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Figure.
Suicide Death Rates According to C-Reactive Protein (CRP) Level and Duration of Follow-up
Suicide Death Rates According to C-Reactive Protein (CRP) Level and Duration of Follow-up

The proportion of deaths by suicide in each of the 3 CRP categories (low [<1 mg/L], intermediate [1-3 mg/L], or high [>3 mg/L]) over the duration of follow-up (0-17 years). Each step signals at least 1 death by suicide. To convert to nanomoles per liter, multiply by 9.524.

Table.  
Association of C-Reactive Protein With Completed Suicidea
Association of C-Reactive Protein With Completed Suicidea
1.
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.PubMedGoogle ScholarCrossref
2.
Brundin  L, Erhardt  S, Bryleva  EY, Achtyes  ED, Postolache  TT.  The role of inflammation in suicidal behaviour.  Acta Psychiatr Scand. 2015;132(3):192-203.PubMedGoogle ScholarCrossref
3.
Black  C, Miller  BJ.  Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients.  Biol Psychiatry. 2015;78(1):28-37.PubMedGoogle ScholarCrossref
4.
Kuo  CJ, Chen  VC, Lee  WC,  et al.  Asthma and suicide mortality in young people: a 12-year follow-up study.  Am J Psychiatry. 2010;167(9):1092-1099.PubMedGoogle ScholarCrossref
5.
Russ  TC, Stamatakis  E, Hamer  M, Starr  JM, Kivimäki  M, Batty  GD.  Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies.  BMJ. 2012;345:e4933.PubMedGoogle ScholarCrossref
6.
Allebeck  P, Allgulander  C, Henningsohn  L, Jakobsson  SW.  Causes of death in a cohort of 50,465 young men–validity of recorded suicide as underlying cause of death.  Scand J Soc Med. 1991;19(4):242-247.PubMedGoogle Scholar
Research Letter
September 2016

Association of Systemic Inflammation With Risk of Completed Suicide in the General Population

Author Affiliations
  • 1Department of Epidemiology and Public Health, University College London, London, England
  • 2Department of Public Health and Primary Care, University of Cambridge, Cambridge, England
  • 3Charles Perkins Centre and Prevention Research Collaboration, Sydney School of Public Health, University of Sydney, Sydney, Australia
JAMA Psychiatry. 2016;73(9):993-995. doi:10.1001/jamapsychiatry.2016.1805

There is a growing prima facie case for inflammation being associated with suicide. In cohort studies,1 elevated levels of inflammatory markers have been linked to the future occurrence of depression, a known risk factor for suicide. In psychiatric patients, inflammation is positively associated with the intensity of self-reported suicidal ideation,2 and those who commit suicide have higher cytokine levels post mortem relative to control patients.3 Furthermore, individuals with asthma, a condition characterized by inflammation, experience higher rates of suicide mortality than their nonatopic counterparts.4

While these various lines of evidence may implicate inflammation in the pathophysiology of suicide, there has been no prospective examination of the link between inflammation and future suicide events.

Methods

Data were pooled from a series of independent, geographically representative, near-identical surveys of individuals living in private households, conducted from January 1998 to May 2007 in the United Kingdom.5 In 7 surveys (the 1998, 1999, 2003, 2004, and 2006 Health Surveys for England; the 1998 and 2003 Scottish Health Surveys), serum C-reactive protein (CRP) levels were ascertained using the N Latex CRP mono-immunoassay on the Behring Nephelometer II analyzer (Dade Behring). Study members were linked to national cause-of-death registers until February 2011 for the Health Survey for England or December 2009 for the Scottish Health Survey. Death certification for suicide has a high level of agreement with other sources of evidence (eg, forensic reports, police reports, and toxicological and histological data).6 Covariates included psychological distress, which was determined by caseness (ie, a score greater than 3) on the 12-item General Health Questionnaire, self-reported long-standing mental illness, and the use of psychotropic medication. Ethical approval for each survey was granted by local research ethics committees, and study members provided informed consent at the time of the survey. Approval and informed consent were not required for the present analyses.

Results

In an analytical sample of 39 349 participants with data on inflammation, age, sex, and mortality, a mean (SD) duration of 8.6 (3.3) years of follow-up gave rise to 26 deaths ascribed to suicide (7.7 events per 100 000 person-years). Age- and sex-adjusted hazard ratios (HRs) and 95% CIs were calculated for study covariates; being a cigarette smoker (current vs never/former: HR, 9.67; 95% CI, 3.82-24.52), male (male vs female: HR, 2.64; 95% CI, 1.15-6.07), socioeconomically disadvantaged (manual vs nonmanual social class: HR, 4.02; 95% CI, 1.60-10.13), and psychologically distressed (score >3 vs ≤3: HR, 4.89; 95% CI, 2.22-10.80) were associated with an elevated rate of suicide.

