An Omega-6 Fatty Acid May Reduce the Risk for Bipolar Disorder

A genetic propensity to higher circulating levels of lipids containing arachidonic acid, an omega-6 polyunsaturated fatty acid found in eggs, poultry, and seafood, has been found to be linked with a lower risk for bipolar disorder, according to a new study(opens in new tab/window) in Biological Psychiatry(opens in new tab/window), published by Elsevier. This new evidence paves the way for potential lifestyle or dietary interventions.

Bipolar disorder is a debilitating mood disorder characterized by recurring episodes of mania and depression. Although its etiology is still unclear, previous studies have shown that bipolar disease is highly heritable. The findings of this study indicate a link between bipolar disorder and altered metabolite levels, supporting the notion that circulating metabolites play an important etiological role in bipolar disease and other psychiatric disorders.

Lead investigator David Stacey, PhD, Australian Centre for Precision Health, University of South Australia; UniSA Clinical and Health Sciences; and South Australian Health and Medical Research Institute, Adelaide, Australia, explains, “Accumulating evidence indicates a role for metabolites in bipolar disorder and other psychiatric disorders. By identifying metabolites that play causal roles in bipolar disorder, we hoped to be able to highlight potential lifestyle or dietary interventions."

By applying Mendelian randomization, a powerful causal inference method, the researchers identified 33 out of 913 metabolites studied present in the blood that were associated with bipolar disorder, most of them lipids.

Researchers also found that a bipolar disorder risk gene cluster (FADS1/2/3), which encodes enzymes associated with lipid metabolism, mediated the association between bipolar disorder and the levels of arachidonic acid and other metabolites.

Commenting on the findings, John Krystal, MD, Editor of Biological Psychiatry, says, "Arachidonic acid is typically a widely present omega-6 fatty acid in the body and brain that contributes to the health of cell membranes. This study provides a fascinating step forward in the effort to develop blood biomarkers of bipolar disorder risk, particularly in those patients with bipolar disorder and risk gene variations in the FADS1/2/3 gene cluster.”

Dr. Stacey notes, "Intriguingly, we observed a pattern whereby a genetic propensity to higher levels of lipids containing an arachidonic acid fatty acid side chain was associated with a lower risk of bipolar disorder, while the inverse was true of lipids containing a linoleic acid side chain. Since arachidonic acid is synthesized from linoleic acid in the liver, this suggests arachidonic acid synthesizing pathways are important for bipolar disorder."

Given its presence in human milk, arachidonic acid is considered essential for infant brain development and is added to infant formula in many countries. Therefore, it may exert an effect on bipolar disorder risk by affecting neurodevelopmental pathways, which would be consistent with contemporary views of bipolar disorder as a neurodevelopmental disorder. Arachidonic acid can be sourced directly from meat and seafood products or synthesized from dietary linoleic acid (e.g., nuts, seeds, and oils).

Dr. Stacey concludes, "To our knowledge, ours is the first study to highlight a potential causal role between arachidonic acid and bipolar disorder. Preclinical studies and randomized controlled trials will be necessary to determine the preventive or therapeutic value of arachidonic acid supplements, perhaps with a particular focus on people with a compromised arachidonic acid synthesizing pathway or with poor natural dietary sources. Our findings also support potential avenues for precision health interventions focused on early life nutrition to ensure that infants and children are receiving enough arachidonic acid and other polyunsaturated fatty acids to support optimal brain development, which may also reduce the risk of bipolar disorder."

Notes for editors

The article is "A Metabolome-Wide Mendelian Randomization Study Identifies Dysregulated Arachidonic Acid Synthesis as a Potential Causal Risk Factor for Bipolar Disorder," by David Stacey, PhD, Beben Benyamin, PhD, S. Hong Lee, PhD, and Elina Hyppönen, PhD (https://doi.org/10.1016/j.biopsych.2024.02.1005(opens in new tab/window)). It appears online in Biological Psychiatry(opens in new tab/window), published by Elsevier.

The article is openly available at https://www.biologicalpsychiatryjournal.com/article/S0006-3223(24)01106-5/fulltext(opens in new tab/window).

Copies of this paper are also available to credentialed journalists upon request; please contact Rhiannon Bugno at [email protected](opens in new tab/window). Journalists wishing to interview the authors may contact David Stacey, PhD, at +61 8 8302 8339 or [email protected](opens in new tab/window).

The authors’ affiliations and disclosures of financial and conflicts of interests are available in the article.

John H. Krystal, MD, is Chairman of the Department of Psychiatry at the Yale University School of Medicine, Chief of Psychiatry at Yale-New Haven Hospital, and a research psychiatrist at the VA Connecticut Healthcare System. His disclosures of financial and conflicts of interests are available here(opens in new tab/window).

About Biological Psychiatry

Biological Psychiatry(opens in new tab/window) is the official journal of the Society of Biological Psychiatry(opens in new tab/window), whose purpose is to promote excellence in scientific research and education in fields that investigate the nature, causes, mechanisms, and treatments of disorders of thought, emotion, or behavior. In accord with this mission, this peer-reviewed, rapid-publication, international journal publishes both basic and clinical contributions from all disciplines and research areas relevant to the pathophysiology and treatment of major psychiatric disorders.

The journal publishes novel results of original research which represent an important new lead or significant impact on the field, particularly those addressing genetic and environmental risk factors, neural circuitry and neurochemistry, and important new therapeutic approaches. Reviews and commentaries that focus on topics of current research and interest are also encouraged.

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