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 non-depressed persons. Methods: Nine Dutch cohorts were included, comprising 10,145 controls and 5,283 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 lowmolecular-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 sex, age, smoking, fasting status and lipid-modifying medication were performed within cohort, followed by random-effects meta-analyses. Results: Twenty-one of the 51 lipids, fatty acids and low-molecular-weight metabolites were significantly related to depression (false discovery rate q<0.05). Higher levels of apolipoprotein B, Very Low Density Lipoprotein (VLDL)-cholesterol, triglycerides, diglycerides, total and mono-unsaturated fatty acids, fatty acid chain length, glycoprotein acetyls, tyrosine, and isoleucine, and lower levels of High Density Lipoprotein (HDL)-cholesterol, acetate, and apolipoprotein A1 were associated with increased odds of depression. Analyses of lipid composition indicators confirmed a shift towards less HDL and more VLDL and triglycerides particles in depression. Associations appeared generally consistent across sex, age and body mass index strata, and across cohorts with depressive diagnoses vs. 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. and 184033111. We would like to acknowledge the BBMRI-NL metabolomics consortium (Supplement 16). Netherlands Study of Depression and Anxiety (NESDA): The infrastructure for the NESDA study www.nesda.nl is funded through the Geestkracht program of the Netherlands Organisation for Health Research and Development (ZonMw, grant number 10-000-1002) and financial contributions by participating universities and mental health care organizations (

ObjectiveTo evaluate pharmacologic treatment options for visual snow and to report prevalence of comorbid diseases.MethodsMedical charts of patients with a diagnosis of visual snow at the neurology outpatient clinic were reviewed on prescribed medication, and comorbid migraine, tinnitus, and psychiatric conditions including depression and anxiety.ResultsFrom 2007 to 2018, 58 patients were diagnosed with visual snow. Comorbid migraine was present in 51.7% of patients, lifetime depression in 41.4%, and lifetime anxiety in 44.8%. Lamotrigine was prescribed most frequently (26/58) and resulted in partial remission of symptoms in 5/26 (19.2%). No patients reported complete remission. Adverse events occurred in 13/26 (50.0%) patients. None of the other prescribed drugs (valproate [n = 7], topiramate [n = 4], acetazolamide [n = 2], flunarizine [n = 1]) led to improvement except for topiramate in one patient, who discontinued, however, because of adverse events.ConclusionsOf medication prescribed (lamotrigine, valproate, acetazolamide, flunarizine), only lamotrigine afforded some improvement in a small minority of patients. Migraine, depression, anxiety, and tinnitus were common comorbid diseases.Classification of evidenceThis study provides Class IV evidence that for some patients with visual snow, lamotrigine resulted in partial remission of symptoms.

Cortical hyperexcitability due to enhanced glutamatergic activity has been implicated in migraine pathophysiology but direct evidence is lacking. Here we assessed glutamate levels and intracellular mobility of glutamate in the visual cortex of migraineurs in-between attacks. We included 50 migraineurs (23 with aura and 27 without aura) and 24 age- and gender-matched non-headache controls. We used proton magnetic resonance spectroscopy (1H-MRS) and diffusion weighted spectroscopy at 7 T with a single volume of interest (2 × 2 × 3 cm) located in the primary and secondary visual cortex. For 1H-MRS we used a semi-LASER sequence with water referencing for absolute quantification. For diffusion weighted spectroscopy we used an adapted PRESS sequence with gradients applied in three directions and two different gradient amplitudes. Between-group differences were evaluated using analysis of covariance with the grey matter fraction in the volume of interest as covariate and post hoc comparisons with Bonferroni correction. Glutamate concentrations differed between groups (P = 0.047) and were higher in migraineurs without aura (mean ± standard deviation: 7.02 ± 0.50 mM) compared to controls (mean ± standard deviation: 6.40 ± 0.78 mM, P = 0.042). The apparent diffusion coefficient of glutamate was similar among groups (P = 0.129) suggesting similar inter- and intracellular mobility of glutamate in all three study groups. No differences were observed for concentrations and diffusion constants of other metabolites. The present study suggests that interictal glutamate levels are increased in the visual cortex of migraineurs without aura, supporting the hypothesis of cortical hyperexcitability in migraine.

ObjectiveTo identify a plasma metabolomic biomarker signature for migraine.MethodsPlasma samples from 8 Dutch cohorts (n = 10,153: 2,800 migraine patients and 7,353 controls) were profiled on a 1H-NMR-based metabolomics platform, to quantify 146 individual metabolites (e.g., lipids, fatty acids, and lipoproteins) and 79 metabolite ratios. Metabolite measures associated with migraine were obtained after single-metabolite logistic regression combined with a random-effects meta-analysis performed in a nonstratified and sex-stratified manner. Next, a global test analysis was performed to identify sets of related metabolites associated with migraine. The Holm procedure was applied to control the family-wise error rate at 5% in single-metabolite and global test analyses.ResultsDecreases in the level of apolipoprotein A1 (β −0.10; 95% confidence interval [CI] −0.16, −0.05; adjusted p = 0.029) and free cholesterol to total lipid ratio present in small high-density lipoprotein subspecies (HDL) (β −0.10; 95% CI −0.15, −0.05; adjusted p = 0.029) were associated with migraine status. In addition, only in male participants, a decreased level of omega-3 fatty acids (β −0.24; 95% CI −0.36, −0.12; adjusted p = 0.033) was associated with migraine. Global test analysis further supported that HDL traits (but not other lipoproteins) were associated with migraine status.ConclusionsMetabolic profiling of plasma yielded alterations in HDL metabolism in migraine patients and decreased omega-3 fatty acids only in male migraineurs.

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/).