Fat metabolism is associated with telomere length in six population-based studies.

Telomeres are repetitive DNA sequences located at the end of chromosomes, which are associated to biological aging, cardiovascular disease, cancer and mortality. Lipid and fatty acid metabolism have been associated with telomere shortening. We have conducted an in-depth study investigating the association of metabolic biomarkers with telomere length (LTL). We performed an association analysis of 226 metabolic biomarkers with LTL using data from 11 775 individuals from six independent population-based cohorts (BBMRI-NL consortium). Metabolic biomarkers include lipoprotein lipids and subclasses, fatty acids, amino acids, glycolysis measures and ketone bodies. LTL was measured by quantitative polymerase chain reaction or FlowFISH. Linear regression analysis was performed adjusting for age, sex, lipid-lowering medication and cohort-specific covariates (model 1) and additionally for body mass index (BMI) and smoking (model 2), followed by inverse variance-weighted meta-analyses (significance threshold Pmeta = 6.5 × 10-4). We identified four metabolic biomarkers positively associated with LTL, including two cholesterol to lipid ratios in small VLDL (S-VLDL-C % and S-VLDL-CE %) and two omega-6 fatty acid ratios (FAw6/FA and LA/FA). After additionally adjusting for BMI and smoking, these metabolic biomarkers remained associated with LTL with similar effect estimates. In addition, cholesterol esters in very small VLDL (XS-VLDL-CE) became significantly associated with LTL (P = 3.6 × 10-4). We replicated the association of FAw6/FA with LTL in an independent dataset of 7845 individuals (P = 1.9 × 10-4). To conclude, we identified multiple metabolic biomarkers involved in lipid and fatty acid metabolism that may be involved in LTL biology. Longitudinal studies are needed to exclude reversed causation.

Genomics Research of Lifetime Depression in the Netherlands: The BIObanks Netherlands Internet Collaboration (BIONIC) Project.

In this cohort profile article we describe the lifetime major depressive disorder (MDD) database that has been established as part of the BIObanks Netherlands Internet Collaboration (BIONIC). Across the Netherlands we collected data on Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) lifetime MDD diagnosis in 132,850 Dutch individuals. Currently, N = 66,684 of these also have genomewide single nucleotide polymorphism (SNP) data. We initiated this project because the complex genetic basis of MDD requires large population-wide studies with uniform in-depth phenotyping. For standardized phenotyping we developed the LIDAS (LIfetime Depression Assessment Survey), which then was used to measure MDD in 11 Dutch cohorts. Data from these cohorts were combined with diagnostic interview depression data from 5 clinical cohorts to create a dataset of N = 29,650 lifetime MDD cases (22%) meeting DSM-5 criteria and 94,300 screened controls. In addition, genomewide genotype data from the cohorts were assembled into a genomewide association study (GWAS) dataset of N = 66,684 Dutch individuals (25.3% cases). Phenotype data include DSM-5-based MDD diagnoses, sociodemographic variables, information on lifestyle and BMI, characteristics of depressive symptoms and episodes, and psychiatric diagnosis and treatment history. We describe the establishment and harmonization of the BIONIC phenotype and GWAS datasets and provide an overview of the available information and sample characteristics. Our next step is the GWAS of lifetime MDD in the Netherlands, with future plans including fine-grained genetic analyses of depression characteristics, international collaborations and multi-omics studies.

Prevalence, associations and health outcomes of binge eating in adults with type 1 or type 2 diabetes: Results from Diabetes MILES - The Netherlands.

