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Cited by 331Tryptophan and brain disordersStress Responses and CortisolChild Abuse and Trauma

Clustering of depression and inflammation in adolescents previously exposed to childhood adversity

Open access
Miller, Gregory E., Cole, Steve W.·2012·Biological Psychiatry
DOI 10.1016/j.biopsych.2012.02.034PMC PMC3493164
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Abstract

Background There is mounting interest in the hypothesis that inflammation contributes to the pathogenesis of depression, and underlies depressed patients’ vulnerability to comorbid medical conditions. However, research on depression and inflammation has yielded conflicting findings, fostering speculation that these conditions associate only in certain subgroups, like patients exposed to childhood adversity. Methods We studied 147 adolescent females. All were in good health at baseline, but at high risk for depression by virtue of family history and/or cognitive vulnerability. Subjects were assessed every six months for 2.5 years, undergoing diagnostic interviews and venipuncture for measurement of two inflammatory biomarkers, C-reactive protein (CRP) and interleukin-6 (IL-6). Childhood adversity was indexed by parental separation, low socioeconomic status, and familial psychopathology. Results Multilevel models indicated that childhood adversity promotes clustering of depression and inflammation. Among subjects exposed to high childhood adversity, the transition to depression was accompanied by increases in both CRP and IL-6. The higher CRP remained evident six months later, even after depressive symptoms had abated. These lingering effects were bi-directional, such that among subjects with childhood adversity, high IL-6 forecasted depression six months later, even after concurrent inflammation was considered. This coupling of depression and inflammation was not apparent in subjects without childhood adversity. Conclusions These findings suggest that childhood adversity promotes the formation of a neuroimmune pipeline, wherein inflammatory signaling between the brain and periphery is amplified. Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications.

Integrity signals

Registry

Crossref · 10.1016/j.biopsych.2012.02.034

Cites

41 of 41 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

17 of 33 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    In the Dunedin cohort, depressed subjects who were negative for maltreatment were statistically indistinguishable from controls.

    “However, depressed subjects who were negative for maltreatment were statistically indistinguishable from controls.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Danese, 2008, Elevated inflammation levels in depressed adults with a history of childhood maltreatment, Arch Gen Psychiatry source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.
  • Premisecitation

    In the Dunedin cohort, greater inflammation was also seen among subjects exposed to maltreatment alone.

    “Greater inflammation was also seen among subjects exposed to maltreatment alone.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Danese, 2008, Elevated inflammation levels in depressed adults with a history of childhood maltreatment, Arch Gen Psychiatry source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.
  • Premisecitation

    Recent studies have found that depression and inflammation cluster in persons who experienced childhood adversity.

    “Consistent with this possibility, recent studies have found that depression and inflammation cluster in persons who experienced childhood adversity.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [14] Danese, 2008, Elevated inflammation levels in depressed adults with a history of childhood maltreatment, Arch Gen Psychiatry source
    • cites [17] Pace, 2006, Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress, Am J Psychiatry source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.
  • Interpretationcitation

    The findings contribute to an emerging consensus that childhood social conditions are important in establishing lifecourse trajectories that eventuate in differential vulnerability to disease and disability.

    “More broadly, the findings contribute to an emerging consensus that childhood social conditions are important in establishing lifecourse trajectories that eventuate in differential vulnerability to disease and disability (15, 36).”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [15] Miller, 2011, Psychological stress in childhood and susceptibility to the chronic diseases of aging: Moving toward a model of behavioral and biological mechanisms, Psychol Bull source
    • cites [36] Hertzman, 2010, How experience gets under the skin to create gradients in developmental health, Annu Rev Public Health source
    • The authors state this as an assumption: The outcome (depression status) follows an underlying Bernoulli distribution.
  • Premisecitation

    In the Dunedin cohort, composite inflammation scores were higher among subjects with a maltreatment history and recent depression, relative to controls with neither.

    “Composite scores were higher among subjects with a maltreatment history and recent depression, relative to controls with neither.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Danese, 2008, Elevated inflammation levels in depressed adults with a history of childhood maltreatment, Arch Gen Psychiatry source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.
  • Classified as probably not a substantial claim. 25
  • May combine two claims. 23

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

    Premisecitation

    Other kinds of childhood adversity, such as low socioeconomic status, have been linked to low-grade inflammation in adulthood, as well as mental and physical health problems across the lifespan.

