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Cited by 171Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

C-Reactive protein as a biomarker for major depressive disorder?

Open access
Orsolini, Laura, Pompili, Simone, Tempia Valenta, Silvia, Salvi, Virginio, Volpe, Umberto·2022·International Journal of Molecular Sciences
DOI 10.3390/ijms23031616PMC PMC8836046
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Abstract

The etiopathogenesis of depression is not entirely understood. Several studies have investigated the role of inflammation in major depressive disorder. The present work aims to review the literature on the association between C-Reactive Protein (CRP) and depression. A systematic review was performed for the topics of ‘CRP’ and ‘depression’ using the PubMed database from inception to December 2021. Fifty-six studies were identified and included in the review. Evidence suggested the presence of dysregulation in the inflammation system in individuals with depression. In most studies, higher blood CRP levels were associated with greater symptom severity, a specific pattern of depressive symptoms, and a worse response to treatment. Moreover, about one-third of depressed patients showed a low-grade inflammatory state, suggesting the presence of a different major depressive disorder (MDD) subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis, which could benefit from monitoring of CRP levels and might potentially respond to anti-inflammatory treatments. This work provides robust evidence about the potential role of CRP and its blood levels in depressive disorders. These findings can be relevant to developing new therapeutic strategies and better understanding if CRP may be considered a valuable biomarker for depression.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review examines whether C-reactive protein (CRP) can serve as a biomarker for major depressive disorder. It concludes that elevated CRP is often associated with greater depressive symptom severity, specific symptom patterns, and worse treatment response, with about one-third of depressed patients showing low-grade inflammation, though causality remains unclear.

Key findings

  • Most included studies found a positive association between elevated CRP and depression, while others did not. In a UK Biobank case-control study, CRP was significantly higher in patients with depression than controls (2.4 mg/L vs. 2.1 mg/L, p < 0.001), and low-grade inflammation (CRP > 3 mg/L) was more frequent in MDD patients (21.1% vs. 16.8%).
  • Higher CRP levels were associated with greater symptom severity and specific symptoms, including fatigue (p < 0.001), restless sleep (p = 0.03), low energy (p = 0.02), feeling depressed (p = 0.04), somatic symptoms (p < 0.001), and poorer psychomotor speed/executive functioning.
  • About one-third of depressed patients showed a low-grade inflammatory state (CRP > 3.0 mg/L), suggesting a possible MDD subgroup with distinct etiopathogenesis, clinical course, treatment response, and prognosis; a cited meta-analysis reported low-grade inflammation in 27% of depressed patients and mildly elevated CRP in over half.
  • Elevated baseline CRP was associated with worse antidepressant outcomes in several studies. In one RCT, higher baseline CRP predicted lower baseline-to-week-8 HAMD-17 reduction in females (p < 0.0001) but not males (p = 0.632); another RCT found CRP differentially predicted response to escitalopram vs. nortriptyline (for CRP < 1 mg/L, MADRS improvement was 3 points higher with escitalopram; for higher CRP, 3 points higher with nortriptyline). A celecoxib augmentation RCT found no superior efficacy over placebo.

Methods

  • Systematic review conducted according to Cochrane Collaboration and PRISMA guidelines, searching PubMed from inception to 10 December 2021 using keywords for CRP/hs-CRP and depression.
  • Included human, English-language studies evaluating CRP levels in depressive/MDD/TRD patients with validated semi-structured interviews or rating scales; excluded reviews, meta-analyses, letters, book chapters, case reports/series, duplicates, studies of other biomarkers, depression comorbid with organic or psychiatric disorders, and in vitro/animal studies.
  • The search yielded 2229 results; the abstract states 56 studies were included, while the methods section states 97 met inclusion criteria. Quality assessment using modified Newcastle-Ottawa Scales rated 40 studies as “good” and 16 as “satisfactory.”

Limitations

  • Stated by the paper: included studies had methodological heterogeneity in design, sample sizes, inclusion/exclusion criteria, diagnostic tools, and recruitment settings; not all controlled for potential confounders; samples were dis-homogeneous in gender, race, and ethnicity; studies covered different illness phases; and antidepressant treatment was not always reported.
  • Evident from the text: there is a discrepancy between the abstract’s “56 studies” and the methods section’s “97 met the inclusion criteria,” while the quality assessment covers 56 studies; the review is narrative rather than meta-analytic, and many included studies are cross-sectional, limiting causal inference.

