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Cited by 323Tryptophan and brain disordersTreatment of Major DepressionStress Responses and Cortisol

Association of depressive disorders, depression characteristics and antidepressant medication with inflammation

Open access
Vogelzangs, N, Duivis, H E, Beekman, A T F, Kluft, C, Neuteboom, J, Hoogendijk, W, Smit, J H, de Jonge, P +1 more·2012·Translational Psychiatry
DOI 10.1038/tp.2012.8PMC PMC3309556
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Abstract

Growing evidence suggests that immune dysregulation may be involved in depressive disorders, but the exact nature of this association is still unknown and may be restricted to specific subgroups. This study examines the association between depressive disorders, depression characteristics and antidepressant medication with inflammation in a large cohort of controls and depressed persons, taking possible sex differences and important confounding factors into account. Persons (18-65 years) with a current (N = 1132) or remitted (N = 789) depressive disorder according to DSM-IV criteria and healthy controls (N = 494) were selected from the Netherlands Study of Depression and Anxiety. Assessments included clinical characteristics (severity, duration and age of onset), use of antidepressant medication and inflammatory markers (C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α)). After adjustment for sociodemographics, currently depressed men, but not women, had higher levels of CRP (1.33 versus 0.92 mg l(-1), P<0.001, Cohen's d = 0.32) and IL-6 (0.88 versus 0.72 pg ml(-1), P = 0.01, Cohen's d = 0.23) than non-depressed peers. Associations reduced after considering lifestyle and disease indicators--especially body mass index--but remained significant for CRP. After full adjustment, highest inflammation levels were found in depressed men with an older age of depression onset (CRP, TNF-α). Furthermore, inflammation was increased in men using serotonin-norepinephrine reuptake inhibitors (CRP, IL-6) and in men and women using tri- or tetracyclic antidepressants (CRP), but decreased among men using selective serotonin reuptake inhibitors (IL-6). In conclusion, elevated inflammation was confirmed in depressed men, especially those with a late-onset depression. Specific antidepressants may differ in their effects on inflammation.

AI snapshot

Written from the paper’s full text.

TL;DR

In a large NESDA cohort, current depressive disorder was associated with higher CRP and IL-6 in men but not women, with associations attenuated after lifestyle and disease adjustment. Inflammation was especially elevated in depressed men with later age of onset and in users of SNRI, TCA, or TeCA, whereas SSRI use was associated with lower IL-6 in men.

Key findings

  • Among men, current depressive disorder was associated with higher CRP (1.33 vs 0.92 mg l−1, P<0.001, Cohen’s d=0.32) and IL-6 (0.88 vs 0.72 pg ml−1, P=0.01, Cohen’s d=0.23) after sociodemographic adjustment; after full adjustment, CRP remained higher (1.29 vs 1.04 mg l−1, P=0.02, Cohen’s d=0.21) and IL-6 was marginally higher (0.87 vs 0.76 pg ml−1, P=0.10, Cohen’s d=0.15).
  • No associations between depressive disorders and inflammatory markers were found in women before or after adjustment.
  • In currently depressed men, older age of depression onset was associated with higher CRP and TNF-α; women with more severe depressive symptoms had higher TNF-α, while duration was not associated.
  • Compared with medication-free depressed persons, men using SNRI had higher CRP (1.98 vs 1.21 mg l−1, P=0.02, d=0.44) and IL-6 (1.37 vs 0.91 pg ml−1, P=0.01, d=0.49); men using TCA/TeCA had higher CRP (2.05 vs 1.21 mg l−1, P=0.02, d=0.48); men using SSRI had lower IL-6 (0.70 vs 0.91 pg ml−1, P=0.02, d=−0.32); women using TCA/TeCA showed a trend for higher CRP (2.10 vs 1.53 mg l−1, P=0.08, d=0.28).

