Volume 05 Issue 02 Oct 2012
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 In EPA & DHA Research
Quick Look...

The American Psychiatric Association recommends that all individuals eat fatty fish providing EPA and DHA omega-3s.  It recommends 1,000 mg of EPA and DHA per day for those with mood, impulse-control, or psychotic disorders. More (up to 9 grams per day) is recommended in those with mood disorders. Use of > 3 grams/day should be monitored by a physician7.


Update on Clinical Trials with Long-Chain Omega-3s and Depression 


Depression is a common mental health disorder whose incidence has been increasing in recent decades. It can be chronic or recurrent, and it has a significant impact on individuals, families, care-givers, communities, and the work force. The World Health Organization (WHO) reports that more than 150 million people suffer from depression1. It is the leading cause of disability worldwide and is predicted to be in the top three leading causes of burden of disease by 20302. In 2004, the annual cost of depression was an estimated Euro 118 billion, making it the most costly brain disorder in 28 European countries3.  

An association between low fish consumption and higher prevalence of major depression was first reported in 19984.  Since then, multiple studies have reported a link between low levels of long-chain omega-3 fatty acids and depression5,6.  However, clinical trials have failed to consistently corroborate the findings demonstrated in observational studies. The inconsistencies may be explained by several factors, including variations in study methodologies, doses and forms of supplements, length of intervention, impact of medications and other therapies, as well as the diagnosis and severity of depressive symptoms. Further, dietary and lifestyle habits vary greatly among individuals, and this impacts their existing blood levels of omega-3s.  


Nutrition status impacts brain function. EPA and DHA omega-3s are unique long-chain fatty acids that serve metabolic and structural roles involved in many brain processes, including nerve synapse, neurotransmitter transmission, inflammation, membrane structure and fluidity, and vascular and immune functions involved with the central nervous system7,8.

Several meta-analyses of randomized, double-blind, placebo-controlled trials using EPA and DHA omega-3s for depression and mood disorders have sought to clarify this relationship: 

  • When Lin and Su combined results of 10 systematically selected clinical trials and controlled for variables among the studies, they discovered a significant antidepressant effect of omega-3s in people with depression or bipolar disease9.  
  • When Martins analyzed 28 studies meeting systematic criteria, he observed that overall measures of depression were reduced with long-chain omega-3s and again, significant variations among the studies were evident.  Greater effects were seen in those with major versus mild to moderate depression, with therapeutic use versus prevention, and when omega-3s were used in addition to other therapies10.
  • In a review of 13 selected trials in people with depression or manic behavior, Kraguljac et al., concluded that omega-3 fatty acids are a potential treatment of depressive disorders11.
  • When Appleton, et al., assessed results from 29 research trials, they identified significant and beneficial effects from long-chain omega-3 supplementation in those with more severe-depressive symptoms. Again, study variations were noted12.
  • When Sublette, et al., reviewed 15 systematically selected trials in people with major depression disorder or suffering a major depressive episode in the context of bipolar disorder, they reported greater efficacy in individuals with major depressive disorder with supplements containing at least 60% EPA relative to DHA13. They did not see beneficial results from DHA only13.
  • Finally, Bloch and Hannestad analyzed 13 selected trials and while publication bias was present, they reported small but non-significant benefits of omega-3s in major depression8.  


There is keen interest in the potential role of long-chain omega-3s in mental health disorders. Over 30 clinical trials have been completed and more than 30 trials are currently underway (see clinicaltrials.gov). Although significant variability among studies exist and large trials are needed, human studies to-date demonstrate good safety parameters, greater benefit in those with moderate to severe depression, greater efficacy in supplements containing more EPA relative to DHA, and an overall contribution to health and wellness of those struggling with mood conditions.  

Suggested Citation

Vannice GK, Weatherhead G, Byelashov OA, Rice HB. Advances in EPA & DHA Research: Update on Clinical Trials with Long-Chain Omega-3s and Depression. Quarterly Journal of Significant Omega-3 Research;05(02):2012. 

  1. World Health Organization. Investing in mental health. 2003. Available online: http://www.who.int/mental_health/media/investing_mnh.pdf
  2. Woods SW. The economic burden of bipolar disease. J Clin Psychiatry 2000;61 Supp 13:38-41.
  3. Sobocki P, Jönsson B, Angst J, Rehnberg C. Cost of depression in Europe. J Ment Health Policy Econ 2006;9:87-98.
  4. Hibbeln JR. Fish consumption and major depression. Lancet 1998;351:1213.
  5. Lin PY, Huang SY, Su KP. A meta-analytic review of polyunsaturated fatty acid composition in patients with depression. Biol Psychiatry 2010;68:140-147.
  6. McNamara RK, Hahn CG, Jandacek R, et al. Selective deficits in the omega-3 fatty acid docosahexaenoic acid in the postmortem orbitofrontal cortex of patients with major depressive disorder. Biol Psychiatry 2007;62:17-24.
  7. Freeman MP, Hibbeln JR, Wisner KL, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006;67:1954-1967.
  8. Bloch MH, Hannestad J. Omega-3 fatty acids for the treatment of depression: systematic review and meta-analysis. Molecular Psychiatry 2001:1-11.
  9. Lin P-Y, Su K-P. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry 2007;68:1056-1061.
  10. Martins JG. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: evidence from a meta-analysis of randomized controlled trials. J Am Coll Nutrition 2009;28:525-542.
  11. Kraguljac NV, Montori VM, Pavuluri M, et al.  Efficacy of omega-3 fatty acids in mood disorders - a systematic review and metaanalysis. Psycholpharmacol 2009;42:39-54.
  12. Appleton KM, Rogers PJ, Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010;91:757-770.
  13. Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of Eicosapentaenoic acid (EPA in clinical trials in depression. J Clin Psychiatry 2011;72:1577-1584.
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