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  • Systematic Review
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Inflammation and depression in young people: a systematic review and proposed inflammatory pathways

Molecular Psychiatry volume 27, pages 315–327 (2022)Cite this article

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Abstract

Depression onset peaks during adolescence and young adulthood. Current treatments are only moderately effective, driving the search for novel pathophysiological mechanisms underlying youth depression. Inflammatory dysregulation has been shown in adults with depression, however, less is known about inflammation in youth depression. This systematic review identified 109 studies examining the association between inflammation and youth depression and showed subtle evidence for inflammatory dysregulation in youth depression. Longitudinal studies support the bidirectional association between inflammation and depression in youth. We hypothesise multiple inflammatory pathways contributing to depression. More research is needed on anti-inflammatory treatments, potentially tailored to individual symptom profiles.

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Fig. 1: Immune system.
Fig. 2: Flowchart of study selection for systematic review.
Fig. 3: Proposed pathways between inflammation and individual depressive symptoms.
Fig. 4: Proposed decision tree for commencing anti-inflammatory treatment in young people with depression.

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References

  1. Zisook S, Lesser I, Stewart J, Wisniewski S, Balasubramani GK, Fava M, et al. Effect of age at onset on the course of major depressive disorder. Am J Psychiatry. 2007;164:1539–46.

    Article  PubMed  Google Scholar 

  2. Breslau J, Gilman SE, Stein BD, Ruder T, Gmelin T, Miller E. Sex differences in recent first-onset depression in an epidemiological sample of adolescents. Transl Psychiatry. 2017;7:e1139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Copeland WE, Alaie I, Jonsson U, Shanahan L. Associations of childhood and adolescent depression with adult psychiatric and functional outcomes. J Am Acad Child Adolesc Psychiatry. 2020. https://doi.org/10.1016/j.jaac.2020.07.895.

  4. Fergusson DM, Woodward LJ. Mental health, educational, and social role outcomes of adolescents with depression. Arch Gen Psychiatry. 2002;59:225.

    Article  PubMed  Google Scholar 

  5. McLeod GFH, Horwood LJ, Fergusson DM. Adolescent depression, adult mental health and psychosocial outcomes at 30 and 35 years. Psychol Med. 2016;46:1401–12.

    Article  CAS  PubMed  Google Scholar 

  6. WHO. Global accelerated action for the health of adolescents (AA-HA!) guidance to support country implementation. WHO. 2017. https://www.who.int/publications/i/item/9789241512343.

  7. Davey CG, McGorry PD. Early intervention for depression in young people: a blind spot in mental health care. Lancet Psychiatry. 2019;6:267–72.

    Article  PubMed  Google Scholar 

  8. Cuijpers P, Karyotaki E, Eckshtain D, Ng MY, Corteselli KA, Noma H, et al. Psychotherapy for depression across different age groups: a systematic review and meta-analysis. JAMA Psychiatry. 2020;77:694–702.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Zhou X, Teng T, Zhang Y, Del Giovane C, Furukawa TA, Weisz JR, et al. Comparative efficacy and acceptability of antidepressants, psychotherapies, and their combination for acute treatment of children and adolescents with depressive disorder: a systematic review and network meta-analysis. Lancet Psychiatry. 2020;7:581–601.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Guerry JD, Hastings PD. In search of HPA axis dysregulation in child and adolescent depression. Clin Child Fam Psychol Rev. 2011;14:135–60.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Ryan ND. Psychoneuroendocrinology of children and adolescents. Psychiatr Clin North Am. 1998;21:435–41.

    Article  CAS  PubMed  Google Scholar 

  12. Bair M, Robinson R, Katon W, Kroenke K. Depression and pain comorbidity: a literature review. Arch Intern Med. 2003;163:2433–45.

    Article  PubMed  Google Scholar 

  13. Milaneschi Y, Simmons WK, van Rossum EFC, Penninx BW. Depression and obesity: evidence of shared biological mechanisms. Mol Psychiatry. 2019;24:18–33.

    Article  CAS  PubMed  Google Scholar 

  14. Goodwin RD, Fergusson DM, Horwood LJ. Asthma and depressive and anxiety disorders among young persons in the community. Psychol Med. 2004;34:1465–74.

    Article  PubMed  Google Scholar 

  15. Graff LA, Walker JR, Bernstein CN. Depression and anxiety in iflammatory bowel disease: a review of comorbidity and management. Inflamm Bowel Dis. 2009;15:1105–18.

    Article  PubMed  Google Scholar 

  16. Whooley MA. Depression and cardiovascular disease: healing the broken-hearted. J Am Med Assoc. 2006;295:2874–81.

    Article  CAS  Google Scholar 

  17. Maes M, Capuron L, Ravaud A, Gualde N, Bosmans E, Egyed B, et al. Lowered serum dipeptidyl peptidase IV activity is associated with depressive symptoms and cytokine production in cancer patients receiving interleukin-2-based immunotherapy. Neuropsychopharmacology. 2001;24:130–40.

    Article  CAS  PubMed  Google Scholar 

  18. Bonaccorso S, Marino V, Puzella A, Pasquini M, Biondi M, Artini M, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-α-based immunotherapy are related to interferon-α-induced changes in the serotonergic system. J Clin Psychopharmacol. 2002;22:86–90.

    Article  CAS  PubMed  Google Scholar 

  19. Machado MO, Oriolo G, Bortolato B, Köhler CA, Maes M, Solmi M, et al. Biological mechanisms of depression following treatment with interferon for chronic hepatitis C: a critical systematic review. J Affect Disord. 2017;209:235–45.

    Article  CAS  PubMed  Google Scholar 

  20. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H, Kivimäki M. Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain Behav Immun. 2015;49:206–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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;67:446–57.

    Article  CAS  PubMed  Google Scholar 

  22. Osimo EF, Baxter LJ, Lewis G, Jones PB, Khandaker GM. Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels. Psychol Med. 2019;49:1958–70.

    Article  PubMed  PubMed Central  Google Scholar 

  23. McDade TW. Life history theory and the immune system: steps toward a human ecological immunology. Am J Phys Anthropol. 2003;122:100–25.

    Article  Google Scholar 

  24. Kowalczyk M, Szemraj J, Bliźniewska K, Maes M, Berk M, Su KP, et al. An immune gate of depression – Early neuroimmune development in the formation of the underlying depressive disorder. Pharmacol Rep. 2019;71:1299–307.

    Article  CAS  PubMed  Google Scholar 

  25. Liva SM, Voskuhl RR. Testosterone acts directly on CD4+ T lymphocytes to increase IL-10 production. J Immunol. 2001;167:2060–7.

