Estimating Additive Interaction in Two-Stage Individual Participant Data Meta-Analysis.

Individual participant data (IPD) meta-analysis provides important opportunities to study interaction and effect modification for which individual studies often lack power. While previous meta-analyses have commonly focused on multiplicative interaction, additive interaction holds greater relevance for public health and may in certain contexts better reflect biological interaction. Methodological literature on interaction in IPD meta-analysis does not cover additive interaction for models including binary or time-to-event outcomes. We aimed to describe how the Relative Excess Risk due to Interaction (RERI) and other measures of additive interaction or effect modification can be validly estimated within two-stage IPD meta-analysis. First, we explain why direct pooling of study-level RERI estimates may lead to invalid results. Next, we propose a three-step procedure to estimate additive interaction: 1) estimate effects of both exposures and their product term on the outcome within each individual study; 2) pool study-specific estimates using multivariate meta-analysis; 3) estimate an overall RERI and 95% confidence interval based on the pooled effect estimates. We illustrate this procedure by investigating interaction between depression and smoking and risk of smoking-related cancers using data from the PSYchosocial factors and Cancer (PSY-CA) consortium. We discuss implications of this procedure, including the application in meta-analysis based on published data.

Trends in Norwegian adolescents' substance use between 2014 and 2022: socioeconomic and gender differences.

BACKGROUND: Substance use is a global health concern and early onset among adolescents increases health risks. We explore national overall trends in prevalence and trends in socioeconomic inequalities in past year alcohol intoxication, cannabis use, and use of other illicit drugs among Norwegian adolescents (ages ∼ 15-19 years of age) between 2014 and 2022. METHOD: The present study builds on data from a nationwide repeated cross-sectional survey collected in 2014-2016 (T1), 2017-2019 (T2), 2021 (T3) and 2022 (T4). In total 415,560 adolescents (50.3% girls) completed the questionnaire during the study period. Trends in socioeconomic inequalities were assessed using the Slope Index of Inequality (SII) and the Relative Index of Inequality (RII). RESULTS: While the prevalence of alcohol intoxication remained fairly stable, the prevalence of cannabis and other illicit drug use increased between 2014 and 2022 among upper secondary school boys (13.3-17.6%, and 2.0-5.2%, respectively) and girls (8.8-12.8%, and 1.1-2.7%, respectively). Similar trends were observed among 10th-grade adolescents. Boys were more likely than girls to use cannabis or other illicit drugs, but the gender gap in cannabis use narrowed during the study period. Among upper secondary girls, use of cannabis and other illicit drugs was higher among those from less affluent backgrounds, with absolute and relative inequalities in cannabis use increasing between 2014 and 2022. Small inequalities in cannabis use and decreasing relative inequalities in the use of other illicit drug were observed among upper secondary boys. CONCLUSIONS: The increasing use of cannabis and other illicit drugs among Norwegian adolescents is concerning. Future studies should explore the underlying causes of this rise and explore the complex factors influencing adolescent substance use behaviours. A comprehensive understanding of these factors is essential for developing targeted and effective interventions.

Trends in socioeconomic inequalities in self-rated health and mental distress during four decades in a Norwegian population: a HUNT Study.

BACKGROUND: Socioeconomic inequalities constitute an important focus area for public health, and it has long been established that higher educational level and longer lifespan are correlated. Little is known about decennial time trends in poor self-rated health and mental distress. METHODS: This study linked decennial cross-sectional survey data on self-rated health and mental distress from the Trøndelag Health Study (HUNT) from 1984 to 2019 with educational registry data using personal identification numbers. Survey participation ranged from 50 807 to 77 212. Slope index of inequality (SII) and relative index of inequality (RII) were calculated using generalized linear models in Stata. Analyses were stratified by sex and age, using the age categories of 30-59 years and 60-80 years. RESULTS: Absolute inequalities in self-rated health and mental distress between educational groups have stayed relatively stable throughout all rounds of HUNT. Relative inequalities in self-rated health and mental distress have generally increased, and both men and women with the lowest education level were more likely to experience poor self-rated health and mental distress relative to those with the highest education level. RII in self-rated health increased over time for both sexes and both age groups. RII for mental distress increased in both sexes and both age groups, except for men and women aged 60-80. DISCUSSION: This study shows that relative inequalities in self-rated and mental health in the Norwegian population are still persistent and have increased. Further knowledge about groups with a disadvantageous health situation should have implications for health care resource allocation.

