Women’s Health Update

by Tori Hudson, ND

Omega-3s and Mental Health

Omega-3 Marine Oils and Depression

When it comes to the biological basis for mental health disorders, the presumption is that there is an abnormality of neurotransmitters – whether it be an excess, deficiency, or abnormal interactions with receptors and transporters. While the focus of current pharmacological therapy is the neurotransmitter and its proteins, the impressive role of lipids, particularly long-chain polyunsaturated fatty acids (LC-PUFAs), cannot be overstated. The weight of the brain is roughly 60% lipid, the richest source of fatty acids in the body, and 15% to 30% of those lipids are essential fatty acids (EFAs) and LC-PUFAs. Nerve cell function, membrane fluidity, neuron membrane dynamics, and the subsequent receptors, transporter, and neurotransmitter function are profoundly affected by the lipids that we consume through diet and supplementation. Considerable research including randomized controlled trials now demonstrates the role and efficacy of EFAs in numerous psychiatric disorders.

Several probable mechanisms may explain the link between EFAs and depression. EFAs can modify 5-HT receptors, affect serotonin and dopamine metabolism, lower monoamine oxidase B, modulate cytokine production, and enhance signal transduction. The composition of cell membranes, neurotransmission, and prostaglandin metabolism are all affected by the amounts of EFAs; and while clinical trials are few, there is substantial laboratory and observational evidence of the correlation between low essential fatty acid levels and depression.

According to the American Journal of Psychiatry, depression is one of the 10 most frequent indications for the use of complementary and alternative medicine.1 While many nutraceuticals and botanicals have published evidence to their benefits, omega-3 polyunsaturated fatty acids (PUFAs) are among the more commonly used.2

Epidemiologic studies in several countries suggest that decreased omega-3 fatty acid consumption correlates with increasing rates of depression. One researcher who studied the relationship of fish consumption and the incidence of depression correlated the annual incidence of major depression per 100 people in 9 countries with the consumption of fish.3 He found a high incidence of depression in countries with low fish consumption and a lower incidence of depression in countries with high consumption. For example, New Zealanders have an annual fish consumption of about 40 pounds and an annual incidence rate of depression of 5.8%. Japan on the other hand, with a fish consumption of almost 150 pounds per year, had the lowest incidence of major depression, at 0.12%.

This group also demonstrated that prevalence rates for bipolar affective disorder rise when the annual fish intake falls below 75 lbs of fish per person annually. In Taiwan, for example, there is a 0.04% rate and fish intake is 81.6 lb per person per year as compared with Germany, where the rate is 6.5% at 27.6 lb of fish per person annually. In a survey of 3204 Finnish adults, infrequent fish consumption was associated with depression in women and, although not statistically significant, a trend was seen in men.4 Fish intake also appears to have an influence on suicide, with a reduced risk of death from suicide in individuals with daily fish consumption.5

In a group of 20 patients with moderate to severe depression, the relationship was studied between depression and levels and ratios of omega-3 and omega-6 fatty acids in plasma and erythrocyte phospholipids.6 Using two commonly accepted scales and methods of evaluating depression, researchers found a significant correlation between the ratio of phospholipid arachidonic acid to EPA and the severity of depression. The greater the omega-6 to omega-3 ratio, the greater the severity of the depression.

In 2010, researchers found that patients with major depressive disorders exhibited significantly lower erythrocyte docosahexaenoic acid (DHA) composition compared with healthy controls. Individuals with bipolar disorder appeared to have an even lower DHA level. 7

Other investigations have confirmed that a high concentration of blood plasma DHA levels has been linked to an increase in serotonin turnover, which resulted in lower rates of depression and even suicide. Some science has suggested that switching to a cholesterol-lowering diet may also result in the reduction in measures of depression, although not all studies demonstrate this.8 It appears that there is a consistent positive association between depression and coronary heart disease and heart attacks.9 These conditions may in fact carry a common link, that of elevated cholesterol. Since there is such a strong correlation between depression and coronary artery disease, and a predictive correlation between elevated cholesterol and heart disease, elevated serum cholesterol may also predict increased depression.

