Omega-3 Fatty Acids in Major Depressive Disorder

Patients with major depressive disorder have high rates of cardiovascular disease and other medical comorbidity. Omega-3 fatty acids, particularly those found in fish and seafood, have cardiovascular health benefits and may play an adjunctive role in the treatment of mood disorders. However, existing studies on omega-3 fatty acids in depression have limitations such as small sample sizes and a wide variance in study design, and results regarding efficacy are mixed. The preponderance of data from placebo-controlled treatment studies suggests that omega-3 fatty acids are a reasonable augmentation strategy for the treatment of major depressive disorder. More research is necessary before omega-3 supplements can be recommended as monotherapy for the treatment of depression. For many individuals with major depressive disorder, augmentation with omega-3 fatty acids should be considered, as general health benefits are well established and adjunctive use is low risk.

(J Clin Psychiatry 2009;70[suppl 5]:7–11)

From the Center for Women’s Mental Health, Massachusetts General Hospital, Boston.

This article is derived from the planning teleconference series “The Use of Complementary and Alternative Medicines to Achieve Remission in Major Depressive Disorder,” which was held in May 2009 and supported by an educational grant from Pamlab, LLC.

During the past 3 years, Dr Freeman has received research funding from Forest, GlaxoSmithKline, Eli Lilly, and the US Food and Drug Administration, and has received CME/honorarium from KV Pharmaceuticals, AstraZeneca, Forest (APA Industry-Supported Symposium at annual meeting), DSM Nutritionals (for medical editing), Consulting-Reliant, Ther-Rx, and Pamlab.

Corresponding author: Marlene P. Freeman, MD, Massachusetts General Hospital, Simches Research Building, Floor 2, 185 Cambridge St, Boston, MA 02114 (mfreeman@partners.org).

Omega-3 fatty acids are essential fatty acids, meaning that they are not manufactured by the body and must be taken in as part of the diet. Omega-3 fatty acids are long-chain, polyunsaturated fatty acids, which refers to their multiple double bonds (Figure 1).

Figure 1

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Omega-3 fatty acids compete with other essential fatty acids in enzymatic metabolism; therefore, determining the optimal amount of omega-3 fatty acid intake requires consideration of the intake of other fats in the diet.1 In other words, the absolute amount of omega-3 fatty acids may not be as crucial as the ratio of omega-3 fatty acids to other fatty acids in the diet. Omega-3 fatty acids tend to be low in the typical American diet, while other fatty acids, such as omega-6 fatty acids—another type of essential fatty acid including linoleic acid and arachidonic acid—are overrepresented. Linoleic acid is the most common omega-6 fatty acid in the diet and is derived from a variety of sources including sunflower, safflower, cottonseed, and corn oils. Americans typically take in more than enough omega-6 fatty acids but need to consume more omega-3 fatty acids for optimal health.

For medical benefits, the best-studied omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the most efficient sources of which are marine sources (Table 1). Linolenic acid, the omega-3 fatty acid from plant sources, requires more enzymatic steps to be used by the body than EPA and has not received adequate study in psychiatry. Most of the health benefits that have been demonstrated with omega-3 fatty acids are specifically associated with EPA and DHA. Although DHA is the main omega-3 fatty acid found in the brain, consumption of a combination of EPA and DHA, or EPA alone, may be the most beneficial strategy for the treatment of depression based on available data.2

Table 1

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Medical Benefits and Recommendations

Omega-3 fatty acids are known to have a variety of medical benefits, particularly in the area of cardiovascular health. Experts at the American Heart Association (AHA) have reviewed the cardiovascular benefits of omega-3 fatty acids and made treatment recommendations. They emphasized that omega-3 fatty acids decrease risk for arrhythmias and thrombosis, decrease triglycerides, decrease atherosclerosis, improve endothelial function, may lower blood pressure, and also reduce inflammatory responses.1

The AHA recommends that adults eat fish at least twice per week and that patients with coronary heart disease consume 1 g of EPA and DHA combined per day.3 The AHA recommendations suggest that omega-3 supplementation at 2 to 4 g/d may be useful for patients with hypertriglyceridemia, although consumption of>3 g/d should be monitored by a physician because, at very high doses, omega-3 fatty acids appear to have an anticoagulant effect. While there have been no adverse cases of bleeding reported with omega-3 supplementation, precautionary monitoring is recommended due to the theoretical risk.

