title: Low unesterified:esterified eicosapentaenoic acid (EPA) plasma concentration ratio is associated with bipolar disorder episodes, and omega-3 plasma concentrations are altered by treatment.
abstract: OBJECTIVE
  Omega (n)-3 and n-6 polyunsaturated fatty acids (PUFAs) are molecular modulators of neurotransmission and inflammation. We hypothesized that plasma concentrations of n-3 PUFAs would be lower and those of n-6 PUFAs higher in subjects with bipolar disorder (BD) compared to healthy controls (HCs), and would correlate with symptom severity in subjects with BD, and that effective treatment would correlate with increased n-3 but lower n-6 PUFA levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids.
  
  
  METHODS
  This observational, parallel group study compared biomarkers between HCs (n = 31) and symptomatic subjects with BD (n = 27) when ill and after symptomatic recovery (follow-up). Plasma concentrations of five PUFAs [linoleic acid (LA), arachidonic acid (AA), alpha-linolenic acid (ALA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA)], two saturated fatty acids (palmitic acid and stearic acid) and two monounsaturated fatty acids (palmitoleic acid and oleic acid) were measured in esterified (E) and unesterified (UE) forms. Calculated ratios included UE:E for the five PUFAs, ratios of n-3 PUFAs (DHA:ALA, EPA:ALA and EPA:DHA), and the ratio of n-6:n-3 AA:EPA. Comparisons of plasma fatty acid levels and ratios between BD and HC groups were made with Student t-tests, and between the BD group at baseline and follow-up using paired t-tests. Comparison of categorical variables was performed using chi-square tests. Pearson's r was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis.
  
  
  RESULTS
  UE EPA was lower in subjects with BD than in HCs, with a large effect size (Cohen's d = 0.86, p < 0.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA concentration between the BD and HC groups after Bonferroni correction for 40 comparisons, at p < 0.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA concentration. Exploratory comparison showed lower UE:E EPA in the BD than the HC group (p < 0.0001). At follow-up in the BD group, UE, E DHA:ALA, and UE EPA:ALA were decreased (p < 0.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE:E EPA ratio, and that several plasma levels and ratios correlated with panic disorder and psychosis. Depressive severity was not correlated with any ratio. No plasma fatty acid level or ratio correlated with self-reported n-3 PUFA intake or use of medication by class.
  
  
  CONCLUSIONS
  A large effect size of reduced UE EPA, and a lower plasma UE:E concentration ratio of EPA in the symptomatic BD state may be important factors in vulnerability to a mood state. Altered n-3 PUFA ratios could indicate changes in PUFA metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n-3 and decrease n-6 dietary PUFA intake.
authors.affiliation: Department of Psychiatry, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.|University of Michigan Department of Psychiatry, Ann Arbor, MI, USA.|University of Michigan Depression Center, Ann Arbor, MI, USA.
authors.forename: Erika Fh
authors.initials: EF
authors.lastname: Saunders
authors.affiliation: Department of Psychiatry, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Aubrey
authors.initials: A
authors.lastname: Reider
authors.affiliation: Department of Psychiatry, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Gagan
authors.initials: G
authors.lastname: Singh
authors.affiliation: Department of Psychiatry, Penn State College of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, PA, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Gelenberg
authors.affiliation: Brain Physiology and Metabolism Section, Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Stanley I
authors.initials: SI
authors.lastname: Rapoport
mesh_terms: D000328:Adult; D000928:Antidepressive Agents / Q000494:pharmacology*; D018692:Antimanic Agents / Q000494:pharmacology*; D016718:Arachidonic Acid / Q000378:metabolism; D001526:Behavioral Symptoms / Q000097:blood / Q000188:drug therapy; D015415:Biomarkers / Q000097:blood; D001714:Bipolar Disorder / Q000097:blood / Q000188:drug therapy / Q000523:psychology; D015118:Eicosapentaenoic Acid / Q000378:metabolism / Q000494:pharmacology; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000097:blood*; D043371:Fatty Acids, Omega-6 / Q000097:blood*; D005260:Female; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013223:Statistics as Topic; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D000092864:Suicide Prevention
chemical_list: D000928:Antidepressive Agents; D018692:Antimanic Agents; D015415:Biomarkers; D005229:Fatty Acids, Monounsaturated; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; C008757:palmitoleic acid; D016718:Arachidonic Acid; D015118:Eicosapentaenoic Acid
keywords: bipolar disorder; eicosapentaenoic acid; inflammation; omega-3