Omega-3 Fatty Acids and Mood Disorders
Gordon Parker, M.D., Ph.D, D.Sc., Neville A. Gibson, Ph.D.
Heather Brotchie, M.B.B.S., B.A. Gabriella Heruc, B.B.Sc., B.Sc.
(Hons.) Anne-Marie Rees, B.Sc., F.R.A.N.Z.C.P., D.R.A.N.Z.C.O.G.
Dusan Hadzi-Pavlovic, B.Sc., M.Psychol.
Am J Psychiatry 163:6, June 2006 969 iews and Overviews
Objective: This article is an overview of epidemiological and treatment studies suggesting that deficits in dietary-based omega-3 polyunsaturated fatty acids may make an etiological contribution to mood disorders and that supplementation with omega-3 fatty acids may provide a therapeutic strategy.
Method: Relevant published studies are detailed and considered.
Results: Several epidemiological studies suggest covariation between seafood consumption and rates of mood disorders. Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression.
Conclusions: Deficits in omega-3 fatty acids have been identified as a contributing factor to mood disorders and offer a potential rational treatment approach. This review identifies a number of hypotheses and studies for consideration. In particular, the authors argue for studies clarifying the efficacy of omega-3 supplementation for unipolar and bipolar depressive
disorders, both as individual and augmentation treatment strategies, and
for studies pursuing which omega-3 fatty acid, eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA), is likely to provide the greatest benefit.
It is commonly suggested that there has been an epidemic in depression in recent decades. Any prevalence increase could be artifactual, reflecting changes in attribution, definition, destigmatization, help seeking, or other
factors. Alternatively, there may have been a real increase. Klerman and Weissman (1) considered increased rates in Western societies and concluded that such changes could not be explained by changing diagnostic criteria, changing attitudes of health professionals and societies, reporting biases, differential mortality rates, or other obvious artifactual influences. For any true increase, numerous determinants could be proposed, including genetic factors, greater use of illicit drugs, and many social and environmental
factors. In relation to the last, there has been considerable interest in a dietary contribution, particularly involving omega-3 fatty acids.
Omega-3 fatty acids are long-chain polyunsaturated fatty acids found in various plant and marine life (2). The marine-based omega-3 fatty acids primarily consist of eicosapentaenoic acid (EPA) and docosahexaenoic acid
(DHA) and appear to be highly biologically active. In contrast, those from plants (flaxseed, walnuts, and canola oil) are usually in the form of the parent omega-3 fatty acid, alpha-linolenic acid. Although dietary alpha-linolenic acid can be endogenously converted to EPA and DHA (see the
metabolic pathways in Figure 1), research suggests that this occurs inefficiently to only 10%-15% (3).
In the last 150 years, rapid expansion in Western populations has been associated with a change in diet, with omega-3 polyunsaturated fatty acids from fish, wild game, and plants being replaced by saturated fats from
domestic animals and omega-6 polyunsaturated fatty acids from common vegetable oils (corn, safflower, and soybean) and other sources. These changes have resulted in a large increase in the ratio of omega-6 to omega-3 fatty acids in the general diet from 1:1 to more than 10:1 (4, 5). This has resulted in a high proportion of the common omega-6 fatty acid arachidonic acid, rather than EPA, in the cell membranes of most tissues, leading in turn to a high proportion of inflammatory eicosanoids (6). As shown in Figure 1, an increase in arachidonic acid also affects the production of EPA and DHA, owing to competition for metabolizing enzymes. Such dietary changes in fatty acid intake have been held to have numerous pathological consequences. For example, epidemiological evidence from the U.S. Multiple Risk Factor Intervention Trial for 12,866 middle-aged men identified significant inverse relations between omega-3 levels and cardiovascular disease (7). In relation to depression, both Smith (8) and Hibbeln and Salem (9) suggested that the sharp rises in rates of depression and other neurological disorders in the 20th century are being fueled by increased consumption of vegetable oils rich in omega-6 fatty acids. Indirect support for that hypothesis emerges from data indicating high levels of inflammatory eicosanoids derived from arachidonic acid in both patients
with unipolar depression and those with bipolar depression (10).
As epidemiological research (11) has shown wide variation in the annual prevalence of major depression across countries, a dietary determinant has been considered; several epidemiological studies have examined possible
links between fish consumption and mood disorders. The study results have been intriguing, and there have now been sufficient studies pursuing deficits in omega-3 fatty acids and treatment implications to encourage fine-focused
etiological and treatment studies. As further evidence of the research domain’s importance, the National Institutes of Health conducted a workshop on the links between omega-3 fatty acids and psychiatric disorders in 1998 (12). We now examine the possible contribution of omega-3 fatty acids to both the onset and treatment of mood disorders, by reviewing relevant studies.
