The study complied with the PRISMA statement for systematic reviews and meta-analyses.

    “We complied with the Preferred Reported Items for Systematic Reviews and Meta-analysis (PRISMA) statement (21).”
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    Premisecitation

    A previous meta-analysis found elevated TNF-α and IL-6 levels in depressive patients compared to healthy controls.

    “The previous meta-analysis found elevated levels of TNF-α and IL-6 in depressive patients compared to HCs (7).”
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    Premisecitation

    A recent meta-analysis compared peripheral cytokine levels among patients with schizophrenia, bipolar disorder, and MDD.

    “A recent meta-analysis aimed to compare peripheral levels of cytokines among patients with schizophrenia, bipolar disorder, and also MDD (50).”
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    Study design and conductreasoning

    The authors a priori excluded studies in which participants with MDD had clearly identified comorbidities and examined the influence of other relevant confounders.

    “Therefore, we a priori excluded studies in which participants with MDD had clearly identified comorbidities, and examined the influence of other relevant confounders.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Fixed-effects models may be inaccurate when heterogeneity is large.

    “In addition, a fixed-effects models were used to estimate ESs, which may be inaccurate when heterogeneity is large (27).”
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    Premisecitation

    That recent meta-analysis included only 30 studies.

    “However, this meta-analysis included only 30 studies.”
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    Premisecitation

    That recent meta-analysis also investigated the effects of antidepressant treatment on blood cytokine levels in patients with MDD.

    “This recent meta-analysis also investigated the effects of antidepressant treatment on blood cytokine levels in patients with MDD (50).”
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    Premisecitation

    IL-6 may activate a classical pathway and a trans-signaling pathway, which may have predominantly anti-inflammatory and pro-inflammatory activities, respectively.

    “For example, IL-6 may activate a classical pathway and a trans-signaling pathway, which may have predominantly anti-and proinflammatory activities respectively (58).”
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    Premisecitation

    IL-6 and IL-1β may contribute to the pathophysiology of a subset of patients with MDD via excessive release of corticotrophin releasing hormone and by promoting glucocorticoid receptor resistance, which may ultimately impair negative feedback regulation of the HPA axis.

    “In addition, IL-6 and IL-1β may contribute to the pathophysiology of a subset of patients with MDD via excessive release of corticotrophin releasing hormone (CRH) and by the promotion glucocorticoid receptor resistance, which may ultimately impair the negative feedback regulation of the HPA axis (59,60).”
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    Premisecitation

    Ronald Smith was the first to propose a macrophage theory for depression in the early 1990s.

    “Ronald Smith was the first to propose a macrophage theory for depression in the early 1990's (63).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
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    Premisecitation

    Previous studies found elevated IFN-γ levels in stimulated peripheral blood mononuclear cells of individuals with MDD compared to healthy controls, which may provide a more accurate measure of this cytokine.

    “In addition, previous studies found elevated levels of IFN-γ in stimulated peripheral blood mononuclear cells (PBMCs) of individuals with MDD compared to healthy controls, which may provide a more accurate measure of this cytokine (61,62).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
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    Premisecitation

    Preclinical studies indicate that blockade of the trafficking of peripheral monocytes to the brain reduced proinflammatory cytokine production and decreased depressive-like behaviors in rodent stress models.

    “However, preclinical studies indicate that the blockade of the trafficking of peripheral monocytes to the brain reduced proinflammatory cytokine production and decreased depressive-like behaviors in rodent stress models (66).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [66]

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    Study design and conductown data

    Some possible sources of heterogeneity could not be investigated due to lack of data across studies, and data on other potential moderators such as physical activity and diet quality were not provided by included studies and could not be controlled for.

    “Although we have identified some significant moderators, some possible sources of heterogeneity could not be investigated due to the lack of data across studies, while data on other potential moderators (e.g.physical activity and diet quality) (57) were not provided by included studies, and thus could not be controlled for.”
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    Study design and conductnone given

    A clear limitation of this meta-analysis is that the periphery may not reflect pathophysiological events in the CNS.

    “A clear limitation of this meta-analysis rests on fact that the periphery may not reflect pathophysiological events in the CNS.”
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    Premisecitation

    A previous meta-analysis found suggestive differences in peripheral cytokine levels between acute and chronic MDD relative to healthy controls.

    “Notwithstanding we could not investigate whether length of disease and number of affective episodes as possible moderators of ESs estimates due to the lack of data across studies, a previous meta-analysis, which used a different definition had found suggestive that some differences in peripheral levels of cytokines may occur in acute compared to chronic MDD relative to HCs (50).”
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    Premisecitation

    Emerging preclinical evidence and a recent theoretical framework indicate that TH17 cells could play a significant role in the biology of depression.