Methods

  • Cross-sectional analysis within the Netherlands Study of Depression and Anxiety (NESDA), baseline 2004–2007, ages 18–65; participants had current depressive disorder (N=1132), remitted depressive disorder (N=789), or were healthy controls (N=494), with 2415 persons in the present sample after exclusions for missing inflammatory markers.
  • Depressive disorders were assessed by CIDI according to DSM-IV; depression characteristics included IDS severity, Life Chart duration, and age of onset; inflammatory markers were CRP, IL-6, and TNF-α from fasting morning blood samples.
  • Analyses used analyses of (co)variance and linear regression, testing sex interactions and presenting three models: unadjusted, sociodemographic-adjusted, and additionally adjusted for lifestyle and disease factors including BMI, smoking, alcohol, physical activity, cardiovascular disease, diabetes, chronic diseases, statins, and anti-inflammatory medication.

Limitations

  • The authors state that the cross-sectional design prevents inferences about direction: longitudinal studies are needed to determine whether immune dysregulation precedes or results from depression or treatment.
  • The authors state that circulating inflammatory markers show high intra-individual variation, which could explain the modest overall associations.
  • Evident from the text: antidepressant findings are observational and may reflect indication differences, as the authors note that persons using SNRI, TCA, or TeCA may differ from SSRI users and medication-free depressed persons, and that elevated inflammation before treatment may predict non-response.

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

Integrity signals

Registry

Crossref · 10.1038/tp.2012.8

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

17 of 64 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured

  • Premisecitation

    Inflammation levels fluctuate throughout female life according to hormonal changes owing to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens.

    “Inflammation levels fluctuate throughout female life according to hormonal changes owing to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens,6, 7, 8”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [6] Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999; 100: 717–722. source

      The Abstract (page not specified) reports that postmenopausal hormone treatment increased C-reactive protein and decreased soluble E-selectin, supporting the claim that estrogen use can change inflammation-sensitive markers. The paper does not establish fluctuations throughout female life or effects of menstrual-cycle phase, hormonal contraceptives, or menopause itself. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Dreon DM, Slavin JL, Phinney SD . Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003; 73: 1245–1252. source
    • cites [8] Jilma B, Dirnberger E, Loscher I, Rumplmayr A, Hildebrandt J, Eichler HG et al. Menstrual cycle-associated changes in blood levels of interleukin-6, alpha1 acid glycoprotein, and C-reactive protein. J Lab Clin Med 1997; 130: 69–75. source
  • Premisecitation

    Late-onset depression has been associated with family history of vascular disease and atherosclerosis.

    “In addition, late-onset depression has been associated with family history of vascular disease7 and atherosclerosis.11, 12”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [7] Dreon DM, Slavin JL, Phinney SD . Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003; 73: 1245–1252. source
    • cites [11] Seldenrijk A, van Hout HP, van Marwijk HW, de GE, Gort J, Rustemeijer C et al. Carotid atherosclerosis in depression and anxiety: Associations for age of depression onset. World J Biol Psychiatry 2011; 12: 549–558. source
    • cites [12] Smith PJ, Blumenthal JA, Babyak MA, Doraiswamy PM, Hinderliter A, Hoffman BM et al. Intima-media thickness and age of first depressive episode. Biol Psychol 2009; 80: 361–364. source
  • Premisecitation

    Subclinical vascular dysregulations, such as atherosclerosis, have been found to relate to late-onset depression.

    “subclinical vascular dysregulations, such as atherosclerosis, have been found to relate to late-onset depression.11, 12”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [11] Seldenrijk A, van Hout HP, van Marwijk HW, de GE, Gort J, Rustemeijer C et al. Carotid atherosclerosis in depression and anxiety: Associations for age of depression onset. World J Biol Psychiatry 2011; 12: 549–558. source
    • cites [12] Smith PJ, Blumenthal JA, Babyak MA, Doraiswamy PM, Hinderliter A, Hoffman BM et al. Intima-media thickness and age of first depressive episode. Biol Psychol 2009; 80: 361–364. source
  • Interpretationcitation

    SSRI might have a beneficial effect on inflammation.

    “we found, like others,14 that SSRI might have a beneficial effect on inflammation”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [14] Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741. source

      The Translational Implications section reports that antidepressant treatment was associated with decreased inflammatory markers in 11 of 20 studies. It does not establish that finding specifically for SSRIs, so the drug-class specificity of the claim is unsupported. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
  • Premisecitation

    Hormonal changes throughout female life (menstrual cycle, hormonal contraceptives, menopause, estrogens) greatly impact inflammation levels.

