Prevalence of low-grade inflammation in depression: a systematic review and meta-analysis of CRP levels

Emanuele Felice Osimo, Luke James Baxter, Glyn Lewis, Peter B Jones, Golam M Khandaker, Emanuele Felice Osimo, Luke James Baxter, Glyn Lewis, Peter B Jones, Golam M Khandaker

Abstract

Background: Peripheral low-grade inflammation in depression is increasingly seen as a therapeutic target. We aimed to establish the prevalence of low-grade inflammation in depression, using different C-reactive protein (CRP) levels, through a systematic literature review and meta-analysis.

Methods: We searched the PubMed database from its inception to July 2018, and selected studies that assessed depression using a validated tool/scale, and allowed the calculation of the proportion of patients with low-grade inflammation (CRP >3 mg/L) or elevated CRP (>1 mg/L).

Results: After quality assessment, 37 studies comprising 13 541 depressed patients and 155 728 controls were included. Based on the meta-analysis of 30 studies, the prevalence of low-grade inflammation (CRP >3 mg/L) in depression was 27% (95% CI 21-34%); this prevalence was not associated with sample source (inpatient, outpatient or population-based), antidepressant treatment, participant age, BMI or ethnicity. Based on the meta-analysis of 17 studies of depression and matched healthy controls, the odds ratio for low-grade inflammation in depression was 1.46 (95% CI 1.22-1.75). The prevalence of elevated CRP (>1 mg/L) in depression was 58% (95% CI 47-69%), and the meta-analytic odds ratio for elevated CRP in depression compared with controls was 1.47 (95% CI 1.18-1.82).

Conclusions: About a quarter of patients with depression show evidence of low-grade inflammation, and over half of patients show mildly elevated CRP levels. There are significant differences in the prevalence of low-grade inflammation between patients and matched healthy controls. These findings suggest that inflammation could be relevant to a large number of patients with depression.

Keywords: C-reactive protein; CRP; depression; immunopsychiatry; inflammation; low-grade inflammation; meta-analysis; mood; prevalence; review.

Figures

Fig. 1.
Fig. 1.
Prevalence of low-grade inflammation (CRP >3 mg/L) in depressed patients.
Fig. 2.
Fig. 2.
Odds ratio for low-grade inflammation (CRP >3 mg/L) in depressed patients compared with matched controls.
Fig. 3.
Fig. 3.
Prevalence of elevated CRP (>1 mg/L) in depressed patients.
Fig. 4.
Fig. 4.
Odds ratio for elevated CRP (>1 mg/L) in depressed patients compared with matched controls.

