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1.  Anxiety and depression lowers blood pressure: 22-year follow-up of the population based HUNT study, Norway 
BMC Public Health  2011;11:601.
For decades, symptoms of anxiety and depression have been included among psychological factors associated with development of hypertension. Although this has been questioned in recent studies, most findings have been based on a single assessment of mental distress at baseline. We examined these associations using repeated assessments of anxiety, depression and blood pressure.
Data on 17,410 men and women aged 20 to 67 participating in the Nord-Trøndelag Health Study (HUNT) in Norway in 1984-86 were re-examined 11 and 22 years later. The main outcome was change in mean blood pressure (mm Hg) during follow-up.
We found that a high symptom level score (≥80th percentile) of combined anxiety and depression at baseline, as compared to a lower symptom level, was associated with lower mean systolic (-0.67 mm Hg, p = 0.044) and diastolic (-0.25 mm Hg, p = 0.201) blood pressure at year 22. A high symptom level present at all three examinations was associated with a stronger decrease in mean systolic (-1.59 mm Hg, p = 0.004) and diastolic (-0.78 mm Hg, p = 0.019) blood pressure and with a 20% (p = 0.001) lower risk of developing hypertension (BP ≥140/90 mm Hg) at year 22. The associations were only slightly attenuated in multivariate analyses, with no evidence of a mediating effect of alteration in heart rate.
This study do not support previous hypothesis that emotional stress may be a cause of hypertension. Our findings indicate that symptoms of anxiety and depression are associated with decrease in blood pressure, particularly when a high symptom level can be detected over decades.
PMCID: PMC3162525  PMID: 21797992
2.  The welfare burden of adolescent anxiety and depression: a prospective study of 7500 young Norwegians and their families: the HUNT study 
BMJ Open  2012;2(6):e001942.
To examine the association between anxiety and depression symptoms in adolescents and their families and later medical benefit receipt in young adulthood.
Prospective cohort study. Norwegian population study linked to national registers.
Data from the Nord-Trøndelag Health Study 1995–1997 (HUNT) gave information on anxiety and depression symptoms as self-reported by 7497 school-attending adolescents (Hopkins Symptoms Checklist—SCL-5 score) and their parents (Hospital Anxiety and Depression Scale score). There were 2711 adolescents with one or more siblings in the cohort.
Outcome measures
Adolescents were followed for 10 years in national social security registers, identifying long-term receipt of medical benefits (main outcome) and unemployment benefits for comparison from ages 20–29.
We used logistic regression to estimate OR of benefit receipt for groups according to adolescent and parental anxiety and depression symptom load (high vs low symptom loads) and for a one point increase in the continuous SCL-5 score (range 1–4). We adjusted for family-level confounders by comparing siblings differentially exposed to anxiety and depression symptoms.
Comparing siblings, a one point increase in the mean SCL-5 score was associated with a 65% increase in the odds of medical benefit receipt from age 20–29 (adjusted OR, 1.65, 95% CI 1.10 to 2.48). Parental anxiety and depression symptom load was an indicator of their adolescent's future risk of medical benefit receipt, and adolescents with both parents reporting high symptom loads seemed to be at a particularly high risk. The anxiety and depression symptom load was only weakly associated with unemployment benefits.
Adolescents in families hampered by anxiety and depression symptoms are at a substantially higher risk of medical welfare dependence in young adulthood. The prevention and treatment of anxiety and depression in adolescence should be family-oriented and aimed at ensuring work-life integration.
PMCID: PMC3533058  PMID: 23144262
Public Health; Epidemiology; Anxiety and depression; Adolescents; Social insurance; Family
3.  Prepregnancy cardiovascular risk factors as predictors of pre-eclampsia: population based cohort study 
BMJ : British Medical Journal  2007;335(7627):978.
Objective To examine the effect of cardiovascular risk factors before pregnancy on risk of pre-eclampsia.
Design Population based prospective study.
Setting Linkage between a Norwegian population based study (Nord-Trøndelag health study, HUNT-2) and Norway's medical birth registry.
Participants 3494 women who gave birth after participating in the Nord-Trøndelag health study at baseline; of whom 133 (3.8%) delivered after a pre-eclamptic pregnancy.
Main outcome measure Odds ratio of developing pre-eclampsia.
Results After adjustment for smoking; previous pre-eclampsia; parity; maternal age, education, and socioeconomic position; and duration between baseline measurements and delivery, positive associations were found between prepregnancy serum levels of triglycerides, cholesterol, low density lipoprotein cholesterol, non-high density lipoprotein cholesterol, and blood pressure and risk of pre-eclampsia. The odds ratio of developing pre-eclampsia for women with baseline systolic blood pressures greater than 130 mm Hg (highest fifth) was 7.3 (95% confidence interval 3.1 to 17.2) compared with women with systolic blood pressures less than 111 mm Hg (lowest fifth). Similar results were found for nulliparous and parous women. Women who used oral contraceptives at baseline had half the risk of pre-eclampsia compared with never or former users (0.5, 0.3 to 0.9).
Conclusion Women with cardiovascular risk factors may be predisposed to pre-eclampsia.
PMCID: PMC2072028  PMID: 17975256
4.  Symptoms of anxiety and depression and risk of heart failure: the HUNT Study 
European Journal of Heart Failure  2014;16(8):861-870.
Symptoms of anxiety and depression often co-exist with cardiovascular disease, yet little is known about the prospective risk for heart failure (HF) in people with symptoms of depression and anxiety. We aimed to study these prospective associations using self-reported symptoms of anxiety, depression, and mixed symptoms of anxiety and depression (MSAD) in a large population sample.
Methods and results
In the second wave of the Nord-Trøndelag Health Study (HUNT 2, 1995–1997), Norway, baseline data on symptoms of anxiety and depression, socio-demographic variables, health status including cardiovascular risk factors, and common chronic somatic diseases were registered for 62 567 adults, men and women, free of known HF. The cohort was followed for incident HF from baseline throughout 2008. A total of 1499 cases of HF occurred during a mean follow-up of 11.3 years (SD = 2.9), identified either in hospital registers or by the National Cause of Death Registry. There was no excess risk for future HF associated with symptoms of anxiety or MSAD at baseline. For depression, the multi-adjusted hazard ratios for HF were 1.07 (0.87–1.30) for moderate symptoms and 1.41 (1.07–1.87) for severe symptoms (P for trend 0.026). Established cardiovascular risk factors, acute myocardial infarction (AMI) prior to baseline, and adjustment for incident AMI as a time-dependent covariate during follow-up had little influence on the estimates.
Symptoms of depression, but not symptoms of anxiety or MSAD, were associated with increased risk for HF in a dose–response manner. The increased risk could not be fully explained by cardiovascular or socio-economic risk factors, or by co-morbid AMI.
PMCID: PMC4255780  PMID: 25044493
Depression; Anxiety; Prospective; Risk; Heart failure; Epidemiology
5.  Mental health and wellbeing in spouses of persons with dementia: the Nord-Trøndelag health study 
BMC Public Health  2014;14:413.
Caring for a spouse diagnosed with dementia can be a stressful situation and can put the caregiving partner at risk of loss of mental health and wellbeing. The main aim of this study was to investigate the relationship between dementia and spousal mental health in a population-based sample of married couples older than 55 years of age. The association was investigated for individuals living together with their demented partner, as well as for individuals whose demented partner was living in an institution.
