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Cited by 432Tryptophan and brain disordersStress Responses and CortisolNeuroinflammation and Neurodegeneration Mechanisms

Inflammation-related biomarkers in major psychiatric disorders: a cross-disorder assessment of reproducibility and specificity in 43 meta-analyses

Open access
Yuan, Ning, Chen, Yu, Xia, Yan, Dai, Jiacheng, Liu, Chunyu·2019·Translational Psychiatry
DOI 10.1038/s41398-019-0570-yPMC PMC6751188
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Abstract

Inflammation is a natural defence response of the immune system against environmental insult, stress and injury, but hyper- and hypo-inflammatory responses can trigger diseases. Accumulating evidence suggests that inflammation is involved in multiple psychiatric disorders. Using inflammation-related factors as biomarkers of psychiatric disorders requires the proof of reproducibility and specificity of the changes in different disorders, which remains to be established. We performed a cross-disorder study by systematically evaluating the meta-analysis results of inflammation-related factors in eight major psychiatric disorders, including schizophrenia (SCZ), bipolar disorder (BD), autism spectrum disorder (ASD), major depression disorder (MDD), post-trauma stress disorder (PTSD), sleeping disorder (SD), obsessive–compulsive disorder (OCD) and suicide. A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study. We calculated the effect size and statistical power for every inflammation-related factor in each disorder. Our analyses showed that well-powered case–control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers. After removing underpowered studies, 30 of the 44 inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses. Eleven of them changed in patients of more than two disorders when compared with the controls. A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ). MDD had the largest number of changes while SD has the least. Clustering analysis showed that closely related disorders share similar patterns of inflammatory changes, as genome-wide genetic studies have found. According to the effect size obtained from the meta-analyses, 13 inflammation-related factors would need <50 cases and 50 controls to achieve 80% power to show significant differences ( p < 0.0016) between patients and controls. Changes in different states of MDD, SCZ or BD were also observed in various comparisons. Studies comparing first-episode SCZ to controls may have more reproducible findings than those comparing pre- and post-treatment results. Longitudinal, system-wide studies of inflammation regulation that can differentiate trait- and state-specific changes will be needed to establish valuable biomarkers.

AI snapshot

Written from the paper’s full text.

TL;DR

This cross-disorder systematic review of 43 meta-analyses found that well-powered studies yield more consistent inflammation-related biomarker findings across major psychiatric disorders. After filtering underpowered meta-analyses, 30 of 44 inflammation-related factors showed significant alterations in at least one disorder, with 11 changing in more than two disorders.

Key findings

  • The review included 43 meta-analyses involving 704 publications on 44 inflammation-related factors across eight disorders; 26% of meta-analyses were underpowered (<80%). After removing underpowered data, 30 of 44 factors showed significant alterations in at least one disorder, and 11 changed in more than two disorders.
  • Consistency improved after power filtering: inconsistent case–control results fell from 42% (16/38) to 16% (5/31), and inconsistent state-related results fell from 67% (24/36) to 48% (15/31). Well-powered case–control findings had 84% consistency; SCZ and BD case–control comparisons showed 100% consistency.
  • Specificity examples: IL-4 increased in BD, decreased in suicide, and showed no change in MDD, ASD, PTSD, or SCZ; IL-2 was uniquely low in suicide; sIL-6R was uniquely high in BD; sIL-2R was uniquely not changed in PTSD. IL-6 and CRP were the most commonly increased factors, each changed in four disorders; NGF was the most commonly decreased factor in MDD and SCZ.
  • Based on effect sizes, 13 inflammation-related factors would need <50 cases and 50 controls to achieve 80% power at p < 0.0016. MDD had the largest number of changes and SD the least. Clustering showed BD and SCZ closer to each other, while suicide clustered with PTSD and SD.