    “Previous research in this area has focused on maltreatment, but other kinds of childhood adversity, such as low socioeconomic status (SES), have been linked to low-grade inflammation in adulthood (18–20), as well as mental and physical health problems across the lifespan (21).”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [18] Miller, 2009, Low early-life social class leaves a biological residue manifest by decreased glucocorticoid and increased pro-inflammatory signaling, Proc Natl Acad Sci U S A source
    • cites [19] Taylor, 2006, Relationship of early life stress and psychological functioning to adult C-reactive protein in the coronary artery risk development in young adults study, Biol Psychiatry source
    • cites [20] Tabassum, 2008, Effects of socioeconomic position on inflammatory and hemostatic markers: A life-course analysis in the 1958 British birth cohort, Am J Epidemiol source
    • cites [21] Shonkoff, 2009, Neuroscience, molecular biology, and the childhood roots of health disparities: building a new framework for health promotion and disease prevention, JAMA source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    The study examined alternative explanations by statistically controlling for plausible demographic and biobehavioral confounders.

    “We examined alternative explanations by statistically controlling for plausible demographic and biobehavioral confounders (29).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [29] O'Connor, 2009, To assess, to control, to exclude: Effects of biobehavioral factors on circulating inflammatory markers, Brain Behav Immun source

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

    Premisecitation

    Severe childhood stressors promote the formation of a neural-immune pipeline, wherein inflammatory cytokine signaling between the brain and the periphery is markedly amplified.

    “This hypothesis grows out of mounting evidence that severe childhood stressors promote the formation of a neural-immune pipeline (15), wherein inflammatory cytokine signaling between the brain and the periphery is markedly amplified (16).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Miller, 2011, Psychological stress in childhood and susceptibility to the chronic diseases of aging: Moving toward a model of behavioral and biological mechanisms, Psychol Bull source

      In “Mechanisms of Embedding” (page unavailable), the paper proposes that childhood stress could alter connections between the nervous and immune systems and reports evidence that stress can change those connections. It presents the childhood-stress mechanism as a possibility, rather than establishing that severe childhood stressors form a neural-immune pipeline. The amplified cytokine-signaling clause is attached to a different citation and is not judged here. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • cites [16] Irwin, 2011, Reciprocal regulation of the neural and innate immune systems, Nat Rev Immunol source

      The Abstract and ‘Neural influences on disease’ section describe reciprocal brain–immune signaling and report that acute stress can increase circulating pro-inflammatory cytokines. They do not establish that cytokine signaling between the brain and periphery is markedly amplified; the childhood-stressor premise is attached to a different citation. (LLM, conf=0.84)

      Experimental — accuracy not yet measured
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.

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

    Premisecitation

    Studies of remitted depressed patients show that in some of them CRP remains elevated after symptom remission.

    “These findings converge with and extend studies of remitted depressed patients, in some of whom CRP remains elevated after symptom remission (34).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [34] Kling, 2007, Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A, Biol Psychiatry source

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

    Premisecitation

    Depressive symptoms further exacerbate inflammation and contribute to the pathogenesis of various diseases of aging, many of which involve excessive cytokine activity.

    “These symptoms are thought to further exacerbate inflammation and, in doing so, contribute to the pathogenesis of various diseases of aging (6–8), many of which involve excessive cytokine activity (9, 10).”
    Quote in the paperNot a substantial claim1 of 5 sources checked
    • cites [6] Miller, 2006, Turning up the heat: Inflammation as a mechanism linking chronic stress, depression, and heart disease, Curr Dir Psychol Sci source
    • cites [7] Antoni, 2006, The influence of bio-behavioural factors on tumour biology: Pathways and mechanisms, Nat Rev Cancer source

      The passage indexed as Abstract (page unavailable) says pro-inflammatory cytokines might promote tumorigenesis, supporting the cytokine-related point for cancer. It does not establish that many diseases of aging involve excessive cytokine activity. In the citing sentence, the claim that symptoms exacerbate inflammation has separate citations (6–8), so it is not assessed against this source. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [8] Irwin, 2002, Psychoneuroimmunology of depression: Clinical implications, Brain Behav Immun source
    • cites [9] Nathan, 2010, Nonresolving inflammation, Cell source
    • cites [10] Libby, 2011, Progress and challenges in translating the biology of atherosclerosis, Nature source

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

    Study design and conductcitation

    The study followed published guidelines recommending exclusion of CRP >10 mg/L observations from analyses.