Depression secondary to alcoholism is quite common and occurs in up to 59% of alcoholics. Alcoholism is certainly a complicated illness, with social, psychological, hereditary, physiological, and physical factors to consider. We also know that alcohol is a prooxidant that leads to increased lipid peroxidation. A consequence of increased lipid peroxidation may be a decrease in the concentrations of the more highly unsaturated types of fats, such as PUFAs. Several studies have demonstrated that chronic alcohol abuse depletes long-chain omega-3 polyunsaturated fatty acids from neuronal membranes.10 It is hypothesized that the subsequent effect on the membranes may promote the development of depression.

Interestingly, higher intakes of fish did not have a protective role against depression in more severe situations and have not been associated with a lower risk for suicide in Japan. However, women in Japan with very low intakes of fish did have an increased risk of suicidal death.11

As of August 2011, four meta-analyses have examined the results of randomized controlled trials of omega-3 supplements for unipolar major depression.12^–15 They all concluded that omega-3 supplements have a potential for treating depression. However, these meta-analyses included studies that were small trials and of different EPA-DHA formulations, ratios, and dosages. The most promising results within the meta-analyses are from the Peete-Horrobin trial in 2002, the Nemets-Stahl trial of 2002, and the Su-Huang trial of 2003 discussed below.

A search of the literature examining the therapeutic efficacy of essential fatty acids for depression was published in 2006.16 One double-blind, placebo-controlled RCT examined the use of omega-3 fatty acids in 30 men and women.17 The intervention group received 9.6 g of omega-3 fatty acids from fish oil in addition to their standard pharmacological treatment for 4 months. A Kaplan-Meier survival analysis found that the fish oil group had a significantly longer period of remission than the placebo group and performed better than the placebo group in other outcome measures. Three case control studies of adults with major depression and nondepressed healthy adults all showed a significant difference in levels of omega-3s between depressed and nondepressed adults.18^–20Similarly, a review article suggested that DHA is beneficial for depression as well as several other conditions.21 A second review article discussed the effects of dietary intake patterns on fatty acid balance and potential effect on mood.22

Three intervention studies have been done since the initial literature review that concluded in 2001 and do provide support for the effectiveness of EPA, or a combination of EPA with DHA. In a study of 28 patients with major depression, 9.6 g/day showed significant improvement compared to the placebo group.23 In a study of EPA, 1 g/day demonstrated significant improvement in two different depression scales compared with placebo and no further improvement was seen in higher doses of EPA than 1 g/day.24 A combination of EPA or placebo and conventional pharmaceutical antidepressant treatment in unipolar depression demonstrated that individuals in the EPA group had significantly better effects by the third week. The efficacy of omega-3 supplementation as an antidepressant treatment in individuals with major depressive disorder was also seen in a study published in 2002.25 Twenty-two individuals received 2 g/day of EPA in addition to standard antidepressant medication, and were compared with individuals who just took their standard antidepressant medication and a placebo. In this 3-week study with participants who had treatment-resistant major depression, EPA demonstrated an effect on depressed mood, insomnia, and feelings of guilt and worthlessness.

In a 2012 study, omega-3s along with a prescription antidepressant, citalopram, was conducted over a 9-week period.26 The objective of this study was to explore combination therapy by using citalopram and omega-3 fatty acids versus citalopram plus placebo in the primary treatment of individuals with major depressive disorder. Forty-two subjects received 2 g/day containing a blend of 900 mg EPA, 200 mg DHA, and 100 mg of other omega-3 fatty acids, twice daily, in addition to citalopram, versus the other group who received an olive oil placebo plus citalopram. The omega-3 plus citalopram combination therapy provided significantly greater improvement in Hamilton Depression Rating scales scores beginning at week 4 and continuing throughout the duration of the study. While the combination therapy achieved a decrease in signs and symptoms of major depression, it did not improve the onset of response time.

