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

BMJ 2012; 345 doi: http://dx.doi.org/10.1136/bmj.e4933 (Published 31 July 2012)
Cite this as: BMJ 2012;345:e4933

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Russ et al. conducted a meta-analysis on the predictive ability of sub-clinically psychological distress on the all-cause and some cause-specific mortality (1). Psychological distress were measured by the 12-item General Health Questionnaire (GHQ12) score, and mortality was certified from death certification. As a preparation of baseline data, patients of cardiovascular disease and cancer, and also institutionalized subjects were excluded for the study. As one of the main outcome, there was a positive dose-response relationship between psychological distress and risk of mortality. The fully-adjusted hazard ratio (95% confidence interval) of highly symptomatic psychological distress for all-cause mortality was 1.67 (1.41 to 2.00). About their attractive report, I have two queries.

First, Russ et al. mentioned in the study limitation that there is a possibility of reverse causality, speculating that sub-clinical somatic illness will affect both an increased prevalence of psychological distress and an increased risk of mortality. On this point, they concluded that keeping statistical significance after excluding deaths within five years of follow-up would cause no consideration of "spurious relationship" between psychological distress and mortality via sub-clinical condition. But I propose much more consideration on the reverse causality. Although GHQ12 reflects the state of anxiety and depression, it fundamentally reflects psychological distress and does not become a substitute for specific disease judged by clinical diagnostic criteria. As useful information, the predictive ability of perceived health (Self-rated health state) on the mortality should be considered as an additional evaluation (2,3).

Second, there is a wide range of age in subjects, presenting more than 70 years, and it seems difficult for adjusting age lineally as a confounder. Instead, sub-analysis by the stratification of subjects at the specific age such as 75 years is more understandable. As there is a sex difference in psychological distress and mortality, separation by sex would also elucidate the risk assessment outcome.

Although the statistical power is satisfactory compared with the same research (4), the absolute value of hazard ratio is not high enough for clinical significance (5). Further study is need to understand the mechanism for the predictive ability of psychological distress on the specific mortality using adequate confounding variables as reported recently (6).

1 Russ TC, Stamatakis E, Hamer M, Starr JM, Kivimaki M, Batty GD. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 2012;345:e4933.

2 Ford J, Spallek M, Dobson A. Self-rated health and a healthy lifestyle are the most important predictors of survival in elderly women. Age Ageing 2008;37:194-200.

3 Mackenbach JP, Simon JG, Looman CW, Joung IM. Self-assessed health and mortality: could psychosocial factors explain the association? Int J Epidemiol 2002;31:1162-8.

4 Puustinen PJ, Koponen H, Kautiainen H, Mantyselka P, Vanhala M. Psychological distress measured by the GHQ-12 and mortality: a prospective population-based study. Scand J Public Health 2011:39:577-81.

5 Taubes G. Epidemiology faces its limits. Science 1995;269:164-9.

6 Hamer M, Kivimaki M, Stamatakis E, Batty GD. Psychological distress as a risk factor for death from cerebrovascular disease. CMAJ 2012;184:1461-6.

Competing interests: None declared

Kawada Tomoyuki, Professor

Department of Hygiene and Public Health, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan

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Those as puzzled as I am by the mystery factor now said to be responsible for a considerable part of the increased mortality associated with clinical depression and anxiety might like to search for "Family stigma, sexual selection and the evolutionary origins of severe depression's physiological consequences." This paper initially sruck me as rather implausible but now I am not so sure.

Competing interests: None declared

Alan H Ogden, Retired

Consultant psychiatrist, 9, The Drive, Hopwood, B48 7AH

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Low Distress and Death: Scary Headlines from Confounded Data

A lot of scary headlines and misinformation in the media could have been avoided with more modest claims and better epidemiology in a recent BMJ article concerning the mortality associated with low distress, as well as in its accompanying editorial and BMJ generated press release.

Efforts to relate psychological distress to negative physical health outcomes including mortality have a long and frustrating history. Distress has so many antecedent and concurrent associations that determining whether its relation to outcomes like mortality are spurious and due to its association with antecedents often proves impossible. Distress is related to a host of personal and socioeconomic disadvantages and health problems and health related impairments that can reasonably be expected to affect future morbidity and mortality. Sometimes these alternative explanations of the association between distress and sickness and death can seem to be ruled out in multivariate analyses. But as George Davey Smith and others have repeatedly shown, such multivariate analyses also can produce counterintuitive and nonsensical results, including findings that distress is associated with better health and longevity when particular statistical controls are introduced and others left out. Whenever we examine relations between distress and health, we need to remind ourselves that association is not causality and that is often difficult or impossible to infer public health implications from observational data. We also need to remind ourselves that to rely on multivariate statistics to settle issues of causality in observational studies often requires untenable assumptions about having a model that distinguishes between confounds and simple covariates and that we have identified all relevant confounds and measured them with great precision. Otherwise we can assume that residual confounding and other forms of spuriousness will rear their ugly heads.