Data on dementia were collected from hospitals and nursing homes in the county of Nord-Trøndelag, Norway. These data were combined with data on spousal mental health, which were collected in a population-based health screening: the Nord-Trøndelag Health Study (HUNT). Of 6,951 participating couples (>55 years), 131 included one partner that had been diagnosed with dementia.
Our results indicate that after adjustment for covariates, having a partner with dementia is associated with lower levels of life satisfaction and more symptoms of anxiety and depression than reported by spouses of elderly individuals without dementia. Spouses living together with a partner diagnosed with dementia experienced moderately lower levels of life satisfaction (0.35 standard deviation [SD]) and more symptoms of depression (0.38 SD) and anxiety (0.23 SD) than did their non-caregiving counterparts. Having a partner with dementia that resided in a nursing home was associated with clearly lower life satisfaction. Compared with non-caregivers, these spouses reported lower levels of life satisfaction (1.16 SD), and also more symptoms of depression (0.38 SD), and more symptoms of anxiety (0.42 SD).
Having a partner with dementia is associated with loss of mental health and reduced life satisfaction. The risk of adverse mental health outcomes is greatest after the partner’s nursing home admission.
PMCID: PMC4041138  PMID: 24885732
Dementia; Caregiving; Partner; Depression; Anxiety; Life satisfaction; Ageing
6.  Depression and anxiety in relation to catechol-O-methyltransferase Val158Met genotype in the general population: The Nord-Trøndelag Health Study (HUNT) 
BMC Psychiatry  2008;8:48.
The catechol-O-methyltransferase (COMT) gene contains a functional polymorphism, Val158Met, which has been linked to anxiety and depression, but previous results are not conclusive. The aim of the present study was to examine the relationship between the Val158Met COMT gene polymorphism and anxiety and depression measured by the Hospital Anxiety and Depression Scale (HADS) in the general adult population.
In the Nord-Trøndelag Health Study (HUNT) the association between the Val158Met polymorphism and anxiety and depression was evaluated in a random sample of 5531 individuals. Two different cut off scores (≥ 8 and ≥ 11) were used to identify cases with anxiety (HADS-A) and depression (HADS-D), whereas controls had HADS-A <8 and HADS-D <8.
The COMT genotype distribution was similar between controls and individuals in the groups with anxiety and depression using cut-off scores of ≥ 8. When utilizing the alternative cut-off score HADS-D ≥ 11, Met/Met genotype and Met allele were less common among men with depression compared to the controls (genotype: p = 0.017, allele: p = 0.006). In the multivariate analysis, adjusting for age and heart disease, depression (HADS-D ≥ 11) was less likely among men with the Met/Met genotype than among men with the Val/Val genotype (OR = 0.37, 95% CI = 0.18–0.76).
In this population-based study, no clear association between the Val158Met polymorphism and depression and anxiety was revealed. The Met/Met genotype was less likely among men with depression defined as HADS-D ≥ 11, but this may be an incidental finding.
PMCID: PMC2453123  PMID: 18578865
7.  Prevalence and long-term predictors of persistent chronic widespread pain in the general population in an 11-year prospective study: the HUNT study 
Chronic widespread pain (CWP) is common and associated with prominent negative consequences. The aim of this study was to assess the prevalence of persistent CWP in an 11-year prospective cohort study in the general population, and to examine anxiety, depression, alcohol use, poor sleep, body mass index (BMI) and chronic disease, along with demographic, lifestyle and other health-related variables as possible predictors for the assumed CWP persistence.
CWP was defined as having pain at three or more predefined sites (involving the trunk and upper and lower limbs) for at least three months in the last year. We used a Norwegian general population cohort of 28,367 individuals who responded to both the second (1995–1997) and the third (2006–2008) waves of the Nord-Trøndelag Health Study (HUNT2 and HUNT3, respectively). Data were analysed with logistic regression models.
CWP prevalence in HUNT2 was 17%. Of those reporting CWP in HUNT2, 53% still reported CWP at follow-up in HUNT3. Adjusted analyses revealed that depression and alcohol consumption were not substantially associated with the 11-year prospective CWP outcome. Poor sleep, obesity and chronic disease predicted persistent CWP, and being male and/or 60 years or older was protective.
This cohort study revealed that nearly half of the participants with baseline CWP resolved from CWP 11 years later. Among those whose CWP did not resolve, obesity, sleeping problems and chronic disease predicted CWP persistence, while aging and male sex was protective. Anxiety, mixed anxiety and depression, former smoking, and overweight were weakly associated, while depression, moderate exercise, and alcohol use were not associated with persistent CWP.
PMCID: PMC4089927  PMID: 24951013
Chronic widespread pain; Anxiety; Depression; Alcohol; Prospective cohort study; General population
8.  Symptoms of anxiety and depression and risk of acute myocardial infarction: the HUNT 2 study 
European Heart Journal  2013;35(21):1394-1403.
The nature of the association of depression and anxiety with risk for acute myocardial infarction (AMI) remains unclear. We aimed to study the prospective association of single and recurrent self-reported symptoms of anxiety and depression with a risk of AMI in a large Norwegian population based cohort.
Methods and results
In the second wave of the Nord-Trøndelag Health Study (HUNT2, 1995–97) baseline data on anxiety and depression symptoms, sociodemographic variables, health status including cardiovascular risk factors and common chronic disorders were registered for 57 953 adult men and women free of cardiovascular disease. The cohort was followed up during a mean (SD) 11.4 (2.9) years for a first AMI from baseline through 2008. A total of 2111 incident AMIs occurred, either identified at hospitals or by the National Cause of Death Registry. The multi-adjusted hazard ratios were 1.31 (95% CI 1.03–1.66) for symptoms of depression and 1.25 (CI 0.99–1.57) for anxiety. Two episodes of mixed symptoms of anxiety and depression (MSAD), reported 10 years apart, increased the risk for AMI by 52% (11–108%). After exclusion of the first 5 years of follow-up, the association of depression symptoms with AMI risk was attenuated. Relative risk for AMI with anxiety symptoms and MSAD weakened when participants with chronic disorders were excluded.
Self-reported symptoms of depression and anxiety, especially if recurrent, were moderately associated with the risk of incident AMI. We had some indications that these associations might partly reflect reverse causation or confounding from common chronic diseases.
PMCID: PMC4043317  PMID: 24057077
Depression; Anxiety; Prospective; Risk; Acute myocardial infarction; Epidemiology
9.  Lactation and cardiovascular risk factors in mothers in a population-based study: the HUNT-study 
Lactation has beneficial short term effects on maternal metabolic health, but the long term effects are less well known.
We studied the association between lifetime duration of lactation and cardiovascular risk factors in mothers later in life among 21,368 parous women aged 20 to 85 years attending the second Nord-Trøndelag Health Study (HUNT2) in 1995–1997, Norway, a cross-sectional population-based study. General linear modelling was used to calculate mean values of known cardiovascular risk factor levels in five categories of lifetime duration of lactation. Logistic regression was conducted to estimate odds ratios of hypertension, obesity and diabetes.
