Randomized, placebo-controlled trial of flax oil in pediatric bipolar disorder.

This clinical trial evaluated whether supplementation with flax oil, containing the omega-3 fatty acid alpha-linolenic acid (a-LNA), safely reduced symptom severity in youth with bipolar disorder. Children and adolescents aged 6 to17 years with symptomatic bipolar I or bipolar II disorder (n = 51), manic, hypomanic, mixed, or depressed, were randomized to either flax oil capsules containing 550 mg a-LNA per 1 gram or an olive oil placebo adjunctively or as monotherapy. Doses were titrated to 12 capsules per day as tolerated over 16 weeks. Primary outcomes included changes in the Young Mania Rating Scale, Child Depression Rating Scale-Revised, and Clinical Global Impressions-Bipolar ratings using Kaplan-Meier survival analyses. There were no significant differences in primary outcome measures when compared by treatment assignment. However, clinician rated Global Symptom Severity was negatively correlated with final serum omega-3 fatty acid compositions: % a-LNA (r = 0.45, p < 0.007), % eicosapentaenoic acid (EPA) (r = 0.47, p < 0.005); and positively correlated with final arachidonic acid (AA) (r = 0.36, p < 0.05) and docosapentaenoic acid (DPA) n-6 (r = 0.48, p < 0.004). The mean duration of treatment for a-LNA was 11.8 weeks versus 8 weeks for placebo; however, the longer treatment duration for a-LNA was not significant after controlling for baseline variables. Subjects discontinued the study for continued depressive symptoms.Studies of essential fatty acid supplementation are feasible and well tolerated in the pediatric population. Although flax oil may decrease severity of illness in children and adolescents with bipolar disorder who have meaningful increases in serum EPA percent levels and ⁄ or decreased AA and DPA n-6 levels, individual variations in conversion of a-LNA to EPA and docosahexaenoic acid as well as dosing burden favor the use of fish oil both for clinical trials and clinical practice. Additionally, future research should focus on adherence and analysis of outcome based on changes in essential fatty acid tissue compositions, as opposed to group randomization alone. (Author's Abstract)Omega-3 fatty acids may help stabilize mood by multiple mechanisms, including suppression of neuronal signaling, second messenger generation, calcium channel and protein kinase C activity and proinflammatory cytokines. Omega-3 fatty acids represent an appealing option for treatment in the younger bipolar population as they are likely to be better tolerated and cost less compared with conventional mood-stabilizing agents. In addition, they have appeal to parents and adolescents due to their perception as a natural substance and relative lack of systemic side effects. Restoration of adequate long-chain omega-3 tissue status may be helpful in mood stabilization. In this study,  flax oil did not appear to have any major effect on symptom reduction, although patients in both arms showed small but significant improvement in symptoms and functioning over time. The authors attribute these effects to a low conversion of a-LNA to EPA. Flax oil was well tolerated up to a dose of 12 grams per day in children as young as 6 years of age. This study provides tolerance data that may be useful to investigators in other areas of medicine examining flax oil in the pediatric population. Further research is necessary with an extended follow-up period to evaluate long-term risks and clinical benefits of flax oil usage. Also many of the secondary analyses were based on small numbers of cases and flax oil will have different efficacy within certain subgroups. The present study, although one of the larger RCTs of flax oil to date, is too small to provide more than exploratory analyses with regard to subgroups.  A third limitation is that participants in the trial were predominantly white and middle class. This is important to consider when generalizing these findings to other settings, not only because of differences or similarities in culture, but also because genetic polymorphisms could potentially result in varying efficacy for flax oil augmentation. The effect on mood symptoms for those who are able to respond, may be subtle and not detectable within 16 weeks.  The authors conclude that the result show highly preliminary, possible evidence of improvement in CGI of illness and mania in children and adolescents with bipolar I or bipolar II disorder taking flax oil at the full dose of 10 to 12 capsules a day for subjects who demonstrated an increase in EPA.  The authors further stated that combined EPA and DHA is therefore preferable as conversion rate limitations of a-LNA to EPA are not present and a lower overall dose with fewer capsules is recommended. (Editor's Comments)