Hostname: page-component-745bb68f8f-5r2nc Total loading time: 0 Render date: 2025-01-30T14:32:45.210Z Has data issue: false hasContentIssue false
  • English
  • Français

Generalized anxiety and C-reactive protein levels: a prospective, longitudinal analysis

Published online by Cambridge University Press:  30 April 2012

W. E. Copeland ,
L. Shanahan ,
C. Worthman ,
A. Angold  and
E. J. Costello
W. E. Copeland*
Affiliation:
Duke University Medical Center, Durham, NC, USA
L. Shanahan
Affiliation:
University of North Carolina, Chapel Hill, NC, USA
C. Worthman
Affiliation:
Emory University, Atlanta, GA, USA
A. Angold
Affiliation:
Duke University Medical Center, Durham, NC, USA
E. J. Costello
Affiliation:
Duke University Medical Center, Durham, NC, USA
*
*Address for correspondence: W. E. Copeland, Ph.D., Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Box 3454, Durham, NC 27710, USA. (Email: [email protected])
Get access Rights & Permissions [Opens in a new window]

Abstract

Background

Generalized anxiety disorder (GAD) is highly co-morbid with depression. Depression is associated with elevated levels of the inflammation marker C-reactive protein (CRP), cross-sectionally and over time. To date, no studies have looked at the association between CRP and GAD.

Method

A total of nine waves of data from the prospective population-based Great Smoky Mountains Study (n=1420) were used, covering children in the community aged 9–16, 19 and 21 years old. Structured interviews were used at each assessment to assess GAD symptoms, diagnosis and cumulative episodes. Blood spots were collected and assayed for high-sensitivity CRP levels.

Results

GAD was associated with increased levels of CRP in bivariate cross-sectional analyses. These bivariate associations, however, were attenuated after accounting for demographic, substance-use and health-related covariates. In longitudinal models, there was little evidence that CRP predicted later GAD. Associations from GAD to later CRP were attenuated in models adjusted for health-related coavariates and there was evidence that the GAD–CRP association was mediated by body mass index (BMI) and medication use.

Conclusions

Similar to depression, GAD was associated with elevated levels of CRP, but the effect of GAD on CRP levels was explained by the effect of GAD on health-related behaviors such as BMI and medication use. This study suggests differences in the association between inflammation and depression and GAD.

Keywords

AdolescencechildhoodC-reactive proteinepidemiologygeneralized anxiety disorderinflammation
Type
Original Articles
Information
Psychological Medicine , Volume 42 , Issue 12 , December 2012 , pp. 2641 - 2650
Copyright
Copyright © Cambridge University Press 2012

