Mental och metabol stress - effekter på hälsa och effekter av intervention på stressrelaterad ohälsa. Translation av resultat från epidemiologiska populationsstudier till intervention på primärvårdsnivå.
Mental och metabol stress - effekter på hälsa och effekter av intervention på stressrelaterad ohälsa. Translation av resultat från epidemiologiska populationsstudier till intervention på primärvårdsnivå.
Project number : 68771
Created by: Cecilia Björkelund, 2011-01-17
Last revised by: Cecilia Björkelund, 2018-01-11
Project created in: FoU i Västra Götalandsregionen

PublishedPublished

1. Översiktlig projektbeskrivning

Engelsk titel

Mental and metabolic stress – health effects and health care interventions.
Translational research from population studies to primary care interventions

Populärvetenskaplig sammanfattning av projektet

Den övergripande frågeställningen för projektet är att få ökad kunskap om hälsoeffekter av stress och upplevelsen av stress. Det specifika syftet med projektet är att studera långsiktiga hälsoeffekter av upplevd stress hos kvinnor och män och att också studera effekterna av interventionsprojekt, genomförda i primärvård, vars syften är att minska upplevelsen av stress samt att öka individens egen förmåga att hantera stress och därigenom ha en positiv effekt på depression, metabola störningar och kronisk smärta. Vi kommer att hämta data från två stora longitudinella befolkningsstudier (Populationsundersökningen av Kvinnor i Göteborg samt H70-studierna) för att studera långtids-hälsoeffekter av upplevd stress vad gäller morbiditet, mortalitet och livskvalitet. Interventionseffekter kommer att studeras genom flera interventionsprojekt i primärvården -under 2011-14 två randomiserade kontrollerade studier av behandling av mild till måttlig depression, samt en randomiserad studie av kognitiv gruppbehandling av kronisk smärta, och slutligen en observationsstudie om långtidsuppföljning av patientcentrerad behandling av depression hos aldre samt en större implementeringsstudie i projektfasen i samarbete med regionen - under 2014-19 ytterligare två RCT gällande behandling och uppföljning av mild-måttlig depression i primärvården. Interventionseffekter kring effekter gällande metabol stress studeras genom livsstilsinterventionsprojekt. Tre av de  fyra randomiserade kontrollerade studierna gällande behandling av lindrig till måttlig depression är i utvärderingsfasen, en i planeringsstadiet. Forskargruppens breda förankring både i epidemiologisk populationsforskning och i primärvårdens kliniska miljö ger unik möjlighet till direkt överföring av forskningsresultat från den epidemiologiska forskningen till intervention i kliniken för klinisk testning av hypoteser som genererats via de epidemiologiska studierna.

Vetenskaplig sammanfattning av projektet

Stress and perception of mental stress is an important health related factor in today’s society with several implications. There is need of enhanced knowledge, both about long term health effects of perceived mental stress in women and men and about possible intervention methods, both methods aiming at reducing perception of stress as well as methods promoting the individual’s own capacity to manage stress and the secondary health effects of stress such as depression, metabolic disturbances, and pain.
Work plan:
Specifically, the following aspects will be covered:
A. In population studies
1. Longitudinal analyses of perceived mental stress and its association with stroke, CVD, diabetes, depression, abdominal obesity, and health indices (incl. dental health) in a 40-year perspective
2. Incidence and long-term survival in stroke, sensitivity of hypertension effects
3. Cross-sectional analyses of associations between perceived mental stress, quality of life, family/work, personality, oestrogen medication and dental health
B. In trials in the primary care setting
1. Effects of interventions on mild to moderate depression in primary care and on health-related quality of life.
2. Evaluation of effects of continuity of care in older depressed patients in primary care.
3. Evaluation of intervention to alleviate chest pain and improve HRQOL in patients with UCP by cognitive behavioural counselling. Evaluation if early intervention on patients at risk of prolonged chest pain can be managed by collaboration between specialized hospital care and primary care.

2018-2020: 1.Intervention program on life style. Aim: To implement program “Hälsolyftet” via e-health.

2.Clinical trials on depression/common mental disordersSTRONG[ in the primary care setting.]

Overall Aim: To examine if treatment of depression/common mental disorders in the primary care setting can be improved concerning symptoms of depression and anxiety, quality of life, work ability, health care use, sick-leave and return to work.

1.Intervention program on life style (“Hälsolyftet”) -in evaluation phase

2.Interventions on mild to moderate depression/Common Mental Disorders in the primary care setting.
The aim of 4 intervention projects is to study if treatment of depression/anxiety and stressrelated disorder, in the primary care setting, can be improved by
i) Internet Cognitive Therapy (I-CBT) treatment (PRIM-NET; evaluation phase)
ii) Regular patient- centred monitoring and evaluation of depression symptoms and change by self- assessment instrument, in GP consultation (PRI-SMA; evaluation phase)iii) Care manager function at the primary care center (PRIM-CARE)
iv) Workplace person-centred convergence dialogue (Co-Work-Care)

