linoleic-acid and Bipolar-Disorder

The purpose of this article is to provide a comprehensive review of metabolomics studies for psychosis, as a means of biomarker discovery. Manuscripts were selected for review if they involved discovery of metabolites using high-throughput analysis in human subjects and were published in the last decade. The metabolites identified were searched in Human Metabolome Data Base (HMDB) for a link to psychosis. Metabolites associated with psychosis based on evidence in HMBD were then searched using PubMed to explore the availability of further evidence. Almost all of the studies which underwent full review involved patients with schizophrenia. Ten biomarkers were identified. Six of them were reported in two or more independent metabolomics studies: N-acetyl aspartate, lactate, tryptophan, kynurenine, glutamate, and creatine. Four additional metabolites were encountered in a single metabolomics study but had significant evidence (two supporting articles or more) for a link to psychosis based on PubMed: linoleic acid, D-serine, glutathione, and 3-hydroxybutyrate. The pathways affected are discussed as they may be relevant to the pathophysiology of psychosis, and specifically of schizophrenia, as well as, constitute new drug targets for treatment of related conditions. Based on the biomarkers identified, early diagnosis of schizophrenia and/or monitoring may be possible.

Topics: 3-Hydroxybutyric Acid; Aspartic Acid; Biomarkers; Bipolar Disorder; Creatine; Female; Glutamic Acid; Glutathione; Humans; Kynurenine; Lactic Acid; Linoleic Acid; Male; Metabolome; Metabolomics; Psychotic Disorders; Schizophrenia; Serine; Tryptophan

Dietary deficiency in polyunsaturated fatty acids (PUFAs), including the omega-3 fatty acids eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3), and excesses in omega-6 fatty acids, including linoleic acid (LA; 18:2n-6) and arachidonic acid (AA; 20:4n-6), may be associated with the pathophysiology of bipolar disorder. In an effort to provide clarification regarding the relationship between PUFA biostatus and bipolar disorder, this meta-analysis investigated studies comparing erythrocyte (red blood cell) membrane PUFA composition in patients with bipolar disorder and healthy controls.. A meta-analysis was performed on case-control studies comparing erythrocyte PUFA (EPA, DHA, LA and AA) levels in patients with bipolar I disorder and healthy controls. Standardized effect sizes were calculated and combined using a random effects model.. Six eligible case-control studies comprising n = 118 bipolar I patients and n = 147 healthy controls were included in the analysis. Compared with healthy controls, patients with bipolar I disorder exhibited robust erythrocyte DHA deficits (p = 0.0008) and there was a trend for lower EPA (p = 0.086). There were no significant differences in LA (p = 0.42) or AA (p = 0.64).. Bipolar I disorder is associated with robust erythrocyte DHA deficits. These findings add to a growing body of evidence implicating omega-3 PUFA deficiency in the pathophysiology of bipolar disorder.

Topics: Arachidonic Acid; Bipolar Disorder; Docosahexaenoic Acids; Eicosapentaenoic Acid; Erythrocyte Membrane; Erythrocytes; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Fatty Acids, Unsaturated; Humans; Linoleic Acid; Reference Values

Dietary polyunsaturated fatty acids (PUFA) and inflammatory proteins associate with immune activation and have been implicated in the pathophysiology of mood disorders. We have previously reported that individuals with bipolar disorder (BPD) have decreased PUFA intake, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid (AA); and decreased PUFA concentration of plasma EPA and linoleic acid (LA). We have also reported an association between plasma LA and its metabolites and burden of disease measures in BPD. In the current cross-sectional study we collected blood samples and diet records from both bipolar (n = 91) and control subjects (n = 75) to quantify plasma cytokine concentrations and dietary LA intake, respectively. Using multiple linear regression techniques, we tested for case control differences in plasma cytokine levels and associations between cytokines and dietary LA intake, adjusting for sex, age, BMI, and total energy intake. We found significantly higher plasma levels of interleukin 18 (IL-18) (p = 0.036), IL-18 binding protein (IL-18BP) (p = 0.001), soluble tumor necrosis factor receptor (sTNFR) 1 (p = 0.006), and sTNFR2 (p = 0.007) in BPD compared with controls. Moreover, BPD significantly moderated the associations of dietary LA intake with plasma levels of IL-18, sTNFR1 and sTNFR2, which were inverse associations in bipolar individuals and positive associations in controls (p for dietary LA x BPD diagnosis interaction < 0.05 for all three). These findings suggest potential dysregulation of LA metabolism in BPD, which may extend to a modified influence of dietary LA on specific inflammatory pathways in individuals with BPD compared to healthy controls.