The mediating role of health behaviors in the association between depression, anxiety and cancer incidence: an individual participant data meta-analysis.

BACKGROUND: Although behavioral mechanisms in the association among depression, anxiety, and cancer are plausible, few studies have empirically studied mediation by health behaviors. We aimed to examine the mediating role of several health behaviors in the associations among depression, anxiety, and the incidence of various cancer types (overall, breast, prostate, lung, colorectal, smoking-related, and alcohol-related cancers). METHODS: Two-stage individual participant data meta-analyses were performed based on 18 cohorts within the Psychosocial Factors and Cancer Incidence consortium that had a measure of depression or anxiety (N = 319 613, cancer incidence = 25 803). Health behaviors included smoking, physical inactivity, alcohol use, body mass index (BMI), sedentary behavior, and sleep duration and quality. In stage one, path-specific regression estimates were obtained in each cohort. In stage two, cohort-specific estimates were pooled using random-effects multivariate meta-analysis, and natural indirect effects (i.e. mediating effects) were calculated as hazard ratios (HRs). RESULTS: Smoking (HRs range 1.04-1.10) and physical inactivity (HRs range 1.01-1.02) significantly mediated the associations among depression, anxiety, and lung cancer. Smoking was also a mediator for smoking-related cancers (HRs range 1.03-1.06). There was mediation by health behaviors, especially smoking, physical inactivity, alcohol use, and a higher BMI, in the associations among depression, anxiety, and overall cancer or other types of cancer, but effects were small (HRs generally below 1.01). CONCLUSIONS: Smoking constitutes a mediating pathway linking depression and anxiety to lung cancer and smoking-related cancers. Our findings underline the importance of smoking cessation interventions for persons with depression or anxiety.

School completion and progression to higher education in adolescents with social anxiety: a linkage between Young-HUNT3 and national educational data (2008-2019), Norway.

BACKGROUND: Social anxiety disorder (SAD) most commonly develops in adolescence-a period of life that includes a transition to upper secondary school. The aim of this study is to investigate the extent to which social anxiety in adolescence is associated with the completion of upper secondary school and progression to higher education. METHODS: This longitudinal study includes 8,192 adolescents aged 13-19 years who participated in the Norwegian Young-HUNT 3 population-based study. Social anxiety is measured employing (1) diagnostic interview screening questions (interview) and (2) a self-reported symptom index (questionnaire). Notably, we define the cohorts based on these two methods. Using national educational data (2008-2019), we follow educational attainment among the cohorts until they turn 25 years of age. RESULTS: We found that adolescents who screened positive (SP) for SAD had a predicted probability of upper secondary school completion at 21 years of age that was 14% points lower than those who screened negative (SN). Further, differences remained when looking at completion rates at age 25 years. Moreover, predicted probabilities for completion were inversely associated with increasing levels of self-reported social anxiety symptoms. Similarly, the proportion of the completers of an academic program in the SP group that were enrolled in higher education by 25 years of age, were lower than for the SN group (87 vs. 92%). CONCLUSION: Social anxiety in adolescence, both self-reported symptoms and diagnostic screening, has long-term negative impact on upper secondary school completion and to some extent enrollment to higher education.

Psychosocial factors, health behaviors and risk of cancer incidence: Testing interaction and effect modification in an individual participant data meta-analysis.