    “For example, emerging preclinical evidence and a recent theoretical framework indicates that TH17 cells could play a significant role in the biology of depression (74,75).”
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    Premisecitation

    Previous evidence indicates that antidepressant drugs may impact peripheral cytokine levels at follow-up.

    “However, our exploratory metaregressions could have limited power to detect this effect, and previous evidence indicates that antidepressant drugs may impact peripheral cytokine levels at follow-up (50).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] source

      Not checked in the free run.

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

    Study design and conductnone given

    Although a pre-defined protocol was followed, it was not published or registered in a public database.

    “It is worthy to note that although a pre-defined protocol was followed, we did not publish or otherwise registered it in a public database.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    The characterization of the precise peripheral immune profile associated with MDD remains a work in progress.

    “Thus, the characterization of the precise peripheral immune profile associated with MDD remains a work in progress.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Technical challenges in the assessment of certain mediators such as IL-2 and IFN-γ, as well as differences in assay standardization across laboratories, could have contributed to the heterogeneity of some estimates.

    “Furthermore, technical challenges in the assessment of certain mediators (e.g.IL-2 and IFN-γ) (73) as well as differences in the standardization of assays across different laboratories could have contributed to the heterogeneity of some estimates.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73]

      Not checked in the free run.

62 of 62

  • The paper relies on this without support.

    The methodological quality score devised by the authors validly measures the methodological quality of the included studies.

    “We devised a score to estimate the methodological quality of each study based on the following parameters:”

  • The paper relies on this without support.

    IFN-γ levels were often close to the limit of detection of previously available assay kits, which may lead to analytical variability.

    “Furthermore, levels of IFN-γ were most often close to the limit of detection of previously available assay kits, which may lead to analytical variability.”
2 of 2

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?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Discussion calls IL-1β elevated despite a nonsignificant result

    Major

    The discussion identifies IL-1β as elevated in MDD, but the results report no significant difference between the MDD and control groups.

  • CCL-2 P-value differs between the results and Table 1

    Minor

    The CCL-2 results paragraph reports P = 0.045, whereas Table 1 reports P = 0.002 for the same overall effect.

2 of 2

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Authors
Köhler, C. A., Freitas, T. H., Maes, M., de Andrade, N. Q., Liu, C. S., Fernandes, B. S., Stubbs, B., Solmi, M., Veronese, N., Herrmann, N., Raison, C. L., Miller, B. J., Lanctôt, K. L., & Carvalho, A. F.
Affiliations
  • Universidade Federal do Ceará (BR)
  • Universidade Estadual de Londrina (BR)
  • Translational Psychiatry Research Group and Department of Clinical Medicine Faculty of Medicine Federal University of Ceará Fortaleza CE Brazil
  • University of Toronto (CA)
  • Universidade Federal do Rio Grande do Sul (BR)
  • National Health Service (GB)
  • University of Padua (IT)
  • University of Wisconsin–Madison (US)
  • Augusta University (US)
Corresponding author
Carvalho, A. F.
ORCID
Venue
Acta Psychiatrica Scandinavica
Publisher
Wiley
Published
2017-01-25
Volume
135
Issue
5
Pages
373-387
ISSN
  • 0001-690X (ISSN-L)
  • 1600-0447
DOI
10.1111/acps.12698
OpenAlex
W2582903515
Semantic Scholar
c8ba0132ef96678f0e0a3d8e5530a8249cd924a3
Cited by
1,443
References
74
Citations by year
2026: 134 · 2025: 178 · 2024: 177 · 2023: 195 · 2022: 195 · 2021: 159 · 2020: 146 · 2019: 127 · 2018: 93 · 2017: 38
FWCI
7.46
Type
journal article
Language
en
Open access
Licence
Locations
  • Acta Psychiatrica Scandinavica (publishedVersion)
  • PubMed (publishedVersion)
  • LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (publishedVersion, other-oa)
  • Research Portal (King's College London) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
  • Nova Science Publishers (Nova Science Publishers, Inc.) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
Keywords
major depressive disorder, cytokines, chemokines, interleukin-6, TNF-α, IL-10, interferon-gamma, soluble interleukin-2 receptor, MCP-1, soluble TNF receptor 2, interleukin-1 receptor antagonist, biomarkers, heterogeneity sources
MeSH terms
Major Depressive Disorder, Female, Humans, Male, Cytokines, Chemokines

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

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