    “Thus, we followed published guidelines that recommend excluding such observations from analyses (30).”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [30] Yeh, 2003, Coming of age of C-reactive protein: Using inflammation markers in cardiology, Circulation source

      The opening section and “CRP as a Clinical Test in Cardiovascular Practices” recommend repeating CRP tests above the stated threshold to rule out infection or other inflammatory processes. They do not recommend excluding those observations from analyses, so the cited paper supports the threshold-related caution but not the claimed analytical exclusion. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Premisecitation

    Stress triggers the release of pro-inflammatory cytokines, which access the central nervous system, eliciting neurobehavioral adjustments that manifest as depressive symptoms.

    “Most center around the notion that stress triggers the release of pro-inflammatory cytokines, which access the central nervous system, eliciting neurobehavioral adjustments that manifest as depressive symptoms (3–5).”
    Quote in the paperSubstantial claim3 of 3 sources checked
    • cites [3] Miller, 2009, Inflammation and its discontents: The role of cytokines in the pathophysiology of major depression, Biol Psychiatry source
    • cites [4] Dantzer, 2008, From inflammation to sickness and depression: When the immune system subjugates the brain, Nat Rev Neurosci source

      The review’s ‘Immune signals from periphery to brain’ passage describes how peripheral cytokine signals reach the brain, and its discussion of cytokine-induced depression links those signals to depressive symptoms. It does not establish the claim’s initiating step—that stress triggers the release of pro-inflammatory cytokines; the pathways described here concern peripheral immune responses, including infection. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
    • cites [5] Slavich, 2010, Black sheep get the blues: A psychobiological model of social rejection and depression, Neurosci Biobehav Rev source

  • May combine two claims.

    Interpretationcitation

    The scenario that the observed clustering arises from maltreatment rather than mundane adversity is somewhat unlikely, given prospective data showing that both impoverished and maltreated children go on to have more adult inflammation, and these effects are statistically independent.

    “We view this scenario as somewhat unlikely, given prospective data showing that both impoverished and maltreated children go on to have more adult inflammation, and these effects are statistically independent (45).”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [45] Danese, 2009, Adverse childhood experiences and adult risk factors for age-related disease: Depression, inflammation, and clustering of metabolic risk markers, Arch Pediatr Adolesc Med source

      Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    The CRP findings emerged in only a small group of subjects and were not paralleled by effects for IL-6 or continuous CRP (p's = .14 and .22, respectively).

    “All that said, these findings emerged in only a small group of subjects, and were not paralleled by effects for IL-6 or continuous CRP (see Table 3; p’s = .14 and .22, respectively.)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Alcohol and contraceptive use were stable over follow-up, with intra-class correlations of .72 and .65.

    “Preliminary analyses revealed that alcohol and contraceptive use were stable over follow-up (intra-class correlations = .72, 65).”
    Quote in the paperSubstantial claim

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

    Findingown data

    At study entry, CRP and IL-6 values were well within normal limits, except 8 subjects with CRP > 3 mg/L.

    “At study entry, CRP and IL-6 values were well within normal limits, except 8 subjects with CRP > 3 mg/L.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

  • May combine two claims.

    Findingown data

    Significant cross-level interactions were observed for CRP, both as a continuous and categorical outcome, and for IL-6 (p's from .001-.05).

    “As Table 2 indicates, significant cross-level interactions were observed for CRP, both as a continuous and categorical outcome, and for IL-6 (p’s from .001–.05).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

  • May combine two claims.

    Findingown data

    Childhood adversity was not directly related to the inflammatory biomarkers, either at baseline (p's > .84) or over follow-up (p's > .15).

    “Childhood adversity was not directly related to the inflammatory biomarkers, either at baseline (p’s > .84) or over follow-up (p’s > .15).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Findingown data

    Few subjects received anti-depressant medication for their symptoms (12.5%), and childhood adversity was unrelated to the likelihood of doing so (p = .70).

    “Few subjects received anti-depressant medication for their symptoms (12.5%), and childhood adversity was unrelated to the likelihood of doing so (p = .70).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.

  • May combine two claims.