Depression, anxiety and other psychosocial factors are hypothesized to be involved in cancer development. We examined whether psychosocial factors interact with or modify the effects of health behaviors, such as smoking and alcohol use, in relation to cancer incidence. Two-stage individual participant data meta-analyses were performed based on 22 cohorts of the PSYchosocial factors and CAncer (PSY-CA) study. We examined nine psychosocial factors (depression diagnosis, depression symptoms, anxiety diagnosis, anxiety symptoms, perceived social support, loss events, general distress, neuroticism, relationship status), seven health behaviors/behavior-related factors (smoking, alcohol use, physical activity, body mass index, sedentary behavior, sleep quality, sleep duration) and seven cancer outcomes (overall cancer, smoking-related, alcohol-related, breast, lung, prostate, colorectal). Effects of the psychosocial factor, health behavior and their product term on cancer incidence were estimated using Cox regression. We pooled cohort-specific estimates using multivariate random-effects meta-analyses. Additive and multiplicative interaction/effect modification was examined. This study involved 437,827 participants, 36,961 incident cancer diagnoses, and 4,749,481 person years of follow-up. Out of 744 combinations of psychosocial factors, health behaviors, and cancer outcomes, we found no evidence of interaction. Effect modification was found for some combinations, but there were no clear patterns for any particular factors or outcomes involved. In this first large study to systematically examine potential interaction and effect modification, we found no evidence for psychosocial factors to interact with or modify health behaviors in relation to cancer incidence. The behavioral risk profile for cancer incidence is similar in people with and without psychosocial stress.

Association of Neighborhood Deprivation and Depressive Symptoms With Epigenetic Age Acceleration: Evidence From the Canadian Longitudinal Study on Aging.

BACKGROUND: Neighborhood deprivation and depression have been linked to epigenetic age acceleration. The next-generation epigenetic clocks including the DNA methylation (DNAm) GrimAge, and PhenoAge have incorporated clinical biomarkers of physiological dysregulation by selecting cytosine-phosphate-guanine sites that are associated with risk factors for disease, and have shown improved accuracy in predicting morbidity and time-to-mortality compared to the first-generation clocks. The aim of this study is to examine the association between neighborhood deprivation and DNAm GrimAge and PhenoAge acceleration in adults, and assess interaction with depressive symptoms. METHODS: The Canadian Longitudinal Study on Aging recruited 51 338 participants aged 45-85 years across provinces in Canada. This cross-sectional analysis is based on a subsample of 1 445 participants at baseline (2011-2015) for whom epigenetic data were available. Epigenetic age acceleration (years) was assessed using the DNAm GrimAge and PhenoAge, and measured as residuals from regression of the biological age on chronological age. RESULTS: A greater neighborhood material and/or social deprivation compared to lower deprivation (b = 0.66; 95% confidence interval [CI] = 0.21, 1.12) and depressive symptoms scores (b = 0.07; 95% CI = 0.01, 0.13) were associated with higher DNAm GrimAge acceleration. The regression estimates for these associations were higher but not statistically significant when epigenetic age acceleration was estimated using DNAm PhenoAge. There was no evidence of a statistical interaction between neighborhood deprivation and depressive symptoms. CONCLUSIONS: Depressive symptoms and neighborhood deprivation are independently associated with premature biological aging. Policies that improve neighborhood environments and address depression in older age may contribute to healthy aging among older adults living in predominantly urban areas.

National health registries - a 'goldmine' for studying non-communicable disease occurrence in Norway - the NCDNOR project.

To estimate occurrence of non-communicable diseases (NCDs) over the life-course in the Norwegian population, national health registries are a vital source of information since they fully represent the entire non-institutionalised population. However, as they are mainly established for administrative purposes, more knowledge about how NCDs are recorded in the registries is needed. To establish this, we begin by counting the number of individuals registered annually with one or more NCDs in any of the registries. The study population includes all inhabitants who lived in Norway from 2004 to 2020 (N~6.4m). The NCD outcomes are diabetes, cardiovascular diseases, chronic obstructive lung diseases, cancer and mental disorders/substance use disorders. Further, we included hip fractures in our NCD concept. The data sources used to identify individuals with NCDs, including detailed information on diagnoses in primary and secondary health care and dispensings of prescription drugs, are the Cancer Registry of Norway, The Norwegian Patient Registry, The Norwegian Control and Payment of Health Reimbursement database, and The Norwegian Prescription Database. The number of individuals registered annually with an NCD diagnosis and/or a dispensed NCD drug increased over the study period. Changes over time may reflect changes in disease incidence and prevalence, but also changes in disease-specific guidelines, reimbursement schemes and access to and use of health services. Data from more than one health registry to identify individuals with NCDs are needed since the registries reflect different levels of health care services and therefore may reflect disease severity.

Trends in social inequality and how mental wellbeing vary and covary among Norwegian adolescents and their families: the Young-HUNT Study.