Typ av projekt

Forskningsprojekt

MeSH-termer för att beskriva typ av studier

not checked Kvalitativ forskning (Qualitative Research)
not checked Fokusgrupper (Focus Groups)
not checked Hälso- och sjukvårdsundersökningar (Health Care Surveys)
checked Longitudinella studier (Longitudinal Studies)
checked Prospektiva studier (Prospective Studies)
not checked Retrospektiva studier (Retrospective Studies)
not checked Fall-kontrollstudier (Case-Control Studies)
checked Kohortstudier (Cohort Studies)
checked Tvärsnittsstudier (Cross-Sectional Studies)
checked Befolkningsstudier (Population Surveillance)
checked Klinisk prövning (Clinical Trial)
not checked Klinisk prövning, fas I (Clinical Trial, Phase I)
not checked Klinisk prövning, fas II (Clinical Trial, Phase II)
not checked Klinisk prövning, fas III (Clinical Trial, Phase III)
not checked Klinisk prövning, fas IV (Clinical Trial, Phase IV)
not checked Kontrollerade kliniska prövningar (Controlled Clinical Trial)
checked Randomiserad klinisk prövning (Randomized Controlled Trial)
not checked Multicenterstudie
not checked Litteraturöversikt, principer (Review Literature as Topic)
not checked Översikt (Review)
not checked Genomförbarhetsstudier (Feasibility Studies)
not checked Pilotstudier (Pilot Projects)
not checked Valideringsstudier (Validation Studies)
not checked Programutveckling (Program Development)
not checked Läkemedelsprövning (Drug Evaluation)
not checked Läkemedelstester, prekliniska (Drug Evaluation, Preclinical)
not checked Ingen av ovanstående

MeSH-termer för att beskriva ämnesområdet

information Added MeSH terms
Cardiovascular Diseases
Pathological conditions involving the CARDIOVASCULAR SYSTEM including the HEART; the BLOOD VESSELS; or the PERICARDIUM.
Mental Disorders
Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function.
Behavioral Disciplines and Activities
The specialties in psychiatry and psychology, their diagnostic techniques and tests, their therapeutic methods, and psychiatric and psychological services.

Projektets delaktighet i utbildning

checked Avhandling
not checked Licentiat
not checked Master
not checked D-uppsats / Magisterexamen
not checked C-uppsats / Kandidatexamen
not checked ST-läkarutbildning
not checked ST-tandläkarutbildning
not checked Specialistutbildning psykolog
not checked PTP-tjänst psykolog
not checked Annan utbildning
not checked Ej del i utbildning

2. Projektorganisation och finansiering

Arbetsplatser involverade i projektet

information Added workplaces
Statligt - Universitet - Göteborgs universitet - Sahlgrenska akademin - Institutionen för medicin
Landsting - Västra Götalandsregionen - Närhälsan - Vårdcentraler - Område V5
Landsting - Västra Götalandsregionen - Närhälsan - Vårdcentraler - Område V5

Medarbetare

Boo Johansson
Annan tjänstetitel, Psykologiska institutionen
Ulf Lindblad
Läkare, Närhälsan Hentorp Skövde, Närhälsan FoU Göteborg, Enheten för allmänmedicin på GU
Lauren Lissner
Lärare, Section for Epidemiology and Social Medicine (EPSO), Göteborgs Universitet
Dominique Hange (Andersson-Hange, Andersson)
Docent, Enheten för Allmänmedicin, Närhälsan Svenljunga vårdcentral, FoU-Centrum Borås
Hans Ågren
Läkare, Sektionen för psykiatri, SU
Jörgen Thorn
Annan tjänstetitel, Skaraborgs Sjukhus
Robert Eggertsen
Läkare, Närhälsan Mölnlycke vårdcentral. FoU-centrum Göteborg och södra Bohuslän
Ronny Gunnarsson
Docent, James Cook University Australia and R&D unit for primary health care Sodra Alvsborg County Sweden
Leif Lapidus
Läkare, Verksamhetsområde Medicin
Magnus Hakeberg
Tandläkare, Institutionen för odontologi, SA, GU samt Oral medicin, Odontologen
Maria Larsson
Verksamhetschef, FoU primärvård Göteborg och Södra Bohuslän
Bodil Lernfelt
Läkare, Medicin och Geriatrik och Akutmottagning, SU/Östra sjukhuset
Ingibjörg H. Jonsdottir
Verksamhetschef, Institutet för stressmedicin
Margaretha Jerlock
Sjuksköterska, Institutionen för vårdvetenskap och hälsa GU

Finansiering

Grant provider: Alf Göteborg (Reference number: ALFGBG-142971)
Decided and approved
Grant reciever: Cecilia Björkelund
Applied 2010-10-14 for a contribution of 2,610,000 SEK intended for Stress - effekter på hälsa och effekter av intervention på stressrelaterad ohälsa. Translation av resultat från epidemiologiska populationsstudier till intervention på primärvårdsnivå. Mental stress – health effects and health care interventions. Translational research from population studies to primary care interventions
Decision 2010-12-15 with a contribution of 2,025,000 SEK and is available 2011-2013
Total applied sum: 2,610,000 SEK | Total granted sum: 2,025,000 SEK

3. Processen och projektets redovisning

Hur långt har projektet framskridit?

