Your Family Physician

Best Evidence Reference

Lucas M, Asselin G, Merette C, Poulin M, Dodin S. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr. 2009;89:641-651.

Abstract

This study was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, this study was ranked as 6 for newsworthiness and 7 for relevance by clinicians who used this system.

Summary

Depression affects women disproportionately compared with men, and symptoms of psychological distress may be particularly prevalent during the perimenopausal period. The current study of ethyl-eicosapentaenoic acid for the management of psychological distress among middle-aged women produced primarily negative results, which is consistent with other clinical trials of fish oil for depression. At this time, there is insufficient evidence to recommend fish oil for the treatment of depression.

Background

Depression is one of the most significant international public health problems today, and it affects women disproportionately. The lifetime prevalence of major depression among women varies widely with the population studied, but it is generally between 6% and 17%.^[1] Depression is 1.5 to 3 times more common among women compared with men, and a report from the World Health Organization (WHO) identified depression as the leading cause of disease-related disability among women around the world, with rates of disability 50% higher than among men.^[2]

While the gender difference in the prevalence of depression is evident by adolescence, the question of whether depression is particularly more common during perimenopause and menopause is controversial. Research suggests that rates of depressive symptoms increase in the year prior to and following women's last menstrual period, with a peak prevalence of psychological distress in 28.9% of women in early menopause.^[3] However, some epidemiologic studies have demonstrated no increase in the risk for depression among women at midlife, and there also does not appear to be an increased prevalence of depression in the postmenopausal vs premenopausal period.^[4]

Women have many options to treat depression and its symptoms, but many women may prefer treatment that does not require a prescription. In one study from Finland, 35.4% of a large population-based sample reported the use of complementary and alternative medicine.^[5] Women were more likely to use complementary medicine compared with men, and the presence of depression and anxiety disorders was positively associated with the use of complementary medicine as well.

One popular treatment women may consider for a variety of health benefits is fish oil, and fish oil has some evidence of efficacy in the treatment of depression. In a small study of patients with major depression, the addition of ethyl-eicosapentaenoic acid (E-EPA) to conventional antidepressant therapy significantly improved depression rating scores by week 3 compared with placebo.^[6] On a larger scale, epidemiologic studies suggest that societies that consume higher amounts of fish and omega (n)-3 fatty acids have lower rates of depression.^[7]

Current Trial

The current study examines the effects of E-EPA as monotherapy among middle-aged women with psychological distress. Women between the ages of 40 and 55 years were eligible for study participation. All participants had moderate-to-severe psychological distress, as measured by a score of 72 or less on the Psychological General Well-Being Schedule (PGWB). Women with severe depression were excluded from study participation, as were those who had been in menopause for over 5 years. However, women who met criteria for major depression were allowed into the trial.

Study participants were randomized to receive either E-EPA n-3 fatty acid supplementation or placebo as 500-mg capsules 3 times daily for 8 weeks. The study was double blind, and a small dose of regular fish oil was added to the placebo tablets to mimic any fish taste of the active treatment.

The main study outcome was the change in the PGWB. Researchers also followed multiple other depression rating scales.

One hundred twenty women underwent randomization, and 106 participants provided data at 8 weeks. The number of women dropping out of the study protocol was higher in the placebo compared with the E-EPA group.

Baseline data were similar when comparing randomized groups, except the percentage of women who met criteria for a major depressive episode was higher in the placebo (26.2%) compared with the E-EPA (22%) group. The mean age of participants was 48 years, and three quarters of the women had a college education or more. Nearly half of the women reported being physically active at least 3 times per week, and 20% were smokers.

Over 80% of participants took at least 80% of the study treatments, with no difference between treatment groups. Furthermore, blood tests confirmed that red blood cell concentrations of polyunsaturated fatty acids (PUFAs) increased in the E-EPA group and remained stable in the placebo group during the study period.

While 50% and 6% of women receiving E-EPA and placebo, respectively, noted a fishy taste of the capsule, there was no significant difference between groups in correctly guessing their assigned treatment. Beside the fishy taste, more women receiving E-EPA reported constipation as an adverse event during the study period.