Among women aged 50 years or younger, lifetime duration of lactation was significantly and inversely associated with body mass index (P-trend, < 0.001), waist circumference (P-trend, < 0.001), systolic and diastolic blood pressure (both P-trends, < 0.001), and serum levels of triglycerides, total cholesterol and low density lipoprotein cholesterol (all P-trends, < 0.001) after adjustment for covariates. Parous women aged 50 years or younger who had never lactated had higher prevalence of hypertension, obesity and diabetes. In this age group, compared to women who had lactated for 24 months or more, parous women who had never lactated had an OR for hypertension of 1.88 (95% CI 1.41, 2.51), an OR for obesity of 3.37 (95% CI 2.51, 4.51) and an OR for diabetes of 5.87 (95% CI 2.25, 15.3). Among women older than 50 years there were no clear associations.
Lifetime duration of lactation was associated with long term reduced cardiovascular risk levels in mothers aged 50 years or younger.
PMCID: PMC3489591  PMID: 22713515
10.  Impact of hearing impairment on spousal mental health: the Nord-Trøndelag Health Study 
Background: Previous studies indicate that hearing loss have negative emotional implications also on spouses of the hearing impaired persons. We sought to assess the relationship between hearing impairment and spousal mental health in the general population. Methods: Pure tone audiometry and questionnaires were administered to the adult population of Nord–Trøndelag County, Norway (1996–97). In the age group between 20 and 44 years, the number of cases with hearing impairment was very low; thus, this age group was excluded from analyses. In total, 8607 couples with women over 44 years and 9530 couples with men over 44 years were identified. Associations between measured and self-reported hearing impairment and spousal self-reported symptoms of anxiety and depression, and subjective well-being were estimated. Stratified by sex and adjusting for several covariates, mental health in spouses of persons with hearing impairment was compared with that of spouses of persons with normal hearing using the general linear model. Results: Audiometrically measured hearing was not significantly associated with spousal mental health. Moderate relations between self-reported hearing and spousal mental health were observed. Conclusion: Contrary to previous results based on self-reported hearing loss, our results based on audiometry did not indicate severe loss of mental health among spouses of persons with impaired hearing.
PMCID: PMC2899895  PMID: 19887520
caregivers; hearing; mental health; well-being
11.  Risk Stratification by Self-Measured Home Blood Pressure across Categories of Conventional Blood Pressure: A Participant-Level Meta-Analysis 
PLoS Medicine  2014;11(1):e1001591.
Jan Staessen and colleagues compare the risk of cardiovascular, cardiac, or cerebrovascular events in patients with elevated office blood pressure vs. self-measured home blood pressure.
Please see later in the article for the Editors' Summary
The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP).
Methods and Findings
This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120–129/80–84; high-normal, 130–139/85–89; mild hypertension, 140–159/90–99; and severe hypertension, ≥160/≥100.
Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01–1.62) and 1.22 (1.00–1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03–1.49) and 1.20 (1.06–1.37), respectively, for all cardiovascular events and 1.33 (1.07–1.65) and 1.30 (1.09–1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p≥0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP≥130 mm Hg systolic or ≥85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5–3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries.
HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings.
Please see later in the article for the Editors' Summary
Editors' Summary
Globally, hypertension (high blood pressure) is the leading risk factor for cardiovascular disease and is responsible for 9.4 million deaths annually from heart attacks, stroke, and other cardiovascular diseases. Hypertension, which rarely has any symptoms, is diagnosed by measuring blood pressure, the force that blood circulating in the body exerts on the inside of large blood vessels. Blood pressure is highest when the heart is pumping out blood (systolic blood pressure) and lowest when the heart is refilling (diastolic blood pressure). European guidelines define optimal blood pressure as a systolic blood pressure of less than 120 millimeters of mercury (mm Hg) and a diastolic blood pressure of less than 80 mm Hg (a blood pressure of less than 120/80 mm Hg). Normal blood pressure, high-normal blood pressure, and mild hypertension are defined as blood pressures in the ranges 120–129/80–84 mm Hg, 130–139/85–89 mm Hg, and 140–159/90–99 mm Hg, respectively. A blood pressure of more than 160 mm Hg systolic or 100 mm Hg diastolic indicates severe hypertension. Many factors affect blood pressure; overweight people and individuals who eat salty or fatty food are at high risk of developing hypertension. Lifestyle changes and/or antihypertensive drugs can be used to control hypertension.
Why Was This Study Done?
The current guidelines for the diagnosis and management of hypertension recommend risk stratification based on conventionally measured blood pressure (CBP, the average of two consecutive measurements made at a clinic). However, self-measured home blood pressure (HBP) more accurately predicts outcomes because multiple HBP readings are taken and because HBP measurement avoids the “white-coat effect”—some individuals have a raised blood pressure in a clinical setting but not at home. Could risk stratification across increasing categories of CBP be refined through the use of self-measured HBP, particularly at CBP levels assumed to be associated with no or only mildly increased risk? Here, the researchers undertake a participant-level meta-analysis (a study that uses statistical approaches to pool results from individual participants in several independent studies) to answer this question.
What Did the Researchers Do and Find?
The researchers included 5,008 individuals recruited from five populations and enrolled in the International Database of Home Blood Pressure in Relation to Cardiovascular Outcome (IDHOCO) in their meta-analysis. CBP readings were available for all the participants, who measured their HBP using an oscillometric device (an electronic device for measuring blood pressure). The researchers used information on fatal and nonfatal cardiovascular, cardiac, and cerebrovascular (stroke) events to calculate the hazard ratios (HRs, indicators of increased risk) associated with a 10-mm Hg increase in systolic HBP across standard CBP categories. In participants with optimal CBP, an increase in systolic HBP of 10-mm Hg increased the risk of any cardiovascular event by nearly 30% (an HR of 1.28). Similar HRs were associated with a 10-mm Hg increase in systolic HBP for all cardiovascular events among people with normal and high-normal CBP and with mild hypertension, but for people with severe hypertension, systolic HBP did not significantly add to the prediction of any end point. Among people with optimal, normal, and high-normal CBP, 5%, 18.4%, and 30.4%, respectively, had a HBP of 130/85 or higher (“masked hypertension,” a higher blood pressure in daily life than in a clinical setting). Finally, compared to individuals with optimal CBP without masked hypertension, individuals with masked hypertension had more than double the risk of cardiovascular disease.
What Do These Findings Mean?
These findings indicate that HBP measurements, particularly in individuals with masked hypertension, refine risk stratification at CBP levels assumed to be associated with no or mildly elevated risk of cardiovascular disease. That is, HBP measurements can improve the prediction of cardiovascular complications or death among individuals with optimal, normal, and high-normal CBP but not among individuals with severe hypertension. Clinical trials are needed to test whether the identification and treatment of masked hypertension leads to a reduction of cardiovascular complications and is cost-effective compared to the current standard of care, which does not include HBP measurements and does not treat people with normal or high-normal CBP. Until then, these findings provide support for including HBP monitoring in primary prevention strategies for cardiovascular disease among individuals at risk for masked hypertension (for example, people with diabetes), and for carrying out HBP monitoring in people with a normal CBP but unexplained signs of hypertensive target organ damage.