Seafood Consumption and Community
Rates of Mood Disorders
Hibbeln (13) reported a very strong negative correlation
(r=-0.84) between fish consumption and major depression
in a cross-national depression database. Several
other studies (Table 1) have provided indirect support for
a link between seafood consumption and depression. For
instance, the prevalence of seasonal affective disorder appears
unexpectedly low in
report found no difference between winter and summer
scores for depression and anxiety for either sex in their
sample, arguing against any seasonality effect, and they
proposed that it might reflect some “unique features of the
Icelandic population.” Cott and Hibbeln (20) suggested
that this could be the high consumption of fish (225 lb/
person per year), as
lb/person per year) also had an unexpectedly low rate of
seasonal affective disorder. Other countries, with average
intakes of 50 to 70 lb, had much higher rates of seasonal affective
disorder, despite receiving more winter sunlight. In
support, McGrath-Hanna et al. (21) showed that as the
diet of circumpolar people changed from the traditional
one, based largely on fish and fish-eating animals, to one
of a largely Western nature, so rates of depression, seasonal
affective disorder, anxiety, and suicide rose. Further,
in a survey of 3,204 Finnish adults, Tanskanen et al. (17)
demonstrated that the likelihood of having depressive
symptoms was significantly higher among infrequent fish
consumers than among frequent consumers.
Negative studies have, however, also been reported.
Hakkarainen et al. (14) undertook a correlational study
nested within a randomized, controlled cancer prevention
trial of the antioxidants alpha-tocopherol and beta-carotene
in 29,133 men (ages 50 to 69 years) in
of fatty acids and fish consumption were calculated from a
questionnaire about food use. Self-reported depressed
mood was recorded three times annually, data on hospital
treatments for major depression were derived from the National
Hospital Discharge Register, and suicides were identified
from death certificates. No significant association of
fish consumption or intake of omega-3 fatty acids with any
outcome variable was found. However, as only dietary intake
was assessed and not actual levels of omega-3 fatty acids,
it is difficult to know whether there was any mechanistic interference from the antioxidant supplementation.
Further, the intake of EPA and DHA in this study was less than 0.5 g/day, most of the omega-3 fatty acid intake was alpha-linolenic acid, and as noted earlier, the conversion of alpha-linolenic acid to EPA and DHA is only 10%-15%. A urther possible explanation for these negative findings
may be the male-only cohort, since a recent prospective ohort study in Finland showed low fish consumption to b significantly associated with depression in women only (18), possibly reflecting gender differences in neurotransmitter and phospholipid metabolism.
Noaghiul and Hibbeln (16) examined possible links between seafood consumption and prevalence rates of bipolar disorder and schizophrenia. Simple exponential decay regressions quantified links between greater seafood consumption and lower lifetime prevalence rates of bipolar I,
bipolar II, and bipolar spectrum disorder, with the strongest association for bipolar II (r=-0.91). The lack of any association between seafood consumption and lifetime rate of schizophrenia was interpreted as reflecting specificity of the association to affective disorders.
Hibbeln (15) reported a cross-national ecological analysis of seafood consumption, DHA content of mothers’ milk, and the prevalence rate of postpartum depression. The prevalence varied nearly 50-fold, from 0.5% in
The median DHA intake of women from
third trimester, the fetus accumulates an average of 67 mg/day of DHA, in excess of the dietary intake of many women (23). Such transfer to the baby through the placenta and, subsequently, through breast milk poses a risk
to women of significant depletion of omega-3 fatty acids during pregnancy and lactation, thus possibly contributing to perinatal risk for depression. Hibbeln (15) therefore argued the need for controlled intervention trials to determine whether omega-3 fatty acids could prevent postpartum clinical depression and whether they might provide a viable alternative to pharmacological treatments. If efficacious, any such intervention has other advantages. First, studies in women (24, 25) and animals (26, 27) have indicated that omega-3 supplementation during pregnancy and the postpartum period is safe. Second, in a review of omega-3 fatty acids and postpartum depression (28), we argued that omega-3 supplementation in the perinatal period may have additional benefits for the infant’s neuro-development. Third, that same review highlighted the need to explore safe alternatives to antidepressant drug therapies for use in the perinatal period.
Quantifying Omega-3 and Depression
We now review several articles indicating links between key polyunsaturated fatty acids and the level of depression. One intrinsic advantage to this research domain is the capacity to pursue and quantify the proposed biological marker. Adams et al. (29) investigated relationships between depression severity and the levels and ratios of omega-3 and omega-6 long-chain polyunsaturated fatty acids in plasma and erythrocyte phospholipids in 20 moderately to severely depressed patients. Intakes of arachidonic acid and EPA were calculated from self-reported frequency of intake of a wide variety of foods and use of a locally constructed database of the content of long-chain polyunsaturated fatty acids in different foods. They reported a significant positive relation between depression severity and the ratio of erythrocyte phospholipid arachidonic acid to EPA and a negative relation between erythrocyte EPA and depression. The arachidonic acid/EPA ratio in plasma phospholipids was also significantly correlated
Tiemeier et al. (30) screened 3,884 subjects age 60 or older in
reference subjects. The subjects with depressive disorders had significantly lower concentrations of omega-3 fatty acids and a significantly higher ratio of omega-6 to omega-3 fatty acids. As such associations were not secondary
to inflammation, atherosclerosis, or several other possible confounders, a direct effect of fatty acid composition on mood was inferred.