    Article  CAS  PubMed  Google Scholar 

  26. Weinstein Y, Berkovich Z. Testostrone effect on bone marrow, thymus, and suppressor T cells in the (NZB x NZW)F1 mice: Its relevance to autoimmunity. J Immunol. 1981;126:998–1002.

    Article  CAS  PubMed  Google Scholar 

  27. Wärnberg J, Nova E, Romeo J, Moreno LA, Sjöström M, Marcos A. Lifestyle-related determinants of inflammation in adolescence. Br J Nutr. 2007;98:116–20.

    Article  Google Scholar 

  28. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Salonen R, et al. Sex hormones, inflammation and the metabolic syndrome: a population-based study. Eur J Endocrinol. 2003;149:601–8.

    Article  CAS  PubMed  Google Scholar 

  29. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;6:e1–e34.

    Article  Google Scholar 

  30. Sanderson S, Tatt ID, Higgins JPT. Tools for assessing quality and susceptibility to bias in observational studies in epidemiology: a systematic review and annotated bibliography. Int J Epidemiol. 2007;36:666–76.

    Article  PubMed  Google Scholar 

  31. Henje Blom E, Lekander M, Ingvar M, Åsberg M, Mobarrez F, Serlachius E. Pro-inflammatory cytokines are elevated in adolescent females with emotional disorders not treated with SSRIs. J Affect Disord. 2012;136:716–23.

    Article  CAS  PubMed  Google Scholar 

  32. Pallavi P, Sagar R, Mehta M, Sharma S, Subramanium A, Shamshi F, et al. Serum cytokines and anxiety in adolescent depression patients: gender effect. Psychiatry Res. 2015;229:374–80.

    Article  CAS  PubMed  Google Scholar 

  33. Pérez-Sánchez G, Becerril-Villanueva E, Arreola R, Martínez-Levy G, Hernández-Gutiérrez ME, Velasco-Velásquez MA, et al. Inflammatory profiles in depressed adolescents treated with fluoxetine: an 8-week follow-up open study. Mediators Inflamm. 2018;2018:1–12.

    Article  Google Scholar 

  34. Ho PS, Yen CH, Chen CY, Huang SY, Liang CS. Changes in cytokine and chemokine expression distinguish dysthymic disorder from major depression and healthy controls. Psychiatry Res. 2017;248:20–7.

    Article  CAS  PubMed  Google Scholar 

  35. Lee H, Song M, Lee J, Kim JB, Lee MS. Prospective study on cytokine levels in medication-naïve adolescents with first-episode major depressive disorder. J Affect Disord. 2020;266:57–62.

    Article  CAS  PubMed  Google Scholar 

  36. Xiong P, Zeng Y, Wan J, XiaoHan DH, Tan D, Lu J, et al. The role of NGF and IL-2 serum level in assisting the diagnosis in first episode schizophrenia. Psychiatry Res. 2011;189:72–6.

    Article  CAS  PubMed  Google Scholar 

  37. Gabbay V, Klein RG, Alonso CM, Babb JS, Nishawala M, De Jesus G, et al. Immune system dysregulation in adolescent major depressive disorder. J Affect Disord. 2009;115:177–82.

    Article  PubMed  Google Scholar 

  38. Gabbay V, Klein RG, Guttman LE, Babb JS, Alonso CM, Nishawala M, et al. A preliminary study of cytokines in suicidal and nonsuicidal adolescents with major depression. J Child Adolesc Psychopharmacol. 2009;19:423–30.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Ho PS, Yeh YW, Huang SY, Liang CS. A shift toward T helper 2 responses and an increase in modulators of innate immunity in depressed patients treated with escitalopram. Psychoneuroendocrinology. 2015;53:246–55.

    Article  CAS  PubMed  Google Scholar 

  40. Öztürk M, Sapmaz S, Kandemir H, Taneli F, Aydemir Ö. The role of the kynurenine pathway and quinolinic acid in adolescent major depressive disorder. Int J Clin Pract. 2020;75:e13739.

    PubMed  Google Scholar 

  41. Calarge CA, Devaraj S, Shulman RJ. Gut permeability and depressive symptom severity in unmedicated adolescents. J Affect Disord. 2019;246:586–94.

    Article  PubMed  Google Scholar 

  42. Jha MK, Cai L, Minhajuddin A, Fatt CC, Furman JL, Gadad BS, et al. Dysfunctional adaptive immune response in adolescents and young adults with suicide behavior. Psychoneuroendocrinology. 2020;111:104487.

    Article  CAS  PubMed  Google Scholar 

  43. Miklowitz D, Portnoff L, Armstrong C, Keenan-Miller D, Breen E, Muscatell K, et al. Inflammatory cytokines and nuclear factor-kappa B activation in adolescents with bipolar and major depressive disorders. Psychiatry Res. 2016;241:315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Peters AT, Ren X, Bessette KL, Goldstein BI, West AE, Langenecker SA, et al. Interplay between pro-inflammatory cytokines, childhood trauma, and executive function in depressed adolescents. J Psychiatr Res. 2019;114:1–10.

    Article  PubMed  Google Scholar 

  45. Byrne ML, O’Brien-Simpson NM, Reynolds EC, Walsh KA, Laughton K, Waloszek JM, et al. Acute phase protein and cytokine levels in serum and saliva: a comparison of detectable levels and correlations in a depressed and healthy adolescent sample. Brain Behav Immun. 2013;34:164–75.

    Article  CAS  PubMed  Google Scholar 

  46. Mondin TC, de Azevedo Cardoso T, Moreira FP, Wiener C, Oses JP, de Mattos Souza LD, et al. Circadian preferences, oxidative stress and inflammatory cytokines in bipolar disorder: a community study. J Neuroimmunol. 2016;301:23–9.

    Article  CAS  PubMed  Google Scholar 

  47. Petrov B, Aldoori A, James C, Yang K, Algorta GP, Lee A, et al. Bipolar disorder in youth is associated with increased levels of Vitamin D-binding protein. Transl Psychiatry. 2018;8:4–13.

    Article  Google Scholar 

  48. Su SC, Sun MT, Wen MJ, Lin CJ, Chen YC, Hung YJ. Brain-derived neurotrophic factor, adiponectin, and proinflammatory markers in various subtypes of depression in young men. Int J Psychiatry Med. 2011;42:211–26.

    Article  PubMed  Google Scholar 

  49. Wiener CD, Moreira FP, Cardoso TA, Mondin TC, da Silva Magalhães PV, Kapczinski F, et al. Inflammatory cytokines and functional impairment in drug-free subjects with mood disorder. J Neuroimmunol. 2017;307:33–6.

    Article  CAS  PubMed  Google Scholar 

  50. Hung YJ, Hsieh CH, Chen YJ, Pei D, Kuo SW, Shen DC, et al. Insulin sensitivity, proinflammatory markers and adiponectin in young males with different subtypes of depressive disorder. Clin Endocrinol. 2007;67:784–9.