    “Hormonal changes throughout female life due to phase of menstrual cycle, use of hormonal contraceptives, menopause and use of estrogens greatly impact on inflammation levels,6, 7, 8”
    Quote in the paperSubstantial claim1 of 3 sources checked
    • cites [6] Cushman M, Legault C, Barrett-Connor E, Stefanick ML, Kessler C, Judd HL et al. Effect of postmenopausal hormones on inflammation-sensitive proteins: the Postmenopausal Estrogen/Progestin Interventions (PEPI) Study. Circulation 1999; 100: 717–722. source

      The Abstract reports that postmenopausal hormone therapy substantially increased C-reactive protein but decreased soluble E-selectin, supporting an effect of estrogen-containing therapy on inflammation-sensitive markers. The paper does not establish effects of menstrual-cycle phase, hormonal contraceptives, or menopause itself, so it does not support the claim across female life stages. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [7] Dreon DM, Slavin JL, Phinney SD . Oral contraceptive use and increased plasma concentration of C-reactive protein. Life Sci 2003; 73: 1245–1252. source
    • cites [8] Jilma B, Dirnberger E, Loscher I, Rumplmayr A, Hildebrandt J, Eichler HG et al. Menstrual cycle-associated changes in blood levels of interleukin-6, alpha1 acid glycoprotein, and C-reactive protein. J Lab Clin Med 1997; 130: 69–75. source
  • Classified as probably not a substantial claim. 36
  • May combine two claims. 21
  • The quote only partly states this claim. 1

  • Classified as probably not a substantial claim.

    Premisecitation

    Recent results of two large studies suggest that use of antidepressants, mainly tricyclic antidepressants, is associated with elevated inflammation levels.

    “In contrast, recent results of two large studies suggest that use of antidepressants, mainly tricyclic antidepressants (TCA), is associated with elevated inflammation levels.15”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [15] Hamer M, Batty GD, Marmot MG, Singh-Manoux A, Kivimaki M . Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain Behav Immun 2011; 25: 168–173. source

  • May combine two claims.

    Interpretationcitation

    Prolonged hyperactivity of the HPA-axis could result in blunted anti-inflammatory responses to glucocorticoids, resulting in increased inflammation.

    “prolonged hyperactivity of the hypothalamus–pituitary–adrenal-axis could result in blunted anti-inflammatory responses to glucocorticoids resulting in increased inflammation.35, 36”
    Quote in the paperNot a substantial claim1 of 2 sources checked
    • cites [35] Miller GE, Cohen S, Ritchey AK . Chronic psychological stress and the regulation of pro-inflammatory cytokines: a glucocorticoid-resistance model. Health Psychol 2002; 21: 531–541. source
    • cites [36] Wirtz PH, von KR, Schnorpfeil P, Ehlert U, Frey K, Fischer JE . Reduced glucocorticoid sensitivity of monocyte interleukin-6 production in male industrial employees who are vitally exhausted. Psychosom Med 2003; 65: 672–678. source

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

    Premisecitation

    A distinct etiology in late-onset versus early-onset depression was found by Kendler et al.

    “A distinct etiology in late-onset versus early-onset depression was also found by Kendler et al.28”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Kendler KS, Fiske A, Gardner CO, Gatz M . Delineation of two genetic pathways to major depression. Biol Psychiatry 2009; 65: 808–811. source

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

    Premisecitation

    Depression with an early age of onset was associated with a family history of depression, whereas late-onset depression was associated with a family history of vascular disease.

    “depression with an early age of onset was associated with a family history of depression, whereas late-onset depression was associated with a family history of vascular disease.”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [28] Kendler KS, Fiske A, Gardner CO, Gatz M . Delineation of two genetic pathways to major depression. Biol Psychiatry 2009; 65: 808–811. source

  • May combine two claims.

    Premisecitation

    The metabolic syndrome and in particular visceral fat have been bidirectionally associated with depression in late life, specifically in men.