Fish consumption is an efficient way to increase omega-3 fatty acid intake, but concerns about the mercury levels in seafood may dissuade some people from eating fish, even though not all fish are associated with high levels of mercury. If mercury is a concern, people should avoid tilefish, swordfish, shark, and king mackerel, especially children and pregnant women.1,4 Supplementation with fish oil capsules is also an option for individuals concerned about mercury intake; the over-the-counter capsules tested by Foran et al5 contained insignificant levels of mercury.

Omega-3 Fatty Acids in Psychiatry

Following the precedent set by the AHA, the Omega-3 Fatty Acids Subcommittee of the American Psychiatric Association (APA) examined the evidence to make specific treatment recommendations for the use of omega-3 fatty acids in individuals with psychiatric disorders.2 In fact, the AHA guidelines3 are particularly relevant to individuals with psychiatric disorders owing to high rates of comorbidity between psychiatric disorders and cardiovascular disease. Individuals with major depressive disorder (MDD) and other psychiatric conditions are more likely to smoke, are more likely to be obese, and are less likely to exercise than the general population.6 Additionally, many commonly used psychotropics have metabolic effects that increase the cardiovascular risk for patients.

For Clinical Use

  • Recommend that patients with depressive disorders eat fish at least twice a week.
  • Consider omega-3 supplementation via fish oil capsules as an option for patients concerned about mercury consumption, and educate patients about which types of fish provide the most benefits and least risk.
  • Consider omega-3 fatty acids as a possible adjunctive treatment to standard antidepressant pharmacotherapy.

With these concerns in mind, the APA subcommittee recommended that adults consume fish at least 2 times a week, per the AHA guidelines.2 Those with mood, impulse control, or psychotic disorders should consume at least 1 g/d of EPA and DHA. Supplements may be particularly useful in patients with mood disorders in a dose that provides EPA or a combination of EPA and DHA in a range of 1 to 9 g/d, which has been the range studied specifically for MDD and bipolar depression. Many of the studies that have demonstrated benefit have used the lower end of that range; 1 to 3 g/d of EPA or a combination of EPA and DHA appears to be a promising dose for the adjunctive treatment of MDD.

Several different mechanisms of action by which omega-3 fatty acids may have efficacy in treating psychiatric conditions have been suggested. Potential mechanisms of action include increased serotonergic and dopaminergic neurotransmission7–9 and alteration of protein phosphorylation and protein kinases.10 Omega-3 fatty acids also appear to decrease phosphatidylinositol-associated second messenger activity,11 exert action by vagal mechanisms,12 and have neuroprotective qualities.13,14 Omega-3 fatty acids have also been demonstrated to regulate gene expression,15 increase membrane fluidity,16 and impact the immune system and decrease inflammatory responses.17

Efficacy in Depression

Epidemiologic and treatment evidence suggests that omega-3 fatty acids may play a role in the prevention and amelioration of mood disorders, particularly depressive disorders. For example, cross-national analyses have suggested that higher per capita fish and seafood consumption is associated with lower prevalence rates of MDD,18–20 postpartum depression,21 and bipolar disorder.22 Meta-analyses2,23,24 of omega-3 fatty acid treatment trials for depression have consistently demonstrated the benefit of omega-3 fatty acids over placebo, but results have been heterogeneous across studies (Table 2). Studies have varied in specific omega-3 fatty acids used, duration of study, utilization of omega-3 fatty acids as adjunctive therapy or as monotherapy, and size of dose.