References

    1. Almeida OP, Flicker L, Norman P, Hankey GJ, Vasikaran S, van Bockxmeer FM and Jamrozik K (2007) Association of cardiovascular risk factors and disease with depression in later life. The American Journal of Geriatric Psychiatry 15, 506–513.
    1. Benedetti F, Lucca A, Brambilla F, Colombo C and Smeraldi E (2002) Interleukine-6 serum levels correlate with response to antidepressant sleep deprivation and sleep phase advance. Progress in Neuro-psychopharmacology and Biological Psychiatry 26, 1167–1170.
    1. Benros ME, Waltoft BL, Nordentoft M, Østergaard SD, Eaton WW, Krogh J and Mortensen PB (2013) Autoimmune diseases and severe infections as risk factors for mood disorders: a nationwide study. JAMA Psychiatry 70, 812–820.
    1. Cáceda R, Griffin WST and Delgado PL (2018) A probe in the connection between inflammation, cognition and suicide. Journal of Psychopharmacology 32, 482–488.
    1. Carvalho L, Torre J, Papadopoulos A, Poon L, Juruena M, Markopoulou K, Cleare A and Pariante C (2013) Lack of clinical therapeutic benefit of antidepressants is associated overall activation of the inflammatory system. Journal of Affective Disorders 148, 136–140.
    1. Cepeda MS, Stang P and Makadia R (2016) Depression is associated with high levels of C-reactive protein and low levels of fractional exhaled nitric oxide: results from the 2007–2012 national health and nutrition examination surveys. The Journal of Clinical Psychiatry 77, 1666–1671.
    1. Chamberlain SR, Cavanagh J, de Boer P, Mondelli V, Jones DN, Drevets WC, Cowen PJ, Harrison NA, Pointon L and Pariante CM (2018) Treatment-resistant depression and peripheral C-reactive protein. The British Journal of Psychiatry, 1–9.
    1. Cizza G, Eskandari F, Coyle M, Krishnamurthy P, Wright E, Mistry S and Csako G (2009) Plasma CRP levels in premenopausal women with major depression: a 12-month controlled study. Hormone and Metabolic Research 41, 641.
    1. Courtet P, Jaussent I, Genty C, Dupuy A, Guillaume S, Ducasse D and Olie E (2015) Increased CRP levels may be a trait marker of suicidal attempt. European Neuropsychopharmacology 25, 1824–1831.
    1. Danese A, Moffitt TE, Pariante CM, Ambler A, Poulton R and Caspi A (2008) Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Archives of General Psychiatry 65, 409–415.
    1. Danesh J, Whincup P, Walker M, Lennon L, Thomson A, Appleby P, Gallimore JR and Pepys MB (2000) Low grade inflammation and coronary heart disease: prospective study and updated meta-analyses. British Medical Journal 321, 199–204.
    1. Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB and Gudnason V (2004) C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. New England Journal of Medicine 350, 1387–1397.
    1. Danesh J, Kaptoge S, Mann AG, Sarwar N, Wood A, Angleman SB, Wensley F, Higgins JP, Lennon L and Eiriksdottir G (2008) Long-term interleukin-6 levels and subsequent risk of coronary heart disease: two new prospective studies and a systematic review. PLoS Medicine 5, e78.
    1. Dantzer R, O'Connor JC, Freund GG, Johnson RW and Kelley KW (2008) From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 46.
    1. Dickens C, McGowan L, Clark-Carter D and Creed F (2002) Depression in rheumatoid arthritis: a systematic review of the literature with meta-analysis. Psychosomatic Medicine 64, 52–60.
    1. Dowlati Y, Herrmann N, Swardfager W, Liu H, Sham L, Reim EK and Lanctôt KL (2010) A meta-analysis of cytokines in major depression. Biological Psychiatry 67, 446–457.
    1. Ekinci O and Ekinci A (2017) The connections among suicidal behavior, lipid profile and low-grade inflammation in patients with major depressive disorder: a specific relationship with the neutrophil-to-lymphocyte ratio. Nordic Journal of Psychiatry 71, 574–580.
    1. Euteneuer F, Dannehl K, Del Rey A, Engler H, Schedlowski M and Rief W (2017) Immunological effects of behavioral activation with exercise in major depression: an exploratory randomized controlled trial. Translational Psychiatry 7, e1132.