AIMS: To examine the prevalence and health risks of binge eating in people with diabetes. METHODS: Self-report data were analysed from a subsample (n = 582 type 1 diabetes/735 type 2 diabetes) of Diabetes MILES - the Netherlands, an online survey. Prevalence of binge eating was compared across diabetes type and treatment and between participants with and without binges for eating styles, diabetes treatment and outcomes, weight, BMI and psychological comorbidity. Associations between binge eating, HbA1c , BMI, diabetes distress were assessed using hierarchical linear regression analyses. RESULTS: 23% (n = 308) of participants reported eating binges, with 16% at least monthly, and 6% at least weekly. Prevalence and frequency of binges did not differ across diabetes type or treatment. People reporting binges scored higher on dietary restraint, emotional and external eating and reported higher weight and BMI than those without binges. Only people with type 1 diabetes and eating binges had a higher HbA1c . Hierarchical regression analyses demonstrated that binge eating was independently associated with higher HbA1c (ß = 0.12, p=0.001), BMI (ß = 0.13, p < 0.001) but not with diabetes distress. CONCLUSIONS: This study found binge eating to be associated with eating styles, BMI and HbA1c . However, our cross-sectional data do not allow for conclusions on causality. Future studies could further examine the directions of these associations and their clinical implications.

Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling.

BACKGROUND: Observational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status. METHODS: Multi-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction. RESULTS: Circulating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99-1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96-1.04; p value 0.59). CONCLUSIONS: Lower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Investigating the relationships between unfavourable habitual sleep and metabolomic traits: evidence from multi-cohort multivariable regression and Mendelian randomization analyses.

BACKGROUND: Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease. METHODS: We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions. RESULTS: We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)[95% confidence interval (CI) - 0.12, - 0.03] in AMV and - 0.03SD [- 0.07, - 0.003] in MR), higher glycoprotein acetyls (0.08SD [95% CI 0.03, 0.12] in AMV and 0.06SD [0.03, 0.10) in MR]), lower total very large HDL particles (- 0.04SD [- 0.08, 0.00] in AMV and - 0.05SD [- 0.09, - 0.02] in MR), and lower phospholipids in very large HDL particles (- 0.04SD [- 0.08, 0.002] in AMV and - 0.05SD [- 0.08, - 0.02] in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h [0.01, 0.03] in AMV and 0.15SD [0.02, 0.29] in MR) and with isoleucine in MR analyses (0.22SD [0.08, 0.35]). No consistent evidence was observed for effects of chronotype on metabolomic measures. CONCLUSIONS: Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.

Effects of dietary interventions on depressive symptom profiles: results from the MooDFOOD depression prevention study.

BACKGROUND: Dietary interventions did not prevent depression onset nor reduced depressive symptoms in a large multi-center randomized controlled depression prevention study (MooDFOOD) involving overweight adults with subsyndromal depressive symptoms. We conducted follow-up analyses to investigate whether dietary interventions differ in their effects on depressive symptom profiles (mood/cognition; somatic; atypical, energy-related). METHODS: Baseline, 3-, 6-, and 12-month follow-up data from MooDFOOD were used (n = 933). Participants received (1) placebo supplements, (2) food-related behavioral activation (F-BA) therapy with placebo supplements, (3) multi-nutrient supplements (omega-3 fatty acids and a multi-vitamin), or (4) F-BA therapy with multi-nutrient supplements. Depressive symptom profiles were based on the Inventory of Depressive Symptomatology. RESULTS: F-BA therapy was significantly associated with decreased severity of the somatic (B = -0.03, p = 0.014, d = -0.10) and energy-related (B = -0.08, p = 0.001, d = -0.13), but not with the mood/cognition symptom profile, whereas multi-nutrient supplementation was significantly associated with increased severity of the mood/cognition (B = 0.05, p = 0.022, d = 0.09) and the energy-related (B = 0.07, p = 0.002, d = 0.12) but not with the somatic symptom profile. CONCLUSIONS: Differentiating depressive symptom profiles indicated that food-related behavioral interventions are most beneficial to alleviate somatic symptoms and symptoms of the atypical, energy-related profile linked to an immuno-metabolic form of depression, although effect sizes were small. Multi-nutrient supplements are not indicated to reduce depressive symptom profiles. These findings show that attention to clinical heterogeneity in depression is of importance when studying dietary interventions.

Metabolomic profiles discriminating anxiety from depression.