Table 2

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Of the studies that have demonstrated a positive antidepressant result for omega-3 fatty acids compared with placebo, most have used either EPA or a combination of EPA and DHA with EPA in a higher dose.2 Research comparing EPA with DHA is underway, but sufficient data for assessing differences in treatment response between these 2 types of omega-3 fatty acids are not currently available.

Efficacious, safe nonpharmacologic treatment options are ideal for women who are pregnant or breastfeeding. As such, omega-3 fatty acids have been of particular interest in the area of perinatal depression, especially considering that omega-3 fatty acids may assist optimal neurodevelopment in utero and in infancy.4,25 US Food and Drug Administration warnings about mercury in fish, however, are often misinterpreted as meaning that pregnant women should avoid fish altogether.26 Physicians need to educate pregnant patients about the benefits of omega-3 fatty acids, about which fish to avoid because of mercury risk, and about which sources of omega-3 fatty acids are safe.

Double-blind, placebo-controlled studies27–29 of omega-3 fatty acids in the treatment of perinatal depression have had mixed findings regarding efficacy (Table 3). Two of 3 studies did not demonstrate a benefit over placebo as a monotherapy. One small controlled study27 demonstrated a significant treatment response for omega-3 fatty acids compared with placebo in the treatment of depression during pregnancy. However, all 3 of these studies for perinatal depression were small.27–29 Omega-3 fatty acids have demonstrated neurodevelopmental benefits for infants after in utero exposure and have few contraindications. They are well tolerated in perinatal women, with mild and transient adverse events occurring no more often than with placebo.30 However, more research is needed before omega-3 fatty acid supplementation can be recommended or invalidated as an effective monotherapy treatment for perinatal depression.

Table 3

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Omega-3 fatty acids have been evaluated for treatment efficacy in bipolar depression, and 2 of 3 placebo-controlled, double-blind trials found a benefit for omega-3 fatty acids versus placebo.2 As is the case with omega-3 studies evaluating efficacy in major depression or perinatal depression, the study design and results for omega-3 supplementation in bipolar depression have been highly heterogeneous and more research is needed in this area. Importantly, all of the trials in bipolar disorder have assessed omega-3 fatty acids as adjunctive therapy, with patients continuing to take mood stabilizers and other medications.

Conclusion

The heterogeneous study designs and outcomes from the available clinical research on omega-3 fatty acids and depression complicate interpretation of the literature. Sample sizes in most studies have been small, and omega-3 fatty acids have most often been studied as an adjunctive treatment to standard antidepressants, which makes the recommendation of omega-3 fatty acids as monotherapy difficult.

The preponderance of data supports a role for omega-3 fatty acids as adjunctive treatment in MDD, but appropriate dosage levels and effective omega-3 components or ratios of components—EPA alone, EPA and DHA, or DHA alone—need to be clearly established. More research is needed to elucidate the role of omega-3 fatty acids in MDD.

Food supplements such as fish oil capsules are not regulated with the same vigilance as pharmaceuticals, so assessing safety and quality can be problematic. Supplements such as omega-3 fatty acids are often not covered by insurance. However, because patients with mood disorders have high rates of medical comorbidity, including metabolic syndrome and cardiovascular disease, they would potentially benefit from omega-3 supplementation despite the underwhelming evidence for omega-3 fatty acids as effective depression monotherapy treatment. Patients can be encouraged to consume safe fish and seafood for general health benefits.

Drug name: methylphenidate (Ritalin, Concerta, and others).

Disclosure of off-label usage: The author has determined that, to the best of her knowledge, no investigational information about pharmaceutical agents that is outside US Food and Drug Administration−approved labeling has been presented in this article.

