Fish oil supplementation alters emotion-generated corticolimbic functional connectivity in depressed adolescents at high-risk for bipolar I disorder: A 12-week placebo-controlled fMRI trial

Abstract

Objective: To evaluate the effects of fish oil (FO), a source of the omega-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), on emotion-generated corticolimbic functional connectivity in depressed youth at high risk for developing bipolar I disorder.

Methods: Thirty-nine antidepressant-free youth with a current depressive disorder diagnosis and a biological parent with bipolar I disorder were randomized to 12-week double-blind treatment with FO or placebo. At baseline and endpoint, fMRI (4 Tesla) scans were obtained while performing a continuous performance task with emotional and neutral distractors (CPT-END). Seed-to-voxel functional connectivity analyses were performed using bilateral orbitofrontal cortex (OFC) and amygdala (AMY) seeds. Measures of depression, mania, global symptom severity, and erythrocyte fatty acids were obtained.

Results: Erythrocyte EPA+DHA composition increased significantly in the FO group (+47%, p ≤ 0.0001) but not in the placebo group (-10%, p = 0.11). Significant group by time interactions were found for functional connectivity between the left OFC and the left superior temporal gyrus (STG) and between the right AMY and right inferior temporal gyrus (ITG). OFC-STG connectivity increased in the FO group (p = 0.0001) and decreased in the placebo group (p = 0.0019), and AMY-ITG connectivity decreased in the FO group (p = 0.0014) and increased in the placebo group (p < 0.0001). In the FO group, but not placebo group, the decrease in AMY-ITG functional connectivity correlated with decreases in Childhood Depression Rating Scale-Revised and Clinical Global Impression-Severity Scale scores.

Conclusions: In depressed high-risk youth FO supplementation alters emotion-generated corticolimbic functional connectivity which correlates with changes in symptom severity ratings.

Keywords: adolescent; bipolar disorder; familiar risk; high-risk; omega-3 polyunsaturated fatty acids.

© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Figures

Figure 1.

Erythrocyte EPA+DHA (A) and arachidonic acid (AA)(B) composition, and the AA/(EPA+DHA) ratio (C), at baseline and following 12-week supplementation with FO or placebo. Data are expressed as group mean fatty acid composition (mg fatty acid/100 mg fatty acids) or ratio ± S.E.M. **P≤0.001, ***P≤0.0001 vs. Baseline, ###P≤0.0001 vs. Placebo week 12.

Figure 2.

CDRS-R (A) and CGI-S (B) total scores at baseline and following 12-week supplementation with FO or placebo. Data are expressed as group mean ± S.E.M. ***P≤0.0001 vs. Baseline, #P≤0.01 vs. Placebo week 12.

Figure 3.

Significant group by time interactions for change in functional connectivity between the left OFC (seed, red) and the left superior temporal gyrus (STG) (cluster size = 563 voxels, pA), and between the right AMY (seed, red) and right inferior temporal gyrus (ITG) (cluster size = 573 voxels, p<0.001, FEW corrected)(B). Significant bidirectional baseline-endpoint changes in left OFC-STG (C) and right AMY-ITG (D) functional connectivity within both the placebo and FO groups. **P≤0.001, ***P≤0.0001 within group baseline vs. endpoint.

Figure 4.

Correlations between baseline-endpoint change in AMY-ITG functional connectivity and baseline-endpoint change in CDRS-R (A) and CGI-S (B) total scores in placebo and FO groups. Within group correlations and group interaction terms are presented.