Methods

  • Systematic review of meta-analysis publications in PubMed, Springer, and Web of Science before March 2018, following PRISMA; inclusion required English-language meta-analyses of circulating cytokine/chemokine/inflammation-related factor levels in plasma, serum, or CNS. The final set comprised 43 meta-analyses on 44 factors in eight disorders: SCZ (n = 11), MDD (n = 16), BD (n = 6), OCD (n = 1), suicide (n = 2), ASD (n = 1), PTSD (n = 1), SD (n = 1), and cross-disorder studies (n = 4); anxiety did not meet inclusion criteria.
  • Data were partitioned into trait marker analyses (undifferentiated case–control comparisons; 24 studies), state marker analyses (6 studies), or both (13 studies). Effect sizes were extracted as standardized mean differences, statistical power was calculated with G*Power, and data with power <0.8 were filtered out. Stability across repeated meta-analyses was used as a proxy for reproducibility, and unsupervised clustering assessed cross-disorder similarity.

Limitations

  • The paper states that it is built on meta-analysis results, so it cannot recover signals missed by original studies due to technical limitations, and meta-analyses can be misled by systematic bias in individual data. Independence of samples was problematic because meta-analyses often reuse the same underlying studies, so stability was used as a proxy for reproducibility rather than true independent replication.
  • The paper states that many effect sizes may be inflated because some factors have limited studies, and independent testing is needed. State-related data carry more uncertainty than trait-related data, with frequent inconsistencies in pre- and post-treatment comparisons; first-episode SCZ findings were considered more reliable. Few prior studies reported statistical power, quality control, covariate control, or multiple-testing correction.
  • Evident from the text: most data came from peripheral blood, with only one brain study and limited CSF data; the review covered only eight psychiatric disorders and excluded anxiety; most included studies focused on candidate factors rather than system-wide measures; and longitudinal data were rare, limiting differentiation of trait and state markers.

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

Integrity signals

Registry

Crossref · 10.1038/s41398-019-0570-y

Cites

81 of 81 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 63 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study.

    “A total of 43 meta-analyses involving 704 publications on 44 inflammation-related factors were included in the study.”
    Quote in the paperSubstantial claim
  • Findingown data

    Eleven of the inflammation-related factors changed in patients of more than two disorders when compared with controls.

    “Eleven of them changed in patients of more than two disorders when compared with the controls.”
    Quote in the paperSubstantial claim
  • Findingown data

    Closely related disorders share similar patterns of inflammatory changes.

    “Clustering analysis showed that closely related disorders share similar patterns of inflammatory changes, as genome-wide genetic studies have found.”
    Quote in the paperSubstantial claim
  • Findingown data

    Well-powered case-control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers.

    “Our analyses showed that well-powered case–control studies provided more consistent results than underpowered studies when one factor was meta-analysed by different researchers.”
    Quote in the paperSubstantial claim
  • Findingown data

    Thirty inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses.

    “After removing underpowered studies, 30 of the 44 inflammation-related factors showed significant alterations in at least one disorder based on well-powered meta-analyses.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: All data including those tested only once will have better reproducibility.
  • May combine two claims. 24
  • Classified as probably not a substantial claim. 28

  • May combine two claims.

    Findingown data

    A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ).

    “A few inflammation-related factors showed unique changes in specific disorders (e.g., IL-4 increased in BD, decreased in suicide, but had no change in MDD, ASD, PTSD and SCZ).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingnone given

    MDD had the largest number of changes while SD has the least.

    “MDD had the largest number of changes while SD has the least.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    IL-6 was consistent with the changes detected in blood while IL-1beta was inconsistent.

    “IL-6 was consistent with the changes detected in blood while IL-1beta was inconsistent.”
    Quote in the paperSubstantial claim

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

    Findingown data

    The single meta-analysis of OCD was filtered out because of the insufficient statistical power.

    “The single meta-analysis of OCD was filtered out because of the insufficient statistical power.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    20% of the studies required specific age ranges.

