Researchers performed a randomized controlled trial of a high n-3, low n-6 polyunsaturated fatty acid diet in bipolar disorder.
“Mr Truth” is a 35-year-old African-American male with a 15-year history of bipolar I disorder without psychotic features. He has been clinically stable with no psychiatric hospitalizations in the past 5 years on a regimen of lithium 900 mg daily and hydroxyzine 25 mg TID as needed for anxiety. He works full-time as an insurance salesman. At an outpatient follow-up visit, Mr Truth asks about specific (potential) mental health benefits of fish-oil supplementation for his bipolar disorder. How would you, as his psychiatrist, respond?
Mood instability in bipolar disorder is associated with illness relapse and severity.1 There is a need for nonpharmacologic adjunctive treatments for this patient population. Dietary modifications, particularly n-3 and n-6 polyunsaturated fatty acids (PUFAs), represent one such potential target. PUFAs comprise over one-third of brain lipids and have been implicated in mood disorders.2 There is conflicting evidence regarding the efficacy of n-3 PUFA supplementation in patients with bipolar disorder. There is also evidence that some mood stabilizers may decrease metabolism of n-6 PUFAs.3 Therefore, Saunders et al4 investigated a combined intervention lowering dietary n-6 PUFAs (arachidonic acid [AA] and linoleic acid [LA]) and increased dietary n-3 PUFAs (eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) in patients with bipolar disorder.
The Current Study
They authors hypothesized that this dietary intervention would reduce day-to-day mood instability (as measured by ecological momentary assessment [EMA]) and general psychological distress in individuals with bipolar disorder. The primary clinical outcome was mood variability and general psychosocial distress and functioning. The primary biochemical outcome was change in n-6 AA, n-3 DHA, and their metabolites. The high n-3 EPA + DHA (1500 mg daily) and low n-6 LA (2% energy) diet (H3-L6) was compared to a control diet (CD) standardized to the usual distribution of PUFAs in America (n-3 EPA + DHA [150 mg daily] and low n-6 LA [7% energy]).
Subjects with bipolar disorder were included if they were over age 18, had current hypomanic or depressive symptoms, and were currently engaged in psychiatric treatment. Subjects were excluded if they were currently hospitalized, endorsed suicidal or homicidal ideation, had an active substance use or eating disorder, or had a history of specific food allergies (eg, fish, gluten, dairy). A diagnosis of bipolar disorder was confirmed by a clinician based on the Mini International Neuropsychiatric Interview. Participants were provided with research-programmed Android smartphones for the collection of daily self-report surveys.
After a 2-week baseline period, participants were randomized 1:1 to either H3-L6 or CD for 12 weeks, with in-person assessments every 2 weeks, including meeting with a dietician to review diet adherence and food records, receive dietary counseling, and pick up their food supplies. A mood and stress survey was randomly delivered twice daily in an EMA paradigm, where patients rated mood energy, speed of thoughts, impulsivity, anxiety, irritability, and pain on a 0 to 100 visual analog scale. Blood samples for biochemical analyses were collected at baseline and weeks 4, 8, 12, and 48. Group comparisons between the diet groups were made using either 2-sample t-tests or Wilcoxon rank-sum tests. Linear mixed-effects models were used to analyze continuous PUFA concentration outcomes. Data were analyzed using an intent-to-treat approach.
Eighty-two participants were randomized. The mean age was 43.5, and 83% were female. Self-reported dietary compliance was about 85% in each group. The H3-L6 diet group had significant reductions in variability of mood, energy, speed of thoughts, anxiety, and pain. By contrast, the CD group had significant reductions in the variability of energy and impulsivity. Mean n-6 LA levels were slightly reduced, and n-3 EPA and DHA levels increased over time in the H3-L6 group compared to the CD group. There were no changes in any other measured PUFAs. Dietary-associated adverse events were minimal.
The authors concluded that a high n-3, low n-6 PUFA diet was associated with significant reductions in variability of symptoms and modulation of blood PUFA levels in patients with bipolar disorder over 12 weeks. Dietary trials, particularly dietary intervention versus nutritional supplementation, are noted to be particularly challenging to conduct. Study strengths included the use of dietary-driven interventions delivered by dietitians and the use of EMA for data collection. Study limitations included the relatively small sample size and female predominance.
The Bottom Line
Increasing n-3 EPA and DHA and decreasing n-6 LA through dietary intervention improved day-to-day variability in mood symptoms in patients with bipolar disorder. Findings warrant replication in larger future trials.
Dr Miller is professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, Georgia. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric TimesTM. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.
1. Bauer M, Glenn T, Alda M, et al. Comparison of pre-episode and pre-remission states using mood ratings from patients with bipolar disorder. Pharmacopsychiatry. 2011;44 Suppl 1:S49-S53.
2. Liu JJ, Green P, John Mann J, et al. Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res. 2015;1597:220-246.
3. Saunders EF, Ramsden CE, Sherazy MS, et al. Reconsidering dietary polyunsaturated fatty acids in bipolar disorder: a translational picture. J Clin Psychiatry. 2016;77(10):e1342-e1347.
4. Saunders EFH, Mukherjee D, Myers T, et al. Adjunctive dietary intervention for bipolar disorder: a randomized, controlled, parallel-group, modified double-blinded trial of a high n-3 plus low n-6 diet. Bipolar Disord. 2022;24(2):171-184.