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Associations of C-reactive protein and interleukin-6 with cognitive symptoms of depression: 12-year follow-up of the Whitehall II study

  • D. Gimeno (a1), M. Kivimäki (a1) (a2), E. J. Brunner (a1), M. Elovainio (a2) (a3), R. De Vogli (a1), A. Steptoe (a4), M. Kumari (a1), G. D. O. Lowe (a5), A. Rumley (a5), M. G. Marmot (a1) and J. E. Ferrie (a1)
  • DOI:
  • Published online: 04 June 2008

A lack of longitudinal studies has made it difficult to establish the direction of associations between circulating concentrations of low-grade chronic inflammatory markers, such as C-reactive protein and interleukin-6, and cognitive symptoms of depression. The present study sought to assess whether C-reactive protein and interleukin-6 predict cognitive symptoms of depression or whether these symptoms predict inflammatory markers.


In a prospective occupational cohort study of British white-collar civil servants (the Whitehall II study), serum C-reactive protein, interleukin-6 and cognitive symptoms of depression were measured at baseline in 1991–1993 and at follow-up in 2002–2004, an average follow-up of 11.8 years. Symptoms of depression were measured with four items describing cognitive symptoms of depression from the General Health Questionnaire. The number of participants varied between 3339 and 3070 (mean age 50 years, 30% women) depending on the analysis.


Baseline C-reactive protein (β=0.046, p=0.004) and interleukin-6 (β=0.046, p=0.005) predicted cognitive symptoms of depression at follow-up, while baseline symptoms of depression did not predict inflammatory markers at follow-up. After full adjustment for sociodemographic, behavioural and biological risk factors, health conditions, medication use and baseline cognitive systems of depression, baseline C-reactive protein (β=0.038, p=0.036) and interleukin-6 (β=0.041, p=0.018) remained predictive of cognitive symptoms of depression at follow-up.


These findings suggest that inflammation precedes depression at least with regard to the cognitive symptoms of depression.

Corresponding author
*Address for correspondence: D. Gimeno, Ph.D., International Institute for Society and Health, Department of Epidemiology and Public Health, University College London, 1–19 Torrington Place, London WC1E 6BT, UK. (Email:
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MA Bremmer , AT Beekman , DJ Deeg , BW Penninx , MG Dik , CE Hack , WJ Hoogendijk (2008). Inflammatory markers in late-life depression: results from a population-based study. Journal of Affective Disorders 106, 249255.

E Brunner , G Davey Smith , M Marmot , R Canner , M Beksinska , J O'Brien (1996). Childhood social circumstances and psychosocial and behavioural factors as determinants of plasma fibrinogen. Lancet 347, 10081013.

E Brunner , MJ Shipley , D Blane , GD Smith , MG Marmot (1999). When does cardiovascular risk start? Past and present socioeconomic circumstances and risk factors in adulthood. Journal of Epidemiology and Community Health 53, 757764.

RM Carney , KE Freedland , GE Miller , AS Jaffe (2002). Depression as a risk factor for cardiac mortality and morbidity: a review of potential mechanisms. Journal of Psychosomatic Research 53, 897902.

JM Cyranowski , AL Marsland , JT Bromberger , TL Whiteside , Y Chang , KA Matthews (2007). Depressive symptoms and production of proinflammatory cytokines by peripheral blood mononuclear cells stimulated in vitro. Brain, Behavior, and Immunity 21, 229237.

A Danese , CA Pariante , A Caspi , A Taylor , R Poulton (2007). Childhood maltreatment predicts adult inflammation in a life-course study. Proceedings of the National Academy of Sciences USA 104, 13191324.

J Danesh , JG Wheeler , GM Hirschfield , S Eda , G Eiriksdottir , A Rumley , GD Lowe , MB Pepys , V Gudnason (2004). C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease. New England Journal of Medicine 350, 13871397.

R Dantzer , KW Kelley (2007). Twenty years of research on cytokine-induced sickness behavior. Brain, Behavior, and Immunity 21, 153160.

AN Dentino , CF Pieper , MK Rao , MS Currie , T Harris , DG Blazer , HJ Cohen (1999). Association of interleukin-6 and other biologic variables with depression in older people living in the community. Journal of the American Geriatrics Society 47, 611.

J Fogel , WW Eaton , DE Ford (2006). Minor depression as a predictor of the first onset of major depressive disorder over a 15-year follow-up. Acta Psychiatrica Scandinavica 113, 3643.

DE Ford , TP Erlinger (2004). Depression and C-reactive protein in US adults: data from the Third National Health and Nutrition Examination Survey. Archives of Internal Medicine 164, 10101014.

JK Kiecolt-Glaser , L McGuire , TF Robles , R Glaser (2002). Emotions, morbidity, and mortality: new perspectives from psychoneuroimmunology. Annual Review of Psychology 53, 83107.

A Kingman , G Zion (1994). Some power considerations when deciding to use transformations. Statistics in Medicine 13, 769783.

M Kumari , J Head , M Marmot (2004). Prospective study of social and other risk factors for incidence of type 2 diabetes in the Whitehall II study. Archives of Internal Medicine 164, 18731880.