    1. Feighner JP, Robins E, Guze SB, Woodruff RA, Winokur G and Munoz R (1972) Diagnostic criteria for use in psychiatric research. Archives of General Psychiatry 26, 57–63.
    1. Felger JC, Haroon E, Patel TA, Goldsmith DR, Wommack EC, Woolwine BJ, Le N-A, Feinberg R, Tansey MG and Miller AH (2018) What does plasma CRP tell us about peripheral and central inflammation in depression? Molecular Psychiatry, epub ahead of print
    1. Fernandes B, Steiner J, Bernstein H, Dodd S, Pasco J, Dean O, Nardin P, Goncalves C and Berk M (2016) C-reactive protein is increased in schizophrenia but is not altered by antipsychotics: meta-analysis and implications. Molecular Psychiatry 21, 554.
    1. Ford ES, Giles WH, Mokdad AH and Myers GL (2004) Distribution and correlates of C-reactive protein concentrations among adult US women. Clinical Chemistry 50, 574–581.
    1. Gallagher D, Kiss A, Lanctot K and Herrmann N (2017) Depression with inflammation: longitudinal analysis of a proposed depressive subtype in community dwelling older adults. International Journal of Geriatric Psychiatry 32, e18–e24.
    1. Gimeno D, Kivimäki M, Brunner EJ, Elovainio M, De Vogli R, Steptoe A, Kumari M, Lowe GD, Rumley A and Marmot MG (2009) Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study. Psychological Medicine 39, 413–423.
    1. Goldsmith D, Rapaport M and Miller B (2016) A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Molecular Psychiatry 21, 1696–1709.
    1. Haapakoski R, Mathieu J, Ebmeier KP, Alenius H and Kivimäki M (2015) Cumulative meta-analysis of interleukins 6 and 1β, tumour necrosis factor α and C-reactive protein in patients with major depressive disorder. Brain, Behavior, and Immunity 49, 206–215.
    1. Hannestad J, DellaGioia N, Gallezot J-D, Lim K, Nabulsi N, Esterlis I, Pittman B, Lee J-Y, O'Connor KC and Pelletier D (2013) The neuroinflammation marker translocator protein is not elevated in individuals with mild-to-moderate depression: a [11C] PBR28 PET study. Brain, Behavior, and Immunity 33, 131–138.
    1. Hare DL, Toukhsati SR, Johansson P and Jaarsma T (2013) Depression and cardiovascular disease: a clinical review. European Heart Journal 35, 1365–1372.
    1. Harley J, Luty S, Carter J, Mulder R and Joyce P (2010) Elevated C-reactive protein in depression: a predictor of good long-term outcome with antidepressants and poor outcome with psychotherapy. Journal of Psychopharmacology 24, 625.
    1. Haroon E, Fleischer C, Felger J, Chen X, Woolwine B, Patel T, Hu X and Miller A (2016) Conceptual convergence: increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Molecular Psychiatry 21, 1351.
    1. Higgins J and Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Statistics in Medicine 21, 1539–1558.
    1. Horsdal H, Köhler-Forsberg O, Benros M and Gasse C (2017) C-reactive protein and white blood cell levels in schizophrenia, bipolar disorders and depression-associations with mortality and psychiatric outcomes: a population-based study. European Psychiatry 44, 164–172.
    1. Howren MB, Lamkin DM and Suls J (2009) Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomatic Medicine 71, 171–186.
    1. IL6R Genetics Consortium Emerging Risk Factors Collaboration (2012) Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. The Lancet 379, 1205–1213.
    1. Interleukin-6 Receptor Mendelian Randomisation Analysis Consortium (2012) The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. The Lancet 379, 1214–1224.
    1. Jha MK, Minhajuddin A, Gadad BS, Greer T, Grannemann B, Soyombo A, Mayes TL, Rush AJ and Trivedi MH (2017) Can C-reactive protein inform antidepressant medication selection in depressed outpatients? Findings from the CO-MED trial. Psychoneuroendocrinology 78, 105–113.