Maes and colleagues (31) compared 36 subjects with major depression, 14 with minor depression, and 24 nondepressed patients. Those with major depression had a significantly higher ratio of arachidonic acid to EPA in
both serum cholesteryl esters and phospholipids and a significantly higher omega-6/omega-3 ratio than did the nondepressed subjects and those with minor depression. Such subjects also had significantly lower alpha-linolenic
acid and lower total omega-3 in serum cholesteryl esters and lower EPA in both serum cholesteryl ester and phospholipid fractions. In a study extending these results, Maes et al. (32) studied 34 inpatients with major depression
and 14 normal volunteers. Major depression was associated with lower EPA and total omega-3 levels and a higher omega-6/omega-3 ratio in cholesteryl esters and phospholipids. However, in this study there was no significant
effect of antidepressant treatment on any of the polyunsaturated fatty acids. The authors suggested that major depression is associated with a deficiency of omega-3 fatty acids (which may act as a trait marker) and a compensatory increase of monounsaturated fatty acids and omega-6 fatty acids in phospholipids. Edwards et al. (33) reported a study of 10 depressed patients
and 14 comparison subjects in which erythrocyte membrane fatty acids were measured; the authors took account of age, gender, stress level, and smoking habits and included a full dietary analysis. The erythrocyte membrane
omega-3 levels were significantly lower in the depressed patients. Peet et al. (34) undertook a similar study of 15 depressed patients and 15 healthy well-matched comparison subjects, and they found that the erythrocyte omega-3 levels of the depressed patients were significantly lower. Ten of the depressed patients were retested after 6 weeks’ treatment with either lofepramine or amisulpride. Total omega- 3 and DHA levels had increased from pretreatment levels but were still significantly below those of the comparison subjects. However, erythrocyte samples from both depressed
and comparison subjects were then incubated with hydrogen peroxide, resulting in no significant difference in either total omega-3 or DHA level between any samples. This raises the possibility that the low erythrocyte
omega-3 and DHA levels of the depressed patients may have been due to oxidative attack.
Mamalakis et al. (35) investigated possible relationships between polyunsaturated fatty acids in adipose tissue (an index of long-term or habitual fatty acid intake) and lower mood in a group of 247 healthy adults. The mildly depressed subjects had significantly lower adipose tissue DHA levels than the nondepressed subjects. The authors speculated that, as depression has been reported to be associated with increased cytokine production and as fish oil and omega-3 fatty acids may inhibit inflammatory cytokine synthesis, the observed negative association between adipose DHA and depression may stem from the inhibiting effect of DHA on inflammatory cytokine synthesis. One study (36) examined possible abnormalities in patients with bipolar I disorder. The erythrocyte concentrations
of polyunsaturated fatty acids in 20 patients and 20 comparison subjects were compared. The bipolar subjects had significantly lower levels of arachidonic acid and DHA, but there were no differences between groups in total omega-3 and omega-6 compositions (or in the omega-6/omega-3 ratio).
Possible Mechanisms for Links Between Fatty Acid Abnormalities and
Several neurophysiological mechanisms have been proposed to explain the relationship between omega-3 polyunsaturated fatty acids and depression, such as the one proposed by Mamalakis et al. (35). The two omega-3 fatty
acids, EPA and DHA, appear to decrease the production of inflammatory eicosanoids from arachidonic acid by means of two mechanisms (37). First, they compete with arachidonic acid for incorporation into membrane phospholipids, decreasing both cellular and plasma levels of arachidonic acid. Second, EPA competes with arachidonic acid for the cyclo-oxygenase enzyme system, inhibiting the production of proinflammatory eicosanoids derived from arachidonic acid (e.g., prostaglandins, leukotrienes, and thromboxanes), and prostaglandin E2 and thromboxane B2 have been linked to depression. DHA and EPA also inhibit the release of proinflammatory cytokines, such as interleukin-1 beta, interleukin-2, interleukin-6, interferon-
gamma, and tumor necrosis factor alpha, which depend on eicosanoid release and are also associated with depression (38). Further, omega-3 fatty acids affect brainderived neurotrophic factor, which encourages synaptic
plasticity, provides neuroprotection, enhances neurotransmission,
and has antidepressant effects (39).
Another possible mechanism relates to the abundance of DHA in CNS membrane phospholipids, where it plays a vital role in maintaining membrane integrity and fluidity (40). By varying lipid concentrations in cell membranes, changes in fluidity can affect either the structure or functioning
of proteins embedded in the membrane, including enzymes, receptors, and ion channels, leading to changes in cellular signaling. Support for involvement of omega-3fatty acids in receptor functioning, neurotransmitter levels, and the metabolism of monoamines implicated in depression
has been provided by animal studies (see references 9 and 38).