BACKGROUND: The study had two aims: first, to investigate trends in socioeconomic inequalities in psychological distress and loneliness among Norwegian adolescents, and second, to study variation and covariation of psychological distress and loneliness within adolescents and between siblings within families. METHODS: Multivariate mixed models were used to investigate trends in socioeconomic inequality in psychological distress and loneliness using three separate cohorts of Norwegian adolescents from the Young-HUNT study conducted in 1995-1997 (Young-HUNT1, n = 8980), 2006-2008 (Young-HUNT3, n = 8199) and 2017-2019 (Young-HUNT4, n = 8066). Register data on parental education level was used as a marker of socioeconomic position (SEP), and a unique family number was used to identify adolescents belonging to the same family. A three-level multivariate mixed model was created, consisting of the outcomes at level 1, adolescents at level 2 and families at level 3. RESULTS: No statistically significant difference in scores on loneliness and psychological distress was observed between low and high parental education level in Young-HUNT1, whereas in Young-HUNT4, low parental education level was associated with a higher score on both psychological distress (ß = 0.09; 95% confidence interval (CI), 0.03-0.14) and loneliness (ß = 0.12; 95% CI 0.07-0.17). Analyses of covariation between psychological distress and loneliness showed that they were correlated within adolescents and strongly correlated within families across all timepoints. CONCLUSIONS: Increasing socioeconomic inequalities in psychological distress and loneliness among Norwegian adolescents is worrisome. Further, the family seems to be an important arena for potential prevention of psychological distress and loneliness among adolescents, regardless of parental education level.

Clustering and trajectories of key noncommunicable disease risk factors in Norway: the NCDNOR project.

Noncommunicable diseases (NCDs) are a leading cause of premature death globally and have common preventable risk factors. In Norway, the NCDNOR-project aims at establishing new knowledge in the prevention of NCDs by combining information from national registries with data from population-based health studies. In the present study, we aimed to harmonize data on key NCD risk factors from the health studies, describe clustering of risk factors using intersection diagrams and latent class analysis, and identify long-term risk factor trajectories using latent class mixed models. The harmonized study sample consisted of 808,732 individuals (1,197,158 participations). Two-thirds were exposed to ≥ 1 NCD risk factor (daily smoking, physical inactivity, obesity, hypertension, hypercholesterolaemia or hypertriglyceridaemia). In individuals exposed to ≥ 2 risk factors (24%), we identified five distinct clusters, all characterized by fewer years of education and lower income compared to individuals exposed to < 2 risk factors. We identified distinct long-term trajectories of smoking intensity, leisure-time physical activity, body mass index, blood pressure, and blood lipids. Individuals in the trajectories tended to differ across sex, education, and body mass index. This provides important insights into the mechanisms by which NCD risk factors can occur and may help the development of interventions aimed at preventing NCDs.

Association between engagement in cultural activities and use of general practitioner consultations: 7-year follow-up of adults from the HUNT study, Norway.

OBJECTIVE: Assess whether engagement in a range of cultural activities, both 'passive' and 'active' (ie, receptive and creative) participation, is associated with later demand for general practitioner (GP) consultations. DESIGN: Longitudinal prospective cohort study. SETTING: Data from the population-based the third Survey of Trøndelag Health Study (2006-2008) in Norway was linked to an administrative register including service information from all GP offices nationwide. PARTICIPANTS: This study included 17 396 (54.6%) women and 14 451 (45.4%) men aged 30-79 years. MAIN OUTCOME MEASURES: Multilevel negative binomial regression models assessed the relationship between cultural engagement and GP consultations, and reported as rate ratios. RESULTS: A mean of 3.57 GP visits per patient was recorded during the 7 years of follow-up. Participation in creative activities and a combination of both receptive and creative activities was associated with lower number of GP consultation. Gender-specific analyses suggest that these effects were attributable to men. The rate ratio of GP consultations among men taking part in creative activities less than once, twice and more than twice (<9 times) per week is 0.90, 0.89 and 0.87 times lower, respectively, compared with non-participants. Whereas weekly frequency of receptive and creative activity engagement showed a 0.92, 0.87 and 0.83 times lower rate ratio among engaged men. The variety of activities shows a similar pattern and participation in creative activities lowers the rate ratio among men. Engagement in a wide range/variety of activities, compared with non-engagement, was associated with lower numbers of GP consultations in men, but not women. CONCLUSIONS: Engagement in creative or combined receptive and creative cultural activities was associated with lower numbers of GP consultations among men. Thus, facilitating and promoting a culturally engaged lifestyle, particularly in men, may affect primary healthcare use. However, this study design gives no evidence of a causal relationship between cultural engagement and use of GP consultations.