    “20% of the studies required specific age ranges”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Totally, 48% (15/31 total, 4/10 of BD, 5/6 of MDD and 6/15 of SCZ) of the state-related tests remained inconsistent.

    “Totally, 48% (15/31 total, 4/10 of BD, 5/6 of MDD and 6/15 of SCZ) of the state-related tests remained inconsistent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Most data were generated from peripheral blood without differentiating whole blood, serum and plasma; one study involved three IRFs in the brain, and four meta-analyses were analysed in both blood and the cerebrospinal fluid (CSF).

    “Most data were generated from peripheral blood without differentiating whole blood, serum and plasma; one study involved three IRFs in the brain29, and four meta-analyses were analysed in both blood and the cerebrospinal fluid (CSF)13,29–31.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [29] Black, C. & Miller, B. J. Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients. Biol. Psychiatry 78, 28–37 (2015). source

      Not checked in the free run.

    • cites [13] Miller, B. J., Buckley, P., Seabolt, W., Mellor, A. & Kirkpatrick, B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70, 663–671 (2011). source

      Not checked in the free run.

    • cites [30] Ducasse, D., Olie, E., Guillaume, S., Artero, S. & Courtet, P. A meta-analysis of cytokines in suicidal behavior. Brain Behav. Immun. 46, 203–211 (2015). source

      Not checked in the free run.

    • cites [31] Rao, S. et al. Peripheral blood nerve growth factor levels in major psychiatric disorders. J. Psychiatr. Res. 86, 39–45 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    IL-8 was reported to have no significant changes in MDD by a study of 560 subjects, but it was found to be increased in MDD in a later study of 3788 subjects.

    “IL-8 was reported to have no significant changes in MDD by a study of 560 subjects37, but it was found to be increased in MDD in a later study of 3788 subjects38.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Eyre, H. A. et al. A meta-analysis of chemokines in major depression. Prog. Neuropsychopharmacol. Biol. Psychiatry 68, 1–8 (2016). source

      Not checked in the free run.

    • cites [38] Leighton, S. P. et al. Chemokines in depression in health and in inflammatory illness: a systematic review and meta-analysis. Mol. Psychiatry 23, 48–58 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    All these IRFs changed in some disorders but had no change or even opposite changes in other disorders.

    “All these IRFs changed in some disorders but had no change or even opposite changes in other disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MDD, ASD, PTSD, suicide, SD, BD and SCZ have 16, 7, 3, 5, 2, 8 and 7 IRF changes, respectively.

    “MDD, ASD, PTSD, suicide, SD, BD and SCZ have 16, 7, 3, 5, 2, 8 and 7 IRF changes, respectively”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    The difference of IFN-gamma was not significant between MDD and controls in a study of 238 subjects, but a later meta-analysis that includes a total of 1470 subjects found IFN-gamma to be significantly decreased in MDD patients.

    “For example, the difference of IFN-gamma was not significant between MDD and controls in a study of 238 subjects35, but a later meta-analysis that includes a total of 1470 subjects found IFN-gamma to be significantly decreased in MDD patients36.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Dowlati, Y. et al. A meta-analysis of cytokines in major depression. Biol. Psychiatry 67, 446–457 (2010). source

      Not checked in the free run.

    • cites [36] Kohler, C. A. et al. Peripheral cytokine and chemokine alterations in depression: a meta-analysis of 82 studies. Acta Psychiatr. Scand. 135, 373–387 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    In those 43 meta-analyses, there were 24 trait marker studies, 6 state marker studies and 13 studies containing both trait and state analyses.

    “In those 43 meta-analyses, there were 24 trait marker studies, 6 state marker studies and 13 studies containing both trait and state analyses (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Most previous studies focused on candidate genes, which do not provide system-wide information.

    “Most of those studies focused on candidate genes, which do not provide system-wide information.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    We performed power analysis on the 427 meta-analyses of 44 IRFs done in the eight disorders, 318 of them (74%) have sufficient power (≥0.8), while the rest were under-powered.