    “The metabolic syndrome and in particular visceral fat have been bidirectionally associated with depression in late life,31, 32 specifically in men.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [31] Vogelzangs N, Kritchevsky SB, Beekman AT, Newman AB, Satterfield S, Simonsick EM et al. Depressive symptoms and change in abdominal obesity in older persons. Arch Gen Psychiatry 2008; 65: 1386–1393. source

      The Discussion (page unavailable) reports that depressive symptoms predicted increased abdominal obesity, particularly visceral fat, in older persons. The Results, under “Sex and race differences” (page unavailable), report the association in men and white women, not specifically men. The paper does not establish a bidirectional association or report an association between depression and metabolic syndrome. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [32] Vogelzangs N, Kritchevsky SB, Beekman AT, Brenes GA, Newman AB, Satterfield S et al. Obesity and onset of significant depressive symptoms: results from a prospective community-based cohort study of older men and women. J Clin Psychiatry 2010; 71: 391–399. source

      The Results and Discussion report that high visceral fat predicted the onset of depressive symptoms in older men, and the Discussion describes a reciprocal association between abdominal obesity and depressive symptoms based in part on other longitudinal findings. The paper does not establish a bidirectional association specifically for men, and it does not examine metabolic syndrome as such. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Specific genes might underlie both increased inflammation and depression.

    “specific genes might underlie both increased inflammation and depression, as several inflammation-related genes have been associated with susceptibility to major depression.44”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [44] Wong ML, Dong C, Maestre-Mesa J, Licinio J . Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response. Mol Psychiatry 2008; 13: 800–812. source

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

    Premisecitation

    Two recent large studies found that use of antidepressants, mainly TCA, was associated with elevated inflammation levels.

    “two recent large studies found that use of antidepressants, mainly TCA, was associated with elevated inflammation levels.15”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [15] Hamer M, Batty GD, Marmot MG, Singh-Manoux A, Kivimaki M . Anti-depressant medication use and C-reactive protein: results from two population-based studies. Brain Behav Immun 2011; 25: 168–173. source

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

    Premisecitation

    Behavioral interventions such as exercise improve depressive symptoms to some degree.

    “as well as to improve depressive symptoms to some degree,54”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [54] Mead GE, Morley W, Campbell P, Greig CA, McMurdo M, Lawlor DA . Exercise for depression. Cochrane Database Syst Rev 2009; CD004366. source

  • May combine two claims.

    Premisecitation

    IDO activation catalyzes tryptophan to kynurenine, thereby indirectly reducing serotonin availability.

    “which catalyzes tryptophan, the precursor of serotonin, to kynurenine, thereby indirectly reducing the availability of serotonin.43”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [43] Dantzer R, O'Connor JC, Freund GG, Johnson RW, Kelley KW . From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci 2008; 9: 46–56. source

      Box 1 (page unavailable) states that IDO degrades tryptophan through the kynurenine pathway and that tryptophan is a serotonin precursor. The discussion following Box 1 says reduced tryptophan has the potential to affect serotonin synthesis, but does not establish that IDO activation necessarily reduces serotonin availability. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

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

    Premisecitation

    Earlier studies found decreases in inflammatory marker levels after antidepressant treatment, mainly SSRI.

    “Earlier studies found decreases in inflammatory marker levels after antidepressant treatment, mainly SSRI (see ref. 14 for an overview)”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [14] Miller AH, Maletic V, Raison CL . Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry 2009; 65: 732–741. source

      The Translational Implications section reports decreases in inflammatory markers after antidepressant treatment in 11 of 20 studies, supporting the overview of earlier findings. The passage does not say that those studies mainly used SSRIs, so that qualification is unsupported by our copy. (LLM, conf=0.86)

      Experimental — accuracy not yet measured

  • May combine two claims.

    Findingown data

    Sex hormone use, menstrual cycle phase and postmenopausal status were strongly associated with inflammation levels, but additional adjustment for these factors did not change the results for women.

    “Although sex hormone use, menstrual cycle phase and postmenopausal status were strongly associated with inflammation levels, additional adjustment for these factors did not change the results for women.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Sex interactions were found in the association between antidepressant medication group (no medication, SSRI, SNRI, TCA/TeCA) and CRP and IL-6, but not TNF-α.