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

Integrity signals

Registry

Crossref · 10.3390/ijms23031616

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 110 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    In most studies, higher blood CRP levels were associated with a specific pattern of depressive symptoms.

    “a specific pattern of depressive symptoms”
    Quote in the paperSubstantial claim
  • Findingnone given

    About one-third of depressed patients showed a low-grade inflammatory state.

    “about one-third of depressed patients showed a low-grade inflammatory state”
    Quote in the paperSubstantial claim
  • Findingnone given

    In most studies, higher blood CRP levels were associated with greater symptom severity.

    “In most studies, higher blood CRP levels were associated with greater symptom severity”
    Quote in the paperSubstantial claim
  • Findingnone given

    In most studies, higher blood CRP levels were associated with a worse response to treatment.

    “and a worse response to treatment.”
    Quote in the paperSubstantial claim
  • Findingcitation

    Other retrieved studies did not confirm the association between elevated CRP levels and depression.

    “Conversely, other studies did not confirm this association [49,50,62,68,74,76,86,88,89].”
    Quote in the paperNot a substantial claim
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 35
  • The quote only partly states this claim. 3

  • Classified as probably not a substantial claim.

    Findingnone given

    Fifty-six studies were identified and included in the review.

    “Fifty-six studies were identified and included in the review.”
    Quote in the paperSubstantial claim

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

    Findingown data

    Literature search turned up 2229 results, out of which 97 met the inclusion criteria and were included in the analysis.

    “Literature search turned up 2229 results, out of which 97 met the inclusion criteria and were included in our analysis (Figure 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    40 studies were rated as good and 16 as satisfactory in the quality assessment.

    “Based on our judgment, 40 studies were rated as “good” studies [16,45,46,48,49,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,68,71,72,73,75,76,78,81,83,88,89,90,92,93,94,96,97,98,100] and 16 as “satisfactory” studies [47,50,67,69,70,74,77,79,80,82,84,85,86,87,91,95].”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The main misses in the quality assessment were lack of justified and satisfactory sample size calculation before the study, absence of non-respondent information, and in some studies lack of comparability.

    “The main misses were the lack of justified and satisfactory sample size calculation before the study, the absence of non-respondent information and, in some studies, the lack of comparability (Supplementary: Newcastle-ottawa quality assessment scale Tables S1–S4).”
    Quote in the paperNot a substantial claim

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

    Findingnone given

    Studies retrieved showed different phases of illness (acute, chronic, remitted, early-onset, late-onset, etc.).

    “Furthermore, from a clinical point of view, studies here retrieved showed different phases of illness (i.e., acute, and chronic phase, remitted patients, early-onset or late-onset patients, etc.).”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Several studies have investigated the role of SNPs in the association between CRP levels and depression with mixed results.

    “Furthermore, several studies have investigated the role of SNPs in the association between CRP levels and depression with mixed results [45,46,57,65,85,87].”
    Quote in the paperNot a substantial claim

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

    Findingcitation

    Another study observed no differences in CRP levels across different psychiatric diagnoses.

    “On the contrary, in another study no differences were observed in CRP levels across different psychiatric diagnoses [86].”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Interpretationreasoning

    This MDD subgroup could benefit from monitoring of CRP levels.

    “which could benefit from monitoring of CRP levels”
    Quote in the paperSubstantial claim

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

    Premisecitation

    An increase of blood-brain barrier permeability could be determined by severe stress and/or traumatic brain injury.

    “For instance, it has been suggested that an increase of the blood-brain barrier (BBB) permeability could be determined by severe stress and/or traumatic brain injury [35,36].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Prakash, 2015, Blood−brain barrier breakdown and neovascularization processes after stroke and traumatic brain injury, Curr. Opin. Neurol. source

      Not checked in the free run.

    • cites [36] Menard, 2017, Social stress induces neurovascular pathology promoting depression, Nat. Neurosci. source

      Not checked in the free run.

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

    Study design and conductnone given

    Disagreement was resolved by L.O.

    “Eventually, disagreement was resolved by L.O.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The low-grade inflammatory group also reported a poorer quality of life and an increase in guilty feelings, pessimism, concentration difficulties, and indecision.