Depression, anxiety, and the risk of cancer: An individual participant data meta-analysis.

BACKGROUND: Depression and anxiety have long been hypothesized to be related to an increased cancer risk. Despite the great amount of research that has been conducted, findings are inconclusive. To provide a stronger basis for addressing the associations between depression, anxiety, and the incidence of various cancer types (overall, breast, lung, prostate, colorectal, alcohol-related, and smoking-related cancers), individual participant data (IPD) meta-analyses were performed within the Psychosocial Factors and Cancer Incidence (PSY-CA) consortium. METHODS: The PSY-CA consortium includes data from 18 cohorts with measures of depression or anxiety (up to N = 319,613; cancer incidences, 25,803; person-years of follow-up, 3,254,714). Both symptoms and a diagnosis of depression and anxiety were examined as predictors of future cancer risk. Two-stage IPD meta-analyses were run, first by using Cox regression models in each cohort (stage 1), and then by aggregating the results in random-effects meta-analyses (stage 2). RESULTS: No associations were found between depression or anxiety and overall, breast, prostate, colorectal, and alcohol-related cancers. Depression and anxiety (symptoms and diagnoses) were associated with the incidence of lung cancer and smoking-related cancers (hazard ratios [HRs], 1.06-1.60). However, these associations were substantially attenuated when additionally adjusting for known risk factors including smoking, alcohol use, and body mass index (HRs, 1.04-1.23). CONCLUSIONS: Depression and anxiety are not related to increased risk for most cancer outcomes, except for lung and smoking-related cancers. This study shows that key covariates are likely to explain the relationship between depression, anxiety, and lung and smoking-related cancers. PREREGISTRATION NUMBER: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=157677.

Corrigendum: School functioning and educational aspirations in adolescents with social anxiety-The Young-HUNT3 study, Norway.

[This corrects the article DOI: 10.3389/fpsyg.2021.727529.].

Corrigendum: Sociodemographic correlates and mental health comorbidities in adolescents with social anxiety: the Young-HUNT3 study, Norway.

[This corrects the article DOI: 10.3389/fpsyg.2021.663161.].

Risk of antidepressant initiation among users of cardiovascular agents and metformin. Findings from the Trøndelag Health Study (HUNT) and Norwegian Prescription Database (NorPD), Norway: Findings from the Trøndelag Health Study (HUNT) and Norwegian Prescription Database (NorPD), Norway.

Cardiovascular disease and diabetes are risk factors for depression, yet the relationship between the drug treatments for these diseases and the risk of antidepressant initiation remains unclear. This study aimed to examine possible associations between the use of angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitors (ACEI), acetylsalicylic acid (ASA), beta-blockers (BB), calcium channel blockers (CCB), diuretics, or metformin and risk of antidepressant initiation. The Trøndelag Health Study (HUNT3), Norway, was linked to the Norwegian Prescription Database (NorPD). Participants with no prescriptions of cardiovascular agents, metformin, or antidepressants for at least 6 months before HUNT3 (baseline) were eligible and followed for 10 years. The exposure was the use of cardiovascular agents or metformin, defined as mono- or polytherapy from baseline to end of follow-up. The outcome was the initiation of antidepressant use, indicated by the first drug dispensation during the study period and expressed as hazard ratios (HRs) with 95% confidence intervals (CI). Among 20 227 adults aged 40-70 years at baseline, we observed different associations between cardiovascular agents or metformin and the risk of antidepressant initiation. ARBs or CCB monotherapy was associated with a lower risk of initiating antidepressant use (HR 0.70; 95%CI 0.56-0.88 and HR 0.81; 95%CI 0.61-1.06, respectively) compared to no use of any drugs included in the study (reference). Reduced risk of antidepressant initiation was among ASA or statin polytherapy users, whereas there was a small increased risk among participants on ASA monotherapy. In contrast, there was no statistical evidence of associations between ACEI, BB, diuretics, or metformin and increased or decreased risk of antidepressant initiation. Our mixed findings indicate the possibility that some cardiovascular agents may be associated with a reduced risk of initiating antidepressant use while others may not. However, bias due to the limitations of the study design is possible.