    “We performed power analysis39 on the 427 meta-analyses of 44 IRFs done in the eight disorders, 318 of them (74%) have sufficient power ( ≥ 0.8), while the rest were under-powered.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [39] Faul, F., Erdfelder, E., Buchner, A. & Lang, A. G. Statistical power analyses using G*Power 3.1: tests for correlation and regression analyses. Behav. Res Methods 41, 1149–1160 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Many results were also replicated by Upthegrove et al. except for IL-4 and IFN-gamma.

    “many were also replicated by Upthegrove et al.46 except for IL-4 and IFN-gamma.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [46] Upthegrove, R., Manzanares-Teson, N. & Barnes, N. M. Cytokine function in medication-naive first episode psychosis: a systematic review and meta-analysis. Schizophr. Res. 155, 101–108 (2014). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Findingreasoning

    Only a limited number of genes or proteins involved in immunity and inflammation regulation have been investigated in psychiatric disorders due to constraints of methodology and resources.

    “Only a limited number of them have been investigated in psychiatric disorders due to the constraints of methodology and resources.”
    Quote in the paperSubstantial claim

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

    Findingreasoning

    Candidate gene studies contributed to answering specific questions in biology, but they frequently missed the big picture, without assessing the impact of the genes that changed the most.

    “Candidate gene studies contributed to answering specific questions in biology, but they frequently missed the big picture, without assessing the impact of the genes that changed the most.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing), S4 (based).

    Findingnone given

    Statistical procedures were commonly liberal, leaving more space for false findings.

    “Statistical procedures were commonly liberal, leaving more space for false findings.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Most IRF studies neither evaluate technical variances for their assays, nor did they report data-missing rates.

    “Most IRF studies neither evaluate technical variances for their assays, nor did they report data-missing rates.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A recent meta-analysis of anti-cytokine treatment showed significant antidepressant effects.

    “a recent meta-analysis of anti-cytokine treatment showed significant antidepressant effects10.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Kappelmann N., Lewis G., Dantzer R., Jones P. B., Khandaker G. M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry 23, 335–343 (2018). source

      Not checked in the free run.

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

    Premisecitation

    Changes of some inflammation-related factors (IRFs) have been intensively studied and reviewed in relation to psychiatric disorders.

    “Changes of some inflammation-related factors (IRFs) have been intensively studied and reviewed in relation to psychiatric disorders1–9.”
    Quote in the paperNot a substantial claim0 of 9 sources checked
    • cites [1] Gill, J. M., Saligan, L., Woods, S. & Page, G. PTSD is associated with an excess of inflammatory immune activities. Perspect. Psychiatr. Care 45, 262–277 (2009). source

      Not checked in the free run.

    • cites [2] Michopoulos, V., Powers, A., Gillespie, C. F., Ressler, K. J. & Jovanovic, T. Inflammation in fear- and anxiety-based disorders: PTSD, GAD, and beyond. Neuropsychopharmacology 42, 254–270 (2017). source

      Not checked in the free run.

    • cites [3] Wang, Z. & Young, M. R. PTSD, a disorder with an immunological component. Front. Immunol. 7, 219 (2016).

      Not checked in the free run.

    • cites [4] Tonhajzerova, I. et al. Inflammatory activity in autism spectrum disorder. Adv. Exp. Med. Biol. 861, 93–98 (2015). source

      Not checked in the free run.

    • cites [5] Kern, J. K., Geier, D. A., Sykes, L. K. & Geier, M. R. Relevance of neuroinflammation and encephalitis in autism. Front. Cell. Neurosci. 9, 519 (2015).

      Not checked in the free run.

    • cites [6] Muller, N. Inflammation in schizophrenia: pathogenetic aspects and therapeutic considerations. Schizophr. Bull. 44, 973–982 (2018). source

      Not checked in the free run.