    Article  CAS  Google Scholar 

  51. Tabatabaeizadeh SA, Abdizadeh MF, Meshkat Z, Khodashenas E, Darroudi S, Fazeli M, et al. There is an association between serum high-sensitivity C-reactive protein (hs-CRP) concentrations and depression score in adolescent girls. Psychoneuroendocrinology. 2018;88:102–4.

    Article  CAS  PubMed  Google Scholar 

  52. Perry BI, Oltean BP, Jones PB, Khandaker GM. Cardiometabolic risk in young adults with depression and evidence of inflammation: a birth cohort study. Psychoneuroendocrinology. 2020;116:104682.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Prohan M, Amani R, Nematpour S, Jomehzadeh N, Haghighizadeh MH. Total antioxidant capacity of diet and serum, dietary antioxidant vitamins intake, and serum hs-CRP levels in relation to depression scales in university male students. Redox Rep. 2014;19:133–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tao R, Fu Z, Xiao L. Chronic food antigen-specific IgG-mediated hypersensitivity reaction as a risk factor for adolescent depressive disorder. Genom Proteom Bioinform. 2019;17:183–9.

    Article  Google Scholar 

  55. D’Acunto G, Nageye F, Zhang J, Masi G, Cortese S. Inflammatory cytokines in children and adolescents with depressive disorders: a systematic review and meta-Analysis. J Child Adolesc Psychopharmacol. 2019;29:362–9.

    Article  PubMed  Google Scholar 

  56. Dorn L, Gayles J, Engeland C, Houts R, Cizza G, Denson L. Cytokine patterns in healthy adolescent girls: heterogeneity captured by variable- and person-centered statistical strategies. Psychosom Med. 2016;78:646–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lacourt T, Houtveen J, Doornen L, Benson S, Grigoleit J, Cesko E, et al. Biological and psychological predictors of visceral pain sensitivity in healthy premenopausal women. Eur J Pain. 2014;18:567–74.

    Article  CAS  PubMed  Google Scholar 

  58. Ysseldyk R, McQuaid RJ, McInnis OA, Anisman H, Matheson K. The ties that bind: Ingroup ties are linked with diminished inflammatory immune responses and fewer mental health symptoms through less rumination. PLoS ONE. 2018;13:1–19.

    Article  Google Scholar 

  59. Zorrilla E, Redei E, DeRubeis R. Reduced cytokine levels and T-cell function in healthy males: relation to individual differences in subclinical anxiety. Brain Behav Immun. 1994;8:293–312.

    Article  CAS  PubMed  Google Scholar 

  60. Katsuura S, Kamezaki Y, Yamagishi N, Kuwano Y, Nishida K, Masuda K, et al. Circulating vascular endothelial growth factor is independently and negatively associated with trait anxiety and depressive mood in healthy Japanese university students. Int J Psychophysiol. 2011;81:38–43.

    Article  PubMed  Google Scholar 

  61. Maldonado A, Preciado A, Buchanan M, Pulvers K, Romero D, D’Anna-Hernandez K. Acculturative stress, mental health symptoms, and the role of salivary inflammatory markers among a latino sample. Cult Divers Ethn Minor Psychol. 2018;24:277–83.

    Article  Google Scholar 

  62. Manczak E, Williams D, Chen E. The role of family routines in the intergenerational transmission of depressive symptoms between parents and their adolescent children. J Abnorm Child Psychol. 2017;45:643–56.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Arana AA, Boyd EQ, Guarneri-White M, Iyer-Eimerbrink P, Dougall AL, Jensen-Campbell L. The impact of social and physical peer victimization on systemic inflammation in adolescents. Merrill Palmer Q. 2018;64:12–40.

    Article  Google Scholar 

  64. Quinn M, Stanton C, Slavich G, Joormann J. Executive control, cytokine reactivity to social stress, and depressive symptoms: testing the social signal transduction theory of depression. Stress. 2020;23:60–8.

    Article  CAS  PubMed  Google Scholar 

  65. Chiang J, Bower J, Irwin M, Taylor S, Fuligni A. Adiposity moderates links from early adversity and depressive symptoms to inflammatory reactivity to acute stress during late adolescence. Brain Behav Immun. 2017;66:146–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Plant DT, Pawlby S, Sharp D, Zunszain PA, Pariante CM. Prenatal maternal depression is associated with offspring inflammation at 25 years: a prospective longitudinal cohort study. Transl Psychiatry. 2016;6:e936–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. John-Henderson N, Jacobs EG, Mendoza-Denton R, Francis DD. Wealth, health, and the moderating role of implicit social class bias. Ann Behav Med. 2013;45:173–9.

    Article  PubMed  Google Scholar 

  68. McDade T, Borja J, Adair L, Kuzawa C. Depressive symptoms are not associated with inflammation in younger and older adults in the Philippines. Evol Med Public Heal. 2013;1:18–23.

    Article  Google Scholar 

  69. Slavish DC, Graham-Engeland JE, Engeland CG, Taylor DJ, Buxton OM. Insomnia symptoms are associated with elevated C-reactive protein in young adults. Psychol Heal. 2018;33:1396–415.

    Article  Google Scholar 

  70. Chaiton M, O’Loughlin J, Karp I, Lambert M. Depressive symptoms and C-reactive protein are not associated in a population-based sample of adolescents. Int J Behav Med. 2010;17:216–22.

    Article  PubMed  Google Scholar 

  71. Chen YC, Lin WW, Chen YJ, Mao WC, Hung YJ. Antidepressant effects on insulin sensitivity and proinflammatory cytokines in the depressed males. Mediators Inflamm. 2010;2010:1–7.

    Article  Google Scholar 

  72. Becerril-Villanueva E, Pérez-Sánchez G, Alvarez-Herrera S, Girón-Pérez MI, Arreola R, Cruz-Fuentes C, et al. Alterations in the levels of growth factors in adolescents with major depressive disorder: a longitudinal study during the treatment with fluoxetine. Mediators Inflamm. 2019;2019:1–7.

    Article  Google Scholar 

  73. Amitai M, Taler M, Carmel M, Michaelovsky E, Eilat T, Yablonski M, et al. The relationship between plasma cytokine levelsand response to selective serotonin reuptake inhibitor treatment in children and adolescents with depression and/or anxiety disorders. J Child Adolesc Psychopharmacol. 2016;26:727–32.

    Article  CAS  PubMed  Google Scholar 

  74. Booij S, Bos E, Peter de P, Oldehinkel A. Markers of stress and inflammation as potential mediators of the relationship between exercise and depressive symptoms: findings from the TRAILS study. Psychophysiology. 2015;52:352–8.