    “They also reported a poorer quality of life and an increase in guilty feelings, pessimism, concentration difficulties, and indecision [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Foley, 2021, Clinical phenotypes of depressed patients with evidence of inflammation and somatic symptoms, Compr. Psychoneuroendocrinol. source

      Not checked in the free run.

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

    Premisecitation

    CRP is used in clinical practice mainly as a biomarker of infection, chronic disease state, and chronic low-grade inflammation.

    “and used in clinical practice mainly as a biomarker of infection, chronic disease state, and chronic low-grade inflammation [30,32].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [30] Nehring, S.M., Goyal, A., Bansal, P., and Patel, B.C. (2021, December 20). C Reactive Protein, StatPearls [Internet], Available online: http://www.ncbi.nlm.nih.gov/books/NBK441843/.

      Not checked in the free run.

    • cites [32] Joseph, 2015, Associations of high sensitivity C-reactive protein levels in schizophrenia and comparison groups, Schizophr. Res. source

      Not checked in the free run.

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

    Premisecitation

    Depression is often associated with other conditions where an increased inflammatory state has been documented, such as cardiovascular diseases, obesity, smoking status, and specific nutritional deficits.

    “Likewise, depression is often associated with other conditions where an increased inflammatory state has been documented, such as in cardiovascular diseases, obesity, smoking status, and specific nutritional deficits [24,25,26].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [24] Ridker, 2003, Clinical Application of C-Reactive Protein for Cardiovascular Disease Detection and Prevention, Circulation source

      Not checked in the free run.

    • cites [25] Berk, M., Williams, L.J., Jacka, F.N., O’Neil, A., Pasco, J.A., Moylan, S., Allen, N.B., Stuart, A.L., Hayley, A., and Byrne, M.L. (2013). So depression is an inflammatory disease, but where does the inflammation come from?. BMC Med., 11. source

      Not checked in the free run.

    • cites [26] Benros, 2014, A Nationwide Study on the Risk of Autoimmune Diseases in Individuals With a Personal or a Family History of Schizophrenia and Related Psychosis, Am. J. Psychiatry source

      Not checked in the free run.

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

    Study design and conductnone given

    Disagreement was resolved by discussion and consensus with a third member of the team.

    “The disagreement was resolved by discussion and consensus with a third member of the team (L.O.).”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    CRP is easily measured through a blood sample also in its high-sensitivity form (hs-CRP).

    “It is easily measured through a blood sample also in its high-sensitivity form (hs-CRP) [31]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] Windgassen, 2011, C-Reactive Protein and High-Sensitivity C-Reactive Protein: An Update for Clinicians, Postgrad. Med. source

      Not checked in the free run.

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

    Premisecitation

    CRP is a pentameric acute phase reactant protein secreted mainly by hepatocytes in response to activation of the innate humoral system.

    “CRP is a pentameric acute phase reactant protein secreted mainly by hepatocytes in response to the activation of the innate humoral system [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Nehring, S.M., Goyal, A., Bansal, P., and Patel, B.C. (2021, December 20). C Reactive Protein, StatPearls [Internet], Available online: http://www.ncbi.nlm.nih.gov/books/NBK441843/.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 14,821 Brazilian participants, no association between serum CRP levels, current depression, and use of antidepressants was found.

    “A large cross-sectional study conducted by Menezes et al., 2017, including 14,821 Brazilian participants of the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), investigated the possible association between CRP levels and depression [68]. Current depression was assessed by Clinical Interview Schedule-Revised (CIS-R) and participants were divided into three groups: (a) negative at CIS-R”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Goulart, 2017, Lack of association between depression and C-reactive protein level in the baseline of Longitudinal Study of Adult Health (ELSA-Brasil), J. Affect Disord. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In males, the variance in CRP levels was explained by shared environment and non-shared environment, while in females it was explained by genetic and non-shared environment.

    “Moreover, in males the variance in CRP levels was explained by shared environment and non-shared environment, while in females it was explained by genetic and non-shared environment [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Zavos, 2021, Relationship between CRP and depression: A genetically sensitive study in Sri Lanka, J. Affect. Disord. source

      Not checked in the free run.

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

    Premisecitation

    In 26,638 healthy adults, the association between hs-CRP levels and depression could be more likely explained by obesity status.