    “Sex interactions in the association between antidepressant medication group (no medication, SSRI, SNRI and TCA/TeCA) and inflammatory markers were found (CRP: P-interaction=0.06, IL-6: P-interaction=0.02; TNF-α: P-interaction=0.90).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    BMI weakened the depression-inflammation associations most, followed by number of other chronic diseases.

    “Overall, BMI weakened the associations most, followed by number of other chronic diseases.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given

    Inflammation levels in persons with cardiovascular disease were 1.84 mg l−1 for CRP and 1.06 pg ml−1 for IL-6.

    “For comparison, inflammation levels in persons with cardiovascular disease were 1.84 mg l−1 for CRP and 1.06 pg ml−1 for IL-6”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    For current depressive disorders, sex interactions were found for CRP and IL-6, but not TNF-α.

    “For current depressive disorders, sex interactions were found for CRP (P-interaction<0.001) and IL-6 (P-interaction=0.009), but not TNF-α (P-interaction=0.99).”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Findingown data

    No associations were found between antidepressant medication group and TNF-α.

    “No associations were found for TNF-α.”
    Quote in the paperNot a substantial claim

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

    Findingown data

    Women had higher levels of CRP, but lower levels of IL-6 and TNF-α than men.

    “In addition, women had higher levels of CRP, but lower levels of IL-6 and TNF-α than men.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In men, older age, less education, smoking, heavy or non-drinking, higher BMI, lower physical activity, cardiovascular disease, diabetes, higher number of other chronic diseases, statin use and use of anti-inflammatory medication were associated with higher levels of at least one inflammatory marker.

    “In men, older age, less education, smoking, heavy or non-drinking, higher BMI, lower physical activity, cardiovascular disease, diabetes, higher number of other chronic diseases, statin use and use of anti-inflammatory medication were associated with higher levels of at least one of the inflammatory markers (data not shown).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The Pearson correlations between inflammatory markers were modest and somewhat higher in men than in women.

    “The Pearson's correlations between inflammatory markers were modest, likely reflecting only partial biological overlap, and somewhat higher in men (CRP-IL-6: r=0.40; CRP-TNF-α: r=0.22; IL-6–TNF-α: r=0.17) than in women (CRP-IL-6: r=0.28; CRP-TNF-α: r=0.10; IL-6–TNF-α: r=0.09).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Correlations between inflammatory markers were only modest and were highest between CRP and IL-6.

    “Correlations between inflammatory markers were only modest and were highest between CRP and IL-6.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisenone given

    A large part of previous studies has been conducted within older populations.

    “Furthermore, a large part of previous studies has been conducted within older populations.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The present effect sizes are comparable to those reported by the meta-analysis of Howren, in which stronger effects were found for studies using clinical interviews compared with studies using self-report questionnaires.

    “These effect sizes are comparable to those reported by the meta-analysis of Howren,4 in which stronger effects were found for studies using clinical interviews compared with studies using self-report questionnaires.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Howren,4

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisereasoning

    The effect estimate after a more complete adjustment including several lifestyle and disease factors is not entirely clear.

    “The effect estimate after a more complete adjustment (including several lifestyle and disease factors) is not entirely clear.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    It is largely unknown whether specific depression characteristics indicate immune dysregulation.

    “Second, it is largely unknown whether specific depression characteristics indicate immune dysregulation.3”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK et al. A meta-analysis of cytokines in major depression. Biol Psychiatry 2010; 67: 446–457. source

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

    Study design and conductnone given

    The NESDA research protocol was approved by the Ethical Committee of participating universities, and all respondents provided written informed consent.

    “The research protocol was approved by the Ethical Committee of participating universities, and after complete description of the study all respondents provided written informed consent.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Most of the larger studies examining depression and inflammation have used depressive symptoms questionnaires instead of assessing psychiatric diagnoses by means of clinical interviews.

    “Also, most of the larger studies examining depression and inflammation have used depressive symptoms questionnaires instead of assessing psychiatric diagnoses by means of clinical interviews.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Currently available antidepressant medications largely target monoamine pathways, but treatment of depression is only effective in about a third to a half of patients.