    • cites [7] Muneer, A. Bipolar disorder: role of inflammation and the development of disease biomarkers. Psychiatry Investig. 13, 18–33 (2016). source

      Not checked in the free run.

    • cites [8] Bauer M. E., Teixeira A. L. Inflammation in psychiatric disorders: what comes first? Ann. N. Y. Acad. Sci. 1437, 57–67 (2019). source

      Not checked in the free run.

    • cites [9] Friedrich, M. J. Research on psychiatric disorders targets inflammation. J. Am. Med. Assoc. 312, 474–476 (2014). source

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

    Premisecitation

    Drugs that target IRFs have been proposed for treating psychiatric disorders, including MDD, SCZ, and BD, particularly in a subset of patients with chronic inflammation.

    “On one hand, drugs that target IRFs have been proposed for treating psychiatric disorders, including major depression (MDD)10–12, schizophrenia (SCZ)13 and bipolar disorder (BD)14, particularly in a subset of patients with chronic inflammation10”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [10] Kappelmann N., Lewis G., Dantzer R., Jones P. B., Khandaker G. M. Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Mol. Psychiatry 23, 335–343 (2018). source

      Not checked in the free run.

    • cites [11] Kohler, O., Krogh, J., Mors, O. & Benros, M. E. Inflammation in depression and the potential for anti-inflammatory treatment. Curr. Neuropharmacol. 14, 732–742 (2016). source

      Not checked in the free run.

    • cites [12] Kopschina Feltes, P. et al. Anti-inflammatory treatment for major depressive disorder: implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J. Psychopharmacol. 31, 1149–1165 (2017). source

      Not checked in the free run.

    • cites [13] Miller, B. J., Buckley, P., Seabolt, W., Mellor, A. & Kirkpatrick, B. Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psychiatry 70, 663–671 (2011). source

      Not checked in the free run.

    • cites [14] Rosenblat J. D., McIntyre R. S. Bipolar disorder and immune dysfunction: epidemiological findings, proposed pathophysiology and clinical implications. Brain Sci. 7, (2017). source

      Not checked in the free run.

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

    Premisecitation

    Some current psychotropic drugs, including antipsychotics and antidepressants, have anti-inflammatory effects, though with inconsistent findings.

    “On the other hand, some current psychotropic drugs, including antipsychotics and antidepressants, have anti-inflammatory effects, though with inconsistent findings15–19.”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [15] Maes, M. et al. Effects of atypical antipsychotics on the inflammatory response system in schizophrenic patients resistant to treatment with typical neuroleptics. Eur. Neuropsychopharmacol. 10, 119–124 (2000). source

      Not checked in the free run.

    • cites [16] Stefanovic, V. et al. The effect of antipsychotic drugs on nonspecific inflammation markers in the first episode of schizophrenia. Vojnosanit. Pregl. 72, 1085–1092 (2015). source

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    • cites [17] Zajkowska, Z. & Mondelli, V. First-episode psychosis: an inflammatory state? Neuroimmunomodulation 21, 102–108 (2014). source

      Not checked in the free run.

    • cites [18] Hannestad, J., DellaGioia, N. & Bloch, M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 36, 2452–2459 (2011). source

      Not checked in the free run.

    • cites [19] Lopresti, A. L. Cognitive behaviour therapy and inflammation: a systematic review of its relationship and the potential implications for the treatment of depression. Aust. N.Z. J. Psychiatry 51, 565–582 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisereasoning

    Without comparing studies from different disorders, the specificity of IRFs cannot be determined.

    “Without comparing the studies from different disorders, the specificity of IRFs cannot be determined.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    The literature selection followed the standard by PRISMA.

    “The literature selection followed the standard by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)28 (Supplementary Figure, SF1).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Moher, D., Liberati, A., Tetzlaff, J., Altman, D. G. & Group, P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 6, e1000097 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Trait-related findings are generally more reliable than state-related tests, which have consistencies ranging between 16% and 60%.