    “A recent large cross-sectional study assessing serum hs-CRP levels and depression symptoms using CESD, in 26,638 healthy adults, recruited at the Cooper Clinic in Dallas, Texas, reported an association between hs-CRP levels and depression which could be more likely explained by obesity status [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Khan, 2020, Association between C reactive protein and depression in a population of healthy adults: The Cooper Center Longitudinal Study, J. Investig. Med. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In 16 patients with atypical MDD, 93 with nonatypical MDD, and 1682 healthy individuals, subjects with atypical MDD exhibited higher CRP levels than those without MDD (mean difference = 1.56 mg/L) or nonatypical MDD (mean difference = 1.40 mg/L), even after adjusting for confounders, anxiety disorders, BMI, and smoking.

    “A US-population-based study coming from the National Health and Nutrition Examination Survey (NHANES), recruited 16 patients with atypical MDD, 93 with nonatypical MDD and 1682 healthy individuals, to measure CRP levels [58]. Subjects with atypical MDD exhibited higher CRP levels than those subjects without MDD (mean difference = 1.56 mg/L) or nonatypical MDD (mean difference = 1.40 mg/L) control,”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [58] Hickman, 2014, C-reactive protein is elevated in atypical but not nonatypical depression: Data from the National Health and Nutrition Examination Survey (NHANES) 1999–2004, J. Behav. Med. source

      Not checked in the free run.

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

    Premisecitation

    Neurovascular damage induced by peripheral myeloid cells, pro-inflammatory cytokines, and dysregulation of the complement pathways could be a further potential mechanism of action.

    “Furthermore, neurovascular damage induced by the peripheral myeloid cells, pro-inflammatory cytokines, and the dysregulation of the complement pathways could be a further potential mechanism of action [36,37,38].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [36] Menard, 2017, Social stress induces neurovascular pathology promoting depression, Nat. Neurosci. source

      Not checked in the free run.

    • cites [37] Aveleira, 2010, TNF-Signals Through PKC/NF-B to Alter the Tight Junction Complex and Increase Retinal Endothelial Cell Permeability, Diabetes source

      Not checked in the free run.

    • cites [38] Horn, 2018, Replication and reproducibility issues in the relationship between C-reactive protein and depression: A systematic review and focused meta-analysis, Brain Behav. Immun. source

      Not checked in the free run.

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

    Premisecitation

    Late-onset depression was associated with higher CRP levels.

    “The authors suggested that the late-onset depression was associated with higher CRP levels.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Mishra, 2018, C-reactive protein level in late-onset depression: A case–control study, Indian J. Psychiatry source

      Not checked in the free run.

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

    Study design and conductcitation

    This systematic review was performed according to the guidelines recommended by Cochrane Collaboration and PRISMA.

    “This systematic review was performed according to the guidelines recommended by Cochrane Collaboration [43] and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [44].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Higgins, J., and Green, S. (2009). Cochrane Handbook for Systematic Reviews of Interventions, The Cochrane Collaboration. source

      Not checked in the free run.

    • cites [44] Moher, D., Liberati, A., Tetzlaff, J., Altman, D.G., and PRISMA Group (2009). Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. PLoS Med., 6. source

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    Study design and conductown data

    Two authors independently read all included full-text papers using inclusion and exclusion criteria.

    “Independently, two authors (S.P. and S.T.V.) read all included full-text papers, by using the abovementioned inclusion and exclusion criteria.”
    Quote in the paperNot a substantial claim

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

    Study design and conductcitation

    SP and STV independently assessed the quality of included studies using modified versions of the Newcastle-Ottawa Quality Assessment Scale.

    “SP and STV independently assessed the quality of included studies using the modified versions of the Newcastle-Ottawa Quality Assessment Scale, adopted for cross-sectional (Table 2), case-control (Table 3), cohort studies (Table 4) and RCT (Table 5) [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Wells, G.A., Sher, B., O’Connel, D., Peterson, J., Welch, V., Losos, M., and Tugwell, P. (2014). The Newcastle-Ottawa Scale (NOS) for assessment the quality of nonrandomized studies in meta-analyses. Clin. Epidemiol.

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In subgroup analysis, the association was more prominent in the non-geriatric subsample (≤64 years), in males, in obese adults, and in those who did not report regular aerobic physical activity.

