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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 (mu mol/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 (beta = .002, SE = 0.003,p = .39;beta = .003, SE = 0.005,p = .64;beta = .005, SE = 0.005,p = .29;beta = -.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., European Union FP7 MooDFOOD project, Grant/Award Number: 613598; National Institute for Health Research (NIHR), through the Primary Care Research Network and the NIHR Exeter Clinical Research Facility

Contains fulltext : 220915.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acid (PUFA) alterations in patients with major depressive disorder (MDD) have been shown to persist after remission. Whether these alterations are risk factors for MDD recurrence remains unknown. Here, we examined whether fatty acids predict time until MDD recurrence in remitted MDD patients. METHODS: Data were used from remitted MDD patients of the Netherlands Study of Depression and Anxiety (n = 356) and the Depression Evaluation Longitudinal Therapy Assessment studies (n = 118). Associations of FAs with time until MDD recurrence up to 8-year follow-up were analyzed using Cox regression analyses. Study-specific estimates were pooled using mega- and meta-analysis techniques. RESULTS: 27.5% (NESDA) and 56.8% (DELTA) participants had an MDD recurrence. Pooled results showed that no FA was significantly associated with time until MDD recurrence (n-3 PUFAs: hazard ratio (HR) = 1.17, 95% confidence interval (CI) = 0.98-1.41, P = 0.082; n-6 PUFAs: HR = 1.08, 95% CI = 0.84-1.38, P = 0.55). CONCLUSION: In remitted MDD patients, circulating PUFAs were not associated with prospective risk of MDD recurrence. Consequently, circulating PUFAs are unlikely to reflect a vulnerability marker for recurrence, so correcting n-3 PUFA 'deficits' through supplementation does not seem a promising option to prevent MDD recurrence.

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.

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.

Additional file 2: Figure S1. IVW Mendelian randomization estimates, and age, sex and BMI-adjusted multivariable regression estimates for the associations between short sleep duration and 113 NMR derived metabolites. Figure S2. Comparison of the point estimates of the IVW Mendelian randomization and age, sex and BMI-adjusted multivariable regression analyses for the associations between short sleep duration and 113 NMR derived metabolites. Figure S3. Mendelian randomization and age, sex and BMI-adjusted multivariable regression analyses results for select associations of short sleep duration with NMR metabolites. Figure S4. IVW Mendelian randomization estimates and age, sex and BMI adjusted multivariable regression estimates for the associations between long sleep duration and 113 NMR derived metabolites. Figure S5. Comparison of the point estimates of the IVW Mendelian randomization and age, sex and BMI-adjusted multivariable regression analyses for the associations between long sleep duration and 113 NMR derived metabolites. Figure S6A. Mendelian randomization and age, sex and BMI-adjusted multivariable regression analyses results for select associations of long sleep duration with NMR metabolites. Figure S6B. Mendelian randomization and age, sex and BMI adjusted multivariable regression analyses results for select associations of long sleep duration with NMR metabolites.

BackgroundSleep 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.MethodsWe used AMV (N=17,370) 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.ResultsWe 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-hour [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.ConclusionsWhilst 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.

Background: Temporality of the association of low omega-3 polyunsaturated fatty acid (n-3 PUFA) plasma levels with depression remains questionable. To determine the underlying nature of these associations, this study examined the bidirectional longitudinal associations of n-3 PUFA plasma levels with (presence, onset and course of) depressive disorders and symptoms. Methods: Baseline (n = 2912, 28.6% with current depressive disorder) and 6-year follow-up data (n = 1966, 13.0% with current depressive disorder) of the Netherlands Study of Depression and Anxiety (NESDA) were used. Depression diagnoses and symptoms were based on psychiatric interviews and self-report questionnaires. N-3 PUFA levels (ratio of total fatty acids (mmol%)), were assessed using nuclear magnetic resonance. Results: Using two waves of data, n-3 PUFA levels were lower among depressed persons, as compared to healthy controls (Beta = −0.047, SE = 0.011, p < .001). Nevertheless, baseline n-3 PUFA levels were not consistently associated with subsequent change in depressive symptoms, onset or remission of depressive disorders over 6 years. Furthermore, the difference in n-3 PUFA levels detected at baseline between depressed and non-depressed participants tended to dissipate over 6 years (depression-by-time estimate: p = .011). Finally, subjects depressed both at baseline and at 6-year follow up had consistently lower n-3 PUFA levels over the entire follow-up as compared to those who had never been depressed. Change in depressive disorders across waves was not consistently accompanied by change in n-3 PUFA levels over time. Limitations: No data on intermediate time points and EPA levels were available. Conclusions: Despite significant cross-sectional associations between n-3 PUFA plasma levels and depressive disorders and severity, this 6-year longitudinal study could not confirm an uni- or bidirectional association over time. The association between depression and n-3 PUFA plasma levels is unlikely to be causal.

