Omega-3 fatty acids play a critical role in the development and function of the central nervous system. Emerging research is establishing an association between omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and major depressive disorder. Evidence from epidemiological, laboratory and clinical studies suggest that dietary lipids and other associated nutritional factors may influence vulnerability and outcome in depressive disorders. Research in this area is growing at a rapid pace. The goal of this report is to integrate various branches of research in order to update mental health professionals.

Depression is undoubtedly an extremely complex and heterogeneous condition. This is reflected by the non-universal results obtained using cognitive-behavior and antidepressant medications. As research continues to mount, it is becoming clear that neurobiology/physiology, genetics, life stressors, and environmental factors can all contribute to vulnerability to depression. While much attention has been given to genetics and life stressors, only a small group of international researchers have focused on nutritional influences on depressive symptoms. Collectively, the results of this relatively small body of research indicate that nutritional influences on Major Depressive Disorder are currently underestimated [4]. Omega-3 fatty acids in particular represent an exciting area of research, with eicosapentaenoic acid (EPA) emerging as a new potential agent in the treatment of depression [5].

Omega-3 fatty acids are long-chain, polyunsaturated fatty acids (PUFA) of plant and marine origin. Because these essential fatty acids cannot be synthesized by the human body, they must be derived from dietary sources. Flaxseed, hemp, canola and walnut oils are all generally rich sources of the parent omega-3, alpha linolenic acid (ALA). Dietary ALA can be metabolized in the liver to the longer-chain omega-3 eicosapentaenoic (EPA) and docosahexaenoic acid (DHA). This conversion is limited in human beings, it is estimated that only 5–15% of ALA is ultimately converted to DHA [6]. Aging, illness and stress, as well as excessive amounts of omega-6 rich oils (corn, safflower, sunflower, cottonseed) can all compromise conversion [7]. Dietary fish and seafood provide varying amounts of pre-formed EPA and DHA as highlighted in Table 1.

The dietary intake of omega-3 fatty acids has dramatically declined in Western countries over the last century, the North American diet currently has omega-6 fats outnumbering omega-3 by a ratio of up to 20:1. There are a number of reasons for this skewed ratio, most notably the mass introduction of the aforementioned omega-6 rich oils into the food supply, either directly or through animal rearing practices [8]. The ideal dietary ratio of omega-6 to omega-3 has been recommended by an international panel of lipid experts to be approximately 2:1 [9]. Given that approximately 20% of the dry weight of the brain is made up of PUFA and that one out of every three fatty acids in the central nervous system (CNS) are PUFA, the importance of these fats cannot be argued [7]. Considering that highly-consumed vegetable oils have significant omega-6 to omega-3 ratios (see Table 2), it is quite plausible that, for some individuals, inadequate intake of omega-3 fatty acids may have neuropsychiatric consequences. While far from robust at this time, emerging research suggests that omega-3 fatty acids may be of therapeutic value in the treatment of depression.

A number of epidemiological studies support a connection between dietary fish/seafood consumption and a lower prevalence of depression. Significant negative correlations have been reported between worldwide fish consumption and rates of depression [10]. Examination of fish/seafood consumption throughout nations has also been correlated with protection against post-partum depression [11], bipolar disorder [12] and seasonal affective disorder [13]. Separate research involving a random sample within a nation confirms the global findings, as frequent fish consumption in the general population is associated with a decreased risk of depression and suicidal ideation [14]. In addition, a cross-sectional study from New Zealand found that fish consumption is significantly associated with higher self-reported mental health status [15].

Not all studies support a connection between omega-3 intake and mood. A recent cross-sectional study of male smokers, using data collected between 1985 and 1988, indicated that subjects reporting anxiety or depressed mood had higher intakes of both omega-3 and omega-6 fatty acids [16]. In a large population-based study of older males aged 50–69, there was no association between dietary intake of omega-3 fatty acids or fish consumption and depressed mood, major depressive episodes, or suicide [17].

The epidemiological studies which support a connection between dietary fish and depression clearly do not prove causation. There are a number of cultural, economic and social factors which may confound the results. Most significantly, those who do consume more fish may generally have healthier lifestyle habits, including exercise and stress management. Despite the limitations, the epidemiological data certainly justify a closer examination of omega-3 fatty acids in those actually with depression.

There are a number of methods used to determine EFA status in the human body, notably the plasma and red blood cell (RBC) phospholipids. These are a reflection of dietary fatty acid intake within the preceding few weeks. While not identical, significant correlations exist between blood and brain phospholipids. A number of studies have found decreased omega-3 content in the blood of depressed patients [18-21]. Furthermore, the EPA content in RBC phospholipids is negatively correlated with the severity of depression, and the omega-6 arachidonic acid to EPA ratio positively correlates with the clinical symptoms of depression [18].

More recently, investigators have been utilizing adipose tissue as a longer term measurement of EFA intake (1–3 years). In a study of 150 elderly males from Crete, the parent omega-3 ALA adipose tissue stores were negatively correlated with depression [22]. A separate study found a negative correlation between adipose tissue DHA and rates of depression. In this case, mildly depressed adults had 34.6 percent less DHA in adipose tissue than non-depressed subjects [23].

Relationships between omega-3 status and post-partum depression have also been investigated. In a cohort of 380 Australian women, plasma DHA was investigated at 6 months post-partum. Logistic regression analysis indicated that a 1% increase in plasma DHA was associated with a 59% reduction in the reporting of depressive symptoms [24]. It is well known that during pregnancy there is a significant transfer (up to 2.2 g/day) EFAs to the developing fetus [7]. Increased risk of post-partum depressive symptoms has recently been associated with a slower normalization of DHA levels after pregnancy [25].

Suicide attempts have also been associated with low levels of RBC EPA. In a study involving 100 suicide attempt cases in China compared to 100 hospital admission controls, there was an eightfold difference in suicide attempt risk between the lowest and highest RBC EPA level quartiles [26]. The seasonality of depression and suicide has been described by investigators, with more deaths in spring and summer vs.autumn and winter. Total serum cholesterol has been highly significantly synchronized with the annual rhythms in violent suicide deaths [27]. Recently, investigators found that EFA levels also vary by season, with peaks of EPA and DHA from August to September. The parent omega-3 and 6 levels did not have a seasonal variation, suggesting a seasonal interference with delta-5-desaturase conversion. The authors of this study suggest that the seasonal variation in EPA or DHA may, in part, explain seasonality of violent suicide occurrence [28].

The overlap between cardiovascular disease and depression has also been noted, with omega-3 status emerging as a common thread. Indeed, major depression in acute coronary syndrome patients is associated with significantly lower plasma levels of omega-3 fatty acids, particularly DHA [29]. In addition, elevated homocysteine levels, a known risk factor for cardiovascular disease, has been associated with the excess omega-6 fatty acids found in the Western diet [30]. Finally, lowered intake of the parent omega-3 ALA has been associated with depression in 771 Japanese patients with newly diagnosed lung cancer [31].