References

1. Kris-Etherton PM, Harris WS. Appel LJ for the AHA Nutrition Committee. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Arterioscler Thromb Vasc Biol. 2003;23(2):e20–e30 [Published correction appears in Arterioscler Thromb Vasc Biol. 2003;23(2):e31]. PubMed doi:10.1161/01.ATV.0000038493.65177.94

2. 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(12):1954–1967. PubMed

3. Kris-Etherton PM, Harris WS. Appel LJ for the AHA Nutrition Committee. Omega-3 fatty acids and cardiovascular disease: new recommendations from the American Heart Association. Arterioscler Thromb Vasc Biol. 2003;23(2):151–152. PubMed doi:10.1161/01.ATV.0000057393.97337.AE

4. Oken E, Radesky JS, Wright RO, et al. Maternal fish intake during pregnancy, blood mercury levels, and child cognition at age 3 years in a US cohort. Am J Epidemiol. 2008;167(10):1171–1181. PubMed doi:10.1093/aje/kwn034

5. Foran SE, Flood JG, Lewandrowski KB. Measurement of mercury levels in concentrated over-the-counter fish oil preparations: is fish oil healthier than fish? Arch Pathol Lab Med. 2003;127(12):1603–1605. PubMed

6. Dickerson FB, Brown CH, Daimit GL, et al. Health status of individuals with serious mental illness. Schizophr Bull. 2006;32(3):584–589 [Published correction appears in Schizophr Bull. 2007;33(5):1257]. PubMed doi:10.1093/schbul/sbj048

7. Yao JK, Magan S, Sonel AF, et al. Effects of omega-3 fatty acid on platelet serotonin responsivity in patients with schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 2004;71(3):171–176. PubMed doi:10.1016/j.plefa.2004.03.011

8. Kodas E, Galineau L, Bodard S, et al. Serotoninergic neurotransmission is affected by n-3 polyunsaturated fatty acids in the rat. J Neurochem. 2004;89(3):695–702. PubMed doi:10.1111/j.1471-4159.2004.02401.x

9. Chalon S. Omega-3 fatty acids and monoamine neurotransmission. Prostaglandins Leukot Essent Fatty Acids. 2006;75(4–5):259–269. PubMed doi:10.1016/j.plefa.2006.07.005

10. Mirnikjoo B, Brown SE, Kim HFS, et al. Protein kinase inhibition by omega-3 fatty acids. J Biol Chem. 2001;276(14):10888–10896. PubMed doi:10.1074/jbc.M008150200

11. Engler MB. Vascular effects of omega-3 fatty acids: possible therapeutic mechanisms in cardiovascular disease. J Cardiovasc Nurs. 1994;8(3):53–67. PubMed

12. Mozaffarian D, Stein PK, Prineas RJ, et al. Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. Circulation. 2008;117(9):1130–1137. PubMed doi:10.1161/CIRCULATIONAHA.107.732826

13. Calderon F, Kim HY. Docosahexaenoic acid promotes neurite growth in hippocampal neurons. J Neurochem. 2004;90(4):979–988. PubMed doi:10.1111/j.1471-4159.2004.02520.x

14. Wainwright PE. Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc Nutr Soc. 2002;61(1):61–69. PubMed doi:10.1079/PNS2001130

15. Kitajka K, Puskas LG, Zvara A, et al. The role of n-3 polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci U S A. 2002;99(5):2619–2624. PubMed doi:10.1073/pnas.042698699

16. Kinsella JE, Lokesh B, Stone RA. Dietary n-3 polyunsaturated fatty acids and amelioration of cardiovascular disease: possible mechanisms. Am J Clin Nutr. 1990;52(1):1–28. PubMed

17. Logan AC, Katzman M. Major depressive disorder: probiotics may be an adjuvant therapy. Med Hypotheses. 2005;64(3):533–538. PubMed doi:10.1016/j.mehy.2004.08.019

18. Hibbeln JR. Fish consumption and major depression. Lancet. 1998;351(9110):1213. PubMed doi:10.1016/S0140-6736(05)79168-6