    Findingown data

    Among subjects exposed to higher levels of childhood adversity, the transition to depression was accompanied by a relative increase in CRP and a greater likelihood of having CRP ≥ 3 mg/L.

    “Among subjects exposed to higher levels of childhood adversity, the transition to depression was accompanied by a relative increase in CRP (middle panel), and a greater likelihood of having CRP ≥ 3 mg/L (lower panel), placing them in the elevated risk category by AHA/CDC guidelines.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Findingown data

    Of the 53 total episodes catalogued, 25 met criteria for Major Depression and 28 for Minor Depression.

    “Of the 53 total episodes catalogued, 25 met criteria for Major Depression and 28 for Minor Depression.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    The study involved 147 adolescent females who mirrored the broader Vancouver population in terms of racial/ethnic background.

    “The study involved 147 adolescent females who mirrored the broader Vancouver population in terms of racial/ethnic background (Table 1).”
    Quote in the paperNot a substantial claim

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

    Findingown data

    On six occasions subjects had CRP > 10 mg/L.

    “On six occasions subjects had CRP > 10 mg/L.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

  • May combine two claims.

    Findingown data

    10.7% of the depressed subjects in the high childhood adversity category showed this pattern, whereas none of the other subjects did.

    “In fact, 10.7% of the depressed subjects in the high childhood adversity category showed this pattern, whereas none of the other subjects did.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Findingown data

    Waist-hip ratio increased over time (B = .024, SE = .013, p = .06).

    “By contrast, analyses showed that WHR increased over time (B = .024, SE = .013, p = .06), so we modeled it as a time-varying covariate.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    We observed a relatively small number of depressive episodes, and they were generally of brief duration and mild severity.

    “We observed a relatively small number of depressive episodes, and they were generally of brief duration and mild severity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After outliers were removed, both CRP and IL-6 showed roughly normal distributions.

    “After the outliers were removed, both CRP and IL-6 showed roughly normal distributions.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

  • May combine two claims.

    Findingown data

    Neither the duration nor severity of depressive episodes varied by childhood adversity.

    “Neither the duration (p = .65) nor severity of episodes (p = .49) varied by childhood adversity.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.

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

    Findingown data

    Only 3 subjects were regular smokers at any point in the study, so there was too little variance to justify modeling smoking effects.

    “However, only 3 subjects were regular smokers at any point in the study, so there was too little variance to justify modeling its effects.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Depression heightens risks for morbidity and mortality from chronic diseases associated with aging, including autoimmune, metabolic, and cardiovascular conditions.

    “Additionally, depression heightens risks for morbidity and mortality from chronic diseases associated with aging, including autoimmune, metabolic, and cardiovascular conditions (2).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Evans, 2005, Mood disorders in the medically ill: Scientific review and recommendations, Biol Psychiatry source

  • May combine two claims.

    Interpretationreasoning

    Once established, the neuroimmune pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications.

    “Once established, this pipeline leads to a coupling of depression and inflammation, which may contribute to later affective difficulties and biomedical complications.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

  • May combine two claims.

    Interpretationown data

    Anti-inflammatory treatments would be ineffective for patients without childhood adversity, as depression and inflammation tend to dissociate in them.

    “Our findings suggest that such treatments would be ineffective for patients without childhood adversity, as depression and inflammation tend to dissociate in them.”
    Quote in the paperSubstantial claim
    • The authors state this as an assumption: The outcome (depression status) follows an underlying Bernoulli distribution.

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

    Study design and conductnone given

    From observational data like these, inferences about causality cannot be made.

    “From observational data like these, inferences about causality cannot be made.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Whenever an interview suggested a possible disorder, the entire team reviewed the SCID by audiotape and derived a consensus diagnosis.

    “Whenever an interview suggested a possible disorder, the entire team reviewed the SCID by audiotape, and derived a consensus diagnosis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In a study of immune responses to acute mental stress, adults who were currently depressed and had been maltreated in childhood exhibited larger stress-related increases in plasma IL-6 than healthy controls, as well as enhanced DNA binding of nuclear factor-kappa B.

    “In this work, adults who were currently depressed, and had been maltreated in childhood, exhibited showed larger stress-related increases in plasma IL-6 than healthy controls, as well as enhanced DNA binding of the pro-inflammatory transcription factor nuclear factor-kappa B.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Pace, 2006, Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress, Am J Psychiatry source
    • Rests on an assumption: The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Study design and conductreasoning

    Five IL-6 values > 10 pg/ml were excluded from analyses.