Trends in the use of home care services among Norwegians 70+ and projections towards 2050: The HUNT study 1995-2017.

BACKGROUND: Life expectancy (LE) is increasing worldwide, while there is lack of information on how this affects older individuals' use of formal home care services. AIM: We aimed to decompose LE into years with and without home care services and estimate projected number of users towards 2050 in Norway for people 70 years or older. METHODS: This study is based on a sample of 25,536 participants aged 70 years and older in the Trøndelag Health Study (HUNT) survey 2 (1995-1997), 3 (2006-2008), or 4 (2017-2019) linked with national data on mortality. Prevalence of home care services was standardised to the Norwegian population by age and sex. The Sullivan method was used to estimate expected years with and without home help services and nursing services for the years 1995, 2006 and 2016. Data from HUNT4 and Statistics Norway were used to estimate projected use of these services between 2020 and 2050. RESULTS: During 1995-2017, the use of home help services decreased from 22.6% to 6.2% (p < 0.001), and from 6.4% to 5.5% (p = 0.004) for home nursing services. Adjusted for age and sex, the use of home help services decreased significantly over time (p < 0.001), while home nursing services were stable (p = 0.69). LE at age 70 increased from 11.9 to 15.3 years in men (p < 0.05) during 1995-2017, and from 14.7 to 17.1 in women (p < 0.05). In the same period, the expected years receiving home help decreased from 2.6 to 1.1 in men (p < 0.05), and from 4.4 to 2.1 in women (p < 0.05). The expected years receiving home nursing increased from 0.6 to 0.9 in men (p < 0.05), and from 1.3 to 1.7 in women (p < 0.05). Projected numbers of people 70+ in Norway in need of either of these services were estimated to rise from 64,000 in 2020 to 160,000 in 2050. CONCLUSION: While overall life expectancy increased, the expected years receiving home help have decreased and home nursing slightly increased among the Norwegian population aged 70 years and older during 1995-2017. However, the substantial increase in the projected number of older adults using home care services in the future is an alert for the current health care planners.

HUNT for better public health.

AIMS: The Trøndelag Health Study (HUNT) has collected population data through comprehensive decennial surveys over the last four decades and has so far collected data from 240,000 participants. The participants are identified with the unique Norwegian birth number, which enables them to be followed throughout different life stages, from survey to survey, and to endpoint measures in Norwegian national health registers without attrition bias. METHODS: The study design of HUNT offers several advantages: it provides an overview of the public health development in the population over decades, the data can be used in health services research, clinical epidemiology, studies of causation, trajectories, and consequences of diseases, and to study gene × environment interactions. RESULTS: HUNT data have shown major shifts in public health trends, such as decreasing mean blood pressure and resting heart rate among adults, increasing prevalence of obesity, geographical and socioeconomic inequalities in health, increasing mental health distress among adolescents and young adults with an opposite development among the elderly. Data from HUNT have been used in several major international research projects, where data harmonization with several other population cohorts internationally has been done. HUNT has placed great emphasis on safeguarding research ethics, privacy, and data security. The Norwegian authorities established national regulations for the surveys from the time General Data Protection Regulation was introduced in 2018. CONCLUSIONS: Researchers can apply for HUNT data access from HUNT Research Centre provided they have obtained project approval from the Regional Committee for Medical and Health Research Ethics. Researchers not affiliated to a Norwegian research institution must collaborate with and apply through a Norwegian principal investigator. Information on the application and conditions for data access is available at www.ntnu.edu/hunt/data.

Depressive symptomology and cancer incidence in men and women: Longitudinal evidence from the HUNT study.