Topics: Adult; Age Factors; Biomarkers; Bipolar Disorder; Body Mass Index; Case-Control Studies; Cross-Sectional Studies; Diet; Eating; Enzyme-Linked Immunosorbent Assay; Female; Humans; Interleukin-18; Interview, Psychological; Linear Models; Linoleic Acid; Male; Medical Records; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; Sex Factors

We have shown that bipolar individuals have reduced quality diets, including lower intake of polyunsaturated fatty acids (PUFA). We have also reported reduced plasma levels of the n-6 PUFA, linoleic acid (LA), and the n-3 PUFA, eicosapentaenoic acid (EPA) in bipolar subjects. In the current analysis we hypothesized that LA and EPA plasma levels would mediate lower self-reported mental health and life functioning scores in bipolar subjects. In a cross-sectional study, we collected a 7-day diet record in bipolar (n = 56) and control subjects (n = 46) followed by a fasted blood draw. We used structured equation modeling path analysis to test for mediating effects of dietary intake and plasma levels of LA and EPA on self-reported mental health questionnaire scores, including the Life Functioning Questionnaire (LFQ), the Patient Health Questionnaire (PHQ9), and the Short Form Health Survey (SF12), extracting the mental health component summary score (SF12-MH). We adjusted for age, gender, psychiatric medication use, body mass index (BMI), and total caloric intake as covariates with bipolar disorder as the primary predictor. We found a significant path association from bipolar disorder to lower plasma LA levels (p = 0.03) and significant paths from plasma LA to PHQ9 (p = 0.05), LFQ (p = 0.01) and SF12-MH (p = 0.05) scores, such that lower plasma LA predicted worse outcomes. We found no significant paths from plasma EPA levels to any of the outcome measures. These findings suggest that plasma LA levels partially mediate the effect of bipolar disorder on self-reported measures of mental health and life functioning.

Topics: Adult; Bipolar Disorder; Cross-Sectional Studies; Eicosapentaenoic Acid; Female; Humans; Linoleic Acid; Longitudinal Studies; Male; Mental Health; Middle Aged; Psychiatric Status Rating Scales; Self Report; Surveys and Questionnaires

Polyunsaturated fatty acids (PUFA) profiles associate with risk for mood disorders. This poses the hypothesis of metabolic differences between patients and unaffected healthy controls that relate to the primary illness or are secondary to medication use or dietary intake. However, dietary manipulation or supplementation studies show equivocal results improving mental health outcomes. This study investigates dietary patterns and metabolic profiles relevant to PUFA metabolism, in bipolar I individuals compared to non-psychiatric controls. We collected seven-day diet records and performed metabolomic analysis of fasted plasma collected immediately after diet recording. Regression analyses adjusted for age, gender and energy intake found that bipolar individuals had significantly lower intake of selenium and PUFAs, including eicosapentaenoic acid (EPA) (n-3), docosahexaenoic acid (DHA) (n-3), arachidonic acid (AA) (n-6) and docosapentaenoic acid (DPA) (n-3/n-6 mix); and significantly increased intake of the saturated fats, eicosanoic and docosanoic acid. Regression analysis of metabolomic data derived from plasma samples, correcting for age, gender, BMI, psychiatric medication use and dietary PUFA intake, revealed that bipolar individuals had reduced 13S-HpODE, a major peroxidation product of the n-6, linoleic acid (LA), reduced eicosadienoic acid (EDA), an elongation product of LA; reduced prostaglandins G2, F2 alpha and E1, synthesized from n-6 PUFA; and reduced EPA. These observations remained significant or near significant after Bonferroni correction and are consistent with metabolic variances between bipolar and control individuals with regard to PUFA metabolism. These findings suggest that specific dietary interventions aimed towards correcting these metabolic disparities may impact health outcomes for individuals with bipolar disorder.

Topics: Adult; Arachidonic Acid; Bipolar Disorder; Diet Surveys; Dietary Fats; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; Humans; Linoleic Acid; Male; Middle Aged; Regression Analysis; Risk Factors; Selenium