Additional Information
Please access these websites via the online version of this summary at
This study is further discussed in a PLOS Medicine Perspective by Mark Caulfield
The US National Heart, Lung, and Blood Institute has patient information about high blood pressure (in English and Spanish) and a guide to lowering high blood pressure that includes personal stories
The American Heart Association provides information on high blood pressure and on cardiovascular diseases (in several languages); it also provides personal stories about dealing with high blood pressure
The UK National Health Service Choices website provides detailed information for patients about hypertension (including a personal story) and about cardiovascular disease
The World Health Organization provides information on cardiovascular disease and controlling blood pressure; its A Global Brief on Hypertension was published on World Health Day 2013
The UK charity Blood Pressure UK provides information about white-coat hypertension and about home blood pressure monitoring
MedlinePlus provides links to further information about high blood pressure, heart disease, and stroke (in English and Spanish)
PMCID: PMC3897370  PMID: 24465187
12.  Sex and Age Differences in the Relation of Depressive Symptoms With Blood Pressure 
American Journal of Hypertension  2013;26(12):1413-1420.
Longitudinal associations between depressive symptoms and blood pressure have been inconsistent. Most studies have examined incident hypertension as an outcome, and few have examined effect modification.
This study examined moderating influences of sex and age on coincident trajectories of depressive symptoms and blood pressure among 2,087 participants from the Baltimore Longitudinal Study of Aging (aged 19–97 years; 53% men; 74% white). Participants underwent clinical blood pressure measurement and completed the Center for Epidemiological Studies–Depression (CES-D) scale on up to 14 occasions (mean = 3.8; SD = 2.6) over up to 29 years (mean = 7.8; SD = 6.4). CES-D was log-transformed (CES-D(log)) for analyses.
Mixed-effects regression revealed that prospective relations of CES-D(log) to diastolic blood pressure differed by age in women (b = 0.095; P = 0.001) but not men; greater CES-D(log) attenuated the expected age-related decline in diastolic blood pressure. Across all testing sessions, greater CES-D(log) was associated significantly with higher average systolic blood pressure for women (b = 2.238; P = 0.006) but not men. Age-stratified analyses showed that greater CES-D(log) was associated significantly with higher average systolic (b = 3.348; P = 0.02) and diastolic (b = 1.730; P < 0.03) blood pressure for older adults (≥58.8 years at first visit). In the younger age cohort, sex moderated the relation of CES-D(log) to systolic blood pressure (b = −3.563; P = 0.007); greater CES-D(log) in women, but lesser CES-D(log) in men, was associated with higher systolic blood pressure.
Results demonstrate sex and age differences in the relation between depressive symptoms and blood pressure. Findings suggest the potential importance of preventing, detecting, and lowering depressive symptoms to prevent hypertension among women and older adults.
PMCID: PMC3816627  PMID: 23959543
age factors; blood pressure; depressive symptoms; hypertension; longitudinal studies; older adults; repeated measures; sex factors; women.
13.  Inflammatory Cytokines as Risk Factors for a First Venous Thrombosis: A Prospective Population-Based Study 
PLoS Medicine  2006;3(8):e334.
In case-control studies, elevated levels of interleukins 6 and 8 have been found to be associated with an increased risk of venous thrombosis (VT). Because of the design of these studies, it remained uncertain whether these alterations were a cause or a result of the VT. In order to distinguish between the two, we set out to measure the levels of six inflammatory markers prior to thrombosis in a population-based cohort using a nested case-cohort design.
Methods and Findings
Between August 1995 and June 1997, blood was collected from 66,140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). We identified venous thrombotic events occurring between entry and 1 January 2002. By this date we had registered 506 cases with a first VT; an age- and sex-stratified random sample of 1,464 controls without previous VT was drawn from the original cohort. Levels of interleukins 1β, 6, 8, 10, 12p70, and tumour necrosis factor-α were measured in the baseline sample that was taken 2 d to 75 mo before the event (median 33 mo). Cut-off points for levels were the 80th, 90th, and 95th percentile in the control group. With odds ratios ranging from 0.9 (95% CI: 0.6–1.5) to 1.1 (95% CI: 0.7–1.8), we did not find evidence for a relationship between VT and an altered inflammatory profile.
The results from this population sample show that an altered inflammatory profile is more likely to be a result rather than a cause of VT, although short-term effects of transiently elevated levels cannot be ruled out.
An altered inflammatory profile appears more likely to be a result than a cause of venous thrombosis.
Editors' Summary
Blood clots (thromboses) are a common medical problem, especially in people who have been immobilized for a variety of reasons, who have other medical or surgical conditions, or who take certain types of drugs such as oral contraceptives. As well as these factors, various genetic changes make it more likely that certain people will develop a thrombosis. The most well known of these genetic changes is in a clotting factor, Factor V. Instead of the normal clotting factor V, some people have a variant known as Factor V Leiden, which makes them more likely to develop a thrombosis. (It is so named as it was discovered by researchers in Leiden, Netherlands.) Researchers are trying to find out if other abnormalities, particularly in levels of substances involved in inflammation, might make the chance of thrombosis more common. Identifying such changes might make it easier to predict who might be at risk of getting a thrombosis—for example, when a patient has to have an operation—and thus give them appropriate preventative measures.
Why Was This Study Done?
Previous studies have shown that the levels of inflammatory substances, known as cytokines, are raised around the time of a thrombosis. However, because of the design of these studies it was not clear whether these alterations were a cause or a result of the thrombosis. These researchers wanted to measure the levels of six cytokines before thrombosis in a large group of people and follow them to see if any particular level of cytokine made it more likely that they would go on to develop a thrombosis.
What Did the Researchers Do and Find?
During a three-year period between August 1995 and June 1997, blood was collected from 66,140 people in the second Norwegian Health Study of Nord-Trøndelag (HUNT2). Anyone who had a thrombosis between the start of the study and the beginning of 2002 was identified—506 people in all. Blood samples, taken from these people (cases) between two days and 75 months before the thrombosis happened, were used to measure levels of a number of different cytokines (abbreviated to IL-1β, IL-6, IL-8, IL-10, IL12p70, and tumour necrosis factor alpha [TNF-α]). These levels were then compared with those in samples also taken earlier from 1,464 people who were similar to the cases but had no thrombosis (controls). The authors found no evidence for a relationship between the chance of getting a thrombosis and a change in any of these markers of inflammation.
What Do These Findings Mean?
It seems unlikely that any long-term changes in levels of cytokines make any difference as to whether or not people develop a thrombosis. Hence, any changes seen in previous studies are most likely to have been the result of the thrombosis. However, the researchers could not rule out that changes occurred in the hours or days immediately before the thrombosis, although that seems unlikely. In any case, the levels of these cytokines do not seem to be useful as a clinical tool to predict who is at risk of thrombosis.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus encyclopedia entries on deep venous thrombosis and pulmonary embolus
Omni, a health information service in the UK run by the Resource Discovery Network, has links to pages of information on venous thrombosis
The HUNT studies are described in this Web site
PMCID: PMC1551920  PMID: 16933968
14.  Education-based health inequalities in 18,000 Norwegian couples: the Nord-Trøndelag Health Study (HUNT) 
BMC Public Health  2012;12:998.
Education-based inequalities in health are well established, but they are usually studied from an individual perspective. However, many individuals are part of a couple. We studied education-based health inequalities from the perspective of couples where indicators of health were measured by subjective health, anxiety and depression.