In an 8-week, single-blind, placebo-controlled trial, peri- or postmenopausal women with depressive disorders and hot flashes were given 6 g/day of EPA and DHA. The response rate was 70% and a decrease of 50% or more on the Montgomery-Åsberg Depression Rating Scale (MADRS).27

The efficacy of omega-3 supplementation for major depression was documented in another recent randomized, controlled trial of 8 weeks in which 432 participants with major depression were randomized to 1050 mg of DHA or a matched placebo.28 There was only a small statistical trend toward superior benefits in major depression with the DHA over placebo. However, there was clear benefit of DHA in patients with major depression and anxiety disorders. This has been the largest randomized, controlled trial to date to study the efficacy of omega-3 supplementation for major depressive disorder.

A study of DHA only on the other hand, with a dose of 2 g/day of DHA or placebo in 36 depressed participants, found no significant difference between the DHA and the placebo group. There was, however, a better overall response rate in the DHA group.29

Contrary with some of the negative results with DHA, the antidepressant effect of DHA was examined in 35 depressed adult participants (46% women average age of 42 years) in which the individuals were randomized into one of 3 groups: 1 g/day of oral DHA, 2 g/day of oral DHA or 4 g/day of DHA. Using the Hamilton-Depression scale, the response rates of 50% or more was 83% for 1 g/day , 40% for 2 g/day and 0% for 4 g/day. The two lower dose DHA groups had a significant decrease in the Hamilton-Depression scores, demonstrating that lower doses of DHA may be an effective intervention for depression. 30

A very specific population at risk of developing depression is that of individuals who experienced a recent acute myocardial infarction (AMI). A growing body of evidence suggests a link between psychosocial factors, cardiovascular risk, and prognosis in patients with acute heart attacks. Twenty percent of individuals with AMI have a history of major depression, and 70% to 80% report anxiety. Omega-3 fatty acids are one of the potential issues that link these mood disorders as well as cardiovascular complications. This link has caused researchers to take aim at assessing whether early supplementation of omega-3 fatty acids affects depression and anxiety in participants with AMI and no previous history of mental health disorders. In late 2013, a study was published that enrolled 52 participants with AMI.31 They were randomized to 1 g/day of fish oils plus standard AMI therapy or control group plus standard AMI therapy. The test scores for depression and anxiety were significantly lower for the fish oil group and provide evidence that intervention with fish oils in AMI patients may decrease their anxiety and depression post MI.

It remains quite unclear as to the optimal dosing and ratios of EPA/DHA in the prevention and treatment of depression. Successful studies have used doses ranging from 1 g/day to 9.6 g/day, Some studies have used high-EPA formulas, while others have used DHA-dominant formulas, in low and high doses. The most benefit has been for pure EPA and EPA-DHA mixtures; however, at least one study had benefits with the low doses of DHA at 1 g or 2 g/day.

A 2013 trial sheds light on this issue.32 This single-center, randomized, double-blind, placebo-controlled, multi-arm, parallel-group trial compared the efficacy of EPA versus DHA as adjuvants to maintenance medications for the treatment of mild to moderate depression. Eighty-one mild to moderately depressed individuals randomly received either 1 g/day of EPA or DHA or placebo for 3 months. The primary outcome was the final score of the Hamilton Depression Rating Scale (HDRS). Participants in the EPA group showed a significantly better reduction in the HDRS score as compared with the DHA and placebo groups. There were also more individuals with a 50% response to treatment in the EPA group (6) and none in the DHA or placebo group

A comparison study looked at the omega-3 fatty acid EPA and fluoxetine (a prescription antidepressant) separately and in combination, in individuals with major depression.33 Sixty participants with major depressive disorder were randomly assigned to receive daily either 1000 mg EPA or 20 mg fluoxetine or combination for 8 weeks. EPA plus fluoxetine combination was significantly better than fluoxetine or EPA alone after the 4th week of treatment. Fluoxetine and EPA appeared to be equally effective in controlling depressive symptoms. Response rates (> or = 50% decrease in baseline Hamilton Depression Rating Scale) were 50%, 56%, and 81% in the fluoxetine, EPA, and combination groups, respectively.