    “In the subgroups analysis, the association was more prominent in the non-geriatric subsample (i.e., ≤64 years), in males, in obese adults, and in those who did not report regular aerobic physical activity.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Cho, 2021, Association between high-sensitivity C-reactive protein levels and depression: Moderation by age, sex, obesity, and aerobic physical activity, J. Affect. Disord. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 43,896 adults, depression and higher CRP levels were both associated with worse executive functioning, even after covariates adjustment.

    “A cross-sectional study recruiting 43,896 adults examined the association between CRP levels and depression in terms of executive functioning [56]. MINI and Ruff Figural Fluency Test (RFFT) were administered to the sample. The study reported that depression and higher CRP levels were both associated with worse executive functioning, even after covariates adjustment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Alloy, 2021, Investigating whether a combination of higher CRP and depression is differentially associated with worse executive functioning in a cohort of 43,896 adults, Brain Behav. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CRP levels seem to be related to somatic symptoms and not to apathy.

    “In addition, CRP levels seem to be related to somatic symptoms [48] and not to apathy [91].”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In 1494 women, the hazard ratio for depression increased by 44% for each standard deviation increase in log-transformed hs-CRP, indicating that serum hs-CRP was an independent risk factor for de novo MDD in women.

    “A retrospective cohort study evaluating the association between CRP levels and increased risk of de novo MDD, recruiting 1494 women randomly selected and assessed through the Structured Clinical Interview for DS-IV-TR Research Version, Non-Patient edition (SCID-I/NP), reported a hazard ratio for depression increased by 44% for each standard deviation increase in log-transformed hs-CRP, indicating”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [93] Pasco, 2010, Association of high-sensitivity C-reactive protein with de novo major depression, Br. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 149 MDD patients treated with antidepressants for six weeks, baseline CRP levels were negatively and significantly associated with performance in the FTT and WCST after six weeks of treatment (respectively, p = 0.006 and p = 0.021), reporting a significant association between CRP levels and the domains of attention and executive cognitive function.

    “A cross-sectional study evaluated the association between CRP levels, depressive symptoms, and cognitive impairment in 149 MDD patients treated with antidepressants for six weeks [50]. Scale for Depression (HAM-D), Continuous Performance Test (CPT), Finger-Tapping Test (FTT), and Wisconsin Card-Sorting Test (WCST) were administered to the sample. Baseline CRP levels were negatively and”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [50] Chang, 2012, Treatment response and cognitive impairment in major depression: Association with C-reactive protein, Brain Behav. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Subjects who displayed persistently elevated CRP levels also had increased ORs of moderate/severe depression at 18 years, even though this association was not statistically significant.

    “Subjects who displayed persistently elevated CRP levels also had increased ORs of moderate/severe depression at 18 years, even though this association was not statistically significant.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Osimo, 2019, Longitudinal population subgroups of CRP and risk of depression in the ALSPAC birth cohort, Compr. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 4157 adults, the elevated CRP group (>3 mg/L) showed greater symptom connectivity, concentration, psychomotor difficulties, and treatment-resistant depression.

    “A recent network analysis investigated the association between inflammation and a specific depression phenotype [69]. PHQ-9 was administered to a sample of 4157 adults from the NHANES while hs-CRP levels were measured to identify possible inflammatory phenotypes of depression [69]. The elevated CRP group (>3 mg/L) showed greater symptom connectivity, concentration, psychomotor difficulties, and”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [69] Moriarity, 2020, Inflammatory phenotype of depression symptom structure: A network perspective, Brain, Behav. Immun. source

      Not checked in the free run.

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

    Premisecitation

    CRP levels were not associated with age and about 30% of the sample showed CRP level >3 mg/L.

    “In addition, the authors reported that CRP levels were not associated with age and about 30% of the sample showed CRP level > 3 mg/L [86].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [86] Socha, 2016, Levels of C-reactive protein (CRP) in elderly patients with unipolar depression—Case control analysis, Nord. J. Psychiatry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In US participants, social integration and CRP levels were found to operate independently in their association with depressive symptoms only for the white population but not the black or the Hispanic one.

    “A cross-sectional study evaluated the association between social integration, race/ethnicity, inflammation, and depressive symptoms in US participants through the NHANES survey [51]. Participants were administered PHQ-8 and measured hs-CRP levels. Social integration and CRP levels were found to operate independently in their association with depressive symptoms only for the white population but”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Chapman, 2020, Racial and ethnic differences in the associations between social integration, C-reactive protein and depressive symptoms, SSM-Popul. Health source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Evidence suggests that CRP levels may vary among gender and/or ethnic differences.