BACKGROUND: Depressive symptoms and mood disorders are associated with a host of physical conditions. However, it is inconclusive whether depressive symptoms are also associated with cancer onset. The aim of this study was to investigate whether depressive symptoms are associated with cancer incidence in a large population-based sample of men and women. METHODS: This study examined data from waves two (HUNT 2, 1995-97) and three (HUNT 3, 2006-08) of the Trøndelag Health Study (HUNT). Depressive symptoms were ascertained using the Hospital Anxiety and Depression Scale (HADS-D ≥ 8), cancer onset was identified via linkage with the Cancer Registry of Norway, death records by the national Cause of Death Register (CDR), and information on lifestyle and demographic factors was self-reported. Cox-proportional hazard regression models were used to test associations. Unadjusted, age-adjusted and multivariable best models accounting for smoking, education, marital status and current employment are presented. RESULTS: Men and women (n = 61,985; 46.0 % men) were followed from baseline over a period of 778,802 person-years. During the 20-year study period, there were 6856 (11.1 %) individuals with incident cancers and 12,480 (20.1 %) deaths (n = 2498 attributed to cancer). For men with depressive symptoms, 505 (15.3 %) developed incident cancer during the follow-up period, whereas among those without depressive symptoms, 3164 (12.5 %) developed incident cancer. Following adjustment for age, depressive symptomology was not significantly associated with risk of overall cancer onset, nor among prostate, colon or melanoma subtypes. Depressive symptoms were associated with an increased risk of bronchus and lung cancer both before (HR 1.90, 95 % CI 1.43-2.50, p ≤0.001) and after adjustment for age (HR 1.38, 95 % CI 1.04-1.80, p = 0.025). However, further adjustment for additional possible confounders explained this association. For women with depressive symptoms, 384 (11.2 %) developed incident cancer during the follow-up period, whereas among those with no depressive symptomology, 2803 (9.3 %) developed incident cancer. After accounting for age, depressive symptomology was not associated with risk of overall cancer onset, nor among breast, colon, lung and bronchus, or melanoma subtypes. Additional analyses evaluating relationship of depression symptom severity and cancer onset did not alter findings for men or women. LIMITATIONS: This report is limited by the post-hoc study design and subsequent non-randomised nature. Future prospective studies are required. CONCLUSION: These results suggest that depressive symptoms are not associated with an increased risk of overall or site-specific cancer onset in these men and women. Given the increased co-occurrence of other medical conditions such as cardiovascular disease, diabetes, stroke and musculoskeletal disorders in people with depression, the role of clinically diagnosed depression and other psychiatric disorders in association with cancer onset necessitates further consideration.

Associations of Cardiovascular Agents and Metformin with Depression Symptoms: A Cross-Sectional Analysis from the HUNT Study, Norway.

BACKGROUND: Cardiovascular agents, including angiotensin-converting enzyme inhibitors, angiotensin II receptor inhibitors, acetylsalicylic acid, statins, and metformin, have demonstrated benefits for depression. However, there is scant evaluation of these drugs' antidepressant properties in large population settings. OBJECTIVE: This study aimed to examine cross-sectional associations between depression symptoms and the use of cardiovascular agents and metformin in populations with cardiovascular diseases or diabetes mellitus. METHODS: Participants in the Trøndelag Health Study 2006-08 (HUNT3, n = 40,516) and 2017-19 (HUNT4, n = 42,103) were included and data on their drug use from 2006 to 2019 was retrieved from the Norwegian Prescription Database. The outcome was self-reported depression symptoms defined by the Hospital Anxiety and Depression Scale. Associations between cardiovascular agents or metformin use and self-reported depression were analyzed by multi-level logistic regression in sex-stratified samples. RESULTS: Among men with cardiovascular diseases, use of acetylsalicylic acid was associated with reduced depression symptoms compared with acetylsalicylic acid non-users (reference) in HUNT3 and HUNT4 [risk ratio = 0.76; 95% confidence interval 0.59-0.94, risk ratio = 0.67; 95% CI 0.52-0.82, respectively]. Similarly, male statin users had a lower likelihood of reporting depression than statin non-users in HUNT3 (risk ratio = 0.70; 95% confidence interval 0.54-0.86) and HUNT4 (risk ratio = 0.67; 95% confidence interval 0.51-0.84). Associations between statins or acetylsalicylic acid use and reduced depression symptoms were detected in women with cardiovascular diseases in HUNT4. We found no statistical support for associations between other cardiovascular agents or metformin use and a reduced or increased depression symptom risk. CONCLUSIONS: Results suggest negative associations between acetylsalicylic acid or statin use and depression symptoms. However, longitudinal cohort studies and randomized controlled trials are required to confirm the antidepressant effects of these drugs.