    Article  PubMed  Google Scholar 

  75. Endrighi R, Steptoe A, Hamer M. The effect of experimentally induced sedentariness on mood and psychobiological responses to mental stress. Br J Psychiatry. 2016;208:245–51.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Gazal M, Souza LD, Fucolo BA, Wiener CD, Silva RA, Pinheiro RT, et al. The impact of cognitive behavioral therapy on IL-6 levels in unmedicated women experiencing the first episode of depression: a pilot study. Psychiatry Res. 2013;209:742–5.

    Article  CAS  PubMed  Google Scholar 

  77. Pedrotti Moreira F, Wiener CD, Jansen K, Portela LV, Lara DR, Souza LD, et al. Childhood trauma and increased peripheral cytokines in young adults with major depressive: population-based study. J Neuroimmunol. 2018;319:112–6.

    Article  CAS  PubMed  Google Scholar 

  78. Nasstasia Y, Baker AL, Halpin SA, Lewin TJ, Hides L, Kelly BJ, et al. Pilot study of an exercise intervention for depressive symptoms and associated cognitive-behavioral factors in young adults with major depression. J Nerv Ment Dis. 2017;205:647–55.

    Article  PubMed  Google Scholar 

  79. Pace TWW, Negi LT, Dodson-Lavelle B, Ozawa-de Silva B, Reddy SD, Cole SP, et al. Engagement with cognitively-based compassion training is associated with reduced salivary C-reactive protein from before to after training in foster care program adolescents. Psychoneuroendocrinology. 2013;38:294–9.

    Article  PubMed  Google Scholar 

  80. Walsh E, Eisenlohr-Moul T, Baer R. Brief mindfulness training reduces salivary IL-6 and TNF-α in young women with depressive symptomatology. J Consult Clin Psychol. 2016;84:887–97.

    Article  PubMed  PubMed Central  Google Scholar 

  81. Rengasamy M, Marsland A, McClain L, Kovats T, Walko T, Pan L, et al. Longitudinal relationships of cytokines, depression and anhedonia in depressed adolescents. Brain Behav Immun. 2021;91:74–80.

    Article  CAS  PubMed  Google Scholar 

  82. Berk M, Mohebbi M, Dean OM, Cotton SM, Chanen AM, Dodd S, et al. Youth depression alleviation with anti-inflammatory agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin. BMC Med. 2020;18:16.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Kiecolt-Glaser J, Belury M, Andridge R, Malarkey W, Glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun. 2011;25:1725–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Khandaker GM. Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life. JAMA Psychiatry. 2014;71:1121–8.

    Article  PubMed  PubMed Central  Google Scholar 

  85. Chu AL, Stochl J, Lewis G, Zammit S, Jones PB, Khandaker GM. Longitudinal association between inflammatory markers and specific symptoms of depression in a prospective birth cohort. Brain Behav Immun. 2019;76:74–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Khandaker GM, Stochl J, Zammit S, Goodyer I, Lewis G, Jones PB. Childhood inflammatory markers and intelligence as predictors of subsequent persistent depressive symptoms: a longitudinal cohort study. Psychol Med. 2018;48:1514–22.

    Article  CAS  PubMed  Google Scholar 

  87. Moriarity D, Kautz M, Giollabhui N, Klugman J, Coe C, Ellman L, et al. Bidirectional associations between inflammatory biomarkers and depressive symptoms in adolescents: potential causal relationships. Clin Psychol Sci. 2019. https://doi.org/10.1177/2167702620917458.

  88. Kautz M, Coe C, McArthur B, Giollabhui N, Ellman L, Abramson L, et al. Longitudinal changes of inflammatory biomarkers moderate the relationship between recent stressful life events and prospective symptoms of depression in a diverse sample of urban adolescents. Brain Behav Immun. 2020;86:43–52.

    Article  PubMed  Google Scholar 

  89. Moriarity D, Giollabhui N, Ellman L, Klugman J, Coe C, Abramson L, et al. Inflammatory proteins predict change in depressive symptoms in male and female adolescents. Clin Psychol Sci. 2019;7:754–67.

    Article  PubMed  PubMed Central  Google Scholar 

  90. Moriarity D, McArthur B, Ellman L, Coe C, Abramson L, Alloy L. Immunocognitive model of depression secondary to anxiety in adolescents. J Youth Adolesc. 2018;47:2625–36.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Mac Giollabhui N, Swistun D, Murray S, DP M, Kautz M, Ellman L, et al. Executive dysfunction in depression in adolescence: the role of inflammation and higher body mass. Psycholocial Med. 2020;50:683–91.

    Article  Google Scholar 

  92. Osimo EF, Stochl J, Zammit S, Lewis G, Jones PB, Khandaker GM. Longitudinal population subgroups of CRP and risk of depression in the ALSPAC birth cohort. Compr Psychiatry. 2020;96:152143.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Copeland W, Shanahan L, Worthman C, Angold A, Costello E. Cumulative depression episodes predicts later C-reactive protein levels: a prospective analysis. Biol Psychiatry. 2012;71:15–21.

    Article  CAS  PubMed  Google Scholar 

  94. Jonker I, Rosmalen JGM, Schoevers RA. Childhood life events, immune activation and the development of mood and anxiety disorders: the TRAILS study. Transl Psychiatry. 2017;7:1–9.

    Article  Google Scholar 

  95. Rohleder N, Miller GE. Acute deviations from long-term trait depressive symptoms predict systemic inflammatory activity. Brain Behav Immun. 2008;22:709–16.

    Article  PubMed  Google Scholar 

  96. Walss-Bass C, Suchting R, Olvera R, Williamson D. Inflammatory markers as predictors of depression and anxiety in adolescents: statistical model building with component-wise gradient boosting. J Affect Disord. 2018;234:276–81.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Miller G, Cole S. Clustering of depression and inflammation in adolescents previously exposed to childhood adversity. Biol Psychiatry. 2012;72:34–40.

    Article  PubMed  PubMed Central  Google Scholar 

  98. Mac Giollabhui N, Alloy LB, Hartman CA. Investigating whether depressed youth exhibiting elevated C reactive protein perform worse on measures of executive functioning, verbal fluency and episodic memory in a large, population based sample of Dutch adolescents. Brain Behav Immun. 2021;94:369–80.

    Article  Google Scholar 

  99. Duivis HE, Kupper N, Vermunt JK, Penninx BW, Bosch NM, Riese H, et al. Depression trajectories, inflammation, and lifestyle factors in adolescence: the TRacking Adolescents' individual lives survey. Health Psychol. 2015;34:1047–57.