19. Golding J, Steer C, Emmett P, et al. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish. Epidemiology. 2009;20(4):598–603. PubMed doi:10.1097/EDE.0b013e31819d6a57

20. Tanskanen A, Hibbeln JR, Tuomilehto J, et al. Fish consumption and depressive symptoms in the general population in Finland. Psychiatr Serv. 2001;52(4):529–531. PubMed doi:10.1176/appi.ps.52.4.529

21. Hibbeln JR. Seafood consumption, the DHA content of mothers’ milk and prevalence rates of postpartum depression: a cross-national, ecological analysis. J Affect Disord. 2002;69(1–3):15–29. PubMed doi:10.1016/S0165-0327(01)00374-3

22. Noaghiul S, Hibbeln JR. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am J Psychiatry. 2003;160(12):2222–2227. PubMed doi:10.1176/appi.ajp.160.12.2222

23. Parker G, Gibson NA, Brotchie H, et al. Omega-3 fatty acids and mood disorders. Am J Psychiatry. 2006;163(6):969–978. PubMed doi:10.1176/appi.ajp.163.6.969

24. Lin PY, Su KP. A meta-analytic review of double-blind, placebo-controlled trials of antidepressant efficacy of omega-3 fatty acids. J Clin Psychiatry. 2007;68(7):1056–1061. PubMed

25. Helland IB, Smith L, Saarem K, et al. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatrics. 2003;111(1):e39–e44. PubMed doi:10.1542/peds.111.1.e39

26. Oken E, Kleinman KP, Berland WE, et al. Decline in fish consumption among pregnant women after a national mercury advisory. Obstet Gynecol. 2003;102(2):346–351. PubMed doi:10.1016/S0029-7844(03)00484-8

27. Su KP, Huang SY, Chiu TH, et al. Omega-3 fatty acids for major depressive disorder during pregnancy: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2008;69(4):644–651. PubMed doi:10.4088/JCP.v69n0418

28. Freeman MP, Davis M, Sinha P, et al. Omega-3 fatty acids and supportive psychotherapy for perinatal depression: a randomized placebo-controlled study. J Affect Disord. 2008;110(1–2):142–148. PubMed doi:10.1016/j.jad.2007.12.228

29. Rees AM, Austin MP, Parker GB. Omega-3 fatty acids as a treatment for perinatal depression: randomized double-blind placebo-controlled trial. Aust N Z J Psychiatry. 2008;42(3):199–205 [Published correction appears in Aust N Z J Psychiatry. 2008;42(5):438]. PubMed doi:10.1080/00048670701827267

30. Freeman MP, Sinha P. Tolerability of omega-3 fatty acid supplements in perinatal women. Prostaglandins Leukot Essent Fatty Acids. 2007;77(3–4):203–208. PubMed doi:10.1016/j.plefa.2007.09.004

31. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry. 2002;59(10):913–919. PubMed doi:10.1001/archpsyc.59.10.913

32. Nemets B, Stahl Z, Belmaker RH. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159(3):477–479. PubMed doi:10.1176/appi.ajp.159.3.477

33. Marangell LB, Martinez JM, Zboyan HA, et al. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am J Psychiatry. 2003;160(5):996–998. PubMed doi:10.1176/appi.ajp.160.5.996

34. Su KP, Huang SY, Chiu CC, et al. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol. 2003;13(4):267–271 [Published correction appears in Eur Neuropsychopharmacol. 2004;14(2):173]. PubMed doi:10.1016/S0924-977X(03)00032-4

35. Nemets H, Nemets B, Apter A, et al. Omega-3 treatment of childhood depression: a controlled, double-blind pilot study. Am J Psychiatry. 2006;163(6):1098–1100. PubMed doi:10.1176/appi.ajp.163.6.1098

36. Silvers KM, Woolley CC, Hamilton FC, et al. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot Essent Fatty Acids. 2005;72(3):211–218. PubMed doi:10.1016/j.plefa.2004.11.004