Projektet pågår, rekrytering/datainsamling stängd

Projektstart (när planeringen påbörjas och börjar dokumenteras skriftligt)

2007-01-01

Datum då projektet är slutrapporterat

2017-12-31

Publikationer från detta projekt

  1. Waller M, Blomstrand A, Högberg T, Ariai N, Thorn J, Hange D, Björkelund C.
    Scand J Prim Health Care 2016:34(4):352-359.
  2. Bentham J, Di Cesare M, Stevens G, Zhou B, Bixby H, Cowan M, Björkelund C, Eggertsen R, Lappas G, Lissner L, Rosengren A.
    eLife 2016:5
  3. Di Cesare M, Eggertsen R, Stevens G, Zhou B, Danaei G, Lu Y, Bixby H, Cowan M, Riley L, Björkelund C, Hajifathalian K, Fortunato L, Taddei C, Bennett JE, Ikeda N, Khang YH, Kyobutungi C, Laxmaiah A, Li Y, Lin HH, Miranda JJ, Mostafa A, Turley ML, Paciorek CJ, Gunter M, Ezzati M.
    Lancet 2016:387(10026):1377-96.
  4. Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N, O'Keeffe LM, Gao P, Wood AM, Burgess S, Freitag DF, Pennells L, Peters SA, Hart CL, Håheim LL, Gillum RF, Nordestgaard BG, Psaty BM, Yeap BB, Knuiman MW, Nietert PJ, Kauhanen J, Salonen JT, Kuller LH, Simons LA, van der Schouw YT, Barrett-Connor E, Selmer R, Crespo CJ, Rodriguez B et al [ Björkelund C Nr. 35 ] [ Rosengren A Nr. 54 ] [ Engström G Nr. 83 ];
    Emerging Risk Factors Collaboration.
    JAMA 2015:314(1):52-60.
  5. Leu M, Mehlig K, Hunsberger M, Torinsson Naluai Å, Blennow K, Zetterberg H, Björkelund C, Lissner L.
    Epidemiology Research International 2015:2015(Article ID 581206):1-8.
  6. Wikberg C, Nejati S, Larsson M, Petersson E, Westman J, Ariai N, Kivi M, Eriksson M, Eggertsen R, Hange D, Baigi A, Björkelund C.
    The Primary Care Companion for CNS Disorders 2015:17(3)
  7. Wennström A, Wide Boman U, Ahlqwist M, Björkelund C, Hakeberg M.
    Community Dental Health 2015:32(4)
  8. Linton SJ, Kecklund G, Franklin KA, Leissner LC, Sivertsen B, Lindberg E, Svensson AC, Hansson SO, Sundin Ö, Hetta J, Björkelund C, Hall C.
    Sleep Med Rev 2014:23C:10-19.
  9. Di Angelantonio E, Gao P, Khan H, Butterworth AS, Wormser D, Kaptoge S, Kondapally Seshasai SR, Thompson A, Sarwar N, Willeit P, Ridker PM, Barr EL, Khaw KT, Psaty BM, Brenner H, Balkau B, Dekker JM, Lawlor DA, Daimon M, Willeit J, Njølstad I, Nissinen A, Brunner EJ, Kuller LH, Price JF, Sundström J, Knuiman MW, Feskens EJ, Verschuren WM, Wald N et al [ Rosengren A Nr. 38 ] [ Björkelund C Nr. 40 ] [ Wennberg P Nr. 51 ];
    Emerging Risk Factors Collaboration.
    JAMA 2014:311(12):1225-33.
  10. Billstedt E, Skoog I, Duberstein P, Marlow T, Hällström T, André M, Lissner L, Björkelund C, Östling S, Waern M, Hallstrom T, Bjorkelund C, Ostling S, Andre M.
    Acta psychiatrica Scandinavica 2014:129(1):35-43.
  11. Brotons C, Bulc M, Sammut MR, Sheehan M, Manuel da Silva Martins C, Björkelund C, Drenthen AJ, Duhot D, Görpelioglui S, Jurgova E, Keinanen-Kiukkanniemi S, Kotányi P, Markou V, Moral I, Mortsiefer A, Pas L, Pichler I, Sghedoni D, Tataradze R, Thireos E, Valius L, Vuchak J, Collins C, Cornelis E, Ciurana R, Kloppe P, Mierzecki A, Nadaraia K, Godycki-Cwirko M.
    Fam Pract 2012:29 Suppl 1:i168-i176.
  12. Stenman U, Wennstrom A, Ahlqwist M, Bengtsson C, Bjorkelund C, Lissner L, Hakeberg M.
    Acta Odontol Scand. 2009:67(4):193-9.