BACKGROUND: Depression has been associated with metabolic alterations, which adversely impact cardiometabolic health. Here, a comprehensive set of metabolic markers, predominantly lipids, was compared between depressed and nondepressed persons.METHODS: Nine Dutch cohorts were included, comprising 10,145 control subjects and 5283 persons with depression, established with diagnostic interviews or questionnaires. A proton nuclear magnetic resonance metabolomics platform provided 230 metabolite measures: 51 lipids, fatty acids, and low-molecular-weight metabolites; 98 lipid composition and particle concentration measures of lipoprotein subclasses; and 81 lipid and fatty acids ratios. For each metabolite measure, logistic regression analyses adjusted for gender, age, smoking, fasting status, and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses.RESULTS: Of the 51 lipids, fatty acids, and low-molecular-weight metabolites, 21 were significantly related to depression (false discovery rate q < .05). Higher levels of apolipoprotein B, very-low-density lipoprotein cholesterol, triglycerides, diglycerides, total and monounsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine and lower levels of high-density lipoprotein cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift toward less high-density lipoprotein and more very-low-density lipoprotein and triglyceride particles in depression. Associations appeared generally consistent across gender, age, and body mass index strata and across cohorts with depressive diagnoses versus symptoms.CONCLUSIONS: This large-scale meta-analysis indicates a clear distinctive profile of circulating lipid metabolites associated with depression, potentially opening new prevention or treatment avenues for depression and its associated cardiometabolic comorbidity.

Progress in high-throughput metabolic profiling provides unprecedented opportunities to obtain insights into the effects of drugs on human metabolism. The Biobanking BioMolecular Research Infrastructure of the Netherlands has constructed an atlas of drug-metabolite associations for 87 commonly prescribed drugs and 150 clinically relevant plasma-based metabolites assessed by proton nuclear magnetic resonance. The atlas includes a meta-analysis of ten cohorts (18,873 persons) and uncovers 1,071 drug-metabolite associations after evaluation of confounders including co-treatment. We show that the effect estimates of statins on metabolites from the cross-sectional study are comparable to those from intervention and genetic observational studies. Further data integration links proton pump inhibitors to circulating metabolites, liver function, hepatic steatosis and the gut microbiome. Our atlas provides a tool for targeted experimental pharmaceutical research and clinical trials to improve drug efficacy, safety and repurposing. We provide a web-based resource for visualization of the atlas (http://bbmri.researchlumc.nl/atlas/).

Background: Studies have shown that omega-3 (n-3) Polyunsaturated Fatty Acids (PUFAs), including docosahexaenoic acid (DHA), might have beneficial effects on somatic and mental health, potentially partly due to their mitigating effects on three major biological stress systems: the immune-inflammatory system, the hypothalamic-pituitary-adrenal-axis (HPA-axis) and the autonomic nervous system (ANS). Objective: To examine the association between (cumulative measures of) markers of three biological stress systems and n-3 PUFA and DHA plasma levels. Design: Plasma n-3 PUFA and DHA were measured using Nuclear Magnetic Resonance in 2724 participants from the Netherlands Study of Depression and Anxiety. Linear regression analyses (adjusted for sociodemographic, sampling, lifestyle and somatic disease variables) associated inflammation (C-reactive protein, interleukin-6, tumor necrosis factor alpha), HPA-axis (cortisol awakening response and evening cortisol) and ANS (heart rate, respiratory sinus arrhythmia and pre-ejection period) markers and cumulative indices within and across stress systems as independent variables with n-3 PUFA and DHA levels as dependent variables. Results: Participants had a mean age of 41.8 (SD = 13.1) and 65.7% were female. Higher levels of all three inflammation markers (Beta=−.146 to −.073, all p-values

