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Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies

BMJ 2012; 345 doi: (Published 31 July 2012) Cite this as: BMJ 2012;345:e4933

Re: Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies

We are pleased that our pooled analysis of the association between psychological distress and mortality has attracted the interest of some BMJ readers.[1] In this feedback, some of the themes to emerge were that of underlying mechanisms and alternative (artifactual) explanations.

The latter concerns the role of extant physical disease (reverse causality). We were careful both to exclude individuals entering the study with somatic illness on entry to each cohort study (clinical disease) and also drop deaths in the early stages of follow-up on the understanding that these people had hidden illness at study induction (sub-clinical disease).

Of the potential mechanisms linking psychological distress (or stress) with mortality, those cited include sleep disturbance, impaired immune function, adverse experiences in childhood, and vascular/metabolic disease. We believe that all these factors might contribute to the association between psychological distress and mortality, although there is currently no strong evidence to suggest that any of them is responsible.

Sleep disturbance is hypothesized as a mediator in the distress/stress-mortality association because disturbed sleep is a risk factor for metabolic disorders, such as insulin resistance, adiposity and type 2 diabetes, and these disorders raise mortality risk.[2-4] Genetic studies also support these adverse metabolic effects: risk variants from genes that are related to sleep regulation, such as melatonin receptor 1B and a circadian pacemaker gene cryptochrome 2, are also associated with obesity and diabetes.[5,6].

However, although sleep disturbance appears to increase disease risk, it is still unclear whether sleep also mediates the association between psychological distress and mortality. Some recent data cast doubt on this thesis. First, distinguishing sleep disturbance from psychological distress is problematic as sleep disturbance is one of the symptoms of distress. Second, stress is also associated with adverse metabolic changes and increased risk of obesity and vascular diseases.[7] Distress itself could, therefore, underlie the association between sleep and mortality rather than the other way around. Third, several risk factors, such as obesity, tobacco smoking, and depression, may precipitate sleep disturbances.[8,9] Thus, rather than mediating the association between distress and mortality, sleep disturbance could be an innocent bystander marking other stress mediators. Indeed, Matthews et al. found little evidence that sleep was associated with disease risk independently of obesity[10] and, similarly, interventions to treat sleep disorders have produced little improvement in cardiovascular health.[11]

We consider immune function a promising mechanism as there is a rapidly growing evidence linking systemic inflammation with mental health. For example, exposure to acute inflammatory stimuli, such as typhoid vaccination or cytokine injection, has been shown to elicit symptoms of psychological distress and low mood.[12,13] Observational studies suggest an association between pro-inflammatory cytokines, such as IL-6, and depressive symptoms[14] and a meta-analysis of 22 antidepressant treatment studies found that inflammatory markers, such as IL-6, decreased in response to drug therapy (especially SSRI medication), along with a reduction in depressive symptoms.[15] Further support comes from genetic studies where depression risk alleles have also been associated with immune responses[16] and recent Mendelian randomization analyses suggest a causal link between inflammation and disease risk.[17] Thus, several lines of research provide consistent evidence that there may be an interplay between inflammation, symptoms of distress and disease risk, although as yet it remains unclear whether inflammation is the main reason why persons with distress have increased mortality risk.

Finally, it is also important to consider practical implications. As Lewis noted in his insightful editorial, even if the association were causal, it is not clear how to intervene because removal of all sources of distress is unrealistic, antidepressant drug therapies for subclinically distressed may not be effective,[19, 20] and cognitive therapy to modify stress perception cannot realistically be disseminated to the entire population.[18]


1. Russ TC, Stamatakis E, Hamer M, Starr JM, Kivimäki M, Batty GD. Association between psychological distress and mortality: an individual participant pooled analysis of ten prospective cohort studies. BMJ 2012;345:e4933.

2 Van Cauter, E. Sleep disturbances and insulin resistance. Diabet Med 2011;28:1455–62.

3. Spiegel, K., Tasali, E., Penev, P. & Van Cauter, E. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med 2004;141:846–850.

4. Kivimäki M, Batty GD,Hublin C. Shift work as a risk factor for future type 2 diabetes: evidence, mechanisms, implications, and future research directions. PLoS Med 2011;8:e1001138.

5. Speliotes EK et al. Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index. Nat Genet 2010;42:937–948.

6. Dupuis J. et al. New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk. Nat Genet 2012;42:105–16.

7. Steptoe A,Kivimäki M. Stress and cardiovascular disease. Nat Rev Cardiol 2012;9:360–70.

8. Kopelman PG. Obesity as a medical problem. Nature 2000;404, 635–43.

9. Jaehne A, Loessl B, Bárkai Z, Riemann D,Hornyak M. Effects of nicotine on sleep during consumption, withdrawal and replacement therapy. Sleep Med Rev 2009;13, 363–77.

10. Matthews KA et al. Associations of Framingham risk score profile and coronary artery calcification with sleep characteristics in middle-aged men and women: Pittsburgh SleepSCORE study. Sleep 2011;34:711–16.

11. Calhoun DA, Harding SM. Sleep and hypertension. Chest 2010;138, 434–43.

12. 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;9:46-56.

13. Harrison NA, Brydon L, Walker C, Gray MA, Steptoe A, Critchley HD. Inflammation causes mood changes through alterations in subgenual cingulate activity and mesolimbic connectivity. Biol Psychiatry 2009;66:407-14.

14. Howren MB, Lamkin DM, Suls J. Associations of depression with C-reactive protein, IL-1, and IL-6: a meta-analysis. Psychosom Med 2009;71:171-86.

15. Hannestad J, Della Gioia N, Bloch M. The effect of antidepressant medication treatment on serum levels of inflammatory cytokines: a meta-analysis. Neuropsychopharmacology 2011;36:2452-9.

16. Raison CL, Miller AH. The evolutionary significance of depression in Pathogen Host Defense (PATHOS-D). Mol Psychiatry 2012 [epub ahead of print].

17. IL6MR-Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a Mendelian randomisation analysis. Lancet 2012;379:1214-24

18. Lewis G. Psychological distress and death from cardiovascular disease: May be related in a dose-response manner, but it is not clear how to intervene. BMJ 2012;345:e5177.

19. Paykel ES, Hollyman JA, Freeling P, Sedgwick P. Predictors of therapeutic benefit from amitriptyline in mild depression: a general practice placebo-controlled trial. J Affect Disorders 1988;14:83-95.

20. Fournier JC, DeRubeis RJ, Hollon SD et al. Antidepressant drug effects and depression severity: a patient-level meta-analysis. JAMA-J Am Med Assoc 2010;303:47-53.

Competing interests: No competing interests

08 August 2012
Mika Kivimäki
Professor of Social Epidemiology
Tom C. Russ, Emmanuel Stamatakis, Mark Hamer,John M. Starr, G. David Batty
University College London
Department of Epidemiology and Community Health, 1-19 Torrington Place, London WC1E 6BT