In May 2014, researchers published a study in which they conducted a meta-analysis on the usage of omega-3 fatty acids for the treatment of depression. They specifically looked at randomized, controlled trials with omega-3 PUFAs for the treatment of depression and then analyzed the outcomes among the participants in these studies.34

The meta-analysis considered studies that took place until August 2013 and included people diagnosed with major depression as well as those who had depressive symptoms but were not officially diagnosed. Both these groups of individuals had significant improvements with omega-3 PUFA supplementation. Formulations with mostly EPA (rather than DHA) were more effective.

Another motivation to use omega-3s for depression is that antidepressants can have significant side effects and, even more worrisome in younger people, with an increase in suicides. One group of researchers was motivated by this fact and divided 400 participants aged 15 to 25, all of whom had a major depression diagnosis, with one group receiving cognitive behavioral therapy (CBT) and the other group 1.4 g/day of omega-3 fatty acids plus CBT for 12 weeks. The study found that omega-3 PUFAs provided a significant antidepressant effect, and the authors concluded that they should be used as a “first-line therapy” in young people with major depression.35

A meta-analysis in 2013 highlighted the fact that many studies have cited low levels of omega-3 fatty acids among individuals with depression. They assert that early studies of omega-3 formulations for depression found benefits, but then other studies were not demonstrating significant results. They postulate that the reason for this is due to studies that have DHA-dominant formulations and emphasize the importance of EPA-dominant formulations to achieve efficacy.36

Notes

1. Kessler R,Soukup J, Davis R, et al. The use of complementary and alternative therapies to treat anxiety and depression in the United States. Am J Psychiatry. 2001;158:289–294.

2. Smit E, Muskiet F, Boersma E. The possible role of essential fatty acids in the pathophysiology of malnutrition: a review. Prostaglandins Leukot. Essent. Fat. Acids 2004;71(4):241–250.

3. Hibbeln J. Fish consumption and major depression. Lancet 1998;351, April 18: 1213

4. Tanskanen A, Hibbeln J, Hintikka J, et al. Fish consumption and depression and suicidality in a general population. Archives of General Psychiatry 2001;58:512–513.

5. Hirayama T. Lifes Style and Mortality. A Large Census-Based Cohort Study in Japan. Basel: Karger 1990

6. Adams P, Lawson S, Sanigorski A, Sinclair A. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996;31:157–161.

7. McNamara R, Jandacek R, Rider T, et al. Selective deficits in erythrocyte docosahexaenoic acid composition in adult patients with bipolar disorder and major depressive disorder. J Affective Disorders 2010;126:303–311.

8. Weidner G, Connor S, Hollis J, Connor W. Improvements in hostility and depression in relation to dietary change and cholesterol lowering. Ann Intern Med 1992;117:820–823.

9. Booth-Kewley, Friedman. Psychological predictors of heart disease: a quantitative review. Psychol Bull 1987; 101(3):343–62.

10. Salem N, Ward G. The effects of ethanol on polyunsaturated fatty acid composition. In: Alling C, Diamond I, Leslie S, Sun G, Wood W, eds. Alcohol, cell membranes, and signal transduction in brain. New York: Plenum Press, 1993:33–46.

11. Poudel-Tandukar K, Nanri A, Iwasaki M, et al. Long chain n-3 fatty acids intake, fish consumption and suicide in a cohort of Japanese men and women– The Japan Public Health Center-based prospective study. J Affective Disorders 2011;129:282–288.

12. Appleton K, Hayward R, Gunnell D, et al. Effects of n-3 long-chain polyunsaturated fatty acids on depressed mood: systematic review of published trials. Am J Clin Nutr 2006;84(6):1308–1316.

13. Ross B, Seguin J, Sieswerda L. Omega-3 fatty acids as treatments for mental illness: which disorder and which fatty acid? Lipids Health Dis. 2006(1:21–39)

14. Lin P, Su K. 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.

15. Freeman M, Hibbeln J, Wisner K, et al. Omega-3 fatty acids: evidence basis for treatment and future research I psychiatry. J Clin Psychiatry. 2006;67(12):1954–1967.