    “Currently available antidepressant medications largely target monoamine pathways, but treatment of depression is only effective in about a third to a half of patients.1, 2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Pigott HE, Leventhal AM, Alter GS, Boren JJ . Efficacy and effectiveness of antidepressants: current status of research. Psychother Psychosom 2010; 79: 267–279. source
    • cites [2] Rush AJ, Trivedi MH, Wisniewski SR, Nierenberg AA, Stewart JW, Warden D et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry 2006; 163: 1905–1917. source

  • Classified as probably not a substantial claim.

    Premisecitation

    Several studies showed that antidepressant treatment, mainly selective serotonin reuptake inhibitors, was associated with decreases in inflammatory markers.

    “As summarized by Miller et al.,14 several studies showed that antidepressant treatment, mainly selective serotonin reuptake inhibitors, was associated with decreases in inflammatory markers.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Miller et al.,14

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Classified as probably not a substantial claim.

    Premisecitation

    Stronger, weaker or similar effects have been found for women compared with men for different inflammatory markers.

    “Stronger, weaker or similar effects have been found for women compared with men for different inflammatory markers.4, 5”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Howren MB, Lamkin DM, Suls J . Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009; 71: 171–186. source
    • cites [5] Danner M, Kasl SV, Abramson JL, Vaccarino V . Association between depression and elevated C-reactive protein. Psychosom Med 2003; 65: 347–356. source

  • Classified as probably not a substantial claim.

    Premisecitation

    The vascular depression hypothesis suggests that vascular damage in the brain predisposes to late-onset depression.

    “the vascular depression hypothesis, which suggests that vascular damage in the brain predisposes to late-onset depression.29”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] Alexopoulos GS, Meyers BS, Young RC, Campbell S, Silbersweig D, Charlson M . Vascular depression' hypothesis. Arch Gen Psychiatry 1997; 54: 915–922. source

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

    Study design and conductnone given

    The study had adequate adjustment for potential confounders.

    “adequate adjustment for potential confounders”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Analyses were adjusted for a large set of covariates, taking possible differences in lifestyle or disease factors into account.

    “we adjusted our analyses for a large set of covariates and have therefore taken possible differences in lifestyle or disease factors into account.”
    Quote in the paperSubstantial claim

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

    Study design and conductown data

    The study assessed multiple inflammatory markers.

    “assessment of multiple inflammatory markers”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductown data

    Associations between depressive disorders and inflammatory markers were examined with three models: unadjusted, adjusted for sociodemographics, and additionally adjusted for lifestyle and disease factors.

    “To take the effects of important confounding factors into account, three different models were tested: unadjusted, adjusted for sociodemographics (sex, age and education) and additionally adjusted for lifestyle and disease (smoking status, alcohol intake, BMI, physical activity, cardiovascular disease, diabetes, number of other chronic diseases, statins and anti-inflammatory medication).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Depression has been associated with dysregulation of the autonomic nervous system.

    “and the autonomic nervous system.34”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Licht CM, de Geus EJ, Zitman FG, Hoogendijk WJ, Van DR, Penninx BW . Association between major depressive disorder and heart rate variability in the Netherlands Study of Depression and Anxiety (NESDA). Arch Gen Psychiatry 2008; 65: 1358–1367. source

  • May combine two claims.

    Interpretationreasoning

    Inflammation is involved in depression, but it is still unclear which part of the immune system is most critically involved.

    “This seems to suggest that inflammation is indeed involved in depression, but it is still unclear which part of the immune system is most critically involved.”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The study used clinical diagnoses of depression.

    “clinical diagnoses of depression”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    The study had the ability to examine the role of depression characteristics and antidepressant medication.

    “the ability to examine the role of depression characteristics and antidepressant medication”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Circulating levels of inflammatory markers show a high degree of intra-individual variation.

    “we assessed circulating levels of inflammatory markers, which show a high degree of intra-individual variation”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Reduced hippocampal volume is seen in depression.

    “which is also seen in depression.41”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Campbell S, Marriott M, Nahmias C, MacQueen GM . Lower hippocampal volume in patients suffering from depression: a meta-analysis. Am J Psychiatry 2004; 161: 598–607. source

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

    Premisecitation

    Increased sympathetic nervous system activity has been associated with increased inflammation.