A sample of 35,980 women and men (17,990 couples) was derived from the Norwegian Nord-Trøndelag Health Study 1995–97 (HUNT 2). Educational data and family identification numbers were obtained from Statistics Norway. The dependent variables were subjective health (four-integer scale), anxiety (21-integer scale) and depression (21-integer scale), which were captured using the Hospital Anxiety and Depression Scale. The dependent variables were rescaled from 0 to 100 where 100 was the worst score. Cross-sectional analyses were performed using two-level linear random effect regression models.
The variance attributable to the couple level was 42% for education, 16% for subjective health, 19% for anxiety and 25% for depression. A one-year increase in education relative to that of one’s partner was associated with an improvement of 0.6 scale points (95% confidence interval = 0.5–0.8) in the subjective health score (within-couple coefficient). A one-year increase in a couple’s average education was associated with an improvement of 1.7 scale points (95% confidence interval = 1.6–1.8) in the subjective health score (between-couple coefficient). There were no education-based differences in the anxiety or depression scores when partners were compared, whereas there were substantial education-based differences between couples in all three outcome measures.
We found considerable clustering of education and health within couples, which highlighted the importance of the family environment. Our results support previous studies that report the mutual effects of spouses on education-based inequalities in health, suggesting that couples develop their socioeconomic position together.
PMCID: PMC3533525  PMID: 23157803
Anxiety; Couples; Depression; Education; Family health; Multilevel analysis; Subjective health
15.  Risk factors for suicidal thoughts in adolescence-a prospective cohort study: the Young-HUNT study 
BMJ Open  2014;4(8):e005867.
Examining the associations between health and lifestyle factors recorded in the participants’ early teens and development of suicidal thoughts recorded 4 years later.
Population-based prospective cohort study.
All students in the two relevant year classes in Nord-Trøndelag County were invited, 80% attended both waves of data collection.
2399 secondary school students who participated in the Young-HUNT1 study in 1995–1997 (13–15 years old) were included in a follow-up study 4 years later (17–19 years old).
Primary outcome measure
Suicidal thoughts reported at age 17–19 years.
408 (17%, 95% CI 15.5% to 18.5%) of the adolescents reported suicidal thoughts at follow-up, 158 (14.2%, CI 13.6% to 16.4%) boys and 250 (19.5%, CI 18.8% to 22.0%) girls. Baseline anxiety and depressive symptoms (adjusted OR (aOR) 1.9, CI 1.4 to 2.6), conduct problems (aOR 1.8, CI 1.3 to 2.6), overweight (aOR 1.9 CI 1.4 to 2.4), and muscular pain and tension (aOR 1.8, CI 1.4 to 2.4), were all associated with reporting suicidal thoughts at follow-up.
One in six young adults experienced suicidal thoughts, girls predominating. Suicidal thoughts were most strongly associated with symptoms of anxiety/depression, conduct problems, pain/tension and overweight reported when participants were 13–15 years old. Specific preventive efforts in these groups might be indicated. Future research should investigate whether similar associations are seen with suicide/suicidal attempts as endpoints.
PMCID: PMC4139646  PMID: 25142264
Preventive Medicine
16.  Pattern of declining blood pressure across replicate population surveys of the WHO MONICA project, mid-1980s to mid-1990s, and the role of medication 
BMJ : British Medical Journal  2006;332(7542):629-635.
Objective Declining mean systolic and diastolic blood pressures were observed in most populations of the World Health Organization MONICA (monitoring trends and determinants in cardiovascular disease) project from the mid-1980s to mid-1990s. We tested whether pooled results would show mean change associated with decline in high readings only, resulting from better antihypertensive medication, or with similar falls in low, middle, and high readings, implying other causes.
Design Independent, random sample, cross sectional population surveys, each end of the MONICA decade.
Setting 38 populations in 21 countries across four continents.
Participants Design target in each survey of 200 participants in each 10 year age and sex group from age 35 to 64
Main outcome measures Changes in the population in mean systolic and diastolic blood pressure, and in low, middle, and high readings—the 20th, 50th, and 80th centiles—and the differences between these changes.
Results Individual populations differed considerably, but pooling the 38 population results gave mean changes in systolic blood pressure of -2.2 mm Hg in men, -3.3 mm Hg in women, and in diastolic blood pressure of -1.4 mm Hg in men and -2.2 mm Hg in women (overall average -2.26 mm Hg, population median -1.55 mm Hg). Antihypertensive medication, associated with high readings, rose by 0.5% to 11.4%. However, average falls in low and middle blood pressure readings were so similar to those in high readings and in the mean that no effect from improving treatment of hypertension was detected. Results in contrasted subgroups were consistent.
Conclusions Blood pressure fell across 38 MONICA populations at all levels of readings, with no differential fall in high readings attributable to better control of hypertension. Despite the importance of medication to individuals, in that decade other determinants of blood pressure lowering must have been more pervasive and powerful in whole populations.
PMCID: PMC1403225  PMID: 16531419
17.  Estimates of Outcomes Up to Ten Years after Stroke: Analysis from the Prospective South London Stroke Register 
PLoS Medicine  2011;8(5):e1001033.
Charles Wolfe and colleagues collected data from the South London Stroke Register on 3,373 first strokes registered between 1995 and 2006 and showed that between 20% and 30% of survivors have poor outcomes up to 10 years after stroke.
Although stroke is acknowledged as a long-term condition, population estimates of outcomes longer term are lacking. Such estimates would be useful for planning health services and developing research that might ultimately improve outcomes. This burden of disease study provides population-based estimates of outcomes with a focus on disability, cognition, and psychological outcomes up to 10 y after initial stroke event in a multi-ethnic European population.
Methods and Findings
Data were collected from the population-based South London Stroke Register, a prospective population-based register documenting all first in a lifetime strokes since 1 January 1995 in a multi-ethnic inner city population. The outcomes assessed are reported as estimates of need and included disability (Barthel Index <15), inactivity (Frenchay Activities Index <15), cognitive impairment (Abbreviated Mental Test < 8 or Mini-Mental State Exam <24), anxiety and depression (Hospital Anxiety and Depression Scale >10), and mental and physical domain scores of the Medical Outcomes Study 12-item short form (SF-12) health survey. Estimates were stratified by age, gender, and ethnicity, and age-adjusted using the standard European population. Plots of outcome estimates over time were constructed to examine temporal trends and sociodemographic differences. Between 1995 and 2006, 3,373 first-ever strokes were registered: 20%–30% of survivors had a poor outcome over 10 y of follow-up. The highest rate of disability was observed 7 d after stroke and remained at around 110 per 1,000 stroke survivors from 3 mo to 10 y. Rates of inactivity and cognitive impairment both declined up to 1 y (280/1,000 and 180/1,000 survivors, respectively); thereafter rates of inactivity remained stable till year eight, then increased, whereas rates of cognitive impairment fluctuated till year eight, then increased. Anxiety and depression showed some fluctuation over time, with a rate of 350 and 310 per 1,000 stroke survivors, respectively. SF-12 scores showed little variation from 3 mo to 10 y after stroke. Inactivity was higher in males at all time points, and in white compared to black stroke survivors, although black survivors reported better outcomes in the SF-12 physical domain. No other major differences were observed by gender or ethnicity. Increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
Between 20% and 30% of stroke survivors have a poor range of outcomes up to 10 y after stroke. Such epidemiological data demonstrate the sociodemographic groups that are most affected longer term and should be used to develop longer term management strategies that reduce the significant poor outcomes of this group, for whom effective interventions are currently elusive.