The hypothesis that omega-3 polyunsaturated fatty acids can affect cell membrane fluidity is supported by a recent study using magnetic resonance imaging (41). Twelve women with bipolar disorder received omega-3 fatty acids for 4 weeks and were contrasted with two nontreatment groups. T2 whole-brain relaxation times were used to detect changes in membrane fluidity, measured at baseline and 4 weeks after treatment initiation. The bipolar subjects receiving omega-3 fatty acids had significant decreases in
T2 values, with a dose-dependent effect shown by subdividing the treatment group into patients receiving a high dose (10 g/day) and those receiving a low dose (2 g/day). Another postulated, more direct mechanism involves gene expression and the binding of fatty acids to specific nuclear receptors early in life, leading to genetic transcription (42) and predisposing to a range of diseases with DHA and EPA depletion later in life, such as Alzheimer’s disease, cardiac disease, and depression.
We now review a series of treatment studies, summarized in Table 2 with effect sizes calculated by us for relevant studies.
Stoll et al. (48) undertook a 4-month double-blind, placebo-controlled trial with patients who had bipolar disorder; 14 received omega-3 fatty acids, and 16 received placebo (olive oil). As most were also receiving a mood
stabilizer, this was essentially an augmentation strategy, and the principal outcome measure was the duration of time before symptom exacerbation led to study exit. Those in the omega-3 group reported greater symptom reduction and remained in remission for a significantly longer time. Consideration of the noncompleters in the 4-month study is of some interest. In the omega-3 group, three of the 14 were noncompleters because of mania, hypomania, and worsening of a mixed state, respectively. In the placebo group, 10 of the 16 were noncompleters, nine because of worsening depression and one because of a “continued mixed state.” Such indicative data were interpreted as demonstrating an antidepressant effect of omega-3 fatty acids, while the authors noted that the baseline clinical state of their subjects did not allow evaluation of any antimanic effect of omega-3 fatty acids. Thus, while this study is commonly viewed as demonstrating the benefits of omega-3 fatty acids for bipolar disorder, it may also be that this study demonstrated more the antidepressant potential of omega-3 fatty acids. Subsequently, Osher et al. (45) reported an open-label study with patients who had bipolar I disorder and reported depressive symptoms and/or being functionally impaired. Their current pharmacotherapy was maintained during adjunct treatment.
Of the 10 patients who attained 1-month follow-up, eight had a 50% or greater reduction in depression score within 1 month. Su et al. (49) reported a double-blind, placebo-controlled trial of omega-3 fatty acids for major depression in 22 patients, 12 treated with omega-3 fatty acids and 10
with an olive oil placebo, in addition to their existing medication.
Participants in the omega-3 group had a significantly lower score on the Hamilton Depression Rating Scale from the 4th treatment week. Effects on erythrocyte fatty acid composition were also examined. The mean post-reatment level of DHA in the omega-3 patient group was significantly higher than at pretreatment, whereas the posttreatment level of EPA was not significantly different from the pretreatment level. By contrast, there were no significant differences between pre- and posttreatment levels of DHA or EPA for patients in the placebo group. Nemets et al. (44) reported a 4-week parallel-group, double-blind addition of either placebo or ethyl-EPA to
ongoing antidepressant therapy for 20 patients with recurrent unipolar depressive disorder. Improvement in the group receiving EPA was significant from week 2 and was highly significant from week 3, and at the end of the 4 weeks the mean reduction in
points for the EPA group and 1.6 points for the placebo
group. However, in another controlled augmentation trial
for community-recruited subjects with moderate levels of
depression, Silvers et al. (47) found no support for 3 g/day of fish oil supplementation of antidepressant medication, despite significant increases in both EPA and DHA in erythrocyte membranes.
Peet and Horrobin (46) studied the effects of ethyl-EPA in patients with ongoing depression despite apparently adequate treatment with standard antidepressant drugs. The 70 patients (ages 18 to 70, male and female) were divided into four groups of approximately equal size. One group took four capsules of paraffin oil placebo per day, the second group took one capsule containing 1g of ethyl-EPA and three of placebo, the third group received two capsules of ethyl-EPA and two of placebo, and the fourth group took four capsules of ethyl-EPA. Thus, the group members consumed 0, 1, 2, and 4 g of ethyl-EPA per day, respectively. All patients continued to received their antidepressant medications. The group taking 1 g/day showed strong beneficial effects on items rating depression, anxiety, sleep, lassitude, libido, and suicidality. The group taking 2 g/day showed little evidence of efficacy, whereas the group taking 4 g/day showed nonsignificant improvement.
The suggested curvilinear dose response (across three depression measures) in this omega-3 augmentation study may reflect the relatively low group numbers or a valid dose difference.