    “Trait-related findings are generally more reliable than state-related tests, which have consistencies ranging between 16% and 60%.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Premisenone given

    Acute and chronic inflammation can have very different impacts and consequences in aetiology and pathology.

    “Acute and chronic inflammation can have very different impacts and consequences in aetiology and pathology.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    Since many of the IRFs have limited studies, their effect sizes in Table 2 may be inflated.

    “Certainly, since many of the IRFs have limited studies, their effect sizes in this table may be inflated.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Genomic and epigenetic methods have been applied to adipose tissue and blood leucocytes, leading to the discovery of large inflammatory response networks.

    “Genomic and epigenetic methods have been applied to adipose tissue49 and blood leucocytes50, leading to the discovery of large inflammatory response networks.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Toubal, A., Treuter, E., Clement, K. & Venteclef, N. Genomic and epigenomic regulation of adipose tissue inflammation in obesity. Trends Endocrinol. Metab. 24, 625–634 (2013). source

      Not checked in the free run.

    • cites [50] Calvano, S. E. et al. A network-based analysis of systemic inflammation in humans. Nature 437, 1032–1037 (2005). source

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

    Premisecitation

    Regulation of inflammatory responses occurs at various levels including genetic, transcriptional, translational, protein modification and protein interaction, and involves many signalling pathways.

    “Regulation of inflammatory responses occurs at various levels including genetic, transcriptional, translational, protein modification and protein interaction, and involves many signalling pathways47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Hanada, T. & Yoshimura, A. Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev. 13, 413–421 (2002). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Meta-analyses can be misled by systematic bias in individual data.

    “Meta-analyses can be misled by systematic bias in individual data.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Many physical and psychological stressors, environmental insults including acute smoking, acute ethanol intoxication, long-term smoking, binge drinking, psychological stress, diet, air pollution and infection all can induce inflammation.

    “Many physical and psychological stressors, environmental insults including acute smoking56, acute ethanol intoxication57, long-term smoking58,59, binge drinking60, psychological stress61–63, diet64, air pollution65 and infection all can induce inflammation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [56] van der Vaart, H., Postma, D. S., Timens, W. & ten Hacken, N. H. Acute effects of cigarette smoke on inflammation and oxidative stress: a review. Thorax 59, 713–721 (2004). source

      Not checked in the free run.

    • cites [57] Neupane, S. P., Skulberg, A., Skulberg, K. R., Aass, H. C. & Bramness, J. G. Cytokine changes following acute ethanol intoxication in healthy men: a crossover study. Mediators Inflamm. 2016, 3758590 (2016). source

      Not checked in the free run.

    • cites [58] Rom, O., Avezov, K., Aizenbud, D. & Reznick, A. Z. Cigarette smoking and inflammation revisited. Respir. Physiol. Neurobiol. 187, 5–10 (2013). source

      Not checked in the free run.

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

    Premisecitation

    Multiplex protein assay has been used in studies of alcoholism, depression and autism, with up to 41 IRFs examined simultaneously.

    “It has been used in studies of alcoholism52, depression53 and autism54, with up to 41 IRFs examined simultaneously52,53.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [52] Manzardo, A. M., Poje, A. B., Penick, E. C. & Butler, M. G. Multiplex immunoassay of plasma cytokine levels in men with alcoholism and the relationship to psychiatric assessments. Int. J. Mol. Sci. 17, 472 (2016). source

      Not checked in the free run.

    • cites [53] Kiraly, D. D. et al. Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Transl. Psychiatry 7, e1065 (2017). source

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    • cites [54] Masi, A. et al. Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder. Mol. Autism 8, 63 (2017). source

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

    Premisecitation

    Multiplex protein assay is a technology getting more attention recently.