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

Andrews, G, Hobbs, MJ, Borkovec, TD, Beesdo, K, Craske, MG, Heimberg, RG, Rapee, RM, Ruscio, AM, Stanley, MA (2010). Generalized worry disorder: a review of DSM-IV generalized anxiety disorder and options for DSM-V. Depression and Anxiety 27, 134–147.CrossRefGoogle ScholarPubMed
Angold, A, Costello, E (2000). The Child and Adolescent Psychiatric Assessment (CAPA). Journal of the American Academy of Child and Adolescent Psychiatry 39, 39–48.CrossRefGoogle ScholarPubMed
Angold, A, Costello, EJ (1995). A test–retest reliability study of child-reported psychiatric symptoms and diagnoses using the Child and Adolescent Psychiatric Assessment (CAPA-C). Psychological Medicine 25, 755–762.CrossRefGoogle ScholarPubMed
Angold, A, Costello, EJ, Erkanli, A (1999 a). Comorbidity. Journal of Child Psychology and Psychiatry 40, 57–87.CrossRefGoogle ScholarPubMed
Angold, A, Cox, A, Prendergast, M, Rutter, M, Simonoff, E, Costello, EJ, Ascher, BH (1999 b). The Young Adult Psychiatric Assessment (YAPA). Duke University Medical Center: Durham, NC.Google Scholar
APA (1994). Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV). American Psychiatric Press, Inc.: Washington, DC.Google Scholar
Ascher, BH, Farmer, EMZ, Burns, BJ, Angold, A (1996). The Child and Adolescent Services Assessment (CASA): description and psychometrics. Journal of Emotional and Behavioral Disorders 4, 12–20.CrossRefGoogle Scholar
Baron, RM, Kenny, DA (1986). The moderator–mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations. Journal of Personality and Social Psychology 51, 1173–1182.CrossRefGoogle ScholarPubMed
Copeland, WE, Shanahan, L, Worthman, C, Angold, A, Costello, EJ (2012). Cumulative depression episodes predict later C-reactive protein levels: a prospective analysis. Biological Psychiatry 71, 15–21.CrossRefGoogle ScholarPubMed
Costello, EJ, Angold, A, Burns, B, Stangl, D, Tweed, D, Erkanli, A, Worthman, C (1996). The Great Smoky Mountains Study of Youth: goals, designs, methods, and the prevalence of DSM-III-R disorders. Archives of General Psychiatry 53, 1129–1136.CrossRefGoogle ScholarPubMed
Costello, EJ, Mustillo, S, Erkanli, A, Keeler, G, Angold, A (2003). Prevalence and development of psychiatric disorders in childhood and adolescence. Archives of General Psychiatry 60, 837–844.CrossRefGoogle ScholarPubMed
Danese, A, Moffitt, TE, Pariante, CM, Ambler, A, Poulton, R, Caspi, A (2008). Elevated inflammation levels in depressed adults with a history of childhood maltreatment. Archives of General Psychiatry 65, 409–415.CrossRefGoogle ScholarPubMed
Dantzer, R, O'Connor, JC, Freund, GG, Johnson, RW, Kelley, KW (2008). From inflammation to sickness and depression: when the immune system subjugates the brain. Nature Reviews Neuroscience 9, 46–56.CrossRefGoogle ScholarPubMed
DSM-5 Anxiety Disorders Work Group (2010). Proposed Revisions for Generalized Anxiety Disorder (http://www.dsm5.org/ProposedRevisions/Pages/proposedrevision.aspx?rid=167). American Psychiatric Association: Washington, DC.Google Scholar
Eley, T, Stevenson, J (1999). Exploring the covariation between anxiety and depression symptoms: a genetic analysis of the effects of the age and sex. Journal of Child Psychiatry 40, 1273–1282.CrossRefGoogle ScholarPubMed
Elovainio, M, Keltikangas-Järvinen, L, Pulkki-Råback, L, Kivimäki, M, Puttonen, S, Viikari, L, Räsänen, L, Mansikkaniemi, K, Viikari, J, Raitakari, OT (2006). Depressive symptoms and C-reactive protein: The Cardiovascular Risk in Young Finns Study. Psychological Medicine 36, 797–805.CrossRefGoogle ScholarPubMed
Gimeno, D, Kivimäki, M, Brunner, EJ, Elovainio, M, De Vogli, R, Steptoe, A, Kumari, M, Lowe, GDO, Rumley, A, Marmot, MG, Ferrie, JE (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.CrossRefGoogle ScholarPubMed
Hoehn-Saric, R, McLeod, DR, Lee, YB, Zimmerli, WD (1991). Cortisol levels in generalized anxiety disorder. Psychiatry Research 38, 313–315.CrossRefGoogle ScholarPubMed
Howren, MB, Lamkin, DM, Suls, J (2009). Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosomatic Medicine 71, 171–186.CrossRefGoogle ScholarPubMed
Janicki Deverts, D, Cohen, S, Dilillo, VG, Lewis, CE, Kiefe, C, Whooley, M, Matthews, KA (2010). Depressive symptoms, race, and circulating C-reactive protein: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. Psychosomatic Medicine 72, 734–741.CrossRefGoogle Scholar
Kaufman, J, Martin, A, King, R, Charney, D (2001). Are child-, adolescent-, and adult-onset depression one and the same disorder? Biological Psychiatry 49, 980–1001.CrossRefGoogle ScholarPubMed