After basic adjustment, people in the highest inflammation group were 4 times more likely to die by suicide relative to those in the lowest group (HR, 4.20; 95% CI, 1.44-12.25) (Table). A graded association was apparent across the 3 categories (P value = .007), with a 1-SD increase in inflammation associated with a 55% increase in suicide risk (HR, 1.55; 95% CI, 1.05-2.30). This gradient was attenuated somewhat after adjustment for smoking, although accounting for other covariates had little impact.

Excluding people at various thresholds of high CRP (ie, at 4, 6, 8, and 10 mg/L [to convert to nanomoles per liter, multiply by 9.524]) did not materially alter our findings. While a positive association between CRP and suicide rates was apparent across the full duration of follow-up (Figure), on partitioning (≤5 vs >5 years), the magnitude of this association was somewhat stronger in the early phase (multivariable-adjusted HR for a 1-SD increase in CRP: HR, 1.63; 95% CI, 0.87-3.05) relative to the later phases (HR, 1.17; 95% CI, 0.69-1.96).

Discussion

We found up to a 4-fold increased risk of completed suicide in individuals with elevated levels of inflammation compared with those with low levels. That this gradient was only partially explained by controlling for a series of covariates raises the likelihood that other mechanisms underlie the association. Our finding that suicide was associated with a series of known risk factors gives us some confidence in our novel results for inflammation.

Conclusions

In conclusion, this is the first prospective cohort study to examine the link between systemic inflammation and future suicide risk, but it is not without its shortcomings. Despite a large sample size, the number of completed suicides herein was modest, leading to low statistical power. Our results warrant testing using the present study design and other approaches, such as mendelian randomization and large-scale pharmacological trials of inflammation reduction.

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Article Information

Corresponding Author: G. David Batty, DSc, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, England (david.batty@ucl.ac.uk).

Published Online: August 10, 2016. doi:10.1001/jamapsychiatry.2016.1805.

Author Contributions: Drs Stamatakis and Bell had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Batty.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Batty.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Bell.
Obtained funding: Stamatakis.
Administrative, technical, or material support: Stamatakis.
Study supervision: Batty, Kivimäki.

Conflict of Interest Disclosures: None reported.

Funding/Support: Dr Bell was supported by grants from the European Research Council and UK Medical Research Council/Alcohol Research UK. Dr Kivimäki is supported by the UK Medical Research Council, NordForsk, the Nordic Research Programme on Health and Welfare, and a professorial fellowship from the UK Economic and Social Research Council. Dr Stamatakis is supported by a National Health and Medical Research Council (Australia) Senior Research Fellowship.

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; or the decision to submit the manuscript for publication.

Additional Contributions: We thank the 2 anonymous referees for their careful reading of our original manuscript and helpful suggestions for improvement.

References
1.
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.PubMedGoogle ScholarCrossref
2.
Brundin  L, Erhardt  S, Bryleva  EY, Achtyes  ED, Postolache  TT.  The role of inflammation in suicidal behaviour.  Acta Psychiatr Scand. 2015;132(3):192-203.PubMedGoogle ScholarCrossref
3.
Black  C, Miller  BJ.  Meta-analysis of cytokines and chemokines in suicidality: distinguishing suicidal versus nonsuicidal patients.  Biol Psychiatry. 2015;78(1):28-37.PubMedGoogle ScholarCrossref
4.
Kuo  CJ, Chen  VC, Lee  WC,  et al.  Asthma and suicide mortality in young people: a 12-year follow-up study.  Am J Psychiatry. 2010;167(9):1092-1099.PubMedGoogle ScholarCrossref
5.
Russ  TC, Stamatakis  E, Hamer  M, Starr  JM, Kivimäki  M, Batty  GD.  Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies.  BMJ. 2012;345:e4933.PubMedGoogle ScholarCrossref
6.
Allebeck  P, Allgulander  C, Henningsohn  L, Jakobsson  SW.  Causes of death in a cohort of 50,465 young men–validity of recorded suicide as underlying cause of death.  Scand J Soc Med. 1991;19(4):242-247.PubMedGoogle Scholar
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