Our diets contain two families of polyunsaturated fatty acids, omega-3s and omega-6s, which differ in their chemical structure. The main omega-3s are alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). The main omega-6s include linoleic acid, gamma-linolenic acid, dihomo-gamma-linolenic acid and arachidonic acid. Linoleic acid and the omega-3 fatty acids are considered essential as the body cannot synthesize them from scratch. A small amount of ALA can be converted to the long-chain forms of omega 3s, but not in quantities sufficient to meet the body’s needs.
The fatty acids in each family with 20 or more carbons are known as long-chain fatty acids and they behave differently from those such as linoleic acid and ALA that have 18 carbons. ALA is present in plant foods such as soybean, canola, walnut and flax, whereas EPA and DHA are present principally in fish, omega-3-enriched eggs and some omega-3-fortified foods (see table).* Evidence for a strong connection between long-chain omega-3s and depression comes from epidemiological, experimental and clinical studies.
Depression on the Increase
Depression is a common mental disorder associated with depressed mood, loss of interest or pleasure, feelings of guilt or low self-worth, disturbed sleep or appetite, low energy and poor concentration. These mental problems can become chronic or recurrent and lead to impaired ability to handle everyday activities and responsibilities. According to the World Health Organization, depression is among the leading causes of disability, affecting about 121 million people worldwide. In a given year, close to 10% of the US population age 18 and older—that is, approximately 21 million American adults—are affected by mood disorders, including mild and major depressive disorder, and bipolar disorder (formerly called manic-depressive disorder). The earlier age of onset and increased frequency of depression over the last 100 years are likely related to neurobiology, physiology, genetics, stress and environmental factors, but a role for nutrition in depressive symptoms may be underestimated. Long-chain omega-3s in particular may be potential agents in the treatment and possible prevention of depression.
Dietary Omega-3 and Clinical Depression
Nerve tissue possesses one of the highest concentrations of fatty acids in the body, with approximately 20% of the dry weight of the brain comprised of long-chain fatty acids. These long-chain fatty acids provided in food are essential for both the structure and function of nerve cells. Omega-3s promote transmission of the chemical messengers that facilitate communication between nerve cells and are associated with emotional stability (e.g., serotonin) and positive emotions (e.g., dopamine). Omega-3s have been linked to depressive conditions such as bipolar disorder (a disorder with both depression and mania phases), unipolar depression (depression without mania), borderline personality disorder, premenstrual syndrome and perinatal depression. Analyses of blood fatty acids show that depressed people have lower levels of omega-3s and higher levels of omega-6s compared with people who are not depressed. For example, several studies reported lower EPA and DHA levels in depressed compared with non-depressed people, whereas total omega-3s (including ALA) were reduced in all depressed patients except in one study. Overall, the reports showed that the severity of depression was greater as the concentrations of EPA, DHA, ALA and total omega-3s fell. Although some of these findings were not of statistical significance, there was a consistent shift away from omega-3s toward omega-6s in depressed people.
Because omega-3s come from our diet, how do food patterns relate to the observations about depression and levels of these fatty acids in tissues? Two types of studies are used to obtain information about the effects of diets and nutrients on depression. Epidemiological or observational studies carried out in populations identify or measure the effects of factors related to the condition, but do not establish cause. Clinical studies involve treatments and outcomes in patients and a comparison group. The best clinical studies use a “control” group similar to the patient participants treated only with a placebo. These studies can establish causation. Observational studies have shown that populations with higher consumption of fish and intakes of long-chain omega-s (EPA and DHA) exhibit lower rates of depression (Figure) and better mental health status compared with those consuming the least amount of fish. Also, people with a higher fish consumption have a lower risk of seasonal affective disorder and postpartum depression in women.
Clinical studies show that individuals with depression have lower levels of blood omega-3s. Intake of pure EPA improves the symptoms of treatment-resistant depression, as shown by a study where a low 1-g daily dose of EPA for three months significantly improved depressive symptoms, sleep, anxiety, lassitude, libido and thoughts of suicide.
At least seven double-blind randomized controlled clinical trials have reported the effect of omega-3 supplementation in patients with depression. Five studies investigated the effect of treatment with EPA alone, DHA alone or EPA plus DHA on unipolar depression, with three reporting significant benefits. Of the other studies, one reported a significant beneficial effect of EPA plus DHA on bipolar depression and the other found no effect of DHA on postpartum depression.