OBJECTIVE: Depression has been associated with metabolomic alterations. Depressive and anxiety disorders are often comorbid diagnoses and are suggested to share etiology. We investigated whether differential metabolomic alterations are present between anxiety and depressive disorders and which clinical characteristics of these disorders are related to metabolomic alterations. METHODS: Data were from the Netherlands Study of Depression and Anxiety (NESDA), including individuals with current comorbid anxiety and depressive disorders (N = 531), only a current depression (N = 304), only a current anxiety disorder (N = 548), remitted depressive and/or anxiety disorders (N = 897), and healthy controls (N = 634). Forty metabolites from a proton nuclear magnetic resonance lipid-based metabolomics panel were analyzed. First, we examined differences in metabolites between disorder groups and healthy controls. Next, we assessed whether depression or anxiety clinical characteristics (severity and symptom duration) were associated with metabolites. RESULTS: As compared to healthy controls, seven metabolomic alterations were found in the group with only depression, reflecting an inflammatory (glycoprotein acetyls; Cohen's d = 0.12, p = 0.002) and atherogenic-lipoprotein-related (e.g., apolipoprotein B: Cohen's d = 0.08, p = 0.03, and VLDL cholesterol: Cohen's d = 0.08, p = 0.04) profile. The comorbid group showed an attenuated but similar pattern of deviations. No metabolomic alterations were found in the group with only anxiety disorders. The majority of metabolites associated with depression diagnosis were also associated with depression severity; no associations were found with anxiety severity or disease duration. CONCLUSION: While substantial clinical overlap exists between depressive and anxiety disorders, this study suggests that altered inflammatory and atherogenic-lipoprotein-related metabolomic profiles are uniquely associated with depression rather than anxiety disorders.

Measurement and genetic architecture of lifetime depression in the Netherlands as assessed by LIDAS (Lifetime Depression Assessment Self-report).

BACKGROUND: Major depressive disorder (MDD) is a common mood disorder, with a heritability of around 34%. Molecular genetic studies made significant progress and identified genetic markers associated with the risk of MDD; however, progress is slowed down by substantial heterogeneity as MDD is assessed differently across international cohorts. Here, we used a standardized online approach to measure MDD in multiple cohorts in the Netherlands and evaluated whether this approach can be used in epidemiological and genetic association studies of depression. METHODS: Within the Biobank Netherlands Internet Collaboration (BIONIC) project, we collected MDD data in eight cohorts involving 31 936 participants, using the online Lifetime Depression Assessment Self-report (LIDAS), and estimated the prevalence of current and lifetime MDD in 22 623 unrelated individuals. In a large Netherlands Twin Register (NTR) twin-family dataset (n ≈ 18 000), we estimated the heritability of MDD, and the prediction of MDD in a subset (n = 4782) through Polygenic Risk Score (PRS). RESULTS: Estimates of current and lifetime MDD prevalence were 6.7% and 18.1%, respectively, in line with population estimates based on validated psychiatric interviews. In the NTR heritability estimates were 0.34/0.30 (s.e. = 0.02/0.02) for current/lifetime MDD, respectively, showing that the LIDAS gives similar heritability rates for MDD as reported in the literature. The PRS predicted risk of MDD (OR 1.23, 95% CI 1.15-1.32, R2 = 1.47%). CONCLUSIONS: By assessing MDD status in the Netherlands using the LIDAS instrument, we were able to confirm previously reported MDD prevalence and heritability estimates, which suggests that this instrument can be used in epidemiological and genetic association studies of depression.

Supplementation-induced increase in circulating omega-3 serum levels is not associated with a reduction in depressive symptoms: Results from the MooDFOOD depression prevention trial.