The authors make unwarranted assumptions about what is represented by low scores on the Brief Symptom Inventory. Even when scores are above the established cutpoints, most high scores do not represent psychiatric disorders. Assumption about the validity and substantive interpretation of scores above established cutpoints do not generalize to low scores. Low scores may variously represent moderate endorsement of a number of items that are not symptoms of psychopathology and may even represent diffuse physical health complaints. Alternatively, low scores may represent stronger endorsement of a small number of items such as sleep disturbance that may be related to other factors, which turn may directly contribute to morbidity and mortality. The meaning of low scores is much more ambiguous than the meaning of high scores.

The authors could have discouraged misinterpretation if they presented their results in terms of differences in absolute risk. Readers could thereby see that we are talking about small differences. Even as they are presented, results are not in the range that we can consider as having public health implications. Instead, they are well within the range that could expected with residual confounding and the failure to specify and adequately measure the full range of confounding variables. This basic criticism is aside from the question of not knowing what public health interventions could banish such low levels of distress. The authors have indeed assembled a large data set of individual level data, but such large data sets carry the risk of overinterpreting small effects of a spurious nature.

The authors put too much effort into trying to defend their results concerning distress and cancer. First, it is incorrect to state, as they did, that the association between distress and cancer death remained in the fully adjusted model because the confidence interval included .99. More importantly however, the authors accepted uncritically the findings of a meta-analysis [1]concerning the influence of psychological factors on cancer incidence, progression and outcome. That meta-analysis would have yielded only trivial effects for psychological factors if it had appropriately excluded the discredited data of Eysenck and Grossarth-Maticek. Whereas most hazard ratios clustered around 1.0, the data of Eysenck and Grossarth-Maticek yielded hazard ratios in the implausible realm of 23.8 to 74.2 [2]. These data have been widely discredited [3] and Eysenck is now known to have received large undisclosed payments from lawyers for American tobacco companies to publish these data. Regardless, even without this knowledge, the extreme deviation from other data would 'have justified exclusion of these data from these studies as outliers. Aside from all the other issues posed by this BMJ article, it represents yet another instance of the persistent influence of suspect data on our understanding of the association between psychological variables and cancer. Let's keep these data out of the literature, but let’s also stick to more modest claims and make a better effort to explain ambiguous results to lay audiences if press releases are sent out.

1.Chida, Y., Hamer, M., Wardle, J. & Steptoe, A. Do stress-related psychosocial factors contribute to cancer incidence and survival? Nature Clinical Practice Oncology. 2008. 5, 466–475.
2.Van der Ploeg, H.M. . What a wonderful world it would be: a reanalysis of some of the work of Grossarth-Maticek. Psychological Inquiry. 1991. 2, 280-285.
3.Coyne, J. C., Ranchor, A. V., & Palmer, S. C. Meta-analysis of stress-related factors in cancer. Nature Reviews Clinical Oncology, 2010. 7(5).

Competing interests: None declared

James C. Coyne, Professor

Perelman School of Medicine at the University of Pennsylvania, 3535 Market St, Rm 676, Philadelphia, PA 19104

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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]

References

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: None declared

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

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This article on links between psychological distress and mortality (1) is important for two reasons.

Firstly, the linkages between immune function and depression and its consequences to morbidity and mortality are becoming increasingly recognised (2).

The second reason lies hidden in Figure 2 of this study where a cycle in mortality over time can be observed with a notable minimum in 2002. This minimum is shared with international trends relating to medical and mental health hospital admissions and bed occupancy (3-11), A&E attendance (12) and GP referrals, especially to Mental Health (13), the incidence of particular cancers (14) and deaths (15).

My interest in this phenomenon has been largely directed to the financial and operational consequences of such cycles and, as such, this work has been published in a management journal (16-20).It has been proposed that these cycles arise from recurring ‘outbreaks’ of some form of infectious immune impairment.

Cytomegalovirus has been tentatively proposed as a likely candidate given its known immune impairing effects, links with depression and particular cancers (21). A study investigating the proposal that these cycles arise from infectious ‘outbreaks’ is about to be published in September. In this study the increase in GP referrals at different locations in Scotland and Wales at monthly intervals have been investigated following the 2007 ‘outbreak’ to reveal a time-dependant patchwork spread of sudden increases in GP referral (22).