Detaljerad projektbeskrivning

Bakgrundsbeskrivning

Major societal changes in psycho-social and socioeconomic factors together with improvements in health care have positively influenced public health during the last forty years, but also contributed to marked changes in the relation between somatic and mental health. Today, the individual is more exposed to long term mental and psychosocial stress than earlier generations (1), resulting in e.g. decreased performance, chronic fatigue, depressed mood, anxiety, sleep problems, and chronic pain. In the Swedish National Public Health Report 2009, the percentage stating sleep problems because of their work had increased from 23 % 1990 to 30 % 2003 in women and 25 to 27% in men (1). Mental stress and mental problems and distress were also major components of the increase in sick-listing, from around 10 to around 30 % of women’s total sickness absence from 1990 to 2003 (2). Furthermore, mental stress and anxiety have been reported to be important risk factors for cardiovascular diseases (CVD), such as stroke and myocardial infarction (3), and for diabetes (4)
The physiological response to stress, resulting in a fight-or-flight reaction, mediated via the autonomic nerve system and increased stress-hormone production, in turn leading to increased pulse and blood pressure, is developed as an immediate defence reaction. Under constant stress, the human body instead reacts with resignation, mediated via hippocampus and dominated by increased activity in the hypothalamic-pituitary-axis (HPA-axis) and increased cortisol production. This in turn ultimately leads to glucose, blood lipid, and blood pressure disturbances, as well as effects on the immune system (Fig 1). This explains the hypothesized relation between socioeconomic status and increased morbidity and mortality via e.g. cardiovascular diseases, depression and diabetes, highlighted by a.o. Michael Marmont and coworkers (5, 6).
From The Population Study of Women in Gothenburg (PPSWG, a prospective study, initiated in 1968 and still ongoing)we can report a clear improvement in risk factor levels compared to earlier generations of middle-aged women, partly associated to contemporary improvements in life-style and diet, but, also, at the same time, large increases in perceived mental stress (7). This seems to be the factor that has changed most in a presumable negative direction since 1968. In 1968, 32% of the participating women stated mental stress, in 2004 75% stated mental stress (Fig 2). Furthermore, abdominal obesity, recorded as waist-hip-ratio, has increased, despite the increased level of physical activity and decreased intake of fat (8). Increased stress-related cortisol production could be the reason for the increased abdominal ratio. Abdominal adiposity is a highly important risk factor in women, shown to be a risk factor of myocardial infarction, stroke, and diabetes (9). For the PPSWG research group network, the Swedish FAS Research Council has financed further studies on the health significances of the increasing perception of stress in modern society in the WISH project- Women Investigating Stress and Health (6.4 SEK 2008-2011).
Also, mean duration of sleep has decreased in 38-year-old women (from 7.3 to 7.1 hours) but not in 50-year-old women (10). In 1968, only 60% of the participating women aged 38 - 50 worked outside the home, compared to 90 % in the same age groups in 2004 (11). In the National Public Health Report 2009, more than 20% of younger women and 13 % of younger men stated stress related physical or mental symptoms, with the greatest ten year increase in women (1).

Stress and cardiovascular disease
Women have lower incidence of cardiovascular disease (CVD) throughout life, but because women live longer than men, ultimately as many women as men die from CVD. Stroke mortality in women as well as men has decreased but incidence has not decreased to the same extent, with one report suggesting an increase for younger women (12). Could the rising experience of perceived mental stress in women, registered as e.g. risk factors as hypertension and hyperlipidemia, and ultimately as stroke and other CVD morbidity, be one factor in the changing pattern? Secondary life style effects of stress as smoking, reduced exercise, unhealthy diet, and alcohol habits also contribute to negative health effects of stress.
Health promotion and prevention is an important part in the management of metabolic effects of stress, both in primary prevention and lifestyle intervention, as well as secondary prevention when combining lifestyle and pharmacological treatment. Health check screening does not lead to reductions in mortality or morbidity, but interventions in the primary care setting, specially targeted to the individual, promoting and supporting the individual’s own motivation and health resources seem to be effective, also concerning socio-economically vulnerable groups. Interventions mediated via primary care to counteract effects of metabolic and mental stress in the population should therefore be developed.

Stress and depression
Depression is one of the leading causes of disability and a serious illness, affecting around 10-15% of the population (13). Recently, national epidemiological surveys showed an increase of depressive symptoms in the younger part of the Swedish population (1). The lifetime depression risk for women is almost 45% and for men about 20% (13). Depression is a common problem in patients visiting primary health care, often initially presented as physical symptoms as unspecified pain, chest or abdominal symptoms etc (13). In late life, perception of mental stress impacts on both physical and mental health.
Around 70% of all patients with depression are treated in primary care (14). About 75% of antidepressants are prescribed by general practitioners (GPs). Depression guidelines recommend cognitive behavioural therapy (CBT) in minor and moderate depression and also regular evaluation and monitoring of symptom severity and change for patients with mild to moderate depression (14). However, these guidelines are largely based on consensus or expert opinion. There is a lack of research in primary care providing recommendations for “best practice”. No randomized controlled trials have evaluated depression treatment using computerized/internet-based CBT or the treatment effects of systematic monitoring of symptom change in patients in the primary care context. Knowledge and recommendations of today on management of depression are almost exclusively based on research in psychiatric settings (13).
Stress and pain
Psychosocial factors seem to be associated with unexplained chest pain (UCP) and ought to be taken into consideration when the patient seeks care (15, 16). Patients with UCP have impaired health related quality of life (HRQOL), are more physically inactive, report more sleep problems, more mental strain at work, more stress at home, and more negative life events than a reference control population free from ischemic heart disease. In addition, women, but not men with UCP, have a higher prevalence of cardiovascular risk factors (obesity, smoking, diabetes, and hypertension) than controls.