BACKGROUND: There is ambiguity on how omega-3 (n-3) polyunsaturated fatty acids (PUFAs) are associated with depression, and what the temporality of the association might be. The present study aimed to examine whether (intervention-induced changes in) n-3 PUFA levels were associated with (changes in) depressive symptoms. METHODS: Baseline, 6- and 12-month follow-up data on 682 overweight and subclinically depressed persons from four European countries that participated in the MooDFOOD depression prevention randomized controlled trial were used. Participants were allocated to four intervention groups: (a) placebos, (b) placebos and food-related behavioral activation therapy (F-BA), (c) multinutrient supplements (fish oil and multivitamin), and (d) multinutrient supplements and F-BA. Depressive symptoms were measured using the inventory of depressive symptomatology. PUFA levels (µmol/L) were measured using gas chromatography. Analyses were adjusted for sociodemographics, lifestyle, and somatic health. RESULTS: Increases in n-3 PUFA, docosahexaenoic acid, and eicosapentaenoic acid levels over time were significantly larger in the supplement groups than in placebo groups. Change in PUFA levels was not significantly associated with the change in depressive symptoms (ß = .002, SE = 0.003, p = .39; ß = .003, SE = 0.005, p = .64; ß = .005, SE = 0.005, p = .29; ß = -.0002, SE = 0.0004, p = .69). Baseline PUFA levels did not modify the intervention effects on depressive symptoms. CONCLUSIONS: In overweight and subclinical depressed persons, multinutrient supplements led to significant increases in n-3 PUFA levels over time, which were not associated with changes in depressive symptoms. Multinutrient supplements do not seem to be an effective preventive strategy in lowering depressive symptoms over time in these at-risk groups.

Association of food groups with depression and anxiety disorders.

PURPOSE: Adherence to the Mediterranean diet has been associated with fewer depressive symptoms, however, it is unknown whether this is attributed to some or to all components. We examined the association between the individual food groups of the Mediterranean Diet Score (MDS), in isolation and in combination, with depression and anxiety (symptom severity and diagnosis). METHODS: Data from 1634 adults were available from the Netherlands Study of Depression and Anxiety. Eleven energy-adjusted food groups were created from a 238-item food frequency questionnaire. In regression analysis, these were associated in isolation and combination with (1) depressive and anxiety disorders (established with the Composite International Diagnostic Interview) (current disorder n = 414), and (2) depression and anxiety severity [measured with the Inventory of Depressive Symptomatology (IDS), the Beck Anxiety Inventory (BAI) and the Fear Questionnaire (FEAR)]. RESULTS: Overall, the MDS score shows the strongest relationships with depression/anxiety [Diagnosis: odds ratio (OR) 0.77 per SD, 95% confidence interval (95% CI) 0.66-0.90, IDS: standardised betas (ß) - 0.13, 95% CI - 0.18, - 0.08] and anxiety (BAI: ß - 0.11, 95% CI - 0.16, - 0.06, FEAR: ß - 0.08, 95% CI - 0.13, - 0.03). Greater consumption of non-refined grains and vegetables was associated with lower depression and anxiety severity, whilst being a non-drinker was associated with higher symptom severity. Higher fruit and vegetable intake was associated with lower fear severity. Non-refined grain consumption was associated with lower odds and being a non-drinker with greater odds of current depression/anxiety disorders compared to healthy controls, these associations persisted after adjustment for other food groups (OR 0.82 per SD, 95% CI 0.71-0.96, OR 1.26 per SD 95% CI 1.08-1.46). CONCLUSION: We can conclude that non-refined grains, vegetables and alcohol intake appeared to be the driving variables for the associated the total MDS score and depression/anxiety. However, the combined effect of the whole diet remains important for mental health. It should be explored whether an increase consumption of non-refined grains and vegetables may help to prevent or reduce depression and anxiety.

Effect of food-related behavioral activation therapy on food intake and the environmental impact of the diet: results from the MooDFOOD prevention trial.

PURPOSE: Food-based dietary guidelines are proposed to not only improve diet quality, but to also reduce the environmental impact of diets. The aim of our study was to investigate whether food-related behavioral activation therapy (F-BA) applying Mediterranean-style dietary guidelines altered food intake and the environmental impact of the diet in overweight adults with subsyndromal symptoms of depression. METHODS: In total 744 adults who either received the F-BA intervention (F-BA group) or no intervention (control group) for 12 months were included in this analysis. Food intake data were collected through a food frequency questionnaire at baseline and after 6 and 12 months. Greenhouse gas emissions (GHGE), land use (LU), and fossil energy use (FEU) estimates from life-cycle assessments and a weighted score of the three (pReCiPe score) were used to estimate the environmental impact of each individual diet at each timepoint. RESULTS: The F-BA group reported increased intakes of vegetables (19.7 g/day; 95% CI 7.8-31.6), fruit (23.0 g/day; 9.4-36.6), fish (7.6 g/day; 4.6-10.6), pulses/legumes (4.0 g/day; 1.6-6.5) and whole grains (12.7 g/day; 8.0-17.5), and decreased intake of sweets/extras (- 6.8 g/day; - 10.9 to - 2.8) relative to control group. This effect on food intake resulted in no change in GHGE, LU, and pReCiPe score, but a relative increase in FEU by 1.6 MJ/day (0.8, 2.4). CONCLUSIONS: A shift towards a healthier Mediterranean-style diet does not necessarily result in a diet with reduced environmental impact in a real-life setting. TRIAL REGISTRATION: ClinicalTrials.gov. Number of identification: NCT02529423. August 2015.

Childhood overweight and obesity and the risk of depression across the lifespan.

BACKGROUND: Obesity has been longitudinally associated with depression but only few studies take a life course approach. This longitudinal study investigates whether being overweight or obese at age 8 and 13 years is associated with depressive symptoms more than 60 years later and whether this association is independent of late-life body mass index (BMI). We also investigated the association of being overweight/obese at age 8 or 13 years with ever having major depressive disorder (lifetime MDD). METHOD: This analysis is based on a sub-sample of 889 AGES-Reykjavik participants with measured BMI data from early life. Late-life depressive symptoms were measured with the Geriatric Depression Scale (GDS) and lifetime MDD was assessed at late-life using the Mini International Neuropsychiatric Interview. Logistic regression analysis was used to estimate the relationships between BMI (continuous and categorical) at age 8 or 13 years, and late-life depressive symptoms (measured as GDS ≥ 5) or lifetime MDD, adjusted for sex, education, physical activity, smoking status and alcohol use. In a separate model, additional adjustments were made for late-life BMI. RESULTS: One hundred and one subjects (11%) had depressive symptoms at late-life (GDS ≥ 5), and 39 subjects (4.4%) had lifetime MDD. Being overweight or obese at age 8 or 13 years was not associated with higher depressive symptoms during late-life, irrespective of late-life BMI. Being overweight or obese at age 8 years, but not age 13 years was associated with an increased risk of lifetime MDD (Odds Ratio (OR) (95% confidence interval [CI]) for age 8 = 4.03[1.16-13.96]P = 0.03 and age 13 = 2.65[0.69-10.26] P = 0.16, respectively). CONCLUSION: Being overweight in childhood was associated with increased odds of lifetime MDD, although the magnitude of the risk is uncertain given the small numbers of participants with lifetime MDD. No clear association was observed between childhood and adolescent overweight/obesity and late-life depressive symptoms irrespective of late life BMI.

Depression and eating styles are independently associated with dietary intake.

Depression and eating styles are two important, interrelated factors associated with dietary intake. However, it remains unclear whether depression and eating styles are independently associated with dietary intake, and whether associations between depression and dietary intake are mediated by eating styles. Therefore, the aim of the current study was to investigate the associations of, and interplay between depression and eating styles in relation to different aspects of dietary intake. Cross-sectional data from 1442 participants (healthy controls (22.7%), remitted (61.0%) and current patients (16.3%)) from the Netherlands Study of Depression and Anxiety were used. Linear regression analyses were used to determine associations of depressive disorders (DSM-IV based psychiatric interview), self-reported depressive symptoms (Inventory of Depressive Symptomatology), emotional, external and restrained eating (Dutch Eating Behavior Questionnaire) with 4 measures of dietary intake (total energy intake (kcal/d), Mediterranean diet score (MDS), intake of sweets foods (g/d), and snack/fast-food (g/d)) measured with a 238-item food frequency questionnaire. Statistical mediation analyses were used to study whether associations between depression and dietary intake were mediated by eating styles. Current depression diagnosis and severity were associated with lower MDS and higher intake of sweet foods and snack/fast-food. Emotional and external eating were associated with higher intakes of snack/fast-food; external eating was also associated with higher total energy intake. Restrained eating was associated with lower total energy and intake of sweet foods, and higher MDS. Associations between current depression or severity and intake of snack/fast-food were mediated by external eating. In general, depression and eating styles contributed independently to poorer diet quality and higher intake of sweet and snack/fast-food. The association between depression and higher intake of snack/fast-food was mediated by external eating.

Effect of Multinutrient Supplementation and Food-Related Behavioral Activation Therapy on Prevention of Major Depressive Disorder Among Overweight or Obese Adults With Subsyndromal Depressive Symptoms: The MooDFOOD Randomized Clinical Trial.

Importance: Effects of nutritional interventions on the prevention of major depressive disorder (MDD) in overweight adults are unknown. Objective: To examine the effect of 2 nutritional strategies (multinutrient supplementation, food-related behavioral activation therapy) and their combination for prevention of a new MDD episode in overweight adults with subsyndromal depressive symptoms. Design, Setting, and Participants: This multicenter 2 × 2 factorial randomized clinical trial included overweight adults (body mass index, 25-40) with elevated depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] scores ≥5) and no MDD episode in the past 6 months from 4 European countries. A total of 1025 adults were randomized (July 30, 2015-October 12, 2016) and followed up for 1 year (October 13, 2017). Interventions: Daily multinutrient supplements (1412-mg omega-3 fatty acids, 30-µg selenium, 400-µg folic acid, and 20-µg vitamin D3 plus 100-mg calcium) vs placebo and 21 individual or group therapy sessions vs none (blinded to researchers) for 1 year. Participants were allocated to placebo without therapy (n = 257), placebo with therapy (n = 256), supplements without therapy (n = 256), and supplements with therapy (n = 256). Main Outcome and Measures: Cumulative 1-year onset of MDD via the Mini International Neuropsychiatric Interview at 3, 6, and 12 months. Logistic regression using effect-coded variables (-1 indicating control, 1 indicating intervention) evaluated intervention effects both individually and in combination (interaction) on MDD onset. Results: Among 1025 participants (mean age, 46.5 years; 772 women [75%]; mean BMI, 31.4), 779 (76%) completed the trial. During the 12-month follow-up, 105 (10%) developed MDD: 25 (9.7%) patients in the placebo without therapy, 26 (10.2%) in the placebo with therapy, 32 (12.5%) in the supplement without therapy, and 22 (8.6%) in the supplement with therapy group. None of the treatment strategies affected MDD onset. The odds ratio (OR) for supplements was 1.06 (95% CI, 0.87-1.29); for therapy, 0.93 (95% CI, 0.76-1.13); and for their combination, 0.93 (95% CI, 0.76-1.14; P for interaction, .48). One person in the supplementation with therapy group, died. Twenty-four patients in each of the placebo groups and 24 patients in the supplementation with therapy group were hospitalized, and 26 patients in the supplementation-only group were hospitalized. Conclusions and Relevance: Among overweight or obese adults with subsyndromal depressive symptoms, multinutrient supplementation compared with placebo and food-related behavioral activation therapy compared with no therapy did not reduce episodes of major depressive disorder during 1 year. These findings do not support the use of these interventions for prevention of major depressive disorder. Trial registration: ClinicalTrials.gov Identifier: NCT02529423.

The relation between obesity and depressed mood in a multi-ethnic population. The HELIUS study.