    “Multiplex protein assay is a technology getting more attention recently51.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Belzeaux, R. et al. How to: measuring blood cytokines in biological psychiatry using commercially available multiplex immunoassays. Psychoneuroendocrinology 75, 72–82 (2017). source

      Not checked in the free run.

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

    Study design and conductreasoning

    Since longitudinal studies are still rare, we can neither differentiate acute and chronic changes nor can we discern trait and state markers.

    “Since longitudinal studies are still rare, we can neither differentiate acute and chronic changes nor can we discern trait and state markers.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    Meta-analyses cannot recover signals that may be missed by original studies due to technical limitations.

    “At the same time, meta-analyses cannot recover signals that may be missed by original studies due to technical limitations.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    One GWAS of inflammation quantitative trait locus (QTL) identified some potential genetic regulators of inflammation.

    “One GWAS of inflammation quantitative trait locus (QTL) identified some potential genetic regulators of inflammation48.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Naitza, S. et al. A genome-wide association scan on the levels of markers of inflammation in Sardinians reveals associations that underpin its complex regulation. PLoS Genet. 8, e1002480 (2012). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Study design and conductreasoning

    Our study was built upon meta-analysis results, which represented the consensus of multiple individual studies, less influenced than original individual studies by biological or technical noises or variations from individual studies.

    “It should be noted that our study was built upon meta-analysis results, which represented the consensus of multiple individual studies, less influenced than original individual studies by biological or technical noises or variations from individual studies.”
    Quote in the paperNot a substantial claim

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

    Interpretationreasoning

    The other genes discovered from system-wide hunting may be better biomarker candidates.

    “The other genes discovered from system-wide hunting may be better biomarker candidates.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Candidate genes are generally not the top signals in genome-wide or system-wide studies.

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

    Interpretationnone given

    Among state-related studies, findings from first-episode SCZ studies are likely more reliable.

    “Among these state-related studies, findings from first-episode SCZ studies are likely more reliable.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisereasoning

    These experimental factors can impact data quality.

    “These experimental factors can impact data quality.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Postmortem brain data are valuable, and the PsychENCODE project brought more insights into the inflammation status of brains affected by SCZ, BD and ASD.

    “Postmortem brain data are valuable, and the PsychENCODE project72 brought more insights into the inflammation status of brains affected by SCZ, BD and ASD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Psych, E. C. et al. The PsychENCODE project. Nat. Neurosci. 18, 1707–1712 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The blood-brain barrier separates the central nervous system from peripheral circulation and responds to inflammation under its own regulation.

    “This may be particularly true in relation to the blood–brain barrier, which separates the central nervous system from peripheral circulation and responds to inflammation under its own regulation70,71.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [70] Sonar, S. A. & Lal, G. Blood-brain barrier and its function during inflammation and autoimmunity. J. Leukoc. Biol. 103, 839–853 (2018). source

      Not checked in the free run.

    • cites [71] Webb, A. A. & Muir, G. D. The blood-brain barrier and its role in inflammation. J. Vet. Intern. Med 14, 399–411 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Changes of IRFs are not limited to neuropsychiatric disorders; they are also reported in patients with cardiovascular and metabolic diseases, as well as cancer.

    “Changes of IRFs are not limited to neuropsychiatric disorders; they are also reported in patients with cardiovascular and metabolic diseases66, as well as cancer67,68.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Lopez-Candales A., Hernandez Burgos P. M., Hernandez-Suarez D. F., Harris D. Linking chronic inflammation with cardiovascular disease: from normal aging to the metabolic syndrome. J. Nat. Sci. 3, (2017).

      Not checked in the free run.

    • cites [67] Grivennikov, S. I., Greten, F. R. & Karin, M. Immunity, inflammation, and cancer. Cell 140, 883–899 (2010). source

      Not checked in the free run.

    • cites [68] Korniluk, A., Koper, O., Kemona, H. & Dymicka-Piekarska, V. From inflammation to cancer. Ir. J. Med. Sci. 186, 57–62 (2017). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Much remains to be learned about the specificity of each individual IRF as related to various psychiatric and non-psychiatric diseases.