Canadian researchers reported that intake of Antarctic krill oil (400 mg EPA, 240 mg DHA) improved depressive symptoms associated with premenstrual syndrome, and 1 g per day of pure EPA improved depression and aggression in patients with borderline personality disorder. Although numerous clinical studies reported positive outcomes in the treatment of depressive conditions, it is important to note that not all studies in depressed patients have reported improvements with omega-3s. Poor study design, small numbers of participants and multiple treatments without appropriate controls sometimes limit the usefulness of clinical studies. For example, in one study of major depressive disorder, EPA was more effective than a placebo substance, but the difference did not reach statistical significance, probably as a result of the small sample size and patients dropping out of the study. Another study found that DHA alone was no better than the placebo in patients with major depressive symptoms. Collectively, several studies support a beneficial relationship between omega-3s and depression, with EPA the most effective omega-3, although combinations of EPA and DHA as found in fish oil may be helpful. It is likely that low concentrations of omega-3s resulting from abnormal metabolism and reduced intake contribute to a susceptibility to depression.
Omega-3 Fatty Acids in Perinatal and Postpartum Depression
Perinatal major depressive disorder, including antenatal and postpartum depression, affects between 10% and 20% of perinatal women. The term “perinatal” broadly refers to the time during the last half of pregnancy until 4 to 6 weeks after delivery. Depressive disorder in this period has serious consequences, and may adversely affect the child’s attachment, behavior and neurocognitive development. Epidemiological and preclinical data support a positive role of omega-3s in perinatal treatment of depression, but the evidence is not entirely consistent.
Perinatal major depressive disorder has been treated with EPA or a combination of EPA and DHA based on promising data. Although one study found that seafood intake was related to a lower occurrence of depressive symptoms in postpartum women, another found no association between postnatal depression and either fish consumption in early pregnancy or the mother’s omega-3 status after birth. Recent trials assessing omega-3s compared with a placebo for perinatal depression reported conflicting results or no effect. Studies to date suggest that dose of 1 g per day of EPA added to the patient’s current treatment may be effective in reducing the symptoms of depression. Further study with more participants and adequate placebo controls is warranted. At this time, combination treatment with EPA and DHA is recommended for perinatal major depressive disorder.
Maternal concentrations of EPA and DHA normally decrease during pregnancy, particularly in the third trimester, and it can take up to 1 year to normalize DHA concentrations following pregnancy. This is important as increased risk of postpartum depressive symptoms has been associated with a slower normalization of DHA levels after pregnancy. However, a 1% increase in plasma DHA was associated with a 60% reduction in the reporting of depressive symptoms. Another study observed lower concentrations of omega-3s among women with postpartum depression compared with non-depressed women. Both studies suggest, but do not prove, that omega-3 status may influence the risk of developing postpartum depression.
Findings to date intriguingly suggest that treatment of postpartum depression with diets or a supplement rich in long-chain omega-3s might benefit both mother and baby. However, it will take large intervention studies to establish the effectiveness of long-chain omega-3s in perinatal mental health. One challenge in eating sufficient omega-3s to meet our nutritional needs is that the intake of these fatty acids in Western countries has decreased, while consumption of omega-6s has increased over the last century. Intake of omega-6s now exceeds that of omega-3s by about 20 times. Interestingly, the rates of depression have increased concurrently. Perhaps more important to the average person is the knowledge that consuming 2 meals a week of fatty fish such as salmon or rainbow trout will provide an amount of omega-3s equivalent to the recommended intake of 500 mg per day.
In spite of its shortcomings, current evidence supports the involvement of omega-3s in the prevention and management of depression. There is convincing evidence that omega-3s influence brain function; however, the mechanisms by which they might affect depression are unclear. Fish oil supplements or purified omega-3s are usually well tolerated and have a long-term safety record at doses of up to 3 g daily. Further, they appear to have beneficial effects on affective and mood disorders and contribute to the structure and function of the infant’s brain. However, the appropriate dose of omega-3s and which ones are most effective for depression remain to be determined.
*A fully referenced version of this article is available from the editor.