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 baseline-endpoint 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.

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

Conflict of interest statement

R.K.M. has received research support from Martek Biosciences, Inc., Royal DSM Nutritional Products, LLC, Inflammation Research Foundation, Ortho-McNeil Janssen, AstraZeneca, Eli Lilly, NARSAD, and National Institutes of Health (NIH), and previously served on the scientific advisory board of the Inflammation Research Foundation. J.R.S. has received research support from Edgemont, Shire, Neuronetics, Otsuka, Allergan, and NIH, and received material support from and served as a consultant to Assurex/Genesight. He receives royalties from Springer Publishing and UpToDate and has received honoraria from CMEology and Current Psychiatry. M.P.D. receives research support from NIH, PCORI, Acadia, Allergan, Janssen, Johnson and Johnson, Lundbeck, Otsuka, Pfizer, and Sunovion. She is also a consultant, is on the advisory board, or has received honoraria for speaking for Alkermes, Allergan, Assurex, CMEology, Janssen, Johnson and Johnson, Lundbeck, Myriad, Neuronetics, Otsuka, Pfizer, Sunovion, and Supernus. The remaining authors do not have disclosures.

Figures

FIG. 1.

Diagram illustrating the flow of subject recruitment and attrition.

FIG. 2.

Changes in CDRS-R (after subtracting the 17-item base score) (A), YMRS (B), CGAS (C), and CGI-S (D) total scores for placebo and fish oil groups over the 12-week trial. Values are group mean ± 95% CI. CI, confidence interval; CDRS-R, Childhood Depression Rating Scale-Revised; YMRS, Young Mania Rating Scale; CGAS, Children's Global Assessment Scale; CGI-S, Clinical Global Impression-Severity. Color images are available online.

FIG. 3.

Baseline to endpoint changes in metabolite levels in the ACC (A), left (B), and right (C) VLPFC of patient treated with placebo or fish oil. Values are group mean baseline-endpoint change. *p = 0.024, **p = 0.0042 versus placebo. mI, myo-inositol; NAA, N-acetyl-aspartate; Cr, creatine; Cho, choline; Glu, glutamate; ACC, anterior cingulate cortex; VLPFC, ventrolateral prefrontal cortex. Color images are available online.