QUESTION AT ISSUE
Taken together, stress and perception of mental stress is an important health related factor in today’s society with several implications. There is need of enhanced knowledge, both about long term health effects of perceived mental stress in women and men and about possible intervention methods, both methods aiming at reducing perception of stress as well as methods promoting the individual’s own capacity to manage stress and the secondary health effects of stress such as depression, metabolic disturbances, and pain.

Syfte

WORK PLAN
Specifically, the following aspects will be covered:
A. In population studies
1. Longitudinal analyses of perceived mental stress and its association with stroke, CVD, diabetes, depression, abdominal obesity, and health indices (incl. dental health) in a 40-year perspective
2. Incidence and long-term survival in stroke, sensitivity of hypertension effects
3. Cross-sectional analyses of associations between perceived mental stress, quality of life, family/work, personality, oestrogen medication and dental health
B. In trials in the primary care setting
1. Effects of interventions on mild to moderate depression in primary care and on health-related quality of life.
2. Evaluation of effects of continuity of care in older depressed patients in primary care.
3. Evaluation of intervention to alleviate chest pain and improve HRQOL in patients with UCP by cognitive behavioural counselling. Evaluation if early intervention on patients at risk of prolonged chest pain can be managed by collaboration between specialized hospital care and primary care.

Frågeställning / Hypoteser

There is need of enhanced knowledge, both about long term health effects of perceived mental stress in women and men and about possible intervention methods, both methods aiming at reducing perception of stress as well as methods promoting the individual’s own capacity to manage stress and the secondary health effects of stress such as depression, metabolic disturbances, and pain.
Specifically,questions at issue concerning the clinical intervention studies are:
Can treatment of depression, in the primary care setting, be improved by computerized CBT treatment as well as regular patient centered monitoring and evaluation of depression symptoms and change by MADRS-S, in the General Practitioner’s consultation, regarding management, outcome of care, and patient satisfaction, compared to treatment as usual?

Metod: Urval

A. The following local population based studies will be included
•Prospective Population Study of Women in Gothenburg (PPSWG) (9):
This is a multi-disciplinary study on a representative sample of women born 1908, 1914, 1918, 1922 and 1930. The cohort has now been examined on up to 7 occasions, most recently ongoing in 2009-10. In 2016-2017 the fifth examination of 38 and 50-year-old women was effected with 570 participants per June 1 st 2017, of which the 50-year-old women were followed up from examination 2004-05 (then 38 years old). Started in 1968, this is historically one of the original epidemiological studies devoted to women’s health issues. Some topics of most recent interest include CVD risk factors, menopause, oestrogen therapy, sleep disturbances, perception of stress. The investigators have completed a 36 year follow-up of survivors among the original 1462 participants. The PPSWG study originated in the Department of Primary Health Care.
•H70 Gerontological and Geriatric Studies in Gothenburg.
Initiated in 1971, this is a unique population-based study of normative aging in 70 year old populations, which focuses on both medical and cognitive measures. The H70 study is coordinated by several research groups, primarily Geriatrics, Primary Health Care, Psychiatry, and Epidemiology.
Our ongoing epidemiological studies with already existing multiple data will be used by the research group to illuminate the issues raised by the present research project, as well as coupling existing national register data to study data and clinical intervention studies.
i). Computerized CBT treatment (trial CBT)
Design
A randomized controlled trial of two groups (intervention and treatment as usual). Randomization on patient level.
Population of study
The subjects of the study are consecutive patients aged 18 and older, attending in primary care in a well defined district of VG Region (Södra Älvsborg). Comparison is made between treatment of mild/moderate depression with computerized CBT and treatment as usual (TAU). All patients, attending the primary care centre (PPC), who are identified by the GP or nurse with a probable diagnosis of mild/moderate depression disorder are asked if they are willing to participate in a study, where one of the treatment arms is computerized CBT. All patients who agree, take part in a diagnostic assessment, comprising a psychologist diagnostic interview with M.I.N.I. version 6 and BDI–II instrument (19). The recruitment of about intended totally 200 subjects was started in Mars 2010 (Fig. 3).

Metod: Intervention

Data collection
In the PPSWG perceived mental stress has been registered in all examinations 1968-2010(except 1992-93). This gives the opportunity to assess associations between mental stress and later CVD especially stroke, and also to estimate the significance of health indices, including life-style, socio-economic factors, education, work, reproduction, menopausal status, medication (including estrogen), quality of life, dental health, and biochemical parameters in the analyses. A detailed analysis of all deaths up to 2009 in the study has been performed. Death certificates have been scrutinized, and post mortem autopsy has been documented. Matching has been performed in collaboration with the national hospital register and myocardial infarction and stroke registers. Diabetes diagnoses have been thoroughly scrutinized (17). Dental panorama x-rays have been performed in every examination. Quality of life has been measured by the Göteborg Quality of Life instrument (18) since 1980. Since 1992, H70-cohorts have been examined by the same protocol.