Unfortunately the data on mortality and psychological distress in the work of Maes et al was only available up to 2004 and it will be interesting to see if the measures of mortality reach another minimum in 2007. Further study is required to see if the linkage with immune function can also be demonstrated although it has already been largely inferred (2)and to see if the infectious outbreak hypothesis is related to these effects.

References

1.Russ T, Hamer M, Starr J, Kivimäki M, Batty G. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 2012;345:e4933

2.Maes M, Berk M, Goehler L et al. Depression and sickness behaviour are Janus-faced responses to shared inflammatory pathways. BMC Medicine 2012; 10: 66

3.Jones R. Trends in emergency admissions. British Journal of Healthcare Management 2009; 15(4): 188-196.

4.Jones R. Cycles in emergency admissions. British Journal of Healthcare Management 2009; 15(5): 239-246.

5.Jones R. Emergency admissions and hospital beds. British Journal of Healthcare Management 2009; 15(6): 289-296.

6.Jones R. Emergency admissions and financial risk. British Journal of Healthcare Management 2009; 15(7): 344-350.

7.Jones R. Unexpected, periodic and permanent increase in medical inpatient care: man-made or new disease. Medical Hypotheses 2010; 74: 978-83.

8.Jones R. Can time-related patterns in diagnosis for hospital admission help identify common root causes for disease expression. Medical Hypotheses 2010; 75: 148-154.

9.Jones R. The case for recurring outbreaks of a new type of infectious disease across all parts of the United Kingdom. Medical Hypotheses 2010; 75(5): 452-457.

10.Jones R. Emergency preparedness. British Journal of Healthcare Management 2010; 16 (2): 94-95.

11.Jones R. Bed occupancy – the impact on hospital planning. British Journal of Healthcare Management 2011; 17(7): 307-313.

12.Jones R. Forecasting emergency department attendances. British Journal of Healthcare Management 2010; 16(10): 495-496.

13.Jones R. Are there cycles in outpatient costs? British Journal of Healthcare Management 2012; 18(5): 276-277.

14.Jones R. Financial risk in commissioning: cancer costs. British Journal of Healthcare Management 2012; 18(6): 315-324.

15.Jones R. End of life and financial risk in GP commissioning. British Journal of Healthcare Management 2012; 18(7): 374-381.

16.Jones R. Nature of health care costs and financial risk in commissioning. British Journal of Healthcare Management 16(9): 424-430.

17.Jones R. Trends in programme budget expenditure. British Journal of Healthcare Management 16(11): 518-526.

18.Jones R. Cycles in inpatient waiting time. British Journal of Healthcare Management 17(2): 80-81.

19.Jones R. Time to re-evaluate financial risk in GP commissioning. British Journal of Healthcare Management 2012; 18(1): 39-48.

20.Jones R. Why is the ‘real world’ financial risk in commissioning so high? British Journal of Healthcare Management 2012; 18(4): 216-217.

21.Jones R. Could cytomegalovirus be causing widespread outbreaks of chronic poor health? Hypotheses in Clinical Medicine, Chapter 4; Eds M. Shoja et al., New York: Nova Science Publishers Inc (due 4th quarter 2012).

22.Jones R. Unexplained increases in GP referrals: collective jump or infectious push? British Journal of Healthcare Management 2012; 18(9): in press.

Competing interests: The author provides consultancy to healthcare organisations.

Rodney P Jones, Statistical Advisor

Healthcare Analysis & Forecasting, Honister Walk, Camberley

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Early exposure to adverse experiences in childhood have been clearly shown to adversely effect health in multiple areas.(1) Life is a marathon, not a sprint,so it is not surprising that being programmed for maladpative stress responses in childhood has adverse effects upon cardiovascular health. Could it be otherwise?

(1) http://www.cdc.gov/ace/year.htm

Competing interests: None declared

Stephen R Workman, Physician

QEII HSC Halifax Nova Scotia, QEII HSC Halifax Nova Scotia Canada

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“The best bridge between despair and hope is a good night's sleep” [E. Joseph Cossman]

We read with interest the article by Dr Russ and colleagues (1), showing a dose-response relationship between ‘psychological distress’ (measured with the GHQ-12) and mortality. The authors should be commended for their rigorous analysis, including appropriate modelling of relevant covariates. Consistent with campaigns to improve lifestyle and well-being factors, like diet and physical activity, we would also agree that increased recognition and appropriate management of sub-clinical psychological distress be considered.

We’re left wondering, however, what role insomnia and sleep disturbance may play in contributing to some of the observed relationships. We know, for example, that primary insomnia (poor sleep in the absence of co-morbid mental or physical illness) is associated with sub-clinical levels of psychological distress, in addition to general daytime and quality of life impairment (2,3). Longitudinally, insomnia is an independent risk factor for the future development of major depression (4) and anxiety disorder (5). Indeed, insomnia has been linked, in a number of studies, with both suicidal ideation and suicide death (see 6).