Please see later in the article for the Editors' Summary
Editors' Summary
Every year, 15 million people have a stroke. About 5 million of these people die within a few days, and another 5 million are left disabled. Stroke occurs when the brain's blood supply is suddenly interrupted by a blood clot blocking a blood vessel in the brain (ischemic stroke, the commonest type of stroke) or by a blood vessel in the brain bursting (hemorrhagic stroke). Deprived of the oxygen normally carried to them by the blood, the brain cells near the blockage die. The symptoms of stroke depend on which part of the brain is damaged but include sudden weakness or paralysis along one side of the body, vision loss in one or both eyes, and confusion or trouble speaking or understanding speech. Anyone experiencing these symptoms should seek immediate medical attention because prompt treatment can limit the damage to the brain. Risk factors for stroke include age (three-quarters of strokes occur in people over 65 years old), high blood pressure, and heart disease.
Why Was This Study Done?
Post-stroke rehabilitation can help individuals overcome the physical disabilities caused by stroke, and drugs and behavioral counseling can reduce the risk of a second stroke. However, people can also have problems with cognition (thinking, awareness, attention, learning, judgment, and memory) after a stroke, and they can become depressed or anxious. These “outcomes” can persist for many years, but although stroke is acknowledged as a long-term condition, most existing data on stroke outcomes are limited to a year after the stroke and often focus on disability alone. Longer term, more extensive information is needed to help plan services and to help develop research to improve outcomes. In this burden of disease analysis, the researchers use follow-up data collected by the prospective South London Stroke Register (SLSR) to provide long-term population-based estimates of disability, cognition, and psychological outcomes after a first stroke. The SLSR has recorded and followed all patients of all ages in an inner area of South London after their first-ever stroke since 1995.
What Did the Researchers Do and Find?
Between 1995 and 2006, the SLSR recorded 3,373 first-ever strokes. Patients were examined within 48 hours of referral to SLSR, their stroke diagnosis was verified, and their sociodemographic characteristics (including age, gender, and ethnic origin) were recorded. Study nurses and fieldworkers then assessed the patients at three months and annually after the stroke for disability (using the Barthel Index, which measures the ability to, for example, eat unaided), inactivity (using the Frenchay Activities Index, which measures participation in social activities), and cognitive impairment (using the Abbreviated Mental Test or the Mini-Mental State Exam). Anxiety and depression and the patients' perceptions of their mental and physical capabilities were also assessed. Using preset cut-offs for each outcome, 20%–30% of stroke survivors had a poor outcome over ten years of follow-up. So, for example, 110 individuals per 1,000 population were judged disabled from three months to ten years, rates of inactivity remained constant from year one to year eight, at 280 affected individuals per 1,000 survivors, and rates of anxiety and depression fluctuated over time but affected about a third of the population. Notably, levels of inactivity were higher among men than women at all time points and were higher in white than in black stroke survivors. Finally, increased age was associated with higher rates of disability, inactivity, and cognitive impairment.
What Do These Findings Mean?
Although the accuracy of these findings may be affected by the loss of some patients to follow-up, these population-based estimates of outcome measures for survivors of a first-ever stroke for up to ten years after the event provide concrete evidence that stroke is a lifelong condition with ongoing poor outcomes. They also identify the sociodemographic groups of patients that are most affected in the longer term. Importantly, most of the measured outcomes remain relatively constant (and worse than outcomes in an age-matched non-stroke-affected population) after 3–12 months, a result that needs to be considered when planning services for stroke survivors. In other words, these findings highlight the need for health and social services to provide long-term, ongoing assessment and rehabilitation for patients for many years after a stroke.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Institute of Neurological Disorders and Stroke provides information about all aspects of stroke (in English and Spanish); the US National Institute of Health SeniorHealth Web site has additional information about stroke
The Internet Stroke Center provides detailed information about stroke for patients, families, and health professionals (in English and Spanish)
The UK National Health Service Choices Web site also provides information about stroke for patients and their families
MedlinePlus has links to additional resources about stroke (in English and Spanish)
More information about the South London Stroke Register is available
PMCID: PMC3096613  PMID: 21610863
18.  Mental disorder and caregiver burden in spouses: the Nord-Trøndelag health study 
BMC Public Health  2010;10:516.
Researchers generally agree that mental disorder represents a burden to the family. The present study concerns the subjective burden of living with a person with mental disorder, more specifically the association between mental disorder in the index person and subjective well-being and symptoms of anxiety and depression in the spouse.
Data were obtained from questionnaires administered to the adult population of Nord-Trøndelag County, Norway during the period 1995-1997. The present study is based on a subsample where 9,740 couples were identified. Subjective burden in spouses of persons with mental disorder was compared with subjective burden in spouses of persons without mental disorder, using analysis of variance (ANOVA). All analyses were stratified by sex.
Adjusting for several covariates, spouses of persons with mental disorder scored significantly lower on subjective well-being and significantly higher on symptoms of anxiety and depression compared to spouses of index persons without mental disorder. Although highly significant, the effect sizes were moderate, corresponding to a difference in standard deviations ranging from .34 - .51.
Our study supports the notion that there is an association between mental disorder in one partner and subjective burden in the spouse, but not to the same extent that have been reported in earlier studies, as our results do not indicate that a large proportion of the spouses reach a symptom level of anxiety and depression that reflects clinical mental disorder.
PMCID: PMC2936431  PMID: 20796279
19.  Combination of anxiety and depression is associated with an increased headache frequency in migraineurs: a population-based study 
BMC Neurology  2014;14(1):238.
Although anxiety and depression have been classified as distinct traits of affective disorders, previous studies have reported their co-occurrence in subjects with migraine. However, few reports are available on the clinical implications of this comorbidity. This study is to assess the comorbidity of anxiety and depression in subjects with migraine and its clinical implications in a population-based sample from Korea.
We selected Korean subjects aged 19–69 years by the stratified random sampling method, and evaluated them using a semi-structured interview, designed to identify headache type, anxiety, and depression. We used Goldberg Anxiety Scale questions and Patient Health Questionnnaire-9 for the diagnosis of anxiety and depression, respectively.
Of the 2,762 participants who completed the interview, 147 subjects (5.4%) were classified as having a migraine during the previous year. Among these 147 subjects, 17 (11.6%) had anxiety and depression, 28 (19.0%) had anxiety alone, 9 (6.1%) had depression alone, and 93 (63.3%) had neither anxiety nor depression. Headache frequency per month was remarkably higher in subjects having migraine with anxiety and depression (median [25–75 percentile values], 8.0 [2.5–21.0]) than in those having migraine with anxiety alone (2.0 [1.0–5.0], p = 0.003), migraine with depression alone (1.0 [0.3–4.0], p = 0.001), and migraine without anxiety or depression (1.0 [0.3–3.0], p < 0.001). The migraine with anxiety alone (7.0 [6.0–8.0], p = 0.011) group and migraine with anxiety and depression (7.0 [5.0–9.0], p = 0.018) group showed higher Visual Analogue Scale scores for pain intensity compare to migraine without anxiety or depression (6.0 [5.0-7.0]) group.