Marangell et al. (43) reported a randomized, doubleblind, placebo-controlled trial of DHA monotherapy for patients with a major depressive episode. The patients were randomly assigned to receive either DHA (N=18) or placebo (N=17) for 6 weeks. The response rates were 27.8% in the DHA group and 23.5% in the placebo group, and the difference was not formally significant. The differing results across the last three studies have been interpreted as possibly reflecting differential antidepressant efficacy of EPA and DHA. Zanarini and Frankenburg (50) studied the comparative efficacy of EPA and placebo in female subjects meeting formal criteria for a borderline personality disorder, not in receipt of any psychotropic medication, and not formally meeting criteria for a current major depressive episode. In contrast to the trial of Marangell et al. (43), the 8-week study (20 participants taking ethyl-EPA and 10 taking mineral oil placebo) established that those treated with EPA experienced a significantly greater reduction in depressive symptoms””as well as in overall aggression. Earlier, we noted the suggested link between seafood consumption and postpartum depression. Llorente et al. (51) reported a double-blind intervention study in which they sought to determine the effect of DHA supplementation on plasma phospholipid DHA content and on depression indices. Mothers planning to breast-feed were randomly assigned to receive either DHA (â‰ˆ200 mg/day) or placebo for 4 months after delivery, with depression levels assessed at baseline (delivery), 3 weeks, 2 months, and 4 months. At baseline, the mean plasma phospholipid DHA level was 3.15 mg/dl in the DHA-supplementation group and 3.31 mg/dl in the placebo group. At 4 months, the plasma phospholipid DHA levels were 8% higher (3.40 mg/dl) in the supplementation group and 31% lower (2.27 mg/dl) in the placebo group. While there were no group differences on depression measures at 4 months, this was a prevention study and the women did not have depression when recruited.
Do Omega-3 Fatty Acids Induce Switching?
As examined in controlled trials and reported in case study series, all antidepressant drugs appear to have some capacity to induce manic “switching,” although such a propensity appears less evident with the selective serotonin reuptake inhibitors and dual-action drugs than with tricyclic antidepressants and monoamine oxidase inhibitors (52). In fact, it was long held by many clinicians that an “effective antidepressant” should induce switching. Kinrys (53) reported the case of a woman with a history of major depressive disorder who had not taken antidepressants for 8 months. Five days after she began taking a aily dose of 1980 mg of DHA and 1320 mg of EPA, she became hypomanic, but after the cessation of this treatment she was euthymic in 2 days. In response to the suggestion that omega-3 fatty acids might have mood-elevating effects, Stoll et al. (54) replied that their group had treated more than 300 patients with various open-label omega-3 preparations, including high DHA/low EPA fish oil, high EPA/low DHA fish oil, and flaxseed oil, which contains alpha- linolenic acid (a shorter-chain polyunsaturated fatty acid), and they observed “fewer than 10 cases of apparent omega-3-induced hypomania or mania, almost all from flaxseed oil preparations.”
Do Omega-3 Fatty Acids Link Depression to Cardiovascular Disease?
Earlier we noted a large epidemiological study (7) identifying inverse relationships between omega-3 levels and cardiovascular disease. A number of studies have examined the nature of those associations in societies where
there is a high dietary intake of omega-3 fatty acids. In one such study (55), Newman et al. established that the extent of atherosclerotic lesions was lower in
fatty acids by Eskimos) and not genetic in origin. It is not surprising then that the well-known association between depression and cardiovascular disease has been interpreted (56, 57) as reflecting a common factor””a deficiency of omega-3 fatty acids. Severus et al. (56) noted numerous
studies showing that omega-3 fatty acids reduce the risk of primary cardiac arrest or sudden cardiac death (presumably through their antiarrhythmic properties and impact on heart rate variability) and that a high ratio of
arachidonic acid to DHA (omega-6/omega-3) ratio has been reported (58) in the heart muscle of men following sudden cardiac death. Low heart rate variability is a risk factor for sudden cardiac death and has been shown to be
associated with a reduced content of omega-3 fatty acids in platelet membranes of patients following myocardial infarction (59). In addition, fish oil supplementation led to an increase in heart rate variability in these patients (60). Severus et al. (57) concluded that the higher rate of cardiovascular disease in patients with depression may be the result of one or more still-unrecognized underlying physiological factors predisposing to both depression and cardiovascular disease, with omega-3 deficiency and a high homocysteine level being two possible determinants. A recent article is therefore of some relevance. Frasure-Smith et al. (61) recruited 812 individuals experiencing an acute coronary syndrome and contrasted a
subset of 54 who had major depression with another subset of age- and sex-matched nondepressed subjects. The depressed patients had significantly lower concentrations of total omega-3 and DHA than the matched comparison subjects and higher arachidonic acid/DHA, arachidonic
acid/EPA, and omega-6/omega-3 ratios. The authors noted that to their knowledge, while there had been many studies demonstrating low omega-3 levels in people who later develop coronary artery disease, this was the first
study showing lower omega-3 levels in plasma phospholipids of depressed patients with coronary artery disease. They reviewed studies indicating that depression is associated with lower total omega-3 levels; some of these studies identified significantly lower DHA, others indicated lower EPA, and others found a lower DHA-EPA combination. In addition, they noted that, while there were some variations in the studies examining omega-3 fatty acids as risk factors for coronary artery disease, “the most consistent
results parallel those for depression” (p. 894), and they argued the need for trials of dietary supplementation with long-chain omega-3 fatty acids in both patients with coronary artery disease and patients with depression. As a relative deficiency in essential omega-3 fatty acids has been strongly implicated as providing an increased risk for coronary artery disease and for depression, a deficiency in omega-3 fatty acids may act as a higher-order
variable increasing their independent risk and creating a spurious association.