    “Therefore, much remains to be learned about the specificity of each individual IRF as related to various psychiatric and non-psychiatric diseases.”
    Quote in the paperNot a substantial claim
45 of 45

  • The authors state this as an assumption.

    Stable findings are more likely to be reproducible than unstable ones.

    “Even though stability is not a true measure of reproducibility, we assume that stable findings are more likely to be reproducible than unstable ones.”

  • The authors state this as an assumption.

    All data including those tested only once will have better reproducibility.

    “We applied this filter to all data, assuming that all data including those tested only once will have better reproducibility.”

  • The paper relies on this without support.

    Candidate genes are generally not the top signals in genome-wide or system-wide studies.

    “Candidate genes are generally not the top signals in genome-wide or system-wide studies.”

  • The paper relies on this without support.

    Sample size is one of the major drivers of statistical power and is a limiting factor for many studies.

    “Sample size, one of the major drivers of statistical power, is a limiting factor for many studies.”

  • The paper relies on this without support.

    Genetic studies of candidate genes have produced a large number of false positives in small-sample studies due to loose statistical criteria.

    “Genetic studies of candidate genes have produced a large number of false positives in small-sample studies due to loose statistical criteria.”

  • The paper relies on this without support.

    Inflammation levels likely also fluctuate temporally due to environmental and circadian rhythm changes regardless of health status.

    “The inflammation levels likely also fluctuate temporally due to environmental and circadian rhythm changes regardless of health status.”

  • The paper relies on this without support.

    The clinical symptoms can change through the disease course while the diagnosis remains unchanged.

    “The clinical symptoms can change through the disease course while the diagnosis remains unchanged.”

  • The paper relies on this without support.

    Hundreds of genes or proteins are involved in immunity and inflammation regulation.

    “Hundreds of genes or proteins are involved in immunity and inflammation regulation and should be studied in relation to psychiatric disorders.”
8 of 8

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.

  • IGF-1 is labeled increased despite a negative effect size

    Major

    The MDD table labels IGF-1 as increased but gives it an effect size of −0.48. The figure caption defines negative effect sizes as decreased changes.

  • Chance agreement is 33%, not 11%

    Major

    With three equally likely states, two independent results agree in any one of the three states with probability 1/3, or about 33%. The stated 11% counts agreement in only one particular state, understating the chance-agreement baseline used to interpret consistency.

    Reported 11 · recomputed 33.333333

2 of 2

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Related

Authors
Yuan, N., Chen, Y., Xia, Y., Dai, J., & Liu, C.
Affiliations
Central South University (CN)
Corresponding author
Liu, Chunyu
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-09-18
Volume
9
Issue
1
Pages
233-233
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/s41398-019-0570-y
PMC
PMC6751188
OpenAlex
W2974338024
Cited by
428
References
81
Citations by year
2026: 44 · 2025: 77 · 2024: 80 · 2023: 59 · 2022: 76 · 2021: 59 · 2020: 31 · 2019: 2
FWCI
13.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • National Natural Science Foundation of China (31871276)
  • Central South University
  • Hunan University
  • Natural Science Foundation of Hunan Province
  • National Institutes of Health
  • National Institute on Aging (R21AG045789)
  • National Institute of Mental Health (U01MH116489, R01MH110920, U01MH103340)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
inflammation, inflammatory markers, mental illness, cross-disorder analysis, reproducibility, statistical power, underpowered studies, schizophrenia, bipolar disorder, autism spectrum disorder, major depressive disorder, post-traumatic stress disorder, sleep disorders, obsessive-compulsive disorder, suicide, IL-4, first-episode schizophrenia, meta-analysis
MeSH terms
Mental Disorders, Humans, Inflammation, Sensitivity and Specificity, Meta-Analysis as Topic, Reproducibility of Results, Biomarkers

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

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