PURPOSE: To examine the association between obesity and depressed mood in a large multi-ethnic population and check for consistency in this association across six ethnic groups. METHODS: Data of 21,030 persons (18-70 years) were sourced from the HELIUS study. Cross-sectional relationships between obesity measures [body mass index (kg/m2) and waist circumference (cm)] and depressed mood (PHQ-9 score ≥ 10) were analysed. Consistency of associations was investigated across ethnic groups by interaction terms (ethnicity*obesity measures) in basic (age, sex, education) and fully (health behaviours and somatic health) adjusted models. RESULTS: Obesity was prevalent in all ethnic groups, but varied substantially. After sociodemographic adjustment, obesity measures were associated with increased odds of depressed mood but this was inconsistent across ethnic groups. Obesity (BMI ≥ 30 or highest waist circumference quartile) was strongly and significantly associated with depressed mood in the Dutch [Odds Ratio (OR) = 1.72; 95% Confidence intervals (CI) 1.24-2.40, and OR = 1.86; 95% CI 1.38-2.50], respectively, and African Surinamese (OR = 1.60; 95% CI 1.29-1.98 and OR = 1.59; 95% CI 1.27-2.00, respectively) but had a weaker, non-significant association in other ethnic groups (South-Asian Surinamese, Ghanaian, Moroccan, Turkish groups). Adjustment for health behaviours and somatic health had limited effect on this pattern. CONCLUSION: Obesity was associated with a higher risk of depressed mood. However, ethnic differences were found: the obesity-depressed mood association was strong in the Dutch and African Surinamese populations, but not in other ethnic groups. Future studies should explore whether differential normative values or pathophysiology across ethnic groups explain why the obesity-depression association is inconsistent across ethnic groups.

Anxiety and new onset of cardiovascular disease: critical review and meta-analysis.

BACKGROUND: Anxiety has been associated with new-onset cardiovascular disease (CVD), but the quality of this relationship is unclear. Only if anxiety is a causal, independent cardiovascular risk factor might it be a target for CVD prevention. AIMS: To determine and examine the independent association and causality between anxiety and incident CVD. METHOD: PubMed, EMBASE and PsycINFO databases were searched up to October 2013. A review of Hill's criteria for causality and random effects meta-analysis were conducted of prospective, population-based studies examining anxiety and incident CVD in people free from CVD at baseline. RESULTS: The meta-analysis comprised 37 papers (n = 1 565 699). The follow-up ranged from 1 to 24 years. Anxiety was associated with a 52% increased incidence of CVD (hazard ratio = 1.52, 95% CI 1.36-1.71). The risk seemed independent of traditional risk factors and depression. The evaluation of Hill's criteria largely argued in favour of causality. CONCLUSIONS: Anxiety may be of interest for CVD prevention. Future research should examine biological and behavioural underpinnings of the association in order to identify targets for intervention.

Identification of an Immune-Neuroendocrine Biomarker Panel for Detection of Depression: A Joint Effects Statistical Approach.

BACKGROUND/AIMS: Less than half of depression patients are correctly diagnosed within the primary care setting. Previous proteomic studies have identified numerous immune and neuroendocrine changes in patients. However, few studies have considered the joint effects of biological molecules and their diagnostic potential. Our aim was to develop and validate a diagnostic serum biomarker panel identified through joint effects analysis of multiplex immunoassay profiling data from 1,007 clinical samples. METHODS: In stage 1, we conducted a meta-analysis of two independent cohorts of 78 first-/recent-onset drug-naive/drug-free depression patients and 156 controls and applied the 10-fold cross-validation with least absolute shrinkage and selection operator regression to identify an optimal diagnostic prediction model (biomarker panel). In stage 2, we tested the discriminatory performance of this biomarker panel using the naturalistic Netherlands Study of Depression and Anxiety (NESDA) cohort of 468 depression patients and 305 controls. RESULTS: An optimal panel of 33 immune-neuroendocrine biomarkers and gender was selected in the meta-analysis. Testing this biomarker-gender panel using the NESDA cohort resulted in a moderate to good performance to differentiate patients from controls (0.69 < AUC < 0.86), particularly the first-episode patients free of chronic non-psychiatric diseases or medications and following incorporation of sociodemographic covariates (0.76 < AUC < 0.92). CONCLUSION: Despite the need for additional validation studies, we demonstrated that a blood-based biomarker-sociodemographic panel can detect depression in naturalistic healthcare settings with good discriminatory power. Further refinements of blood biomarker panels aiding in the diagnosis of depression may provide a cost-effective means to increase accuracy of clinical diagnosis within the primary care setting.