3. In the PPSWG, cohorts of 38 and 50-year-old women have been examined in four different examinations over 36 years: 1968-69, 1980-81, 1992-93 and 2004-05. This gives the possibility to assess associations cross-sectionally and analyze trends and associated factors to secular changes.

Principles for data processing and analysis
We will analyze associations between
•perception of mental stress and association to stroke in a 40-year perspective
•perception of mental stress and development of dental health
•perception of mental stress and development of ECG-changes (q-wave, atrial fibrillation, sick sinus syndrome) in 70-year and older men and women
•perception of mental stress in 70-year and older men and women and possible health effects
•association of mental stress and perceived nervousness and moodiness
•perceived mental stress and personality traits (measured by the CMPS and Eysenck scales) in 1968-69 and 2004-05 and analyse differences and resemblances, as well as associations between assumed trends and changes in socio-economic and societal conditions
•perceived mental stress and quality of life, family/work, personality, oestrogen medication and dental health in cross-sectional analyses and cohort comparisons
by using regression models, especially the Cox proportional hazards models using both baseline and updated covariate models.

B. Clinical intervention studies
1. Intervention on mild to moderate depression in the primary care setting
The aim of two intervention projects is to examine if treatment of depression, in the primary care setting, can be improved by
i) computerized Cognitive Behavioural Therapy (CBT) treatment (trial CBT);
ii) regular patient centred monitoring and evaluation of depression symptoms and change by MADRS-S, in the general practitioner’s consultation (trial MADRS-S)

regarding management, outcome of care, and patient satisfaction, compared to treatment as usual.

Metod: Datainsamling

I. The following paragraph describes the different parts of the population studies project
1+2: Longitudinal analyses of perceived mental stress and association to stroke, CVD, and health indices (incl. dental health) in a 32-year perspective
Data collection
In the PPSWG perceived mental stress has been registered in all examinations 1968-2010(except 1992-93). This gives the opportunity to assess associations between mental stress and later CVD especially stroke, and also to estimate the significance of health indices, including life-style, socio-economic factors, education, work, reproduction, menopausal status, medication (including estrogen), quality of life, dental health, and biochemical parameters in the analyses. A detailed analysis of all deaths up to 2009 in the study has been performed. Death certificates have been scrutinized, and post mortem autopsy has been documented. Matching has been performed in collaboration with the national hospital register and myocardial infarction and stroke registers. Diabetes diagnoses have been thoroughly scrutinized (17). Dental panorama x-rays have been performed in every examination. Quality of life has been measured by the Göteborg Quality of Life instrument (18) since 1980. Since 1992, H70-cohorts have been examined by the same protocol.
3. In the PPSWG, cohorts of 38 and 50-year-old women have been examined in four different examinations over 36 years: 1968-69, 1980-81, 1992-93 and 2004-05. This gives the possibility to assess associations cross-sectionally and analyze trends and associated factors to secular changes.

II. Data collection RCT
i)We invited all primary health care centers in the region to participate in the intervention. Before start of intervention, nurses, GPs and psychologists from the PCCs have participated in a joint education program, where all parts of the trial have been talked over, to ensure inter-rater reliability.
During the intervention, three persons (one GP and two psychologists) from the research group are supporting the staff on the different PCCs.
Patients are randomized to either computerized CBT or treatment as usual (TAU).
Description of intervention
Patients randomized to computerized CBT have weekly internet contact with the psychologist by special intranet IT arrangement, designed for the project by the IT-department of VG Region. The CBT program is basically designed by Linköping University and PsykologPartners and thereafter adjusted for use in primary care (Fig 4). Both treatment groups of patients (computerized CBT and TAU) are asked to fill in the MADRS-S electronically by week 3, 7 and 12.
ii)  The MADRS-S trial: Population of study
Patients aged 18- 74 attending primary health care centers in the city of Gothenburg, identified by the GP with diagnosis of mild/moderate depression disorder according to PRIME-MD (Fig. 5).
We invited all primary health care centres in the district to participate in the intervention. Of these about ten agreed to participate. The intervention takes place at one clinic a time, approximately 2 weeks apart. During the intervention a research nurse is placed full-time on the current primary health care centre in order to organize the study, to collect patient data, and support the staff.

Metod: Databearbetning

Principles for data processing and analysis
We will analyze associations between
•perception of mental stress and association to stroke in a 40-year perspective
•perception of mental stress and development of dental health
•perception of mental stress and development of ECG-changes (q-wave, atrial fibrillation, sick sinus syndrome) in 70-year and older men and women
•perception of mental stress in 70-year and older men and women and possible health effects
•association of mental stress and perceived nervousness and moodiness
•perceived mental stress and personality traits (measured by the CMPS and Eysenck scales) in 1968-69 and 2004-05 and analyse differences and resemblances, as well as associations between assumed trends and changes in socio-economic and societal conditions
•perceived mental stress and quality of life, family/work, personality, oestrogen medication and dental health in cross-sectional analyses and cohort comparisons
by using regression models, especially the Cox proportional hazards models using both baseline and updated covariate models.