    Article  PubMed  Google Scholar 

  100. Nelson B, Byrne M, Simmons J, Whittle S, Schwartz O, O’Brien-Simpson N, et al. Adolescent temperament dimensions as stable prospective risk and protective factors for salivary C-reactive. Br J Health. Psychol. 2018;23:186–207.

    Article  PubMed  Google Scholar 

  101. Oddy WH, Allen KL, Trapp GSA, Ambrosini GL, Black LJ, Huang RC, et al. Dietary patterns, body mass index and inflammation: pathways to depression and mental health problems in adolescents. Brain Behav Immun. 2018;69:428–39.

    Article  PubMed  Google Scholar 

  102. Brody GH, Yu T, Miller GE, Chen E. Discrimination, racial identity, and cytokine levels among african-american adolescents. J Adolesc Heal. 2015;56:496–501.

    Article  Google Scholar 

  103. Raposa EB, Bower JE, Hammen CL, Najman JM, Brennan PA. A developmental pathway from early life stress to inflammation: the role of negative health behaviors. Psychol Sci. 2014;25:1268–74.

    Article  PubMed  Google Scholar 

  104. Reid BM, Doom JR, Argote RB, Correa-Burrows P, Lozoff B, Blanco E, et al. Pathways to inflammation in adolescence through early adversity, childhood depressive symptoms, and body mass index: a prospective longitudinal study of Chilean infants. Brain Behav Immun. 2020;86:4–13.

    Article  PubMed  Google Scholar 

  105. Slopen N, Kubzansky L, McLaughlin K, Koenen K. Childhood adversity and inflammatory processes in youth: a prospective study. Psychoneuroendocrinology. 2013;38:188–200.

    Article  PubMed  Google Scholar 

  106. Mac GN, Ng T, Ellman LM, Alloy LB. The longitudinal associations of inflammatory biomarkers and depression revisited: systematic review, meta-analysis and meta-regression. Biol Psychiatry. 2020;87:S450.

    Article  Google Scholar 

  107. Boyle CC, Kuhlman KR, Dooley LN, Haydon MD, Robles TF, Ang YS, et al. Inflammation and dimensions of reward processing following exposure to the influenza vaccine. Psychoneuroendocrinology. 2019;102:16–23.

    Article  CAS  PubMed  Google Scholar 

  108. Draper A, Koch RM, Van Der Meer JW, Apps MA, Pickkers P, Husain M, et al. Effort but not reward sensitivity is altered by acute sickness induced by experimental endotoxemia in humans. Neuropsychopharmacology. 2018;43:1107–18.

    Article  PubMed  Google Scholar 

  109. Lasselin J, Treadway MT, Lacourt TE, Soop A, Olsson MJ, Karshikoff B, et al. Lipopolysaccharide alters motivated behavior in a monetary reward task: a randomized trial. Neuropsychopharmacology. 2017;42:801–10.

    Article  CAS  PubMed  Google Scholar 

  110. Eisenberger NI, Berkman ET, Inagaki TK, Rameson LT, Nehjla M, Irwin MR. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68:748–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Eisenberger N, Inagaki T, Mashal N, Irwin M. Inflammation and social experience: an inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain Behav Immun. 2010;24:558–63.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Inagaki TK, Muscatell KA, Irwin MR, Cole SW, Eisenberger NI. Inflammation selectively enhances amygdala activity to socially threatening images. Neuroimage. 2012;59:3222–6.

    Article  PubMed  Google Scholar 

  113. Moieni M, Irwin MR, Jevtic I, Olmstead R, Breen EC, Eisenberger NI. Sex differences in depressive and socioemotional responses to an inflammatory challenge: Implications for sex differences in depression. Neuropsychopharmacology. 2015;40:1709–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Muscatell KA, Moieni M, Inagaki TK, Dutcher JM, Jevtic I, Breen EC, et al. Exposure to an inflammatory challenge enhances neural sensitivity to negative and positive social feedback. Brain Behav Immun. 2016;57:21–9.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry. 2009;66:407–14.

    Article  PubMed  PubMed Central  Google Scholar 

  116. Kuhlman KR, Robles TF, Dooley LN, Boyle CC, Haydon MD, Bower JE. Within-subject associations between inflammation and features of depression: Using the flu vaccine as a mild inflammatory stimulus. Brain Behav Immun. 2018;69:540–7.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Reichenberg A, Yirmiya R, Schuld A, Kraus T, Haack M, Morag A, et al. Cytokine-associated emotional and cognitive disturbances in humans. Arch Gen Psychiatry. 2001;58:445–52.

    Article  CAS  PubMed  Google Scholar 

  118. Irwin MR, Cole S, Olmstead R, Breen EC, Cho JJ, Moieni M, et al. Moderators for depressed mood and systemic and transcriptional inflammatory responses: a randomized controlled trial of endotoxin. Neuropsychopharmacology. 2019;44:635–41.

    Article  CAS  PubMed  Google Scholar 

  119. Schmaal L, Hibar DP, Sämann PG, Hall GB, Baune BT, Jahanshad N, et al. Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group. Mol Psychiatry. 2017;22:900–9.

    Article  CAS  PubMed  Google Scholar 

  120. Wray NR, Ripke S, Mattheisen M, Trzaskowski M, Byrne EM, Abdellaoui A, et al. Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. Nat Genet. 2018;50:668–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Muscatell K, Brosso S, Humphreys K. Socioeconomic status and inflammation: a meta-analysis. Mol Psychiatry. 2020;25:2189–99.

    Article  PubMed  Google Scholar 

  122. Costello H, Gould RL, Abrol E, Howard R. Systematic review and meta-analysis of the association between peripheral inflammatory cytokines and generalised anxiety disorder. BMJ Open. 2019;9:1–16.

    Article  Google Scholar 

  123. Eisenberger NI, Inagaki TK, Rameson LT, Mashal NM, Irwin MR. An fMRI study of cytokine-induced depressed mood and social pain: the role of sex differences. Neuroimage. 2009;47:881–90.

    Article  CAS  PubMed  Google Scholar 

  124. Ashton MM, Dean OM, Marx W, Mohebbi M, Berk M, Malhi GS, et al. Diet quality, dietary inflammatory index and body mass index as predictors of response to adjunctive N-acetylcysteine and mitochondrial agents in adults with bipolar disorder: a sub-study of a randomised placebo-controlled trial. Aust NZ J Psychiatry. 2020;54:159–72.

    Article  Google Scholar 

  125. Miller GE, Freedland KE, Carney RM, Stetler CA, Banks WA. Pathways linking depression, adiposity, and inflammatory markers in healthy young adults. Brain Behav Immun. 2003;17:276–85.