There are now several cross-sectional studies showing associations between seafood consumption and rates of both depression and bipolar disorder. Such research postulates a plausible etiological factor. Further, and unusual in any pursuit of a psychiatric disorder, the biological risk factor can be measured, with several studies identifying lower concentrations of omega-3 fatty acids in patients with depression. Most, but not all, studies have examined levels in plasma rather than red blood cells. In terms of intervention, there are now several studies supporting omega-3 supplementation as having a distinct
antidepressant role. Predictably, because of the complexities intrinsic to the domain, much work will be required to determine which omega-3 fatty acid (and in what ratio to omega-6 fatty acids) is likely to have the greatest benefit and at what dose. Currently, there appears to be somewhat stronger support for EPA than for DHA in terms of antidepressant strength. However, this is of theoretical interest principally, as the two omega-3 fatty acids are not normally separated but given together as fish oil. It presently remains unclear whether omega-3 supplementation alone has antidepressant properties or whether omega-3 fatty acids may have greater potential as augmenters of standard antidepressants. Finally, while there are two
studies indicating efficacy of omega-3 supplementation for patients with bipolar disorder, it remains to be further investigated whether its identified benefits derive from a mood-stabilizing propensity or an antidepressant effect. Our review therefore suggests a raft of possible studies, as now noted. First, measurement issues need further clarification. Specifically, what is the most useful modality for measuring polyunsaturated fatty acids (i.e., adipose tissue, red blood cells, plasma), while there is a need to refine and calibrate questionnaires on food frequency and diet to ensure their links to measured levels of the biological markers (e.g., DHA, EPA, and arachidonic acid). Second, placebocontrolled trials require careful selection of an appropriate
placebo, given the possible influence of some oils (e.g., olive oil) on mood, the ethical considerations of using a proinflammatory omega-6 placebo, and the obvious fish aftertaste in intervention groups, risking identification.
Third, clarification of the risk factor is required. Specifically, which omega-3 fatty acid deficiency (DHA or EPA) or what ratio of omega-6 to omega-3 provides the greatest risk for mood disorders in general and for subsets of disorders (bipolar, unipolar, postpartum), what factors influence that risk factor (e.g., diet, maternal depletion during pregnancy), and what duration of dietary supplementation is required to correct any anomaly in polyunsaturated fatty acids. Fourth, further treatment studies should examine whether supplementation is beneficial””and which omega-3 fatty acid (EPA, DHA, or some combination) is optimal and whether there is specificity to differing mood disorder types. Fifth, does such supplementation have general effects on mood state or is it weighted toward antidepressant or mood-stabilizing effects, and therefore preferentially relevant to unipolar or bipolar disorder, or does it have even wider benefits (e.g., for anxiety or sleep disorders)? Sixth, treatment studies should identify whether such supplementation is of relevance only if there is an established omega-3 deficiency and whether supplementation has primary mood effects or is more an augmentor requiring a primary drug, such as an antidepressant. Thus, the study designs would broadly be compatible with those of standard pharmacotherapy trials but would have the advantage of being able to measure process issues, such as the biological markers. Seventh, if benefits from short-term treatment are demonstrated, extension studies would need to pursue their prophylactic potential. Eighth, treatment studies should be associated with pursuit of likely mechanisms, by means of functional MRI (as noted earlier) or other technologies. Ninth, the hypothesis that abnormal levels of omega-3 fatty acids may act as a higher-order variable that independently increases risk for coronary artery disease and for depression (and so suggesting a causal link between those two outcome variables) would benefit from refined studies. In this article we have reviewed components of an intriguing hypothesis linking a dietary contribution to variable rates of mood disorders. There is now a clear hypothesis linking disorder diathesis and variation with an identifiable risk factor and allowing a rational treatment approach. There is great opportunity for more specific etiological and treatment intervention studies. Further research into the essential polyunsaturated fatty acids and their relevance to psychiatric, cardiac, and more general health areas would benefit from fast tracking and enhancement of coordinated research endeavors.
1. Klerman G, Weissman MM: Increasing rates of depression. JAMA 1989; 261:2229-2235
2. Leaf A, Weber PC: A new era for the science of nutrition. Am J Clin Nutr 1987; 45:1048-1053
3. Eaton SB, Konner M: Paleolithic nutrition: a consideration of its nature and current implications. N Engl J Med 1985; 312:283-289
4. Holub BJ: Clinical nutrition, 4: omega-3 fatty acids in cardiovascular care. Can Med Assoc J 2002; 166:608-615
5. Emken EA, Adlof RO, Gulley RM: Dietary linoleic acid influences desaturation and acylation of deuterium-labeled linoleic and