There are also strong relationships between insomnia and physical ill-health. At a cross-sectional level, insomnia is a risk factor for hypertension (7) and type II diabetes (8). Relatively recent data also suggest that insomnia with objective short sleep duration is a risk factor for early mortality, after controlling for several relevant covariates (9; see, also, 10). Finally, insomnia, in the absence of co-morbidity, has been associated with attenuated heart-rate (11) and blood pressure ‘dipping’ (12), from wake-to-sleep, as well elevated secretion of inflammatory markers (13) and increased activity of the HPA axis (14). Clearly, sleep timing, quality and duration are essential for optimal health and well-being (15).

Similar to Russ et al., we encourage greater investigation of the mechanisms linking psychological distress to adverse health outcomes and mortality, and would suggest focussed attention be placed on sleep as a potential contributing, yet modifiable (16) factor.

Relevant references

(1). Russ TC, Stamatakis E, Hamer M, et al. Association between psychological distress and mortality: individual participant pooled analysis of 10 prospective cohort studies. BMJ 2012; 345: e4933.
(2). Buysse DJ, Thompson W, Scott J, et al. Daytime symptoms of primary insomnia: A prospective analysis using ecological momentary assessment. Sleep Med 2007; 8: 198-208.
(3). Kyle SD, Morgan K, Espie CA. Insomnia and health-related quality of life. Sleep Med Rev 2010; 14: 69-82.
(4). Baglioni C, Battagliese G, Feige B, et al. Insomnia as a predictor of depression: A meta-analytic evaluation of longitudinal epidemiological studies. J Affect Disord 2011; 135: 10-19.
(5). Neckelmann D, Mykletun A, Dahl AA. Chronic insomnia as a risk factor for developing anxiety and depression. Sleep 2007; 30: 873-80.
(6). McCall WV, Blocker JN, D’Agostino R, et al. Insomnia severity is an indicator of suicidal ideation during a depression clinical trial. Sleep Med 2010; 11: 822-827.
(7). Vgontzas AN, Liao D, Bixler EO, et al. Insomnia with objective short sleep duration is associated with a high risk for hypertension. SLEEP 2009; 32: 491-497.
(8). Vgontzas AN, Liao D, Pejovic S, et al. Insomnia with objective short sleep duration is associated with type 2 diabetes: a population-based study. Diabetes Care 2009; 32: 980-5.
(9). Vgontzas AN, Liao D, Pejovic S, et al. Insomnia with Short Sleep Duration and Mortality: The Penn State Cohort. SLEEP 2010; 33: 1159-1164.
(10). Dew MA, Hoch CC, Buysse DJ, et al. Healthy older adults sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom Med 2003; 65: 63-73.
(11). Spiegelhalder K, Fuchs L, Ladwig J, et al. Heart rate and heart rate variability in primary insomnia. J Sleep Res 2011; 20: 137-145.
(12). Lanfranchi PA, Pennestri MH, Fradette L, et al. Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk. SLEEP 2009; 32: 760-766.
(13). Burgos I, Richter L, Klein T, et al. Increased nocturnal interleukin-6 excretion in patients with primary insomnia: A pilot study. Brain Behav Immun 2006; 20: 246-253.
(14). Vgontzas AN, Bixler EO, Lin HM, et al. Chronic insomnia is associated with nyctohemeral activation of the hypothalamic–pituitary–adrenal axis: clinical implications. J Clin Endocrinol Metab 2001; 86: 3787–94.
(15). Luyster FS, Strollo PJ, Zee P, et al. Sleep: A health imperative. SLEEP 2012; 35: 727-734.
(16). Riemann, D, Perlis ML. The treatments of chronic insomnia: A review of benzodiazepine receptor agonists and psychological and behavioral therapies. Sleep Medicine Reviews 2009; 13: 205-214.

Competing interests: Prof. Espie is Clinical and Scientific Director of Sleepio Limited (an organization dedicated to helping people sleep better through raising awareness, research, and dissemination of behavioral advice) but has not received any income from the company.

Simon D Kyle, Post-Doctoral Research Associate

Kenneth M. MacMahon, Colin A. Espie

University of Glasgow Sleep Centre, Sackler Institute of Psychobiological Research, Southern General Hospital, Glasgow G51 4TF

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This artilce is very important! How about marital distress with 2ndary depression superimposed on preexisting Diabetes, ASHD, hypertension?

Competing interests: None declared

Bernard A. Yablin, ret ass clin prof Peds

URMC, Rochester,NY 14642

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