Kendler, KS (1996). Major depression and generalised anxiety disorder. Same genes, (partly) different environments – revisited. British Journal of Psychiatry Supplement 30, 68–75.CrossRefGoogle Scholar
Kendler, KS, Gardner, CO, Gatz, M, Pedersen, NL (2007). The sources of co-morbidity between major depression and generalized anxiety disorder in a Swedish national twin sample. Psychological Medicine 37, 453–462.CrossRefGoogle Scholar
Kendler, KS, Walters, EE, Neale, MC, Kessler, RC, Heath, AC, Eaves, LJ (1995). The structure of the genetic and environmental risk factors for six major psychiatric disorders in women. Phobia, generalized anxiety disorder, panic disorder, bulimia, major depression, and alcoholism. Archives of General Psychiatry 52, 374–383.CrossRefGoogle ScholarPubMed
Kessler, RC, Chiu, WT, Demler, O, Walters, EE (2005). Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the national comorbidity survey replication. Archive of General Psychiatry 62, 617–627.CrossRefGoogle ScholarPubMed
Kuzma, JM, Black, DW (2004). Integrating pharmacotherapy and psychotherapy in the management of anxiety disorders. Current Psychiatry Reports 6, 268–273.CrossRefGoogle ScholarPubMed
MacKinnon, D, Lockwood, C, Hoffman, J, West, S, Sheets, V (2002). A comparison of methods to test mediation and other intervening variable effects. Psychological Methods 7, 83–104.CrossRefGoogle ScholarPubMed
Mantella, RC, Butters, MA, Amico, JA, Mazumdar, S, Rollman, BL, Begley, AE, Reynolds, CF, Lenze, EJ (2008). Salivary cortisol is associated with diagnosis and severity of late-life generalized anxiety disorder. Psychoneuroendocrinology 33, 773–781.CrossRefGoogle ScholarPubMed
Matthews, KA, Schott, LL, Bromberger, JT, Cyranowski, JM, Everson-Rose, SA, Sowers, M (2010). Are there bi-directional associations between depressive symptoms and C-reactive protein in mid-life women? Brain Behavior and Immunity 24, 96–101.CrossRefGoogle ScholarPubMed
McDade, TW, Burhop, J, Dohnal, J (2004). High-sensitivity enzyme immunoassay for C-reactive protein in dried blood spots. Clinical Chemistry 50, 652–654.CrossRefGoogle ScholarPubMed
McDade, TW, Hawkley, LC, Cacioppo, JT (2006). Psychosocial and behavioral predictors of inflammation in middle-aged and older adults: The Chicago Health, Aging, and Social Relations Study. Psychosomatic Medicine 68, 376–381.CrossRefGoogle Scholar
McDade, TW, Leonard, WR, Burhop, J, Reyes-García, V, Vadez, V, Huanca, T, Godoy, RA (2005). Predictors of C-reactive protein in Tsimane' 2 to 15 year-olds in lowland Bolivia. American Journal of Physical Anthropology 128, 906–913.CrossRefGoogle ScholarPubMed
McDade, W, Stallings, JF, Worthman, CM (1997). Psychosocial stress and cell-mediated immune function: validation of a blood spot method for Epstein–Barr virus antibodies. American Journal of Physical Anthropology 24 (Suppl.), 164–165.Google Scholar
Mei, JV, Alexander, JR, Adam, BW, Hannon, WH (2001). Use of filter paper for the collection and analysis of human whole blood specimens. Journal of Nutrition 131, 1631S–1636S.CrossRefGoogle ScholarPubMed
Middeldorp, C, Birley, A, Cath, D, Gillespie, N, Willemsen, G, Statham, D, De Geus, E, Andrews, J, Van Dyck, R, Beem, A, Sullivan, P, Martin, N, Boomsma, D (2005). Familial clustering of major depression and anxiety disorders in Australian and Dutch twins and siblings. Twin Research and Human Genetics 8, 609–615.CrossRefGoogle ScholarPubMed
Moffitt, TE, Caspi, A, Harrington, H, Milne, BJ, Melchior, M, Goldberg, D, Poulton, R (2007 a). Generalized anxiety disorder and depression: childhood risk factors in a birth cohort followed to age 32. Psychological Medicine 37, 441–452.CrossRefGoogle Scholar
Moffitt, TE, Harrington, H, Caspi, A, Kim-Cohen, J, Goldberg, D, Gregory, AM, Poulton, R (2007 b). Depression and generalized anxiety disorder: cumulative and sequential comorbidity in a birth cohort followed prospectively to age 32 years. Archives of General Psychiatry 64, 651–660.CrossRefGoogle Scholar
National Center for Health Statistics (1988). Child Health Supplement. In: Current Estimates from the National Health Interview Survey ( ed. Adams, P. and Hardy, A.), Hyattsville, MD.Google Scholar
O'Donovan, A, Hughes, BM, Slavich, GM, Lynch, L, Cronin, M-T, O'Farrelly, C, Malone, KM (2010). Clinical anxiety, cortisol and interleukin-6: evidence for specificity in emotion–biology relationships. Brain, Behavior and Immunity 24, 1074–1077.CrossRefGoogle ScholarPubMed