    “Evidence suggested also that CRP levels may vary among gender and/or ethnic differences.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    CRP levels were higher among men who had a recent episode of depression and who had recurrent depression.

    “Moreover, CRP levels were higher among men who had a recent episode of depression and who had recurrent depression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Ford, 2004, Depression and C-reactive protein in US adults: Data from the Third National Health and Nutrition Examination Survey, Arch. Intern. Med. source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In 596 participants, elevated CRP levels were independently associated with depressive symptoms in elderly Koreans, but this association was observed only in men both before and after adjusting for covariates.

    “Similar findings were found in another Korean cross-sectional study, in which 596 participants (224 men and 345 women) from the Korean Social life, Health and Aging Project Health Examination (KSHAP-HE) cohort, were assessed for depressive symptoms through the CES-D and for serum CRP levels [71]. The authors reported that elevated CRP levels were independently associated with depressive symptoms”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Song, 2015, Association between C reactive protein level and depressive symptoms in an elderly Korean population: Korean Social Life, Health and Aging Project, BMJ Open source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 231 individuals with MDD, higher CRP levels were significantly associated with greater overall depressive symptoms severity, which was significant among women but not in men.

    “A population-based study investigating the role of gender in the association between CRP levels and depressive severity, recruited 231 individuals (142 female and 89 men) with MDD from the Genome-Based Therapeutics Drugs Depression (GENDEP) study [63]. The subjects were assessed for hs-CRP levels and depression using the Montgomery Åsberg Depression Rating Scale (MADRS). Findings showed that”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [63] Tansey, 2017, Association between C-reactive protein (CRP) with depression symptom severity and specific depressive symptoms in major depression, Brain, Behav. Immun. source

      Not checked in the free run.

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

    Interpretationcitation

    The occurrence of multiple depressive episodes seems to improve later CRP levels, possibly by increasing the risk for cardiovascular and metabolic disease.

    “and the occurrence of multiple depressive episodes seems to improve later CRP levels, maybe by increasing the risk for cardiovascular and metabolic disease [89].”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In 5909 patients, CRP levels were associated with symptoms of fatigue (p < 0.001), restless sleep (p = 0.03), low energy (p = 0.02) and feeling depressed (p = 0.04).

    “A study involving 5909 patients aimed at investigating the possible association between inflammation and specific depressive symptoms, found that CRP levels were associated with symptoms of fatigue (p < 0.001), restless sleep (p = 0.03), low energy (p = 0.02) and feeling depressed (p = 0.04) [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] White, 2017, Association of inflammation with specific symptoms of depression in a general population of older people: The English Longitudinal Study of Ageing, Brain Behav. Immun. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A higher prevalence of depression was reported in men with high CRP levels, and the association was not observed in women.

    “Lee et al. (2019) [64] reported a higher prevalence of depression in men with high CRP levels. The association was not observed in women.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lee et al. (2019) [64] source

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In 563 adolescent girls, serum hs-CRP levels were 0.61 (0.30-0.88) mg/L in the non-depressed group, 0.97 (0.50-1.82) mg/L in the group with a mild depression score, 1.04 (0.57-1.60) mg/L in those with a moderate depression score, and 0.84 (0.45-2.64) mg/L in girls with severe depression (p < 0.001).

    “A cross-sectional study included 563 adolescent girls, aged 12–18 years, aimed at investigating the association between hs-CRP levels and depressive symptomatology assessed through BDI-II [72]. Serum hs-CRP levels were 0.61 (0.30–0.88) mg/L in the non-depressed group, 0.97 (0.50–1.82) mg/L in the group with a mild depression score, 1.04 (0.57–1.60) mg/L in those with a moderate depression score,”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Tabatabaeizadeh, 2018, There is an association between serum high-sensitivity C-reactive protein (hs-CRP) concentrations and depression score in adolescent girls, Psychoneuroendocrinology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In 6914 participants, a history of MDD was associated with elevated CRP levels and this association was much stronger among men than women.

