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We hypothesized that plasma concentrations of n\u20103 PUFA<\/jats:styled-content>s would be lower and those of n\u20106 PUFA<\/jats:styled-content>s higher in subjects with bipolar disorder (BD<\/jats:styled-content>) compared to healthy controls (HC<\/jats:styled-content>s), and would correlate with symptom severity in subjects with BD<\/jats:styled-content>, and that effective treatment would correlate with increased n\u20103 but lower n\u20106 PUFA<\/jats:styled-content> levels. Additionally, we explored clinical correlations and group differences in plasma levels of saturated and monounsaturated fatty acids.<\/jats:p><\/jats:sec>Methods<\/jats:title>This observational, parallel group study compared biomarkers between HC<\/jats:styled-content>s (n\u00a0=\u00a031) and symptomatic subjects with BD<\/jats:styled-content> (n\u00a0=\u00a027) when ill and after symptomatic recovery (follow\u2010up). Plasma concentrations of five PUFA<\/jats:styled-content>s [linoleic acid (LA<\/jats:styled-content>), arachidonic acid (AA<\/jats:styled-content>), alpha\u2010linolenic acid (ALA<\/jats:styled-content>), docosahexaenoic acid (DHA<\/jats:styled-content>), and eicosapentaenoic acid (EPA<\/jats:styled-content>)], 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<\/jats:styled-content>) forms. Calculated ratios included UE<\/jats:styled-content>:E for the five PUFA<\/jats:styled-content>s, ratios of n\u20103 PUFA<\/jats:styled-content>s (DHA<\/jats:styled-content>:ALA<\/jats:styled-content>, EPA<\/jats:styled-content>:ALA<\/jats:styled-content> and EPA<\/jats:styled-content>:DHA<\/jats:styled-content>), and the ratio of n\u20106:n\u20103 AA<\/jats:styled-content>:EPA<\/jats:styled-content>. Comparisons of plasma fatty acid levels and ratios between BD<\/jats:styled-content> and HC<\/jats:styled-content> groups were made with Student t<\/jats:italic>\u2010tests, and between the BD<\/jats:styled-content> group at baseline and follow\u2010up using paired t<\/jats:italic>\u2010tests. Comparison of categorical variables was performed using chi\u2010square tests. Pearson's r<\/jats:italic> was used for bivariate correlations with clinical variables, including depressive and manic symptoms, current panic attacks, and psychosis.<\/jats:p><\/jats:sec>Results<\/jats:title>UE EPA<\/jats:styled-content> was lower in subjects with BD<\/jats:styled-content> than in HC<\/jats:styled-content>s, with a large effect size (Cohen's d<\/jats:italic>\u00a0=\u00a00.86, p\u00a0<\u00a00.002); however, it was not statistically significant after correction for multiple comparisons. No statistically significant difference was seen in any plasma PUFA<\/jats:styled-content> concentration between the BD<\/jats:styled-content> and HC<\/jats:styled-content> groups after Bonferroni correction for 40 comparisons, at p\u00a0<\u00a00.001. Neither depressive severity nor mania severity was correlated significantly with any PUFA<\/jats:styled-content> concentration. Exploratory comparison showed lower UE<\/jats:styled-content>:E EPA<\/jats:styled-content> in the BD<\/jats:styled-content> than the HC<\/jats:styled-content> group (p\u00a0<\u00a00.0001). At follow\u2010up in the BD<\/jats:styled-content> group, UE<\/jats:styled-content>, E DHA<\/jats:styled-content>:ALA<\/jats:styled-content>, and UE EPA<\/jats:styled-content>:ALA<\/jats:styled-content> were decreased (p\u00a0<\u00a00.002). Exploratory correlations of clinical variables revealed that mania severity and suicidality were positively correlated with UE<\/jats:styled-content>:E EPA<\/jats:styled-content> 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\u2010reported n\u20103 PUFA<\/jats:styled-content> intake or use of medication by class.<\/jats:p><\/jats:sec>Conclusions<\/jats:title>A large effect size of reduced UE EPA<\/jats:styled-content>, and a lower plasma UE<\/jats:styled-content>:E concentration ratio of EPA<\/jats:styled-content> in the symptomatic BD<\/jats:styled-content> state may be important factors in vulnerability to a mood state. Altered n\u20103 PUFA<\/jats:styled-content> ratios could indicate changes in PUFA<\/jats:styled-content> metabolism concurrent with symptom improvement. Our findings are consistent with preclinical and postmortem data and suggest testing interventions that increase n\u20103 and decrease n\u20106 dietary PUFA<\/jats:styled-content> intake.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bdi.12337","type":"journal-article","created":{"date-parts":[[2015,10,1]],"date-time":"2015-10-01T07:17:01Z","timestamp":1443683821000},"page":"729-742","source":"Crossref","is-referenced-by-count":32,"title":["Low unesterified:esterified eicosapentaenoic acid (EPA<\/scp>) plasma concentration ratio is associated with bipolar disorder episodes, and omega\u20103 plasma concentrations are altered by treatment"],"prefix":"10.1111","volume":"17","author":[{"given":"Erika FH","family":"Saunders","sequence":"first","affiliation":[{"name":"Department of Psychiatry Penn State College of Medicine Penn State Milton S. 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