    Article  CAS  PubMed  Google Scholar 

  126. Syk M, Ellström S, Mwinyi J, Schiöth HB, Ekselius L, Ramklint M, et al. Plasma levels of leptin and adiponectin and depressive symptoms in young adults. Psychiatry Res. 2019;272:1–7.

    Article  CAS  PubMed  Google Scholar 

  127. Mamalakis G, Kiriakakis M, Tsibinos G, Hatzis C, Flouri S, Mantzoros C, et al. Depression and serum adiponectin and adipose omega-3 and omega-6 fatty acids in adolescents. Pharmacol Biochem Behav. 2006;85:474–9.

    Article  CAS  PubMed  Google Scholar 

  128. François M, Schaefer JM, Bole-Feysot C, Déchelotte P, Verhulst FC, Fetissov SO. Ghrelin-reactive immunoglobulins and anxiety, depression and stress-induced cortisol response in adolescents. The TRAILS study. Prog Neuropsychopharmacol Biol Psychiatry. 2015;59:1–7.

    Article  PubMed  Google Scholar 

  129. Irwin MR, Olmstead R, Carroll JE. Sleep disturbance, sleep duration, and inflammation: a systematic review and meta-analysis of cohort studies and experimental sleep deprivation. Biol Psychiatry. 2016;80:40–52.

    Article  PubMed  Google Scholar 

  130. Lopresti AL, Hood SD, Drummond PD. A review of lifestyle factors that contribute to important pathways associated with major depression: diet, sleep and exercise. J Affect Disord. 2013;148:12–27.

    Article  PubMed  Google Scholar 

  131. Hannestad J, Dellagioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology. 2011;36:2452–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kuhlman KR, Robles TF, Haydon MD, Dooley L, Boyle CC, Bower JE. Early life stress sensitizes individuals to the psychological correlates of mild fluctuations in inflammation. Dev Psychobiol. 2020;62:400–8.

    Article  CAS  PubMed  Google Scholar 

  133. Baumeister D, Akhtar R, Ciufolini S, Pariante CM, Mondelli V. Childhood trauma and adulthood inflammation: a meta-analysis of peripheral C-reactive protein, interleukin-6 and tumour necrosis factor-α. Mol Psychiatry. 2016;21:642–9.

    Article  CAS  PubMed  Google Scholar 

  134. Chiang JJ, Cole SW, Bower JE, Irwin MR, Taylor SE, Arevalo J, et al. Depressive symptoms and immune transcriptional profiles in late adolescents. Brain Behav Immun. 2019;80:163–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kéri S, Szabó C, Kelemen O. Expression of Toll-Like Receptors in peripheral blood mononuclear cells and response to cognitive-behavioral therapy in major depressive disorder. Brain Behav Immun. 2014;40:235–43.

    Article  PubMed  Google Scholar 

  136. Khandaker GM, Zammit S, Burgess S, Lewis G, Jones PB. Association between a functional interleukin 6 receptor genetic variant and risk of depression and psychosis in a population-based birth cohort. Brain Behav Immun. 2018;69:264–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Swartz JR, Prather AA, Di Iorio CR, Bogdan R, Hariri AR. A functional interleukin-18 haplotype predicts depression and anxiety through increased threat-related amygdala reactivity in women but not men. Neuropsychopharmacology. 2017;42:419–26.

    Article  CAS  PubMed  Google Scholar 

  138. Tartter M, Hammen C, Bower J, Brennan P, Steven C. Effects of chronic interpersonal stress exposure on depressive symptoms are moderated by genetic variation at IL6 and IL1β in youth. Brain Behav Immun. 2015;46:104–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Fried EI, Nesse RM. Depression is not a consistent syndrome: an investigation of unique symptom patterns in the STAR*D study. J Affect Disord. 2015;172:96–102.

    Article  PubMed  Google Scholar 

  140. Lamers F, Milaneschi Y, de Jonge P, Giltay EJ, Penninx BWJH. Metabolic and inflammatory markers: associations with individual depressive symptoms. Psycholocial Med. 2018;48:1102–10.

    Article  CAS  Google Scholar 

  141. Simmons WK, Burrows K, Avery JA, Potter W, Teague TK, Drevets WC, et al. Appetite changes reveal depression subgroups with distinct endocrine, metabolic, and immune states. Mol Psychiatry. 2018. https://doi.org/10.1038/s41380-018-0093-6.

  142. Lamers F, Vogelzangs N, Merikangas KR, de Jonge P, Beekman ATF, Penninx BWJH. Evidence for a differential role of HPA-axis function, inflammation and metabolic syndrome in melancholic versus atypical depression. Mol Psychiatry. 2013;18:692–9.

    Article  CAS  PubMed  Google Scholar 

  143. Lasserre AM, Strippoli MPF, Glaus J, Gholam-Rezaee M, Vandeleur CL, Castelao E, et al. Prospective associations of depression subtypes with cardio-metabolic risk factors in the general population. Mol Psychiatry. 2017;22:1026–34.

    Article  CAS  PubMed  Google Scholar 

  144. Milaneschi Y, Lamers F, Berk M, Penninx BWJH. Depression heterogeneity and its biological underpinnings: toward immunometabolic depression. Biol Psychiatry. 2020;88:1–12.

    Article  Google Scholar 

  145. Penninx BWJH, Milanesch Y, Lamers F, Vogelzangs N. Understanding the somatic consequences of depression: Biological mechanisms and the role of depression symptom profile. BMC Med. 2013;11:1–14.

    Article  Google Scholar 

  146. Luppino FS, de Wit LM, Bouvy PF, Stijnen T, Cuijpers P, Penninx BWJH. Overweight, obesity, and depression. a systematic review and meta-analysis of longitudinal studies. Arch Gen Psychiatry. 2010;67:220

    Article  Google Scholar 

  147. Majd M, Saunders EFH, Engeland CG. Inflammation and the dimensions of depression: a review. Front Neuroendocrinol. 2019;56:100800.

    Article  PubMed  Google Scholar 

  148. van Eeden WA, van Hemert AM, Carlier IVE, Penninx BWJH, Lamers F, Fried EI, et al. Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression. Transl Psychiatry. 2020;10:1–12.

    Google Scholar 

  149. Cui H, López M, Rahmouni K. The cellular and molecular bases of leptin and ghrelin resistance in obesity. Nat Rev Endocrinol. 2017;13:338–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Chen K, Li F, Li J, Cai H, Strom S, Bisello A, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med. 2006;12:425–32.

    Article  CAS  PubMed  Google Scholar 

  151. Chen L, Chen R, Wang H, Liang F. Mechanisms Linking Inflammation to Insulin Resistance. Int J Endocrinol. 2015;2015:1–9.

    Google Scholar 

  152. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review. Obes Rev. 2007;8:21–34.