Mean baseline scores on the PGWB indicated that 63.8% were under severe psychological distress, and 36.2% women were experiencing moderate distress. At 8 weeks, the PGWB score improved to a similar extent in both treatment groups. Similarly, the overall scores on the depression scales improved slightly in both the E-EPA and placebo groups.

Despite these negative main results, E-EPA was more successful in improving both psychological distress and depression scores in the subgroup of women without a major depressive episode. However, placebo therapy was associated with better performance compared with E-EPA among women with major depression.

Commentary

The study discussion focuses on the benefit of E-EPA among women without major depression, although this ignores the fact that this was a largely negative trial. E-EPA failed to improve the main study outcome compared with placebo, and placebo was actually more effective than E-EPA among women with major depression. This latter result particularly calls into question any benefit of E-EPA in this population.

The negative results of this trial are consistent with larger studies of fish oil for depression. In one 12-week trial comparing EPA and docosahexaenoic acid (DHA) with placebo among 218 patients with mild to moderate depression, the active treatment was not associated with improved mood, mental health, or cognitive function outcomes.^[8] In addition, another trial by Grenyer and colleagues^[9] of 83 patients receiving oral antidepressants failed to demonstrate any benefit of fish oil supplementation compared with placebo, despite evidence of good compliance with study treatment. Finally, a trial of EPA plus DHA among 302 community-dwelling older adults failed to improve depression scores or mental well-being compared with placebo.^[10] In this trial, both low-dose and high-dose fish oil supplementation were ineffective after a fairly long (26 weeks) intervention.

There are mixed results in reviews of supplementation with PUFAs for depression. One review published in 2006 noted that EPA improved depression in 4 of 7 randomized trials.^[11] In all of the positive trials, EPA was added to existing antidepressant or mood-stabilizing medications. Another systematic review of 18 randomized controlled trials found limited effects of PUFAs on depression and significant heterogeneity of results due to publication bias in the accumulated scientific literature.^[12] Finally, a meta-analysis from 2007 found that omega-3 PUFAs did have a significant antidepressant effect among patients with either depression or bipolar disorder.^[13] However, study heterogeneity and publication bias precluded the researchers from recommending omega-3 PUFAs to treat depression.

Depression and depressive symptoms are frequently comorbidities associated with other chronic disease, particularly among middle-aged and older adults. Many adults consume fish or take fish-oil supplements to reduce lipid levels, which is well supported in the scientific literature. EPA appears most effective in reducing triglyceride levels, with minimal effects on low- and high-density lipoprotein cholesterol.^[14] This treatment can improve the rate of cardiac events, and the prospect of combination treatment with fish oil and a medication from the statin class of drugs appears particularly promising. A trial of EPA combined with a statin with 4.6 years of follow-up demonstrated that combination treatment was associated with a significant 19% reduction in major coronary events compared with statin treatment alone.^[15] In addition, fish oil has a modest effect in reducing blood pressure among patients with hypertension, and it has been demonstrated to reduce morning stiffness and the number of painful joints among patients with rheumatoid arthritis.^[14]

Fish oil also appears safe and is generally well-tolerated. Patients should certainly consider making fish a regular part of their diet, provided that they avoid consuming large quantities of fish associated with high levels of mercury. Fish oil supplements are another viable treatment option, particularly for patients at higher risk for cardiovascular disease. However, the current study and collective body of research do not provide the level of evidence necessary to recommend fish oil to improve mood, whether for the management of psychological distress or major depression.

Clinical Pearls

• Depressive symptoms are more common in the perimenopausal period, although the prevalence of depression among women does not increase significantly after menopause.
• In the current study, E-EPA failed to improve psychological distress and measures of depression in a cohort of middle-aged women with moderate-to-severe psychological distress at baseline.
• However, when the study analysis was limited to women without a major depressive episode, E-EPA was associated with significant improvements in psychological distress and depression scores.
• The body of clinical data regarding the efficacy of fish oil in improving mood is mixed and does not currently support a recommendation to use fish oil for this indication.