    “For similar reasons we excluded five IL-6 values > 10 pg/ml.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Interpretationreasoning

    The increased exposure to inflammatory mediators may also heighten these patients' vulnerability to comorbid medical conditions, like diabetes, autoimmune disorders, and cardiovascular disease.

    “The increased exposure to inflammatory mediators may also heighten these patients’ vulnerability to comorbid medical conditions, like diabetes, autoimmune disorders, and cardiovascular disease.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The outcome (depression status) follows an underlying Bernoulli distribution.

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

    Interpretationreasoning

    This clustering has implications for our understanding of depression's pathogenesis, the mechanisms by which it confers susceptibility to comorbidities, and possibly for targeted application of anti-inflammatory therapy.

    “This clustering has implications for our understanding of depression’s pathogenesis, the mechanisms by which it confers susceptibility to comorbidities, and possibly for targeted application of anti-inflammatory therapy.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: The outcome (depression status) follows an underlying Bernoulli distribution.

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

    Study design and conductown data

    Re-analysis of the data including outliers yielded identical findings.

    “Re-analysis of the data including outliers yielded identical findings.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

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

    Study design and conductown data

    The median weighted kappa for independent SCID ratings was .69.

    “The median weighted kappa was .69.”
    Quote in the paperNot a substantial claim

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

    Study design and conductreasoning

    In the absence of maltreatment data, it remains uncertain whether the observed clustering arises from the "mundane" adversity captured by the index versus unmeasured but co-occurring experiences with maltreatment.

    “In the absence of such data, it remains uncertain whether the observed clustering arises from the “mundane” adversity captured by our index, versus unmeasured but co-occuring experiences with maltreatment.”
    Quote in the paperNot a substantial claim

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

    Study design and conductown data

    The intra-class correlation for HRSD ratings was .64.

    “The intra-class correlation for HRSD ratings was .64.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Research has documented associations between syndromal depression and inflammatory biomarkers, as well as a graded, linear relation of the latter with dysphoric symptoms.

    “Research has documented associations between syndromal depression and inflammatory biomarkers, as well as a graded, linear relation of the latter with dysphoric symptoms (11).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Raison, 2006, Cytokines sing the blues: Inflammation and the pathogenesis of depression, Trends Immunol source
38 of 38

  • The paper relies on this without support.

    The childhood adversity index formed from parental age, familial disruption, parental affective illness, low household education, and limited economic resources validly captures the childhood adversity relevant to depression-inflammation clustering.

    “Using data from baseline interviews, we formed a childhood adversity index. One point was assigned for each of the following risks: (a) birth to a teenage mother, who was < 20 years old at delivery, (b) familial disruption before age 15, caused by the death of a parent or divorce; or separation from a parent that lasted more than one year; (c) a history of affective illness in parents/guardians; (”

  • The paper relies on this without support.

    CRP and IL-6 measurements validly index the inflammatory processes relevant to depression.

    “CRP was measured by high-sensitivity chemiluminescence on an Immulite 2000 (Diagnostic Products Corporation, Los Angeles, CA).”
    “IL-6 was measured in duplicate by commercially available high-sensitivity ELISA (R&D Systems; Minneapolis, MN).”

  • The authors state this as an assumption.

    The outcome (depression status) follows an underlying Bernoulli distribution.

    “Using multilevel models that assumed an underlying Bernoulli distribution of the outcome”
3 of 3

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?

  • Adolescents without a history of early life stress exhibited reductions in CRP as their depressive symptoms abated, whereas those with a history of early life stress showed no such association, instead exhibiting elevations in CRP that persisted in the absence of depression.

    “whereas adolescents in this study who did not have a history of early life stress exhibited reductions in CRP as their depressive symptoms abated, those with a history of early life stress showed no such association, instead exhibiting elevations in CRP that persisted in the absence of depression”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller & Cole, 2012

    Split into 2 atoms — 1 confirmed, 0 partially supported, 1 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Checked by a reasoning model — may be wrong.

    Experimental — accuracy not yet measured

  • Most findings, but not all, suggest a robust correlation between ELS/CT and adult CRP levels.

    “Most findings, but not all, suggest a robust correlation between ELS/CT and adult CRP levels (165, 166, 170, 199–202).”