    Article  CAS  PubMed  Google Scholar 

  153. Dyzma M, Boudjeltia KZ, Faraut B, Kerkhofs M. Neuropeptide Y and sleep. Sleep Med Rev. 2010;14:161–5.

    Article  PubMed  Google Scholar 

  154. Juruena MF, Bocharova M, Agustini B, Young AH. Atypical depression and non-atypical depression: Is HPA axis function a biomarker? A systematic review. J Affect Disord. 2018;233:45–67.

    Article  CAS  PubMed  Google Scholar 

  155. Herane-Vives A, de Angel V, Papadopoulos A, Wise T, Chua KC, Strawbridge R, et al. Short-term and long-term measures of cortisol in saliva and hair in atypical and non-atypical depression. Acta Psychiatr Scand. 2018;137:216–30.

    Article  CAS  PubMed  Google Scholar 

  156. Elenkov IJ. Neurohormonal-cytokine interactions: Implications for inflammation, common human diseases and well-being. Neurochem Int. 2008;52:40–51.

    Article  CAS  PubMed  Google Scholar 

  157. Yoon HK, Kim YK, Lee HJ, Kwon DY, Kim L. Role of cytokines in atypical depression. Nord J Psychiatry. 2012;66:183–8.

    Article  PubMed  Google Scholar 

  158. Farr OM, Tsoukas MA, Mantzoros CS. Leptin and the brain: Influences on brain development, cognitive functioning and psychiatric disorders. Metabolism. 2015;64:114–30.

    Article  CAS  PubMed  Google Scholar 

  159. Watson K, Nasca C, Aasly L, McEwen B, Rasgon N. Insulin resistance, an unmasked culprit in depressive disorders: Promises for interventions. Neuropharmacology. 2018;136:327–34.

    Article  CAS  PubMed  Google Scholar 

  160. López JF, Chalmers DT, Little KY, Watson SJ. Regulation of serotonin(1A), glucocorticoid, and mineralocorticoid receptor in rat and human hippocampus: Implications for the neurobiology of depression. Biol Psychiatry. 1998;43:547–73.

    Article  PubMed  Google Scholar 

  161. Martino M, Rocchi G, Escelsior A, Fornaro M. Immunomodulation mechanism of antidepressants: interactions between serotonin/norepinephrine balance and Th1/Th2 balance. Curr Neuropharmacol. 2012;10:97–123.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Rothermundt M, Arolt V, Fenker J, Gutbrodt H, Peters M, Kirchner H. Different immune patterns in melancholic and non-melancholic major depression. Eur Arch Psychiatry Clin Neurosci. 2001;251:90–7.

    Article  CAS  PubMed  Google Scholar 

  163. Spanemberg L, Caldieraro MA, Vares EA, Wollenhaupt-Aguiar B, Kauer-Sant’Anna M, Kawamoto SY, et al. Biological differences between melancholic and nonmelancholic depression subtyped by the CORE measure. Neuropsychiatr Dis Treat. 2014;10:1523–31.

    Article  PubMed  PubMed Central  Google Scholar 

  164. Carrillo-Vico A, García-Mauriño S, Calvo JR, Guerrero JM. Melatonin counteracts the inhibitory effect of PGE2 on IL-2 production in human lymphocytes via its mt1 membrane receptor. FASEB J. 2003;17:755–7.

    Article  CAS  PubMed  Google Scholar 

  165. Savitz J. The Kynurenine pathway: a finger in every pie. Mol Psychiatry. 2020;25:131–47.

    Article  PubMed  Google Scholar 

  166. Felger JC, Treadway MT. Inflammation effects on motivation and motor activity: role of dopamine. Neuropsychopharmacology. 2017;42:216–41.

    Article  CAS  PubMed  Google Scholar 

  167. Maes M. Depression is an inflammatory disease, but cell-mediated immune activation is the key component of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2011;35:664–75.

    Article  CAS  PubMed  Google Scholar 

  168. Irwin MR, Miller AH. Depressive disorders and immunity: 20 years of progress and discovery. Brain Behav Immun. 2007;21:374–83.

    Article  CAS  PubMed  Google Scholar 

  169. Kühlwein E, Irwin M. Melatonin modulation of lymphocyte proliferation and Th1/Th2 cytokine expression. J Neuroimmunol. 2001;117:51–7.

    Article  PubMed  Google Scholar 

  170. Osimo EF, Pillinger T, Rodriguez IM, Khandaker GM, Pariante CM, Howes OD. Inflammatory markers in depression: a meta-analysis of mean differences and variability in 5,166 patients and 5,083 controls. Brain Behav Immun. 2020;87:901–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Rohleder N. Acute and chronic stress induced changes in sensitivity of peripheral inflammatory pathways to the signals of multiple stress systems—2011 Curt Richter Award Winner. Psychoneuroendocrinology. 2012;37:307–16.

    Article  CAS  PubMed  Google Scholar 

  172. Himmerich H, Patsalos O, Lichtblau N, Ibrahim MAA, Dalton B. Cytokine research in depression: Principles, challenges, and open questions. Front Psychiatry. 2019;10:30.

    Article  PubMed  PubMed Central  Google Scholar 

  173. Ray A. Cytokines and their role in health and disease: a brief overview. MOJ Immunol. 2016;4:1–9.

    Article  Google Scholar 

  174. Decker ML, Grobusch MP, Ritz N. Influence of age and other factors on cytokine expression profiles in healthy children—a systematic review. Front Pediatr. 2017;5:255.

    Article  PubMed  PubMed Central  Google Scholar 

  175. Arteaga-Henríquez G, Simon MS, Burger B, Weidinger E, Wijkhuijs A, Arolt V, et al. Low-grade inflammation as a predictor of antidepressant and anti-inflammatory therapy response in MDD patients: a systematic review of the literature in combination with an analysis of experimental data collected in the EU-Moodinflame consortium. Front Psychiatry. 2019;10:1–15.

    Article  Google Scholar 

  176. Bai S, Guo W, Feng Y, Deng H, Li G, Nie H, et al. Efficacy and safety of anti-inflammatory agents for the treatment of major depressive disorder: A systematic review and meta-analysis of randomised controlled trials. J Neurol Neurosurg Psychiatry. 2020;91:21–32.

    Article  PubMed  Google Scholar 

  177. Köhler-Forsberg O, Lydholm CN, Hjorthøj C, Nordentoft M, Mors O, Benros ME. Efficacy of anti-inflammatory treatment on major depressive disorder or depressive symptoms: meta-analysis of clinical trials. Acta Psychiatr Scand. 2019;139:404–19.

    Article  PubMed  Google Scholar 

  178. Paolucci EM, Loukov D, Bowdish DME, Heisz JJ. Exercise reduces depression and inflammation but intensity matters. Biol Psychol. 2018;133:79–84.

