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Research Letter
January 2016

Inflammation and Specific Symptoms of Depression

Author Affiliations
  • 1Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
  • 2Finnish Institute of Occupational Health, Helsinki, Finland
  • 3Department of Epidemiology and Public Health, University College London, London, England
  • 4Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, Scotland
JAMA Psychiatry. 2016;73(1):87-88. doi:10.1001/jamapsychiatry.2015.1977

Elevated levels of inflammatory markers, such as C-reactive protein, are well-documented in people with depression.1,2 Raison and Miller3 suggested that this association may, in fact, be symptom-specific. Higher levels of inflammation are particularly likely to underlie depression symptoms that characterize sickness behavior, including fatigue, reduced appetite, withdrawal, and inhibited motivation. From an evolutionary perspective, such symptoms have the beneficial effect of preserving energy resources for use in fighting infection and promoting healing processes.4,5 Here, we tested the hypothesis that the association between C-reactive protein and depression is symptom-specific.


Data were collected from 3 cross-sectional studies: the US National Health and Nutrition Surveys of 2005-2006 (n = 4593), 2007-2008 (n = 5151), and 2009-2010 (n = 5327) that underwent National Center for Health Statistics institutional research ethics review board approval.6 Written informed consent was obtained from all participants. We included all 15 071 participants with relevant data (mean age, 47.5 years; 50.1% female) whether or not they had specific symptoms of depression. C-reactive protein was measured using standard procedures (median, 2 mg/L; interquartile range, 0.8-4.7 mg/L; to convert to nanomoles per liter, multiply by 9.524).6 C-reactive protein values were log-transformed and standardized (SD = 1). Depressive symptoms were assessed using the Depression Screener Questionnaire as part of computer-assisted personal interviews.6 The 9 items of the questionnaire are used to quantify how often the participant had been bothered by specific symptoms during the last 2 weeks, each self-rated on a 4-point scale (Figure). We coded the items as dichotomous variables with responses “More than half the days” and “Nearly every day” indicating the presence of the symptom.

Associations Between C-Reactive Protein and Depression Symptoms Pooled With Meta-analysis Across 3 US National Health and Nutrition Surveys Cohort Studies (N = 15 071)
Associations Between C-Reactive Protein and Depression Symptoms Pooled With Meta-analysis Across 3 US National Health and Nutrition Surveys Cohort Studies (N = 15 071)

Values are odds ratios (ORs) and their 95% CIs per 1-SD increase in log-transformed C-reactive protein. Filled squares denote statistically significant ORs (P < .05) and empty squares statistically nonsignificant ORs. Single associations with depression symptoms are adjusted for age, sex, and race/ethnicity. Mutually adjusted associations are further adjusted for the sum of all the other depression symptoms besides the outcome symptom.

This current cross-sectional survey study did not require institutional review board approval because the analysis involved existing and publicly available data without participant identifiers.

First, we examined associations between C-reactive protein and all depression items in separate models, adjusting for sex, age, and race/ethnicity (single associations). To assess independent associations with specific symptoms—which took into account the overlap between different depressive symptoms—we additionally adjusted these models for the sum of the remaining depression items (mutually adjusted associations). Across the 9 depression symptoms, the average Pearson correlation coefficient between individual symptoms and the sum of all the other depression symptoms was r = 0.60 (range, 0.36-0.71). All analyses were first fitted separately in the 3 cohort studies using logistic regression analysis with appropriate sampling weights and then pooled together using fixed-effect meta-analysis.


When not adjusted for the other depression symptoms, C-reactive protein was associated with all the specific depression symptoms (Figure). When these associations were adjusted for the other depression symptoms, independent associations were apparent only with sleep problems (odds ratio [OR], 1.14; 95% CI, 1.07-1.21), tiredness or lack of energy (OR, 1.22; 95% CI, 1.15-1.30), and changes in appetite (OR, 1.17; 95% CI, 1.09-1.27) (Figure). The independent association with anhedonia was close to statistical significance (P = .06). When C-reactive protein was categorized into quartiles, independent dose-response patterns were observed for sleeping problems (ORs of 1.29, 1.33, and 1.51 for the second, third, and fourth C-reactive protein quartiles, respectively, compared with the first; P < .001), tiredness or lack of energy (ORs of 1.02, 1.32, and 1.68 for the second, third, and fourth quartiles, respectively; P < .001), and changes in appetite (ORs of 1.18, 1.23, and 1.65 for the second, third, and fourth quartiles, respectively; P < .001).


Inflammation was associated with a range of depression symptoms, particularly with tiredness, lack of energy, sleep problems, and changes in appetite. These symptoms characterize sickness behaviors that are observed in people who are physically ill.4 Inflammation was also associated with the cognitive and emotional symptoms of depression (eg, anhedonia, depressed mood, feelings of self-worth, concentration, and suicidal ideation); however, these associations were not independent of the other depression symptoms. This pattern of results is consistent with the evolutionary view linking inflammation and depression with pathogen host defense2 because tiredness, lack of energy, and reduced appetite are primary characteristics of sickness behavior. Further research is needed to determine whether changes in inflammation predict changes in specific symptoms and to identify metabolic pathways that mediate such changes.

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Article Information

Corresponding Author: Markus Jokela, PhD, Institute of Behavioural Sciences, University of Helsinki, PO Box 9, Siltavuorenpenger 1A, Helsinki 00014, Finland (markus.jokela@helsinki.fi).

Published Online: November 18, 2015. doi:10.1001/jamapsychiatry.2015.1977.

Author Contributions: Dr Jokela had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jokela, Kivimäki.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jokela.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Jokela.

Obtained funding: Kivimäki.

Study supervision: Jokela, Kivimäki.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Virtanen is supported by the Academy of Finland (grants 258598 and 292824). Dr Kivimäki is supported by the UK Medical Research Council (grant K013351), the Economic and Social Research Council (grant ES/J023299), and NordForsk, the Nordic Programme on Health and Welfare (grant 75021).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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;49:206-215.PubMedArticle
Raison  CL, Miller  AH.  The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D).  Mol Psychiatry. 2013;18(1):15-37.PubMedArticle
Miller  AH, Raison  CL.  Are anti-inflammatory therapies viable treatments for psychiatric disorders? where the rubber meets the road.  JAMA Psychiatry. 2015;72(6):527-528.PubMedArticle
Dantzer  R, O’Connor  JC, Freund  GG, Johnson  RW, Kelley  KW.  From inflammation to sickness and depression: when the immune system subjugates the brain.  Nat Rev Neurosci. 2008;9(1):46-56.PubMedArticle
Haroon  E, Raison  CL, Miller  AH.  Psychoneuroimmunology meets neuropsychopharmacology: translational implications of the impact of inflammation on behavior.  Neuropsychopharmacology. 2012;37(1):137-162.PubMedArticle
Centers for Disease Control and Prevention; National Center for Health Statistics.  National Health and Nutrition Examination Survey. http://www.cdc.gov/nchs/nhanes.htm. Accessed July 1, 2015.