i+ii : Variables Computer CBT and MADRS-S studies
Outcome variables
The patients are followed up to 1 year after the inclusion by an individual interview (the first visit and after 3, 6 and 12 months). Depressive symptoms are assessed using the Beck Depression Inventory (BDI-II) and MADRS-S (18,19). Other analysis outcome variables are: patient’s quality of life (EuroQoL-5D scale) (21), General health Questionnaire (22) activity/work ability (WAI, Job Strain Model) (23), antidepressants prescription, number of days with sick leave benefits. Initial collection of data also includes socio-demographic and economic variables, alcohol consumption, physical activity, and ethnicity. Analysis of covariance, controlling for baseline value, will be used to estimate the overall treatment effectiveness (difference in score) at final follow ups.
Health economic evaluation
Cost-effectiveness analysis with QALY as measure of effect will be performed. EQ-5D measures five dimensions of quality of life (15). Change from week 0 to week 12, 24 and 52 will be related to generated costs comprising PCC visits, medication, computer and IT, education, and labour loss.
Sample size and power calculations
The main outcome variable is level of depression (measured by BDI-II). If we expect an improvement by 10% in the intervention group and 0% in the control group with (α = 0.05, power = 0.80), each group should include 75 (CBT-trial)/90 (MADRS-S study) participants. Anticipating a 10% dropout rate, the total sample size is rounded to 200 participants.

Methodology and work plan for 2018-20

1. Design: Cohort comparisons and cross-sectional analyses concerning 38-and 50-year old female generations from 1968-69, 1980-81, 1992-93, 2004-05, 2016-17.

i. Stress levels in relation to cardiovascular risk factors, BMI/obesity, waist-hip ratio/abdominal obesity,

ii. Use of estrogen-hormonal medication (contraceptives and HRT): cohort comparisons in 38-and 50-year-old women in relation to mental symptoms, pregnancies, menopause.

iii. Use of antidepressant medication, and physical activity, mental symptoms, QoL.

iv. Associations between iron status and stress levels, QoL, and physical activity 1968-2017.

2. Design: Longitudinal studies of female generations from 1968-69 and H70-generations.

Studies concerning cardiovascular health in women

i). Continuous perception of stress, level of physical activity and stroke incidence: Associations between stress, and longitudinal development from mid- to late life of metabolic risk factors in women, with consideration of socioeconomic gradient, work situation, education and level of physical activity. Despite decreasing stroke mortality in women as well as in men, incidence has reported increase in age 30-65 years and association to work strain (9). Could the rising experience of perceived mental stress, especially in combination with perception of poor work situation in women be associated with development of risk factors as hypertension, hyperlipidemia and diabetes, and ultimately as stroke and other CVD morbidity (10)?

ii). Metabolic stress and heart failure and associations with physical activity:

In a recent publication from PPSWG and H70, we could show an association between obesity in young and middle-aged women and later development of heart failure (11). We are now working on analyses of possible associations between change in physical activity levels and change in body composition and risk of development of heart failure. Can change in physical activity level reduce the risk of later development of heart failure in obese individuals?

Statistical methods and competence: We cooperate with statisticians with great knowledge of epidemiological methods for analyzis of possible associations by regression analyses, especially Cox proportional hazards models using both baseline and updated covariate models. In the multivariate models we include relevant covariates to calculate Hazard Ratios (HRs) and 95% confidence intervals (CIs). Relevant cooperation partners are the EpiLife Centre ( http://epilife.sahlgrenska.gu.se) and the Health Metrics unit at SA.

B. Clinical intervention studies in primary care

1.Intervention program on life style. Aim: To implement program “Hälsolyftet” via e-health.

2.Clinical trials on depression/common mental disordersSTRONG[ in the primary care setting.]

Overall Aim: To examine if treatment of depression/common mental disorders in the primary care setting can be improved concerning symptoms of depression and anxiety, quality of life, work ability, health care use, sick-leave and return to work.

iii) PRIM-CARE study

RCT: Care Manager - coordinating care for person-centered management of depression in primary care (PRIM-CARE).
Specific aims:
a) To develop and evaluate an evidence-based care manager program for patients with mild/ moderate depression; b) To compare the evidence-based care manager program to treatment as usual (TAU) in terms of short- and long-term effects on symptom remission, treatment adherence, care satisfaction, and self-efficacy; c) To perform a cost - effectiveness analysis of the care manager program; d) To gain a comprehensive understanding of patients’ and clinicians’ perceptions and experiences of the care manager program.

Design and Methods: Research questions a+b+c tested in a cluster RCT, randomization at primary care center level, with follow-up at 3, 6 and 12 months in primary care in cooperation between universities of Gothenburg, Karolinska Institute and primary care centres (PCC) of VGR, and Dalarna. Research question d): Patients’, GPs’ and nurses’ perceptions explored by focus group interviews. Personnel’s opinion surveyed by validated questionnaire.

Population: Patients aged 18 and older, that visit one of around 20 different urban and rural primary care centers. Intervention: At the intervention practices, a nurse devoted around 15-25% of working time as care manager for the patients diagnosed (via PRIME-MD) with mild/moderate depression according to MADRS-S<35. Control: Treatment as usual.