HK Kuo , CJ Yen , CH Chang , CK Kuo , JH Chen , F Sorond (2005). Relation of C-reactive protein to stroke, cognitive disorders, and depression in the general population: systematic review and meta-analysis. Lancet Neurology 4, 371380.

H Kuper , M Marmot (2003). Job strain, job demands, decision latitude, and risk of coronary heart disease within the Whitehall II study. Journal of Epidemiology and Community Health 57, 147153.

CY Li , FC Sung (1999). A review of the healthy worker effect in occupational epidemiology. Occupational Medicine 49, 225229.

T Liukkonen , S Silvennoinen-Kassinen , J Jokelainen , P Rasanen , M Leinonen , VB Meyer-Rochow , M Timonen (2006). The association between C-reactive protein levels and depression: results from the northern Finland 1966 birth cohort study. Biological Psychiatry 60, 825830.

M Maes , HY Meltzer , E Bosmans , R Bergmans , E Vandoolaeghe , R Ranjan , R Desnyder (1995 a). Increased plasma concentrations of interleukin-6, soluble interleukin-6, soluble interleukin-2 and transferrin receptor in major depression. Journal of Affective Disorders 34, 301309.

M Maes , E Vandoolaeghe , R Ranjan , E Bosmans , R Bergmans , R Desnyder (1995 b). Increased serum interleukin-1-receptor-antagonist concentrations in major depression. Journal of Affective Disorders 36, 2936.

GB Mancini , B Dahlof , J Diez (2004). Surrogate markers for cardiovascular disease: structural markers. Circulation 109 (Suppl. 1), IV22IV30.

M Marmot , E Brunner (2005). Cohort profile: the Whitehall II study. International Journal of Epidemiology 34, 251256.

MG Marmot , GD Smith , S Stansfeld , C Patel , F North , J Head , I White , E Brunner , A Feeney (1991). Health inequalities among British civil servants: the Whitehall II study. Lancet 337, 13871393.

GL Myers , N Rifai , RP Tracy , WL Roberts , RW Alexander , LM Biasucci , JD Catravas , TG Cole , GR Cooper , BV Khan , MM Kimberly , EA Stein , KA Taubert , GR Warnick , PP Waymack (2004). CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the laboratory science discussion group. Circulation 110, e545e549.

A Nicholson , R Fuhrer , M Marmot (2005). Psychological distress as a predictor of CHD events in men: the effect of persistence and components of risk. Psychosomatic Medicine 67, 522530.

TW Pace , TC Mletzko , O Alagbe , DL Musselman , CB Nemeroff , AH Miller , CM Heim (2006). Increased stress-induced inflammatory responses in male patients with major depression and increased early life stress. American Journal of Psychiatry 163, 16301633.

BW Penninx , SB Kritchevsky , K Yaffe , AB Newman , EM Simonsick , S Rubin , L Ferrucci , T Harris , M Pahor (2003). Inflammatory markers and depressed mood in older persons: results from the Health, Aging and Body Composition study. Biological Psychiatry 54, 566572.

AD Pradhan , JE Manson , N Rifai , JE Buring , PM Ridker (2001). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Journal of the American Medical Association 286, 327334.

CL Raison , L Capuron , AH Miller (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 2431.

N Ranjit , AV Diez-Roux , S Shea , M Cushman , T Seeman , SA Jackson , H Ni (2007). Psychosocial factors and inflammation in the multi-ethnic study of atherosclerosis. Archives of Internal Medicine 167, 174181.

RB Sothern , B Roitman-Johnson , EL Kanabrocki , JG Yager , MM Roodell , JA Weatherbee , MR Young , BM Nenchausky , LE Scheving (1995). Circadian characteristics of circulating interleukin-6 in men. Journal of Allergy and Clinical Immunology 95, 10291035.

SA Stansfeld , J Head , R Fuhrer , J Wardle , V Cattell (2003). Social inequalities in depressive symptoms and physical functioning in the Whitehall II study: exploring a common cause explanation. Journal of Epidemiology and Community Health 57, 361367.

JC Stewart , DL Janicki , MF Muldoon , K Sutton-Tyrrell , TW Kamarck (2007). Negative emotions and 3-year progression of subclinical atherosclerosis. Archives of General Psychiatry 64, 225233.

H Tiemeier , A Hofman , HR van Tuijl , AJ Kiliaan , J Meijer , MM Breteler (2003). Inflammatory proteins and depression in the elderly. Epidemiology 14, 103107.

M Wichers , M Maes (2002). The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. International Journal of Neuropsychopharmacology 5, 375388.

M Woodward , A Rumley , GD Lowe , H Tunstall-Pedoe (2003). C-reactive protein: associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease. British Journal of Haematology 122, 135141.

M Woodward , A Rumley , H Tunstall-Pedoe , GD Lowe (1999). Associations of blood rheology and interleukin-6 with cardiovascular risk factors and prevalent cardiovascular disease. British Journal of Haematology 104, 246257.

K Yaffe , A Kanaya , K Lindquist , EM Simonsick , T Harris , RI Shorr , FA Tylavsky , AB Newman (2004). The metabolic syndrome, inflammation, and risk of cognitive decline. Journal of the American Medical Association 292, 22372242.

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