linolenic acids in young adult males. Biochim Biophys Acta 1994; 1213:277-288
6. Endres S: Messengers and mediators: interactions among lipids, eicosanoids and cytokines. Am J Clin Nutr 1993; 57(5
7. Dolecek TA: Epidemiological evidence of relationships between
dietary polyunsaturated fatty acids and mortality in the
Multiple Risk Factor Intervention Trial. Proc Soc Exp Biol Med
8. Smith RS: The macrophage theory of depression. Med Hypotheses
9. Hibbeln JR, Salem N Jr: Dietary polyunsaturated fats and depression:
when cholesterol alone doesn’t satisfy. Am J Clin Nutr
10. Lieb J, Karmali R, Horrobin D: Elevated levels of prostaglandin
E2 and thromboxane B2 in depression. Prostaglandins Leukot
Med 1983; 10:361-367
11. Weissman MM, Bland RC, Canino GJ, Faravelli C, Greenwald S,
Hwu HG, Joyce PR, Karam EG, Lee CK, Lellouch J, Lepine JP,
H, Yeh EK: Cross-national epidemiology of major depression
and bipolar disorder. JAMA 1996; 276:293-299
12. Omega-3 Essential Fatty Acids and Psychiatric Disorders, workshop
presented at National Institutes of Health, Sept 2-3,
13. Hibbeln JR: Fish consumption and major depression (letter).
Lancet 1998; 351:1213
14. Hakkarainen R, Partonen T, Haukka J, Virtamo J, Albanes D,
Lonnqvist J: Is low dietary intake of omega-3 fatty acids associated
with depression? Am J Psychiatry 2004; 161:567-569
15. 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; 69:15-
16. Noaghiul S, Hibbeln JR: Cross-national comparisons of seafood
consumption and rates of bipolar disorders. Am J Psychiatry
17. Tanskanen A, Hibbeln JR, Tuomilehto J, Uutela A, Haukkala A,
Viinamaki H, Lehtonen J, Vartiainen E: Fish consumption and
depressive symptoms in the general population in
Psychiatr Serv 2001; 52:529-531
18. Timonen M, Horrobin D, Jokelainen J, Laitinen J, Herva A,
RÃ¤sÃ¤nen P: Fish consumption and depression: the Northern
19. Magnusson A, Axelsson J, Karlsson MM, Oskarsson H: Lack of
seasonal mood change in the Icelandic population: results of a
cross-sectional study, Am J Psychiatry 2000; 157:234-238
20. Cott J, Hibbeln JR: Lack of seasonal mood change in Icelanders
(letter). Am J Psychiatry 2001; 158:328
21. McGrath-Hanna NK, Greene DM, Tavernier RJ, Bult-Ito A: Diet
and mental health in the
for mental health in circumpolar peoples?””a review. Int J Circumpolar
Health 2003; 62:228-241
22. Meyer B, Mann N, Lewis J, Milligan GC, Sinclair AJ, Howe PR: Dietary
intakes and food sources of omega 6 and omega 3 polyunsaturated
fatty acids. Lipids 2003; 38:391-398
23. Innis SM: Perinatal biochemistry and physiology of long-chain
polyunsaturated fatty acids. J Pediatr 2003; 143(4 suppl):S1-S8
24. Onwude JL, Lilford RJ, Hjartardattir H,
randomised double blind placebo controlled trial of fish oil in
high risk pregnancy. Br J Obstet Gynaecol 1995; 102:95-100
25. Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ, Gluud C: Randomized
clinical trials of fish oil supplementation in high risk
pregnancies. Br J Obstet Gynaecol 2000; 107:382-395
26. Burns RA, Wibert GJ, Diersen-Schade DA, Kelly CM: Evaluation
of single-cell sources of docosahexaenoic acid and arachidonic
acid: 3-month rat oral safety study with an in utero phase.
Food Chem Toxicol 1999; 37:23-36
27. Arterburn LM, Boswell KD, Koskelo E, Kassner SL, Kelly C, Kyle
DJ: A combined subchronic (90-day) toxicity and neurotoxicity
study of a single-cell source of docosahexaenoic acid triglyceride
(DHASCO oil). Food Chem Toxicol 2000; 38:35-49
978 Am J Psychiatry 163:6, June 2006
OMEGA-3 FATTY ACIDS
28. Rees AM, Austin MP, Parker G: The role of omega-3 fatty acids
as a treatment for depression in the perinatal period. Aust NZ
J Psychiatry 2005; 39:274-280
29. Adams PB, Lawson S, Sanigorski A, Sinclair AJ: Arachidonic acid
to eicosapentaenoic acid ratio in blood correlates positively
with clinical symptoms of depression. Lipids 1996; 31(March
30. Tiemeier H, van Tuijl HR, Hofman A, Kiliaan AJ, Breteler MM:
Plasma fatty acid composition and depression are associated
in the elderly: the
31. Maes M, Smith R,
H: Fatty acid composition in major depression: decreased
omega-3 fractions in cholesteryl esters and increased C20:4
omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids.
J Affect Disord 1996; 38:35-46
32. Maes M,
HY: Lowered omega 3 polyunsaturated fatty acids in serum
phospholipids and cholesteryl esters of depressed patients.
Psychiatry Res 1999; 85:275-291
33. 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 Disord 1998; 48:149-155
34. Peet M, Murphy B, Shay J, Horrobin D: Depletion of omega-3
fatty acid levels in red blood cell membranes of depressive patients.