    1. Kappelmann N, Lewis G, Dantzer R, Jones PB and Khandaker GM (2018) Antidepressant activity of anti-cytokine treatment: a systematic review and meta-analysis of clinical trials of chronic inflammatory conditions. Molecular Psychiatry 23, 335.
    1. Khandaker GM, Pearson RM, Zammit S, Lewis G and Jones PB (2014) Association of serum interleukin 6 and C-reactive protein in childhood with depression and psychosis in young adult life: a population-based longitudinal study. JAMA Psychiatry 71, 1121–1128.
    1. Khandaker GM, Cousins L, Deakin J, Lennox BR, Yolken R and Jones PB (2015) Inflammation and immunity in schizophrenia: implications for pathophysiology and treatment. The Lancet Psychiatry 2, 258–270.
    1. Khandaker GM, Dantzer R and Jones PB (2017) Immunopsychiatry: important facts. Psychological Medicine 47, 2229–2237.
    1. Khandaker GM, Oltean BP, Kaser M, Dibben CR, Ramana R, Jadon DR, Dantzer R, Coles AJ, Lewis G and Jones PB (2018) Protocol for the insight study: a randomised controlled trial of single-dose tocilizumab in patients with depression and low-grade inflammation. BMJ Open 8, e025333.
    1. Khandaker GM, Zuber V, Rees JMB, Carvalho L, Mason AM, Foley CN, Gkatzionis A, Jones PB and Burgess S (2019) Shared mechanism between depression and coronary heart disease: findings from Mendelian randomization analysis of a large UK population-based cohort. Molecular Psychiatry, epub ahead of print.
    1. Khera A, McGuire DK, Murphy SA, Stanek HG, Das SR, Vongpatanasin W, Wians FH, Grundy SM and de Lemos JA (2005) Race and gender differences in C-reactive protein levels. Journal of the American College of Cardiology 46, 464–469.
    1. Kling MA, Alesci S, Csako G, Costello R, Luckenbaugh DA, Bonne O, Duncko R, Drevets WC, Manji HK and Charney DS (2007) Sustained low-grade pro-inflammatory state in unmedicated, remitted women with major depressive disorder as evidenced by elevated serum levels of the acute phase proteins C-reactive protein and serum amyloid A. Biological Psychiatry 62, 309–313.
    1. Köhler O, Benros ME, Nordentoft M, Farkouh ME, Iyengar RL, Mors O and Krogh J (2014) Effect of anti-inflammatory treatment on depression, depressive symptoms, and adverse effects: a systematic review and meta-analysis of randomized clinical trials. JAMA Psychiatry 71, 1381–1391.
    1. Ladwig K-H, Marten-Mittag B, Löwel H, Döring A and Koenig W (2005) C-reactive protein, depressed mood, and the prediction of coronary heart disease in initially healthy men: results from the MONICA–KORA Augsburg Cohort Study 1984–1998. European Heart Journal 26, 2537–2542.
    1. Lanquillon S, Krieg J-C, Bening-Abu-Shach U and Vedder H (2000) Cytokine production and treatment response in major depressive disorder. Neuropsychopharmacology 22, 370–379.
    1. Legros S, Mendlewicz J and Wybran J (1985) Immunoglobulins, autoantibodies and other serum protein fractions in psychiatric disorders. European Archives of Psychiatry and Neurological Sciences 235, 9–11.
    1. Li Y, Zhong X, Cheng G, Zhao C, Zhang L, Hong Y, Wan Q, He R and Wang Z (2017) Hs-CRP and all-cause, cardiovascular, and cancer mortality risk: a meta-analysis. Atherosclerosis 259, 75–82.
    1. Lim GY, Tam WW, Lu Y, Ho CS, Zhang MW and Ho RC (2018) Prevalence of depression in the community from 30 countries between 1994 and 2014. Scientific Reports 8, 2861.
    1. Liukkonen T, Silvennoinen-Kassinen S, Jokelainen J, Räsänen P, Leinonen M, Meyer-Rochow VB and Timonen M (2006) The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biological Psychiatry 60, 825–830.
    1. Ma Y, Chiriboga DE, Pagoto SL, Rosal MC, Li W, Merriam PA, Hébert JR, Whited MC and Ockene IS (2011) Association between depression and C-reactive protein. Cardiology Research and Practice 2011, 286509.
    1. Maes M, Bosmans E, De Jongh R, Kenis G, Vandoolaeghe E and Neels H (1997) Increased serum IL-6 and IL-1 receptor antagonist concentrations in major depression and treatment resistant depression. Cytokine 9, 853–858.