Ogden, CL, Kuczmarski, RJ, Flegal, KM, Mei, Z, Guo, S, Wei, R, Grummer-Strawn, LM, Curtin, LR, Roche, AF, Johnson, CL (2002). Centers for Disease Control and Prevention 2000 growth charts for the United States: improvements to the 1977 National Center for Health Statistics version. Pediatrics 109, 45–60.CrossRefGoogle Scholar
Pearson, TA, Mensah, GA, Alexander, RW, Anderson, JL, Cannon, RO III, Criqui, M, Fadl, YY, Fortmann, SP, Hong, Y, Myers, GL, Rifai, N, Smith, SC Jr., Taubert, K, Tracy, RP, Vinicor, F (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.CrossRefGoogle Scholar
Pitsavos, C, Panagiotakos, DB, Papageorgiou, C, Tsetsekou, E, Soldatos, C, Stefanadis, C (2006). Anxiety in relation to inflammation and coagulation markers, among healthy adults: The ATTICA Study. Atherosclerosis 185, 320–326.CrossRefGoogle ScholarPubMed
Pradhan, AD, Manson, JE, Rifai, M, Buring, JE, Ridker, PM (2002). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. Journal of the American Medical Association 286, 327–334.CrossRefGoogle Scholar
Raison, CL, Capuron, L, Miller, AH (2006). Cytokines sing the blues: inflammation and the pathogenesis of depression. Trends in Immunology 27, 24–31.CrossRefGoogle ScholarPubMed
Ridker, PM, Buring, JE, Cook, NR, Rifai, N (2003). C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: an 8-year follow-up of 14,719 initially healthy American women. Circulation 107, 391–397.CrossRefGoogle Scholar
Schweizer, EE, Swenson, CM, Winokur, A, Rickels, K, Maislin, G (1986). The dexamethasone suppression test in generalised anxiety disorder. British Journal of Psychiatry 149, 320–322.CrossRefGoogle ScholarPubMed
Shah, T, Casas, JP, Cooper, JA, Tzoulaki, I, Sofat, R, McCormack, V, Smeeth, L, Deanfield, JE, Lowe, GD, Rumley, A, Fowkes, FGR, Humphries, SE, Hingorani, AD (2009). Critical appraisal of CRP measurement for the prediction of coronary heart disease events: new data and systematic review of 31 prospective cohorts. International Journal of Epidemiology 38, 217–231.CrossRefGoogle ScholarPubMed
Shanahan, L, Copeland, W, Costello, EJ, Angold, A (2008). Specificity of putative psychosocial risk factors for psychiatric disorders in children and adolescents. Journal of Child Psychology & Psychiatry 49, 34–42.CrossRefGoogle ScholarPubMed
Sobel, ME (1982). Asymptomic confidence intervals for indirect effects in structural equation models. Sociological Methodology 13, 290–312.CrossRefGoogle Scholar
Stewart, JC, Rand, KL, Muldoon, MF, Kamarck, TW (2009). A prospective evaluation of the directionality of the depression–inflammation relationship. Brain, Behavior and Immunity 23, 936–944.CrossRefGoogle ScholarPubMed
Tamakoshi, K, Yatsya, H, Kondo, T, Hori, Y, Ishikawa, M, Zhang, H, Murata, C, Otsuka, R, Zhu, S, Toyoshima, H (2003). The metabolic syndrome is associated with elevated circulating C-reactive protein in healthy reference range, a systemic low-grade inflammatory state. International Journal of Obesity and Related Metabolic Disorders 27, 443–449.CrossRefGoogle ScholarPubMed
Thapar, A, McGuffin, P (1997). Anxiety and depressive symptoms in childhood: a genetic study of comorbidity. Journal of Child Psychology and Psychiatry 38, 651–656.CrossRefGoogle ScholarPubMed
The Emerging Risk Factors Collaboration (2010). C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet 375, 132–140.CrossRefGoogle Scholar
Tiller, JWG, Biddle, N, Maguire, KP, Davies, BM (1988). The dexamethasone suppression test and plasma dexamethasone in generalized anxiety disorder. Biological Psychiatry 23, 261–270.CrossRefGoogle ScholarPubMed
Toker, S, Shirom, A, Shapira, I, Berliner, S, Melamed, S (2005). The association between burnout, depression, anxiety, and inflammation biomarkers: C-reactive protein and fibrinogen in men and women. Journal of Occupational Health Psychology 10, 344–362.CrossRefGoogle ScholarPubMed
Watson, D (2005). Rethinking the mood and anxiety disorders: a quantitative hierarchical model for DSM-V. Journal of Abnormal Psychology 114, 522–536.CrossRefGoogle ScholarPubMed
Williams, SR, McDade, TW (2009). The use of dried blood spot sampling in the National Social Life, Health, and Aging Project. Journals of Gerontology Series B: Psychological Sciences and Social Sciences 64B, i131–i136.CrossRefGoogle Scholar
Woodward, M, Rumley, A, Lowe, GDO, Tunstall-Pedoe, H (2003). C-reactive protein: associations with haematological variables, cardiovascular risk factors and prevalent cardiovascular disease. British Journal of Haematology 122, 135–141.CrossRefGoogle ScholarPubMed
Worthman, CM, Stallings, JF (1997). Hormone measures in finger-prick blood spot samples: new field methods for reproductive endocrinology. American Journal of Physical Anthropology 103, 1–21.3.0.CO;2-V>CrossRefGoogle Scholar