16. Williams A, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression. J Affective Disorders 2006;93:117–123.

17. Stoll A, Severus W, Freeman M, et al. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Archives of General Psychiatry 1999;56:407–412.

18. Maes M, Christophe A, Delanghe J, et al. Lowered omega 3 polyunsaturated fatty acids in serum phospholipids and cholesteryl esters of depressed patients. Psychiatry Res 1999;85:275–291.

19. Edwards R, Peet M, Shay J, Horrobin D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J Affect Disorders 1998;48(2–3):149–1555.

20. Peete M, Murphy B, Shay J, Horrobin D. Depletion of omega-3 fatty acid levels in red blood cell membranes of depressive patients. Bio. Psychiatry 1998;43(5):315–319.

21. Horrocks L, Yeo Y. Health benefits of docosahexaenoic acid (DHA). Pharmacol Res 1999;22(5–6):474–480.

22. Bruinsma K, Taren D. Dieting, essential fatty acid intake, and depression. Nutr Rev 2000;58(4):98–108.

23. Su K, Huang S, Chiu C, Shen W. Omega-3 fatty acids in major depressive disorder–a preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267–271.

24. Peet M, Horrobin D. 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):913–319.

25. Nemets B, Stahl Z, Belmaker R. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am J Psychiatry. 2002;159:477–479.

26. Gertsik L, Poland R, Bresee C, et al. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J Clinical Psychopharmacology 2012;32(1):00–00.

27. Freeman M, Hibbeln J, Silver M, et al. Omega-3 fatty acids for major depressive disorder associated with the menopausal transition: preliminary open trial. Menopause 2011 18(3):279–284.

28. Lesperance F, Frasure-Smith N, St-Andre E, et al. The efficacy of omega-3 supplementation for major depression: a randomized controlled trial. J Clin Psychiatry 2011;72(8(:1054–1062

29. Marangell L, Martinez J, Zboyan H, 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.

30. Mischoulan D, Best-Popescu C, Laposata M, et al. A double-blind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. European Neuropsychopharmacology 2008;18:639–645.

31. Haberka M, Mizia-Stec K, Mizia M, et al. Effects of n-3 polyunsaturated fatty acids on depressive symptoms, anxiety and emotional state in patients with acute myocardial infarction. Pharmacological Reports 2013;65:59–68.

32. Mozaffari-Khosravi H, Yassini-Ardakani M, Karamati M, et al. Eicosapentaenoic acid versus docosahexaenoic acid in mild-to moderate depression: A randomized, double-blind, placebo-controlled trial. European Neuropsychopharmacology 2013;23:636–644.

33. Jazayeri S¹, Tehrani-Doost M, Keshavarz SA, et al. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust N Z J Psychiatry. 2008 Mar;42(3):192–8.

34. Grosso G, Pajak A, Maventano S, et al. Role of omega fatty acids in the treatment of depressive disorders. A comprehensive meta-analysis of randomized controlled trials. PLOS one. 20146905 9(05)

35. Rice S, Hickie I, Yung A, et al. Youth depression alleviation: the Fish Oil Youth Depression Study (YoDA-F): A randomized, double-blind, placebo-controlled treatment trial. Early Interv Psychiatry. 2014 Aug 13 (epub )

36. Hegarty B¹, Parker G. Fish oil as a management component for mood disorders – an evolving signal. Curr Opin Psychiatry. 2013 Jan;26(1):33–40.

Dr. Tori Hudson graduated from the National College of Naturopathic Medicine (NCNM) in 1984 and has served the college in many capacities over the last 28 years. She is currently a clinical professor at NCNM and Bastyr University; has been in practice for over 30 years; and is the medical director of the clinic A Woman’s Time in Portland, Oregon, and director of research and development for Vitanica, a supplement company for women. She is also a nationally recognized author, speaker, educator, researcher, and clinician.