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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

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: 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.

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.