    “Ford and Erlinger (2004) [55] found in 6914 participants (3154 men and 3760 women), recruited from the NHANES survey, that a history of MDD was associated with elevated CRP levels and that this association was much stronger among men than women.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Ford, 2004, Depression and C-reactive protein in US adults: Data from the Third National Health and Nutrition Examination Survey, Arch. Intern. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    hs-CRP levels seem to be an independent risk factor of depression and elevated hs-CRP levels could be a predictor of the onset of MDD.

    “Moreover, hs-CRP levels seem to be an independent risk factor of depression and elevated hs-CRP levels could be a predictor of the onset of MDD [93].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    This corroborates the hypothesis that inflammation might contribute to developing some types of depression, but not all of them.

    “corroborating the hypothesis that inflammation might contribute to developing some types of depression, but not all of them [75].”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    Antidepressant treatment has not always been reported in the included studies.

    “Finally, antidepressant treatment has not been always reported (i.e., patients with stable antidepressant treatment, patients with not stable antipsychotic medication, free-drug patients, naïve-drug patients, not specific antidepressant medication,”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Anti-inflammatory action of SSRI and SNRIs has been hypothesized through which they can indirectly reduce depressive symptoms, although findings are still contradictory.

    “Indeed, anti-inflammatory action of SSRI and serotonin and noradrenaline inhibitors (SNRIs) has been hypothesized through which they can indirectly reduce depressive symptoms [124,125,126], even though the findings are still contradictory [77].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [124] Tuglu, 2003, Increased serum tumor necrosis factor-alpha levels and treatment response in major depressive disorder, Psychopharmacology source

      Not checked in the free run.

    • cites [125] Mosiołek, A., Pięta, A., Jakima, S., Zborowska, N., Mosiołek, J., and Szulc, A. (2021). Effects of Antidepressant Treatment on Peripheral Biomarkers in Patients with Major Depressive Disorder (MDD). J. Clin. Med., 10. source

      Not checked in the free run.

    • cites [126] Lydholm, 2019, Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: Meta-analysis of clinical trials, Acta Psychiatr. Scand. source

      Not checked in the free run.

    • cites [77] Zwicker, 2018, Genetic disposition to inflammation and response to antidepressants in major depressive disorder, J. Psychiatr. Res. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    This may point out that a chronic low-grade inflammation could be associated with a different MDD subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis.

    “This may point out that a chronic low-grade inflammation could be associated with a different MDD subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis [13,72,121].”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Patients with elevated CRP levels seem to be associated with a greater symptom severity, a specific pattern of depressive symptoms, and a worse treatment response.

    “Indeed, patients with elevated CRP levels seem to be associated with a greater symptom severity, specific pattern of depressive symptoms and a worst treatment response, although it is still unclear if inflammation may contribute directly to the pathogenesis of depression or whether it may rather be a consequence of the illness and covariates interaction.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hanug and Lin (2007) reported persisted high CRP levels in BD-I after adjusting for covariates and not in MDD.

    “The same results come from a study by Hanug and Lin (2007) [59] that reported persisted high CRP levels in BD-I after adjusting for covariates and not in MDD.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Hanug and Lin (2007) [59]

      Not checked in the free run.

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

    Premisecitation

    Chang et al. (2017) suggested that CRP levels of 621.6 mg/L could discriminate between MDD and BD-II in both depressed and euthymic states.

    “Chang et al. (2017) [79] suggested that CRP levels of 621.6 mg/L could discriminate between MDD and BD-II in both depressed and euthymic states.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Chang et al. (2017) [79]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A recent meta-analysis including 13,541 depressed patients and 155,728 controls confirmed that in 27% of depressive patients there was low-grade inflammation (CRP > 3.0 mg/L) and over half showed mildly elevated CRP.

    “Data were confirmed by a recent meta-analysis that included 13,541 depressed patients and 155,728 controls [121]. In 27% of the depressive patients there was a low-grade of inflammation (i.e., CRP > 3.0 mg/L) and over half of the patients showed a mildly elevated CRP level [121].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [121] Osimo, 2019, Prevalence of low-grade inflammation in depression: A systematic review and meta-analysis of CRP levels, Psychol. Med. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    This MDD subgroup may benefit from monitoring of CRP levels and might potentially respond to anti-inflammatory treatments.

    “by suggesting the presence of a different MDD subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis which may benefit of a monitoring of CRP levels and might potentially respond to anti-inflammatory treatments.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The presence of a low-grade inflammatory state suggests a different MDD subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis.