    Article  PubMed  Google Scholar 

  179. Milaneschi Y, Bandinelli S, Penninx BW, Vogelzangs N, Corsi AM, Lauretani F, et al. Depressive symptoms and inflammation increase in a prospective study of older adults: a protective effect of a healthy (Mediterranean-style) diet. Mol Psychiatry. 2011;16:589–90.

    Article  CAS  PubMed  Google Scholar 

  180. Rosenkranz MA, Davidson RJ, Maccoon DG, Sheridan JF, Kalin NH, Lutz A. Active control in modulation of neurogenic inflammation. Brain Behav Immun. 2013;27C:174–84.

    Article  Google Scholar 

  181. Woods JA, Wilund KR, Martin SA, Kistler BM. Exercise, inflammation and aging. Aging Dis. 2012;3:130–40.

    PubMed  Google Scholar 

  182. Lopresti AL. Cognitive behaviour therapy and inflammation: a systematic review of its relationship and the potential implications for the treatment of depression. Aust NZ J Psychiatry. 2017;51:565–82.

    Article  Google Scholar 

  183. Cipriani A, Zhou X, Del Giovane C, Hetrick SE, Qin B, Whittington C, et al. Comparative efficacy and tolerability of antidepressants for major depressive disorder in children and adolescents: a network meta-analysis. Lancet. 2016;388:881–90.

    Article  CAS  PubMed  Google Scholar 

  184. Cipriani A, Furukawa TA, Salanti G, Chaimani A, Atkinson LZ, Ogawa Y, et al. Comparative efficacy and acceptability of 21 antidepressant drugs for the acute treatment of adults with major depressive disorder: a systematic review and network meta-analysis. Lancet. 2018;391:1357–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Köhler CA, Freitas TH, Stubbs B, Maes M, Solmi M, Veronese N, et al. Peripheral alterations in cytokine and chemokine levels after antidepressant drug treatment for major depressive disorder: systematic review and meta-analysis. Mol Neurobiol. 2018;55:4195–206.

    PubMed  Google Scholar 

  186. Keles S, Idsoe T. A meta-analysis of group Cognitive Behavioral Therapy (CBT) interventions for adolescents with depression. J Adolesc. 2018;67:129–39.

    Article  PubMed  Google Scholar 

  187. Cuijpers P, van Straten A, Andersson G, van Oppen P. Psychotherapy for depression in adults: a meta-analysis of comparative outcome studies. J Consult Clin Psychol. 2008;76:909–22.

    Article  PubMed  Google Scholar 

  188. O’Toole MS, Bovbjerg DH, Renna ME, Lekander M, Mennin DS, Zachariae R. Effects of psychological interventions on systemic levels of inflammatory biomarkers in humans: a systematic review and meta-analysis. Brain Behav Immun. 2018;74:68–78.

    Article  PubMed  Google Scholar 

  189. Bailey AP, Hetrick SE, Rosenbaum S, Purcell R, Parker AG. Treating depression with physical activity in adolescents and young adults: a systematic review and meta-analysis of randomised controlled trials. Psychol Med. 2018;48:1068–83.

    Article  CAS  PubMed  Google Scholar 

  190. Kvam S, Kleppe CL, Nordhus IH, Hovland A. Exercise as a treatment for depression: a meta-analysis. J Affect Disord. 2016;202:67–86.

    Article  PubMed  Google Scholar 

  191. Chi X, Bo A, Liu T, Zhang P, Chi I. Effects of mindfulness-based stress reduction on depression in adolescents and young adults: a systematic review and meta-analysis. Front Psychol. 2018;9:1–11.

    Article  CAS  Google Scholar 

  192. Blanck P, Perleth S, Heidenreich T, Kröger P, Ditzen B, Bents H, et al. Effects of mindfulness exercises as stand-alone intervention on symptoms of anxiety and depression: systematic review and meta-analysis. Behav Res Ther. 2018;102:25–35.

    Article  PubMed  Google Scholar 

  193. Allison DJ, Sharma B, Timmons BW. The efficacy of anti-inflammatory treatment interventions on depression in individuals with major depressive disorder and high levels of inflammation: a systematic review of randomized clinical trials. Physiol Behav. 2019;207:104–12.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was funded by a Wellcome Trust Mental Health Priority Area ‘Active Ingredients’ commission awarded to LS at Orygen. LS is supported by a NHMRC Career Development Fellowship (1140764), and the Dame Kate Campbell Fellowship from the Faculty of Medicine, Dentistry and Health Sciences at The University of Melbourne. CGD is supported by an NHMRC Career Development Award (141738). MB is supported by a NHMRC Senior Principal Research Fellowship (1156072). FL is supported by ZonMw: The Netherlands Organisation for Health Research and Development (project number: 636310017).

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  1. These authors contributed equally: Yara J. Toenders, Liliana Laskaris.

Authors and Affiliations

  1. Orygen, Parkville, VIC, Australia

    Yara J. Toenders, Liliana Laskaris, Michael Berk & Lianne Schmaal

  2. Centre for Youth Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Yara J. Toenders, Liliana Laskaris, Michael Berk & Lianne Schmaal

  3. Department of Psychiatry, The University of Melbourne, Melbourne, VIC, Australia

    Christopher G. Davey & Michael Berk

  4. IMPACT—the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Deakin University, Geelong, VIC, Australia

    Michael Berk

  5. Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia

    Michael Berk

  6. Department of Psychiatry, Amsterdam UMC, Department of Amsterdam Public Health Research Institute and Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, Netherlands

    Yuri Milaneschi, Femke Lamers & Brenda W. J. H. Penninx

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The literature search was conducted by YJT and LL, and this process was supervised by LS. All authors contributed to writing and reviewing of the paper.

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Correspondence to Lianne Schmaal.

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Competing interests

MB is a co-inventor of two provisional patents regarding the use of NAC and related compounds for psychiatric indications, which, while assigned to the Mental Health Research Institute, could lead to personal remuneration upon a commercialisation event. MB has served as a speaker for Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck, Merck, Pfizer, Sanofi Synthelabo, Servier, Solvay, and Wyeth; and has served as a consultant to Astra Zeneca, Bristol Myers Squibb, Eli Lilly, Glaxo SmithKline, Janssen Cilag, Lundbeck Merck, and Servier. BP has received (non-related) research funding from Jansen Research and Boehringer Ingelheim. The other authors report no competing interests.

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Toenders, Y.J., Laskaris, L., Davey, C.G. et al. Inflammation and depression in young people: a systematic review and proposed inflammatory pathways. Mol Psychiatry 27, 315–327 (2022). https://doi.org/10.1038/s41380-021-01306-8

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