    “increased sympathetic nervous system activity38 have been associated with increased inflammation.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Johnson JD, Campisi J, Sharkey CM, Kennedy SL, Nickerson M, Greenwood BN et al. Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 2005; 135: 1295–1307. source

  • May combine two claims.

    Study design and conductcitation

    The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders and was administered by specially trained research staff.

    “The CIDI is a highly reliable and valid instrument for assessing depressive and anxiety disorders18 and was administered by specially trained research staff.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Wittchen HU . Reliability and validity studies of the WHO--Composite International Diagnostic Interview (CIDI): a critical review. J Psychiatr Res 1994; 28: 57–84. source

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

    Premisecitation

    Pro-inflammatory cytokines might inhibit hippocampal neurogenesis.

    “pro-inflammatory cytokines might inhibit hippocampal neurogenesis,39”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Ekdahl CT, Claasen JH, Bonde S, Kokaia Z, Lindvall O . Inflammation is detrimental for neurogenesis in adult brain. Proc Natl Acad Sci USA 2003; 100: 13632–13637. source

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

    Interpretationreasoning

    Noradrenergic effects may drive increased inflammation mechanisms.

    “Possibly, noradrenergic effects are driving increased inflammation mechanisms.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    History of depression was associated with CRP levels in men, but not women, in another large and relatively young cohort study.

    “history of depression was associated with CRP levels in men, but not women.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Danner M, Kasl SV, Abramson JL, Vaccarino V . Association between depression and elevated C-reactive protein. Psychosom Med 2003; 65: 347–356. source

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

    Study design and conductnone given

    The study had a large sample size.

    “a large sample size”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Sex interactions were tested by including a sex-depressive disorder interaction term.

    “To investigate possible sex differences, we tested for sex interactions by including a sex-depressive disorder interaction term.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Men are more likely to experience related inflammation and depression because they possess higher amounts of visceral fat compared with women.

    “Men possess higher amounts of visceral fat compared with women and are therefore more likely to experience related inflammation and depression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Men possess higher amounts of visceral fat compared with women.

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

    Premisecitation

    One study found positive effects on mood in medically healthy, major depressed patients.

    “One study found positive effects on mood in medically healthy, major depressed patients.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Muller N, Schwarz MJ, Dehning S, Douhe A, Cerovecki A, Goldstein-Muller B et al. The cyclooxygenase-2 inhibitor celecoxib has therapeutic effects in major depression: results of a double-blind, randomized, placebo controlled, add-on pilot study to reboxetine. Mol Psychiatry 2006; 11: 680–684. source

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

    Premisecitation

    Preliminary evidence suggests anti-inflammatory agents may have beneficial effects on mood.

    “Preliminary evidence from studies among patients treated with anti-inflammatory agents for other indications suggests that these agents may have beneficial effects on mood.51”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Muller N, Riedel M, Schwarz MJ . Psychotropic effects of COX-2 inhibitors--a possible new approach for the treatment of psychiatric disorders. Pharmacopsychiatry 2004; 37: 266–269. source

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

    Premisecitation

    Noradrenaline is a part of the human stress response and has been suggested to potentiate cytokine production.

    “Noradrenaline is a part of the human stress response and has been suggested to potentiate cytokine production.45”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Elenkov IJ, Chrousos GP . Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann N Y Acad Sci 2002; 966: 290–303. source

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

    Premisecitation

    Use of SNRI, TCA and TeCA has been observed to disturb functioning of autonomic nervous system, blood pressure and the metabolic syndrome.

    “Use of SNRI, TCA and TeCA has also been observed to disturb functioning of autonomic nervous system,46 blood pressure47 and the metabolic syndrome.48”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [46] Licht CM, de Geus EJ, Van DR, Penninx BW . Longitudinal evidence for unfavorable effects of antidepressants on heart rate variability. Biol Psychiatry 2010; 68: 861–868. source
    • cites [47] Licht CM, de Geus EJ, Seldenrijk A, van Hout HP, Zitman FG, Van DR et al. Depression is associated with decreased blood pressure, but antidepressant use increases the risk for hypertension. Hypertension 2009; 53: 631–638. source
    • cites [48] van Reedt Dortland AK, Giltay EJ, van VT, Zitman FG, Penninx BW . Metabolic syndrome abnormalities are associated with severity of anxiety and depression and with tricyclic antidepressant use. Acta Psychiatr Scand 2010; 122: 30–39. source
52 of 52

  • The paper relies on this without support.

    Adjustment for measured sociodemographic, lifestyle and disease factors removes confounding sufficiently to infer a true relationship between depression and inflammation in men.

    “Together with the fact that our results were elaborately adjusted for possibly confounding factors, our findings suggest a true relationship between depression and inflammation in men.”

  • The paper relies on this without support.

    CRP, IL-6 and TNF-α are valid indicators of inflammation.

    “Markers of inflammation were assessed at the baseline NESDA measurement and included CRP, IL-6 and TNF-α.”

  • The paper relies on this without support.

    Men possess higher amounts of visceral fat compared with women.

    “Men possess higher amounts of visceral fat compared with women”

  • The paper relies on this without support.

    Depression is heterogeneous.

    “Considering the heterogeneity of depression”

  • The paper relies on this without support.

    The first three classes of medication (SNRI, TCA, TeCA) have a combined serotonergic/noradrenergic effect, whereas SSRI act purely serotonergic.

    “the first three classes of medication have a combined serotonergic/noradrenergic effect, whereas SSRI act purely serotonergic.”

  • The paper relies on this without support.

    Regulation of the immune system is rather complex and involves many different inflammatory mechanisms.

    “Regulation of the immune system is rather complex and involves many different inflammatory mechanisms.”

  • The paper relies on this without support.

    IL-6 and TNF-α only tap part of the immune system.

    “IL-6 and TNF-α, on the other hand, only tap part of the immune system.”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

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

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

  • Discussion attributes an IL-6 increase to TCA/TeCA users

    Minor

    The discussion says that SNRI, TCA and TeCA users had increased CRP and IL-6. The results report increased IL-6 for SNRI users only; they report a CRP increase, but not an IL-6 increase, for TCA/TeCA users.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, fourth edition. 4th edn. American Psychiatric Association: Washington, DC, 2001.

Cited by

Sorted by citations

Related

Authors
Vogelzangs, N., Duivis, H. E., Beekman, A. T. F., Kluft, C., Neuteboom, J., Hoogendijk, W., Smit, J. H., de Jonge, P., & Penninx, B. W. J. H.
Affiliations
  • Amsterdam Public Health (NL)
  • Tilburg University (NL)
  • GBS Leiden (NL)
  • Erasmus MC (NL)
  • University Medical Center Groningen (NL)
Corresponding author
Vogelzangs, N
ORCID
Venue
Translational Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2012-02-21
Volume
2
Issue
2
Pages
e79-e79
ISSN
2158-3188 (ISSN-L)
DOI
10.1038/tp.2012.8
PMC
PMC3309556
OpenAlex
W2058905991
Cited by
323
References
55
Citations by year
2026: 5 · 2025: 15 · 2024: 15 · 2023: 16 · 2022: 23 · 2021: 26 · 2020: 22 · 2019: 29 · 2018: 24 · 2017: 27 · 2016: 24 · 2015: 29 · 2014: 30 · 2013: 27 · 2012: 5
FWCI
6.94
Type
journal article
Language
en
Open access
Licence
Locations
  • Translational Psychiatry (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, cc-by-nc-nd)
  • Data Archiving and Networked Services (DANS) (submittedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (submittedVersion, cc-by-nc-nd)
  • PubMed Central (submittedVersion, cc-by-nc-nd)
  • Research portal (Tilburg University) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • VU Research Portal (submittedVersion, other-oa)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, cc-by-nc-nd)
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
depressive disorders, inflammation, immune dysregulation, antidepressants, C-reactive protein, interleukin-6, TNF-α, sex differences
MeSH terms
Adult, Antidepressive Agents, Anxiety Disorders, Major Depressive Disorder, Depressive Disorder, Major, Depressive Disorder

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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

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