Effects of Fish Oil Monotherapy on Depression and Prefrontal Neurochemistry in Adolescents at High Risk for Bipolar I Disorder: A 12-Week Placebo-Controlled Proton Magnetic Resonance Spectroscopy Trial

Abstract

Objectives: To evaluate the clinical and neurochemical effects of 12-week fish oil, a source of omega-3 polyunsaturated fatty acids (n-3 PUFAs), in depressed adolescents with a family history of bipolar I disorder. Methods: Adolescents with a current Diagnostic and Statistical Manual of Mental Disorders, 4th edition, Text Revision diagnosis of Major Depressive Disorder or Depressive Disorder not otherwise specified, a Childhood Depression Rating Scale-Revised (CDRS-R) Version raw score of ‡40, and at least one biological parent with bipolar I disorder were randomized to double-blind treatment with fish oil (2100 mg/day) or placebo for 12 weeks. The primary outcome measure was change in CDRS-R total score, and secondary outcomes measures were change in manic symptoms (Young Mania Rating Scale), global symptom and functioning measures (Clinical Global Impression-Severity [CGI-S] /CGI Improvement [CGI-I], Children's Global Assessment Scale, and Child Behavior Checklist), safety and laboratory measures, and anterior cingulate cortex (ACC) and bilateral ventrolateral prefrontal cortex neurometabolite concentrations using proton magnetic resonance spectroscopy at 4 T. Results: Fifty-six patients were randomized, and 42 completed the 12-week trial (placebo: n = 21; fish oil, n = 21). Subjects randomized to fish oil, but not placebo, exhibited a significant baseline to endpoint increase in erythrocyte n-3 PUFAs. Reductions in CDRS-R scores did not differ between treatment groups (p = 0.15), and similar remission (p = 0.58) and response (p = 0.77) rates were observed. Fish oil produced a significantly greater decrease in CGI-S (p = 0.0042) and CGI-I (p = 0.036) scores compared with placebo. Baseline to endpoint change in ACC creatine (p = 0.004) and ACC choline (Cho) (p = 0.024) differed significantly between groups. Baseline ACC Cho levels were inversely correlated with baseline and baseline to endpoint change in CDRS-R scores, and baseline to endpoint change in ACC Cho correlated with baselineendpoint change in CDRS-R scores and n-3 PUFA. There were no group differences in safety and tolerability ratings or laboratory measures. Conclusions: Fish oil monotherapy was not superior to placebo for reducing depressive symptoms in high-risk youth as assessed by the CDRS-R, but was safe and well tolerated and superior to placebo on clinician ratings of global symptom improvement. Associations among ACC Cho levels, depression symptom severity, and n-3 PUFA warrant additional investigation.

Importance of EPA and DHA Blood Levels in Brain Structure and Function

“…Another intervention trial in 60 depressed adolescents saw significant improvement, however [ 88 ]. Similar, but less pronounced, results were seen in another trial with 56 participants [ 89 ]. These positive trials question the overall neutral result of an earlier meta-analysis of four trials in a total of 153 participants [ 90 ].…”

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

“…For example, a preliminary resting‐state MRI study found that feeding a diet enriched with saturated fatty acids, but not a diet enriched with monounsaturated fatty acids, for 12 weeks decreased hippocampal and inferior parietal cortex activity in healthy human subjects 72 . Although supplementation with olive oil did not significantly alter any erythrocyte fatty acid, including saturated and monosaturated fatty acids, 50 the direction of the changes in EPA+DHA and the AA/(EPA+DHA) ratio were opposite to those observed in the FO group. The present findings, therefore, provide additional evidence that dietary enrichment with saturated and monounsaturated fatty acids may significantly alter emotional‐generated corticolimbic functional connectivity, and that the pattern of change is opposite to that produced by FO supplementation.…”

“…Efficacy and safety results from this trial have been reported previously. 50 This study was approved by the Institutional Review Board of University of Cincinnati and was registered at clinicaltrials.gov with identifier NCT00917501. The data that support the findings of this study are available from the corresponding author upon reasonable request.…”

“…Diagnostic instruments were administered by a trained psychiatrist or qualified clinician with established diagnostic reliability (κ>0.9). Inclusion and exclusion criteria are detailed in the parent study 50 . Additionally, subjects were excluded by left‐hand dominance or a contraindication to MRI scans.…”

“…The present study investigated the effects of 12-week FO supplementation on corticolimbic functional connectivity in adolescents at elevated risk for mood dysregulation and progression, that is, they have depressive symptoms and a biological parent with bipolar I disorder, in the context of a randomized placebo-controlled treatment trial. 50 fMRI scans were acquired while patients performed a continuous performance task with emotional and neutral distractors (CPT-END) which engages prefrontal and limbic brain regions. 51 Based on the evidence reviewed above, we selected the bilateral OFC (BA 11/47) and AMY as seed regions and performed seed-to-voxel-based functional connectivity analyses.…”