Approximately 1/3 of migraineurs with anxiety had depression and 2/3 of migraineurs with depression had anxiety. Combination of anxiety and depression was associated with an increased headache frequency. Anxiety was associated with exacerbation of headache intensity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12883-014-0238-4) contains supplementary material, which is available to authorized users.
PMCID: PMC4279894  PMID: 25494868
Migraine; Anxiety; Depression; Epidemiology; Comorbidity
20.  Diabetes related risk factors did not explain the increased risk for urinary incontinence among women with diabetes. The Norwegian HUNT/EPINCONT study 
BMC Urology  2009;9:11.
Previous studies have shown an association between diabetes mellitus (DM) and urinary incontinence (UI) in women, especially severe UI. The purpose of this study was to investigate whether diabetes related variables could explain this association.
The study is part of the EPINCONT study, which is based on the large Nord-Trøndelag Health Study 2 (HUNT 2), performed in the county of Nord-Trøndelag, Norway, during the years 1995 - 1997. Questions on diabetes and UI were answered by a total of 21 057 women aged 20 years and older. Of these 685 were identified as having diabetes, and thus comprise the population of our study. A variety of clinical and biochemical variables were recorded from the participants.
Blood-glucose, HbA1c, albumine:creatinine ratio (ACR), duration of diabetes, diabetes treatment, type of diabetes, cholesterol and triglycerides did not significantly differ in women with and without UI in crude analyses. However, the diabetic women with UI had more hospitalizations during the last 12 months, more homecare, and a higher prevalence of angina and use of oestrogene treatment (both local and oral/patch). After adjusting for age, BMI, parity and smoking, there were statistically significant associations between any UI and angina (OR 1.89; 95% CI: 1.22 - 2.93), homecare (OR 1.72; 95% CI: 1.02 - 2.89), and hospitalization during the last 12 months (OR 1.67; 95% CI: 1.18 - 2.38). In adjusted analyses severe UI was also significantly associated with the same variables, and also with diabetes drug treatment (OR 2.10; 95% CI: 1.07 - 4.10) and stroke (OR 2.47; 95% CI: 1.09 - 5.59).
No single diabetes related risk factor seems to explain the increased risk for UI among women with diabetes. However, we found associations between UI and some clinical correlates of diabetes.
PMCID: PMC2753577  PMID: 19740449
21.  Low blood pressure and depression in older men: a population based study. 
BMJ : British Medical Journal  1994;308(6926):446-449.
OBJECTIVE--To determine if an association exists between low blood pressure and depressive symptoms in older men living in the community. DESIGN--Cross sectional, population based study. SETTING--Town of Rancho Bernardo, California, United States. SUBJECTS--846 men aged 60-89 years. Comparisons between hypotensive, normotensive, and hypertensive groups were limited to 594 men not taking drugs for hypertension. MAIN OUTCOME MEASURES--Mean scores on Beck depression inventory and prevalence of scores > or = 13. RESULTS--Men with diastolic blood pressure < 75 mm Hg had significantly higher depression scores (mean scores 6.35 v 4.96; P < 0.001) and more categorical depression (7.6% v 1.8% with scores > or = 13; P < 0.01) than men with diastolic blood pressure levels between 75 and 85 mm Hg. Men with diastolic blood pressure levels > 85 mm Hg had higher depression scores than men with intermediate blood pressure levels (mean scores 5.85 v 4.96; P < 0.05). Men with diastolic hypotension scored significantly higher on both affective and somatic item subscales of the Beck depression inventory and on individual measures of fatigue, pessimism, sadness, loss of appetite, weight loss, and preoccupation with health. Low diastolic blood pressure was a significant predictor of both mean depression score and prevalence of categorical depression, independent of age and change in weight since the baseline visit. The presence of several chronic diseases was associated with depressed mood and higher blood pressure but not with low blood pressure. CONCLUSION--The association of relatively low diastolic blood pressure with higher depressive symptom scores and rates of categorical depression was independent of age or weight loss. Since fatigue is a prominent symptom of depression, any association of low blood pressure with fatigue could reflect depressive disorders or clinically important depression.
PMCID: PMC2539519  PMID: 8124175
22.  Life style related to blood pressure and body weight in adolescence: Cross sectional data from the Young-HUNT study, Norway 
BMC Public Health  2008;8:111.
The associations between physical activity, unhealthy dietary habits and cigarette smoking and blood pressure, overweight and obesity are well established in adulthood. This is not the case for similar associations in adolescence. Thus, the purpose of this study is to examine how physical activity, smoking status and dietary habits were related to overweight, obesity and blood pressure in a population of Norwegian adolescents.
Weight, height, systolic (SBP) and diastolic blood pressure (DBP) were measured, and body mass index (BMI) was calculated among 8408 adolescents who participated in a population based study in 1995–97 in the county of Nord-Trøndelag. Internationally accepted cut-off values were used to determine if the adolescents were overweight or obese. The adolescents also completed a detailed questionnaire including dietary habits, physical activity and smoking habits. We calculated adjusted mean blood pressures and odds ratios for being overweight or obese for different exposure categories of life style variables.
Low levels of physically activity were associated with increased odds of being overweight (odds ratio (OR), 1.4; 95% confidence interval (CI), 1.1–1.8 in girls and OR, 2.0; 95% CI, 1.6–2.5 in boys) or obese (girls: OR, 3.1; 95% CI, 1.6–6.0; boys: OR, 3.7; 95% CI, 2.1–6.4). In addition, the least physically active girls had a 1.5 mmHg higher mean DBP compared with the most active (p-trend <0.001), and among boys this difference was 1.0 mmHg (p-trend < 0.001). Smokers were more likely to be obese (OR, 1.6; 95% CI, 1.1–2.5 in girls and 1.4; 95% CI, 0.9–2.1 in boys) compared with non-smokers. Smokers also had lower mean SBP than non-smokers; however, this finding was restricted to smokers with the lowest smoking exposure. Associations between dietary habits and weight status largely disappeared after adjusting for weight losing behaviour.
In this population of adolescents low levels of physical activity were associated with higher mean DBP and higher odds of overweight or obesity. Smoking was also associated with higher odds of overweight and obesity. The paradoxical associations between healthy dietary habits and overweight and obesity are most likely an effect of reverse causality.
PMCID: PMC2375890  PMID: 18400086
23.  Effect of Treatment of Obstructive Sleep Apnea on Depressive Symptoms: Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(11):e1001762.
In a meta-analysis of randomized controlled trials, Matthew James and colleagues investigate the effects of continuous positive airway pressure or mandibular advancement devices on depression.
Please see later in the article for the Editors' Summary
Obstructive sleep apnea (OSA) is associated with increased morbidity and mortality, and decreased quality of life. Treatment with continuous positive airway pressure (CPAP) or mandibular advancement devices (MADs) is effective for many symptoms of OSA. However, it remains controversial whether treatment with CPAP or MAD also improves depressive symptoms.
Methods and Findings
We performed a systematic review and meta-analysis of randomized controlled trials that examined the effect of CPAP or MADs on depressive symptoms in patients with OSA. We searched Medline, EMBASE, the Cochrane Central Registry of Controlled Trials, and PsycINFO from the inception of the databases until August 15, 2014, for relevant articles.