Objective: Low omega (n)-3 polyunsaturated fatty acid (PUFA) levels have been found in patients with various major psychiatric disorders. This study aims to identify whether psychological vulnerabilities (personality and cognitive reactivity) underlying these psychiatric conditions are also associated with n-3 PUFA blood levels. Methods: Data was used from 2912 subjects (mean age 41.9 years, 66.4% female) from the Netherlands Study of Depression and Anxiety (NESDA). Five personality dimensions (NEO Five Factor Inventory) and cognitive reactivity measures (Leiden Index of Depression Sensitivity-Revised and Anxiety Sensitivity Index) were assessed. Plasma n-3 PUFA and docosahexaenoic acid (DHA) levels (as ratios against total fatty acids; mmol%) were assessed using a nuclear magnetic resonance platform. Results: Low n-3 PUFA and DHA levels were associated with high neuroticism (Standardized beta (Beta) = −0.045, 95% Confidence Interval (CI) = −0.079 to −0.010, p = 0.011; Beta = −0.058, 95%CI = −0.093 to −0.022, p = 0.001), low extraversion (Beta = 0.065, 95%CI = 0.031 to 0.099, p < 0.001; Beta = 0.074, 95%CI = 0.039 to 0.109, p < 0.001) and low conscientiousness (Beta = 0.060, 95%CI = 0.027 to 0.093, p < 0.001; Beta = 0.074, 95%CI = 0.039 to 0.108, p < 0.001). Low n-3 PUFA and DHA levels were related to high hopelessness/suicidality (Beta = −0.059, 95%CI = −0.096 to −0.023, p = 0.001; Beta = −0.078, 95%CI = −0.116 to −0.041, p < 0.001), but not with other cognitive reactivity measures. Directions of associations were generally consistent in subjects with and without a current depressive disorder. Conclusion: Low n-3 PUFA and DHA levels are associated with personality (high neuroticism, low extraversion and low conscientiousness) and cognitive reactivity (high hopelessness/suicidality). Effect sizes were rather small, but in line with previous research on personality and chronic diseases. Future research should examine which lifestyle and/or biological pathways underlie these associations.

The authors regret that Fig. 1 is missing a legend. The authors now provide a figure including the legend. The authors would like to apologise for any inconvenience caused. [Figure presented]

Background Blood levels of polyunsaturated fatty acids (PUFAs) have been associated to current depression. However, it is unclear whether this association extends to remitted depression and to anxiety disorders. This study examined the relationship of PUFAs with the presence and clinical characteristics of depressive and anxiety disorders. Methods Cross-sectional data was used from the Netherlands Study of Depression and Anxiety, including persons with current pure depressive disorder (n = 304), current pure anxiety disorder (n = 548), current comorbid depressive and anxiety disorder (n = 529), remitted depressive/anxiety disorder(s) (n = 897), and healthy controls (n = 634). Clinical characteristics included severity, subtypes, age of onset, duration of depression and anxiety and antidepressant use. Absolute values of omega-3 (N-3) and omega-6 (N-6) PUFAs and relative measures (as ratio of total Fatty Acids: the N-3:FA and N-6:FA ratio) in plasma were assessed using a nuclear magnetic resonance platform. Results Compared to controls, current comorbid depressive and anxiety disorder patients had lower N-3 PUFA levels (Cohen’s d=0.09, p = 0.012), and lower N-3:FA ratios (p = 0.002, Cohen’s d = 0.11) as did current pure depressive disorder patients (Cohen’s d = 0.13, p = 0.021), whereas N-6 PUFA levels were not different. No differences in PUFA levels were found between remitted patients and controls. Within patients, lower N-3 PUFA levels were only associated with higher depression severity (Beta = −0.42, p = 0.023), whereas for N-6 PUFA levels and other clinical characteristics no clear association was observed. PUFA alterations were not associated with pure anxiety. Conclusion It can be concluded that patients with a current depressive episode (especially the more severe cases with comorbid anxiety) have circulating N-3 PUFA levels lower than those in remission and healthy controls. No relationship was detected for N-6 PUFA levels.