Data collection: Patients monitored at baseline, 3, 6 and 12 months concerning the same outcome variables as in PRIM-NET and PRI-SMA trials.

Statistical analysis: We have cooperated with Akademistatistik (Statistician C Wessman) concerning statistical analyses, and health economic analyses (Prof Mikael Svensson). We used means of intra-individual change of depressive symptoms and quality of life (QoL) when comparing between intervention group and TAU groups by using mixed model analysis with repeated measures, adjusted for the type of PCC, age, sex, education, antidepressants. Power calculation: need of ~400 patients (design effect of 1.9 to correct for cluster analysis).

Qualitative study: A purposeful sample of patients and health care professionals were interviewed about their experience of their participation in program. Qualitative content analysis according to Malterud.

Preliminary results: Statistically significant reduction of depression symptoms 0-3 months and significant increased rate of back-to-work in intervention group 0-3 months compared to TAU. Patient satisfaction significantly increased in intervention group compared to TAU.

Workplan 2018-20: Continuation of documentation 12 months follow up and qualitative studies. Health economic evaluation. Regional level evaluation of possible differences in sick-leave and diagnose patterns between PCCs with and without Care Manager (n=around 100 each). Quantitative evaluation of personnel survey.

iv) RCT trial: Cooperation for patients with common mental disorders: care manager function at the primary care centre and intervention at the workplace – CO-WORK-CARE; a pragmatic randomised controlled trial.

Background: As a continuation of the development of the Care Manager function for CMD patients at the PCC, a structured cooperation between the Care Manager and the Rehab Coordinator at the PCC coupled with a more structured function regarding work place contact for the Rehab Coordinator will be developed. The work place contact is in the form of a convergence work-place dialogue (CWD) between the employer and employee with the rehab coordinator as the guide.

Aim: To evaluate whether a combination of the Care Manager function in cooperation with a structured workplace intervention by the Rehab Coordinator (CO-WORK-CARE) entails earlier return to work for individuals on sick leave for depression, anxiety syndromes and stress related mental disorder, compared with individuals who have only received the structured Care Manager function and no structured CWD workplace intervention.

Project description: Research questions: a) Does a combination of Care Manager function and Rehab Coordinator workplace intervention (CO-WORK-CARE) give earlier return to work for individuals on sick leave for depression, anxiety and stress related mental disorder, compared with individuals who have only received the structured Care Manager contact?

b) Is intervention at the workplace in model CO-WORK-CARE cost-effective compared to Care Manager care only and no workplace intervention?

Trial Design: A cluster randomized controlled trial of two groups (intervention and control). Randomization at the level of the primary care centers (PCCs). Follow up 3, 6 and 12 months.

Population: 300 patients attending around 20 different urban and rural primary care centers (PCC) with care manager function aged >18 years diagnosed with a new (< 1 month) depression diagnose (F32, F33), anxiety syndrome (F41, F48) or stress related mental disorder (F43) and on sick-leave >14 days.

Intervention: Work place contact in accordance to the convergence dialogue between the employer and employee with the Rehab Coordinator as the guide, based on a structured Care Manager - Rehab Coordinator cooperation. Control: Structured Care Manager function at the PCC with Care Manager contact with the patient during 3 months.

Primary outcome: number of net and gross sick-leave days during 12 months’ follow up. Secondary outcome variables equivalent with PRIM-CARE outcome variables.

Recruitment of participating PCCs: Participating PCCs will be PCCs of VG Region, where a Care Manager function has been implemented during 2015-2016 in a method-development process, conducted in cooperation by the region. All present 100 Care Managers (around 100 Primary Care Centres) have received an education comprising an academic course (Care Manager for CMD, Vårdsamordnare psykisk ohälsa, 3.0 hp) on Care Manager function ( http://www.vgregion.se/sv/Vastra-Gotalandsregionen/startsida/Vard-ochhalsa/Forvardgivare/Vardsamordnare-psykisk-ohalsa-inom-primarvarden/) .

Statistical methods: Analyses will be performed on intention to treat basis and including all randomized patients. To account for the correlation between patients treated by the same PCC, and to handle all observations of the patients, mixed effects models will be used. Multiple imputations will be used to obtain less biased estimates of effect, and use chained equations with all primary and secondary outcomes at both baseline and follow ups, and patients’ demographics; age, sex, and education, as well as practice size.

Cost-effectiveness analysis will use EQ-5D as base when estimating quality-adjusted life years (QALY) (see PRIM-NET).

Sample size and power: The primary variable: number of sick leave days at 12 months will be analyzed in a model with repeated measures. In order to detect an effect of 20% in the difference between the two groups, with a power of 80% and a significance level of 10% 120 patients needed in each group (design effect of 1.9 to correct for having a cluster analysis).

Work Plan 2018-2020: Start of inclusion: September 2017, intervention during 2017-2018, follow up 2018-2019. Documentation 2019-2020.

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Mental och metabol stress - effekter på hälsa och effekter av intervention på stressrelaterad ohälsa. Translation av resultat från epidemiologiska populationsstudier till intervention på primärvårdsnivå., from FoU i Sverige
http://www.researchweb.org/is/en/sverige/project/68771?show_hidden_options=true