In a random effects meta-analysis of 19 identified trials, CPAP treatment resulted in an improvement in depressive symptoms compared to control, but with significant heterogeneity between trials (Q statistic, p<0.001; I2 = 71.3%, 95% CI: 54%, 82%). CPAP treatment resulted in significantly greater improvement in depressive symptoms in the two trials with a higher burden of depression at baseline (meta-regression, p<0.001). The pooled standardized mean difference (SMD) in depressive symptoms with CPAP treatment in these two trial populations with baseline depression was 2.004 (95% CI: 1.387, 2.621), compared to 0.197 (95% CI: 0.059, 0.334) for 15 trials of populations without depression at baseline. Pooled estimates of the treatment effect of CPAP were greater in parallel arm trials than in crossover trials (meta-regression, p = 0.076). Random effects meta-analysis of five trials of MADs showed a significant improvement in depressive symptoms with MADs versus controls: SMD = 0.214 (95% CI: 0.026, 0.401) without significant heterogeneity (I2 = 0%, 95% CI: 0%, 79%). Studies were limited by the use of depressive symptom scales that have not been validated specifically in people with OSA.
CPAP and MADs may be useful components of treatment of depressive symptoms in individuals with OSA and depression. The efficacy of CPAP and MADs compared to standard therapies for depression is unknown.
Please see later in the article for the Editors' Summary
Editors' Summary
Obstructive sleep apnea (OSA) is a sleep-related breathing disorder that is particularly common among middle-aged and elderly people, although most are unaware that they have the condition. It is characterized by the occurrence of numerous brief (ten seconds or so) breathing interruptions during sleep. These “apneas” occur when relaxation of the upper airway muscles decreases airflow, which lowers the level of oxygen in the blood. Consequently, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of OSA include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Mild to moderate OSA can also be treated using a mandibular advancement device (MAD), a “splint” that fits inside the mouth and pushes the jaw and tongue forward to increase the space at the back of the throat and reduce airway narrowing. For severe OSA, doctors recommend continuous positive airway pressure (CPAP), in which a machine blows pressurized air into the airway through a facemask to keep it open.
Why Was This Study Done?
OSA is a serious condition that is associated with an increased risk of illness and death. Clinical depression (long-lasting, overwhelming feelings of sadness and hopelessness), for example, is common among people with OSA. The interaction between these frequently co-morbid (co-existing) conditions is complex. The sleep disruption and weight gain that are often associated with depression could cause or worsen OSA. Conversely, OSA could trigger depression by causing sleep disruption and by inducing cognitive changes (changes in thinking) by intermittently starving the brain of oxygen. If the latter scenario is correct, then treating OSA with CPAP or MADs might improve depressive symptoms. Several trials have investigated this possibility, but their results have been equivocal. Here, the researchers undertake a systematic review and meta-analysis of randomized controlled trials that have examined the effect of CPAP or MADs on depressive symptoms in patients with OSA to find out whether treating co-morbid OSA in patients with depression can help to treat depression. A randomized controlled trial compares the outcomes of individuals chosen to receive different interventions through the play of chance, a systematic review uses predefined criteria to identify all the research on a given topic, and meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 22 trials that investigated the effects of CPAP or MAD treatment in patients with OSA and that measured depressive symptoms before and after treatment. Meta-analysis of the results of 19 trials that provided information about the effect of CPAP on depressive symptoms indicated that CPAP improved depressive symptoms compared to the control intervention (usually sham CPAP) but revealed considerable heterogeneity (variability) between trials. Notably, CPAP treatment resulted in a greater improvement in depressive symptoms in trials in which there was a high prevalence of depression at baseline than in trials in which there was a low prevalence of depression at baseline. Moreover, the magnitude of this improvement in depressive symptoms in trials with a high prevalence of depression at baseline was large enough to be clinically relevant. Meta-analysis of five trials that provided information about the effect of MADs on depressive symptoms indicated that MADs also improved depressive symptoms compared to the control intervention (sham MAD).
What Do These Findings Mean?
These findings suggest that both CPAP and MAD treatment for OSA can result in modest improvements in depressive symptoms and that populations with high initial levels of depressive symptoms may reap the greatest benefits of CPAP treatment. These findings give no indication of the efficacy of CPAP and MADs compared to standard treatments for depression such as antidepressant medications. Moreover, their accuracy may be limited by methodological limitations within the trials included in the meta-analyses reported here. For example, the questionnaires used to measure depression in these trials were not validated for use in people with OSA. Further high-quality randomized controlled trials are therefore needed to confirm the findings of this systematic review and meta-analysis. For now, however, these findings suggest that the use of CPAP and MADs may help improve depressive symptoms among people with OSA.
Additional Information
Please access these websites via the online version of this summary at
The US National Heart, Lung, and Blood Institute has information (including several videos) about sleep apnea (in English and Spanish)
The UK National Health Service Choices website provides information and personal stories about obstructive sleep apnea and depression
The not-for-profit American Sleep Apnea Association provides detailed information about sleep apnea for patients and healthcare professionals, including personal stories about the condition
The US National Institute of Mental Health provides information on all aspects of depression (in English and Spanish)
The Anxiety and Depression Association of America provides information about sleep disorders
The MedlinePlus encyclopedia has a page on obstructive sleep apnea; MedlinePlus provides links to further information and advice about obstructive sleep apnea and about depression (in English and Spanish)
PMCID: PMC4244041  PMID: 25423175
24.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
25.  Potentially traumatic interpersonal events, psychological distress and recurrent headache in a population-based cohort of adolescents: the HUNT study 
BMJ Open  2013;3(7):e002997.
Recurrent headache co-occurs commonly with psychological distress, such as anxiety or depression. Potentially traumatic interpersonal events (PTIEs) could represent important precursors of psychological distress and recurrent headache in adolescents. Our objective was to assess the hypothesised association between exposure to PTIEs and recurrent migraine and tension-type headache (TTH) in adolescents, and to further examine the potential impact of psychological distress on this relationship.
Population-based, cross-sectional cohort study. The study includes self-reported data from youth on exposure to potentially traumatic events, psychological distress and a validated interview on headache.
The adolescent part of the Nord-Trøndelag Health Study 2006–2008 (HUNT), conducted in Norway.
A cohort of 10 464 adolescents were invited to the study. Age ranged from 12 to 20 years. The response rate was 73% (7620), of whom 50% (3832) were girls.
Main outcome measures
Data from the headache interview served as the outcome. Recurrent headache was defined as headache recurring at least monthly during the past year, and was subclassified into monthly, weekly and daily complaints. Subtypes were classified as TTH, migraine, migraine with TTH and/or non-classifiable headache, in accordance with the International Classification of Headache Disorders criteria, second edition.
Multiple logistic regression analysis, adjusted for sociodemographics, showed consistently significant associations between exposure to PTIEs and recurrent headache, regardless of the frequency or subtype of headache. Increasing exposure to PTIEs was associated with higher prevalence of recurrent headache, indicating a dose–response relationship. The strength of associations between exposure to PTIEs and all recurrent headache disorders was significantly attenuated when psychological distress was entered into the regression equation.
The empirical evidence of a strong and cumulative relationship between exposure to PTIEs, psychological distress and recurrent headache indicates a need for the integration of somatic and psychological healthcare services for adolescents in the prevention, assessment and treatment of recurrent headache. Prospective studies are needed.
PMCID: PMC3731723  PMID: 23901028
Public Health

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