    “by suggesting the presence of a different MDD subgroup with a distinct etiopathogenesis, clinical course, treatment response, and prognosis which may benefit of a monitoring of CRP levels and might potentially respond to anti-inflammatory treatments.”
    Quote in the paperSubstantial claim
54 of 54

  • The paper relies on this without support.

    The etiopathogenesis of depression is highly complex and not entirely understood.

    “However, the etiopathogenesis of depression is highly complex and not entirely understood.”
1 of 1

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?

  • Patients with elevated inflammatory markers often show better outcomes with anti-inflammatory treatments and poorer responses to psychotherapy.

    “Patients with elevated inflammatory markers often show better outcomes with anti-inflammatory treatments and poorer responses to psychotherapy, supporting stratified therapeutic approaches (Shi et al., 2022; Jha et al., 2017; Orsolini et al., 2022; Pan et al., 2022).”

    From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Orsolini et al., 2022

    The Discussion (page unavailable) suggests that patients with elevated CRP might be candidates for anti-inflammatory treatment, but calls the findings contradictory. Results §3.6 (page unavailable) reports that baseline inflammation did not predict benefit from celecoxib augmentation. The passages address antidepressant response, not poorer response to psychotherapy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

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.

  • Conflicting counts of included studies

    Major

    The abstract says 56 studies were included, but the methods say 97 met the inclusion criteria and were included in the analysis. The quality assessment also accounts for 56 studies (40 good and 16 satisfactory).

  • Study sex counts exceed the stated total

    Minor

    The stated male and female counts sum to 915, rather than 764 individuals.

    Reported 764 · recomputed 915

  • Study reporting an association is listed among studies finding none

    Minor

    The account of study [88] says baseline high CRP was associated with depressive-symptom severity, but the discussion lists [88] among studies that did not confirm a positive association between elevated CRP and depression.

  • Korean cohort sex counts do not match the total

    Minor

    The stated numbers of men and women sum to 569, not 596 participants.

    Reported 596 · recomputed 569

  • Northern Finland cohort sex counts do not match the total

    Minor

    The stated male and female counts sum to 5469, not 5269 participants.

    Reported 5269 · recomputed 5469

  • Inflammatory group is compared with itself

    Minor

    The study is described as comparing patients with inflammation against those without it, but the reported finding compares the inflammatory group with "the group with inflammation."

  • Discriminating CRP threshold changes units

    Minor

    The results give the threshold as 621.6 ng/mL, whereas the discussion gives the same threshold as 621.6 mg/L. Those units differ by a factor of 1000.

7 of 7

The citation lists haven’t been fetched yet

References 139 · Cited by 171

Research works printed but not linked: 2

  1. Nehring, S.M., Goyal, A., Bansal, P., and Patel, B.C. (2021, December 20). C Reactive Protein, StatPearls [Internet], Available online: http://www.ncbi.nlm.nih.gov/books/NBK441843/.
  2. Salgado, 2018, A new theory of depression based on the serotonin/kynurenine relationship and the hypothalamicpituitary-adrenal axis, Biomedica, 38, 437

Authors
Orsolini, L., Pompili, S., Tempia Valenta, S., Salvi, V., & Volpe, U.
Affiliations
  • Marche Polytechnic University (IT)
  • Unit of Clinical Psychiatry, Department of Neurosciences/DIMSC, Polytechnic University of Marche, 60126 Ancona, Italy
Corresponding author
Volpe, Umberto
ORCID
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2022-01-30
Volume
23
Issue
3
Pages
1616
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms23031616
PMC
PMC8836046
OpenAlex
W4210717906
Semantic Scholar
42c6d7b0cf121c6d91099d0d14d0a911706e3ae8
Cited by
171
References
139
Citations by year
2026: 45 · 2025: 50 · 2024: 40 · 2023: 27 · 2022: 9
FWCI
2.38
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Università Politecnica delle Marche (Università Politecnica delle Marche) (submittedVersion, cc-by)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Keywords
C-reactive protein, major depressive disorder, inflammation, biomarkers, depression severity, treatment response, low-grade inflammation, anti-inflammatory therapy
MeSH terms
C-Reactive Protein, Depressive Disorder, Major, Major Depressive Disorder, Humans, Biomarkers, Up-Regulation, Precision Medicine, Patient Acuity

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 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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