Prevention of depression through nutritional strategies in high-risk persons: rationale and design of the MooDFOOD prevention trial.

BACKGROUND: Obesity and depression are two prevalent conditions that are costly to individuals and society. The bidirectional association of obesity with depression, in which unhealthy dietary patterns may play an important role, has been well established. Few experimental studies have been conducted to investigate whether supplementing specific nutrients or improving diet and food-related behaviors can prevent depression in overweight persons. METHOD/DESIGN: The MooDFOOD prevention trial examines the feasibility and effectiveness of two different nutritional strategies [multi-nutrient supplementation and food-related behavioral change therapy (FBC)] to prevent depression in individuals who are overweight and have elevated depressive symptoms but who are not currently or in the last 6 months meeting criteria for an episode of major depressive disorder (MDD). The randomized controlled prevention trial has a two-by-two factorial design: participants are randomized to daily multi-nutrient supplement (omega-3 fatty acids, calcium, selenium, B-11 vitamin and D-3 vitamin) versus placebo, and/or FBC therapy sessions versus usual care. Interventions last 12 months. In total 1000 participants aged 18-75 years with body mass index between 25-40 kg/m(2) and with a Patient Health Questionnaire-9 score ≥ 5 will be recruited at four study sites in four European countries. Baseline and follow-up assessments take place at 0, 3, 6, and 12 months. Primary endpoint is the onset of an episode of MDD, assessed according to DSM-IV based criteria using the MINI 5.0 interview. Depressive symptoms, anxiety, food and eating behavior, physical activity and health related quality of life are secondary outcomes. During the intervention, compliance, adverse events and potentially mediating variables are carefully monitored. DISCUSSION: The trial aims to provide a better understanding of the causal role of specific nutrients, overall diet, and food-related behavior change with respect to the incidence of MDD episodes. This knowledge will be used to develop and disseminate innovative evidence-based, feasible, and effective nutritional public health strategies for the prevention of clinical depression. TRIAL REGISTRATION: ClinicalTrials.gov. Number of identification: NCT02529423 . August 2015.

Plasma cotinine levels in cigarette smokers: impact of mental health and other correlates.

BACKGROUND/AIMS: We examined in cigarette smokers whether cotinine was associated with depressive and/or anxiety disorders. METHODS: Data were derived from 1,026 smoking adults with and without depressive and/or anxiety disorders participating in the Netherlands Study of Depression and Anxiety (NESDA). Depressive and anxiety disorders were ascertained with the DSM-IV Composite International Diagnostic Interview. Cigarette consumption was inquired about during an interview. Cotinine was assessed in plasma. RESULTS: Currently depressed and/or anxious smokers (n=692) reported smoking a higher number of cigarettes per day (CPD) than smokers with a remitted disorder (n=190) and smokers with no lifetime disorder (n=144). After controlling for CPD and other covariates, depressed and/or anxious smokers had lower cotinine levels compared to smokers with no lifetime disorder (B=-56.0, p=0.001). In the full regression model, CPD was positively associated with cotinine levels, whereas current depression and/or anxiety and high body mass index were inversely associated with cotinine. CONCLUSION: After considering CPD, the presence of current depressive and/or anxiety disorders was associated with lower cotinine levels, which may point to a different smoking topography or a faster cotinine metabolism in individuals with affective disorders. The latter could help to explain the higher number of cigarettes smoked and poorer cessation rates among depressed or anxious patients.