    From Developmental Trajectories of Early Life Stress and Trauma: A Narrative Review on Neurobiological Aspects Beyond Stress System Dysregulation (2019) · cites this paper as [202]

    The Results (Preliminary Analyses; page not provided) say childhood adversity was not directly related to inflammatory biomarkers in this study of adolescent females. The Concurrent Analyses instead find higher CRP when adversity-exposed participants transitioned to depression. The paper also reports an adult study using an inflammation composite that included CRP, but it does not establish that most findings show a robust correlation between childhood adversity and adult CRP levels. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Engagement of these pathways may become self-promoting as a result of neuro-inflammatory sensitization and thus drive heightened levels of inflammation and exaggerated perceptions of social threat for months or years after the original social-environmental impetus has passed.

    “engagement of these pathways may become selfpromoting as a result of neuro-inflammatory sensitization and thus drive heightened levels of inflammation and exaggerated perceptions of social threat for months or years after the original social-environmental impetus has passed”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller & Cole, 2012

    Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • After years of sustained engagement, these dynamics may confer increased risk for inflammation-related disorders, infection, accelerated biological aging, and early mortality.

    “Finally, after years of sustained engagement, these dynamics may confer increased risk for inflammation-related disorders, infection, accelerated biological aging, and early mortality”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller & Cole, 2012

    The Discussion (page not provided) says that lingering inflammatory effects may increase vulnerability to diabetes, autoimmune disorders, and cardiovascular disease, supporting the proposed risk of inflammation-related disorders. The paper does not link these dynamics to infection or accelerated biological aging. It mentions mortality associated with depression and chronic diseases of aging, but does not specifically establish early mortality from the sustained dynamics described in the claim. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Adolescent women at elevated risk for depression with a history of common early life stress had greater increases in both IL-6 and CRP when becoming depressed than their counterparts without a history of these early life stressors.

    “adolescents with a history of more common forms of early life stress, such as low socioeconomic status or parental separation, had greater increases in both IL-6 and CRP when becoming depressed than their counterparts without a history of these early life stressors”

    From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as G. E. Miller & Cole, 2012

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.

  • Lagged IL-6 finding claims an unreported inflammation adjustment

    Minor

    The abstract says IL-6 predicted depression after concurrent inflammation was considered. The described lagged model instead adjusts for prior depression status and other covariates; it does not list concurrent inflammation as an adjustment.

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Related

Authors
Miller, G. E., & Cole, S. W.
Affiliations
  • University of British Columbia (CA)
  • University of California, Los Angeles (US)
Corresponding author
Miller, Gregory E.
ORCID
Venue
Biological Psychiatry
Publisher
Elsevier BV
Published
2012-07
Volume
72
Issue
1
Pages
34-40
ISSN
0006-3223 (ISSN-L)
DOI
10.1016/j.biopsych.2012.02.034
PMC
PMC3493164
OpenAlex
W2037158815
Semantic Scholar
40b98ebc414e522ac6f151029266ea66acadc3e5
Cited by
331
References
42
Citations by year
2026: 6 · 2025: 23 · 2024: 20 · 2023: 22 · 2022: 20 · 2021: 28 · 2020: 32 · 2019: 30 · 2018: 29 · 2017: 20 · 2016: 36 · 2015: 34 · 2014: 11 · 2013: 16 · 2012: 4
FWCI
6.46
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Biological Psychiatry (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Canadian Institutes of Health Research (67191)
  • National Alliance for Research on Schizophrenia and Depression Brain and Behavior Research Fund
  • Heart and Stroke Foundation of Canada
  • National Institute of Child Health and Human Development (R01 HD058502)
Topics
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Social Sciences › Psychology › Clinical Psychology › Child Abuse and Trauma
Keywords
childhood adversity, depression, inflammation, C-reactive protein, interleukin-6, adolescents, adolescent girls, parental separation, low socioeconomic status, inflammatory markers, comorbidities
MeSH terms
Adolescent, Adult, C-Reactive Protein, Canada, Depressive Disorder, Female, Follow-Up Studies, Humans, Inflammation, Interview, Psychological, Life Change Events, Psychiatric Status Rating Scales, Risk Factors, Biomarkers, Interleukin-6, Cluster Analysis, Young Adult

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 2026-10-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

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