Available data suggest high burden on caregivers of patientswith bipolar disorder (BD), yet the well-being of patients with BD increasingly depends on family members, partners and close friends. Aspatients with BD get older, the need for informal care may shift. We aimed to describe the caregivers of older adults with BD (OABD) and explore what patients' and caregivers' characteristics are associated with caregiver burden.Forty-seven caregivers of OABD were questioned about their perceived burden and depressive symptoms. Linear regression analyses were performed to examine the influence of various patients' and caregivers' characteristics on caregiver burden or depression.More than half of all caregivers experienced some degree of burden,and 6.4% reported depressive symptoms. The number of psychiatric admissions and social functioning were the only patients' characteristics associated with higher burden. Caregiver burden was significantly associated with caregiver's other obligations. None of the patient or caregiver characteristics was significantly associated with depression in caregivers of OABD.In OABD, even with few residual symptoms, more than half of all caregivers experience substantial burden. Future studies are needed to confirm if improving social functioning and preventing psychiatric hospitalizations decrease the burden on the caregivers of OABD.

Background:Depression and cognitive decline are highly prevalent in older persons and both are associated with low serum brain derived neurotrophic factor (BDNF). Mutual pathways of depression and cognitive decline in older persons may explain the overlap in symptoms and low serum BDNF. We hypothesized that serum BDNF levels are lower in depressed elderly with poor cognitive performance (global or specifically in working memory, speed of information processing, and episodic memory) compared to depressed elderly without cognitive impairment or non-depressed controls.Methods:BDNF Serum levels and cognitive functioning were examined in 378 depressed persons and 132 non-depressed controls from a large prospective study on late-life depression. The association between BDNF levels and each cognitive domain among the depressed patients was tested by four separate linear regression models adjusted for relevant covariates. An analysis of covariance (ANCOVA) was performed to compare BDNF serum levels in three groups (depression with cognitive impairment, depression without cognitive impairment, and non-depressed controls), when adjusted for potential confounders.Results:No significant linear association was found between BDNF and any of the four cognitive domains tested. There are no differences in BDNF levels between controls and depressed patients with or without cognitive impairment global or in specific domains after controlling for confounders.Conclusions:BDNF serum levels in this cohort of older depressed patients and controls are not related to cognitive functioning. As BDNF is essential for the survival and functioning of neurons, its levels may remain normal in stages of disease where remission is achievable.

Objectives The aim of this study is to explore the family history of psychiatric disorders, childhood abuse, and stressors in older patients with Bipolar Disorder (BD) and the association of these variables with the age at onset of BD. Methods The Questionnaire for Bipolar Disorder (QBP) and the Mini International Neuropsychiatric Interview (MINI-Plus) were obtained from 78 patients aged 60 and over to determine diagnosis, age at onset of the first affective episode, childhood abuse, family history of psychiatric disorders and past and recent stressful life events. Results Increased family history of psychiatric disorders was the only factor associated with an earlier age at onset of BD. Less family history of psychiatric disorders and more negative stressors were significantly associated with a later age at onset of the first (hypo)manic episode. Limitations Age at onset, history of childhood abuse, and past stressful life events were assessed retrospectively. Family members of BD patients were not interviewed. Conclusions Our findings suggest that age at onset can define distinct BD phenotypes. More specifically there was a stronger heredity of BD and other psychiatric disorders in patients with an early age of onset of BD. Negative stressors may play a specific role in patients with a late age at onset of a first (hypo)manic episode.