    1. Miller BJ, Buckley P, Seabolt W, Mellor A and Kirkpatrick B (2011) Meta-analysis of cytokine alterations in schizophrenia: clinical status and antipsychotic effects. Biological Psychiatry 70, 663–671.
    1. Müller N, Schwarz M, Dehning S, Douhe A, Cerovecki A, Goldstein-Müller B, Spellmann I, Hetzel G, Maino K and Kleindienst N (2006) 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. Molecular Psychiatry 11, 680.
    1. Naghashpour M, Amani R, Nematpour S and Haghighizadeh MH (2011) Riboflavin status and its association with serum hs-CRP levels among clinical nurses with depression. Journal of the American College of Nutrition 30, 340–347.
    1. Nicholson A, Kuper H and Hemingway H (2006) Depression as an aetiologic and prognostic factor in coronary heart disease: a meta-analysis of 6362 events among 146 538 participants in 54 observational studies. European Heart Journal 27, 2763–2774.
    1. Nilsson K, Gustafson L and Hultberg B (2008) C-reactive protein: vascular risk marker in elderly patients with mental illness. Dementia and Geriatric Cognitive Disorders 26, 251–256.
    1. O'brien SM, Scott LV and Dinan TG (2006) Antidepressant therapy and C-reactive protein levels. The British Journal of Psychiatry 188, 449–452.
    1. Osimo E, Baxter L, Jones P and Khandaker G (2018a) Prevalence of low-grade inflammation in depression: a review and meta-analysis of CRP data. PROSPERO. Available at .
    1. Osimo EF, Cardinal RN, Jones PB and Khandaker GM (2018b) Prevalence and correlates of low-grade systemic inflammation in adult psychiatric inpatients: an electronic health record-based study. Psychoneuroendocrinology 91, 226–234.
    1. Park S, Joo YH, McIntyre RS and Kim B (2014) Metabolic syndrome and elevated C-reactive protein levels in elderly patients with newly diagnosed depression. Psychosomatics 55, 640–649.
    1. Parloff MB, Kelman HC and Frank JD (1954) Comfort, effectiveness, and self-awareness as criteria of improvement in psychotherapy. American Journal of Psychiatry 111, 343–352.
    1. Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon III RO, Criqui M, Fadl YY, Fortmann SP, Hong Y and Myers GL (2003) Markers of inflammation and cardiovascular disease: application to clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 107, 499–511.
    1. Penninx BW, Kritchevsky SB, Yaffe K, Newman AB, Simonsick EM, Rubin S, Ferrucci L, Harris T and Pahor M (2003) Inflammatory markers and depressed mood in older persons: results from the health, aging and body composition study. Biological Psychiatry 54, 566–572.
    1. Porcu M, Urbano MR, Verri WA Jr, Barbosa DS, Baracat M, Vargas HO, Machado RCBR, Pescim RR and Nunes SOV (2018) Effects of adjunctive N-acetylcysteine on depressive symptoms: modulation by baseline high-sensitivity C-reactive protein. Psychiatry Research 263, 268–274.
    1. Pradhan AD, Manson JE, Rifai N, Buring JE and Ridker PM (2001) C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA 286, 327–334.
    1. Pradhan AD, Manson JE, Rossouw JE, Siscovick DS, Mouton CP, Rifai N, Wallace RB, Jackson RD, Pettinger MB and Ridker PM (2002) Inflammatory biomarkers, hormone replacement therapy, and incident coronary heart disease: prospective analysis from the Women's Health Initiative observational study. JAMA 288, 980–987.
    1. Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, Haroon E and Miller AH (2013) A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry 70, 31–41.
    1. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R and Mischoulon D (2016) Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Molecular Psychiatry 21, 71.
    1. R Core Team (2017). R: A Language and Environment for Statistical Computing [Software]. Vienna, Austria: R Foundation for Statistical Computing.
    1. Ridker PM (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107, 363–369.
    1. Schmidt R, Schmidt H, Curb JD, Masaki K, White LR and Launer LJ (2002) Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Annals of Neurology 52, 168–174.
    1. Schwarzer G (2007) Meta’: an R package for meta-analysis: R news, 7, 40–45.
    1. Shanahan L, Copeland WE, Worthman CM, Angold A and Costello EJ (2013) Children with both asthma and depression are at risk for heightened inflammation. The Journal of Pediatrics 163, 1443–1447.
    1. Shibata M, Ohara T, Yoshida D, Hata J, Mukai N, Kawano H, Kanba S, Kitazono T and Ninomiya T (2018) Association between the ratio of serum arachidonic acid to eicosapentaenoic acid and the presence of depressive symptoms in a general Japanese population: the Hisayama Study. Journal of Affective Disorders 237, 73–79.
    1. Shin Y-C, Jung C-H, Kim H-J, Kim E-J and Lim S-W (2016) The associations among vitamin D deficiency, C-reactive protein, and depressive symptoms. Journal of Psychosomatic Research 90, 98–104.
    1. Sluzewska A, Sobieska M and Rybakowski J (1997) Changes in acute-phase proteins during lithium potentiation of antidepressants in refractory depression. Neuropsychobiology 35, 123–127.
    1. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. European Journal of Epidemiology 25, 603–605.
    1. Sun Y, Wang D, Salvadore G, Hsu B, Curran M, Casper C, Vermeulen J, Kent JM, Singh J and Drevets WC (2017) The effects of interleukin-6 neutralizing antibodies on symptoms of depressed mood and anhedonia in patients with rheumatoid arthritis and multicentric Castleman's disease. Brain, Behavior, and Immunity 66, 156–164.
    1. Sung K-C, Ryu S, Chang Y, Byrne CD and Kim SH (2014) C-reactive protein and risk of cardiovascular and all-cause mortality in 268 803 East Asians. European Heart Journal 35, 1809–1816.
    1. Uher R, Tansey KE, Dew T, Maier W, Mors O, Hauser J, Dernovsek MZ, Henigsberg N, Souery D and Farmer A (2014) An inflammatory biomarker as a differential predictor of outcome of depression treatment with escitalopram and nortriptyline. American Journal of Psychiatry 171, 1278–1286.
    1. Urbanek S and Horner J (2015) Cairo: R graphics device using Cairo graphics library for creating high-quality bitmap (PNG, JPEG, TIFF), vector (PDF, SVG, PostScript) and display (X11 and Win32) output [Software]. CRAN. R-project.
    1. Visser M, Bouter LM, McQuillan GM, Wener MH and Harris TB (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA 282, 2131–2135.
    1. von Känel R, Hepp U, Kraemer B, Traber R, Keel M, Mica L and Schnyder U (2007) Evidence for low-grade systemic proinflammatory activity in patients with posttraumatic stress disorder. Journal of Psychiatric Research 41, 744–752.
    1. von Zerssen D and Cording C (1978) The measurement of change in endogenous affective disorders. Archiv für Psychiatrie und Nervenkrankheiten 226, 95–112.
    1. Wei L, Du Y, Wu W, Fu X and Xia Q (2018) Elevation of plasma neutrophil gelatinase-associated lipocalin (NGAL) levels in schizophrenia patients. Journal of Affective Disorders 226, 307–312.
    1. Wium-Andersen MK, Ørsted DD, Nielsen SF and Nordestgaard BG (2013) Elevated C-reactive protein levels, psychological distress, and depression in 73 131 individuals. JAMA Psychiatry 70, 176–184.
    1. Wium-Andersen MK, Ørsted DD and Nordestgaard BG (2014) Elevated C-reactive protein, depression, somatic diseases, and all-cause mortality: a Mendelian randomization study. Biological Psychiatry 76, 249–257.
    1. Wysokiński A, Margulska A, Strzelecki D and Kłoszewska I (2015) Levels of C-reactive protein (CRP) in patients with schizophrenia, unipolar depression and bipolar disorder. Nordic Journal of Psychiatry 69, 346–353.
    1. Zacho J, Tybjærg-Hansen A and Nordestgaard BG (2010) C-reactive protein and all-cause mortality – the Copenhagen city heart study. European Heart Journal 31, 1624–1632.
    1. Zalli A, Jovanova O, Hoogendijk W, Tiemeier H and Carvalho L (2016) Low-grade inflammation predicts persistence of depressive symptoms. Psychopharmacology 233, 1669–1678.

Source: PubMed

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