Adolescents with or at ultra-high risk for bipolar disorder exhibit erythrocyte docosahexaenoic acid and eicosapentaenoic acid deficits: a candidate prodromal risk biomarker

Abstract

Aim: Mood disorders are associated with low levels of the long-chain omega-3 (LCn-3) fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This study investigated LCn-3 fatty acid biostatus in youth with or at varying risk for developing mania to assess its utility as a prodromal risk biomarker.

Method: Erythrocyte fatty acid composition was determined in healthy adolescents (n = 28, HC), asymptomatic adolescents with a biological parent with bipolar I disorder (n = 30; 'high risk', HR), adolescents with a biological parent with bipolar I disorder and major depressive disorder, or depressive disorder not otherwise specified (n = 36; 'ultra-high risk', UHR), and first-episode adolescent bipolar manic patients (n = 35, BP).

Results: Group differences were observed for DHA (P ≤ 0.0001) and EPA (P = 0.03). Compared with HC, erythrocyte EPA + DHA ('omega-3 index') was significantly lower in BP (-24%, P ≤ 0.0001) and UHR (-19%, P = 0.0006) groups, and there was a trend in the HR group (-11%, P = 0.06). Compared with HC (61%), a greater percentage of HR (77%, P = 0.02), UHR (80%, P = 0.005) and BP (97%, P = 0.001) subjects exhibited EPA + DHA levels of ≤4.0%. Among all subjects (n = 130), EPA + DHA was inversely correlated with manic (r = -0.29, P = 0.0008) and depressive (r = -0.28, P = 0.003) symptom severity. The AA/EPA + DHA ratio was significantly greater in BP (+22%, P = 0.0002) and UHR (+16%, P = 0.001) groups.

Conclusions: Low EPA + DHA levels coincide with the initial onset of mania, and increasing risk for developing bipolar disorder is associated with graded erythrocyte EPA + DHA deficits. Low erythrocyte EPA + DHA biostatus may represent a promising prodromal risk biomarker warranting additional evaluation in future prospective studies.

Keywords: arachidonic acid (AA); eicosapentaenoic acid (EPA); mania; omega-3 index; ultra-high risk.

Figure 1

YMRS (A) and HDRS (B) total scores for healthy comparison subjects (HC, n=28), asymptomatic adolescents with a biological parent with bipolar I disorder (‘high-risk’, HR; n=31), adolescents with a biological parent with bipolar I disorder and MDD or depressive disorder-NOS (‘ultra high-risk’, UHR; n=36), and first-episode bipolar patients (BP, n=35). Values are group mean ± S.E.M. ***P≤0.0001 vs. HC, ^##P≤0.01, ^###P≤0.001 vs. HR, ⁺⁺P≤0.01, ⁺⁺⁺P≤0.001 vs. UHR.

Figure 2

Erythrocyte membrane EPA+DHA (omega-3 index)(A), arachidonic acid (AA)(B), and the AA/EPA+DHA ratio (C) in healthy comparison (HC), high-risk (HR), ultra high-risk (UHR) and first-episode bipolar (BP) groups. Fatty acids are expressed as weight percent of total fatty acids (mg fatty acid/100 mg fatty acids) or ratio. Values are group mean ± S.E.M. ***P≤0.0001 vs. HC, ^#P≤0.05, ^##P≤0.01 vs. HR.

Figure 3

Percentage of subjects in the healthy comparison (HC), high-risk (HR), ultra high-risk (UHR), and first-episode bipolar (BP) groups with an omega-3 index (EPA+DHA) of ≤4.0% (A) or a AA/EPA+DHA ratio ≤4.6 (median-split)(B). *P≤0.05, **P≤0.01, ***P≤0.0001 vs. HC, ^#P≤0.05, ^###P≤0.001 vs. HR, ⁺⁺⁺P≤0.001 vs. UHR (Chi-Square test).