Biol Psychiatry 1998; 43:315-319
35. Mamalakis G, Tornaritis M, Kafatos A: Depression and adipose
essential polyunsaturated fatty acids. Prostaglandins Leukot
Essent Fatty Acids 2002; 67:311-318
36. Chiu C-C, Huang S-Y, Su K-P, Lu M-L, Huang M-C, Chen C-C, Shen
WW: Polyunsaturated fatty acid deficit in patients with bipolar
mania. Eur Neuropsychopharmacol 2003; 13:99-103
37. Boissonneault GA: Dietary fat, immunity, and inflammatory
disease, in Fatty Acids in Foods and Their Health Implications.
Edited by Chow CK.
possible mechanisms and therapeutic value in major depression.
Altern Med Rev 2003; 8:410-425
39. Ikemoto A, Nitta A, Furukawa S, Ohishi M, Nakamura A, Fujii Y,
Okuyama H: Dietary omega 3 fatty acid deficiency decreases
nerve growth factor content in rat hippocampus. Neurosci Lett
40. Yehuda S, Rabinovitz S, Carasso RL, Mostofsky DI: Fatty acids
and brain peptides. Peptides 1998; 19:407-419
41. Hirashima F, Parow AM, Stoll AL, Demopulos CM, Damico KE,
Rohan ML, Eskesen JG, Zuo CS, Cohen BM, Renshaw PF:
Omega-3 fatty acid treatment and T2 whole brain relaxation
times in bipolar disorder. Am J Psychiatry 2004; 161:1922-
42. Sampath H, Ntambi JM: Polyunsaturated fatty acid regulation
of gene expression. Nutr Rev 2004; 62:333-339
43. Marangell LB,
LJ: A double-blind, placebo-controlled study of the
omega-3 fatty acid docosahexaenoic acid in the treatment of
major depression. Am J Psychiatry 2003; 160:996-998
44. 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; 159:477-479
45. Osher Y, Bersudsky Y, Belmaker RH: Omega-3 eicosapentaenoic
acid in bipolar depression: report of a small open-label
study. J Clin Psychiatry 2005; 66:726-729
46. 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; 59:913-919
47. Silvers KM, Wooley CC,
double-blind placebo-controlled trial of fish oil in the
treatment of depression. Prostaglandins Leukot Essent Fatty
Acids 2005; 72:211-218
48. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond
E, Cress KK, Marangell LB: Omega 3 fatty acids in bipolar
disorder: a preliminary double-blind, placebo-controlled trial.
Arch Gen Psychiatry 1999; 56:407-412
49. Su KP, Huang SY, Chiu CC, Shen WW: Omega-3 fatty acids in major
depressive disorder: a preliminary double-blind, placebocontrolled
trial. Eur Neuropsychopharmacol 2003; 13:267-271
50. Zanarini MC, Frankenburg FR: Omega-3 fatty acid treatment of
women with borderline personality disorder: a double-blind,
placebo-controlled pilot study. Am J Psychiatry 2003; 160:167-
51. Llorente AM, Jensen CL, Voigt RG, Fraley JK, Berretta MC, Heird
WC: Effect of maternal docosahexaenoic acid on postpartum
depression and information processing. Am J Obstet Gynecol
52. Parker G, Parker K: Which antidepressants flick the switch?
Aust NZ J Psychiatry 2003; 37:464-468
53. Kinrys G: Hypomania associated with omega-3 fatty acids (letter).
Arch Gen Psychiatry 2000; 57:715-716
54. Stoll AL, Damico KE, Marangell LB, Severus WE: Reply to Su K-P,
Shen WW, Huang S-Y: Are ïƒ¹3 fatty acids beneficial in depression
but not mania? (letter). Arch Gen Psychiatry 2000; 57:716-
55. Newman WP, Middaugh JP,
in Alaska Natives and non-natives. Lancet 1993; 341:1056-
56. Severus WE, Ahrens B, Stoll AL: Omega-3 fatty acids””the missing
link? (letter). Arch Gen Psychiatry 1999; 56:380-381
57. Severus WE,
and the increased risk of cardiovascular mortality
in major depressive disorder. Harv Rev Psychiatry 2001; 9:280-
58. Gudbjarnason S, Benediktsdottir VE, Skuladottir G: Effects of
omega-3 polyunsaturated fatty acids on coronary heart disease.
Bibl Nutr Dieta 1989; 43:1-12
Dyerberg J, Schmidt EB: Fish consumption, omega-3 fatty acids
in cell membranes, and heart rate variability in survivors of
myocardial infarction with left ventricular dysfunction. Am J
Cardiol 1997; 79:1670-1673
Rasmussen K, Dyerberg J, Schmidt EB: Effect of fish oil on heart
rate variability in survivors of myocardial infarction: a doubleblind
randomized controlled trial. BMJ 1996; 312:677-678
61. Frasure-Smith N, Lesperance F, Julien P: Major depression is associated
with lower omega-3 fatty acid levels in patients with
recent acute coronary syndromes. Biol Psychiatry 2004; 55: