After reading this article, you will be familiar with:
•The ω-3 fatty acids.
•The link between ω-3 fatty acids and depression.
•The role of ω-3 fatty acids in the treatment of depression.
•The safety profile of ω-3 fatty acids.
According to the World Health Organization, by 2020, depression will be second only to heart disease as a cause of disability and premature death in established market economies. With unsatisfactory monoamine-based pharmacotherapy and the high comorbidity of medical illnesses in depression, the serotonin hypothesis seems to be insufficient in determining the cause of depression. Recently, ω-3 polyunsaturated fatty acids have been gaining attention as a promising alternative treatment for mood disorders, based on epidemiological evidence, preclinical trials, case-control studies, and clinical trials. This review provides an overview of the efficacy, safety, and possible mechanisms of action of ω-3 polyunsaturated fatty acids in the treatment of depression.
The Essential Fatty Acids
There are 2 main types of essential fatty acids in humans, the ω-3 derived from a-linolenic acid and the v-6 series derived from linoleic acid. Although a-linolenic acid is easily converted to eicosapentaenoic acid (EPA), the conversion from a-linolenic acid to docosahexaenoic acid (DHA) is inefficient in humans (less than 0.1%). Because essential fatty acids cannot be synthesized de novo, they must be obtained from the diet. a-Linolenic acid comes mainly from plant sources, such as flax and canola oil, while EPA and DHA are obtained from marine sources, such as tuna, salmon, mackerel, and sardines. On the other hand, the main sources of v-6 linoleic acid are seed oil–based margarines, soy oil, sunflower oil, and safflower oil. Linoleic acid alone accounts for 10% of all calories in the US diet and by suppressing conversion of a-linolenic acid, creates greater dietary requirements for EPA and DHA consumption to achieve adequate levels in tissue.
Anthropological and epidemiological data indicate that humans evolved on a shore-based diet with abundant seafood and few calories from seed oils. This may have permitted hominid encephalization. In contrast, typical Western diets are now nearly devoid of adequate seafood and have excessive linoleic acid. An excess of v-6 fatty acids leads to increased low-density lipoprotein oxidation, platelet aggregation, and alterations in the cell membrane structure. Thus, high dietary intakes of v-6 fatty acids may cause a shift toward the proinflammatory, prothrombotic, and proconstrictive state, thereby promoting the pathogenesis of many illnesses, such as cardiovascular disease and cancer.
The Link Between Omega-3 Fatty Acids and Depression
Evidence for the benefits of ω-3 fatty acids has been found in animal models as well as in clinical trials. In humans, a cross-national study found that higher fish consumption was well correlated with a lower annual prevalence of major depression. Greater seafood consumption has also been found to predict lower rates of postpartum depression and bipolar disorders in similar cross-national analyses.[8,9] In cross-sectional investigations, infrequent fish consumption has been found to be independently associated with depressive symptoms and a higher rate of depression. However, the association between ω-3 polyunsaturated fatty acid intake and depression is not always consistent in cohort studies.[12,13]
Consistent with the finding that societies with a high consumption of fish appear to have a lower prevalence of mood disorders, abnormal levels of fatty acids in patients with mood disorders have been frequently reported. In 1996, Maes and colleagues found a significant decrease of total ω-3 polyunsaturated fatty acids, a-linolenic acid, and EPA in serum cholesterol esters of patients with major depressive disorder compared with those with minor depression or nondepressed controls.
By measuring polyunsaturated fatty acid levels in the red blood cell membrane, a significant depletion of total ω-3 polyunsaturated fatty acids and DHA was also reported in depressed patients who discontinued their medications for at least 7 days after recruitment. Moreover, a low level of ω-3 fatty acids in red blood cell membranes is a possible risk factor for suicide attempt. Lower levels of total ω-3 fatty acids (compared with the general adult population) were also found in women with postpartum depression. In community studies, percentages of ω-3 polyunsaturated fatty acids and ratios of ω-3 to v-6 polyunsaturated fatty acids were significantly lower in elderly persons with depressive disorders than in controls.
In general, the severity of depression has been found to correlate negatively with red blood cell membrane levels and with dietary intake of ω-3 polyunsaturated fatty acids, and positively with the ratio of arachidonic acid to EPA in plasma and red blood cell membrane phospholipids.[19,20] Patients with bipolar mania had a lower percentage of arachidonic acid and DHA in a case-control study. Manic symptom severity correlated negatively with levels of free arachidonic acid and free EPA, and positively with the ratio of free arachidonic acid/EPA.
The hypothesis regarding the antidepressant effects of ω-3 polyunsaturated fatty acids has been further supported by studies in animals. Carlezon and colleagues first reported that ω-3 fatty acids alone or combined with uridine had an antidepressant effect in rats. The combination of fluoxetine and ω-3 fatty acids was shown to have better antidepressant effects than fluoxetine alone in the forced swimming test in Wistar rats, which suggests a synergistic effect. Moreover, the level of DHA in the brain was negatively correlated with immobility time and was positively correlated with swimming time. Furthermore, feeding rats lithium chloride, valproate, or carbamazepine reduced arachidonic acid turnover within brain phospholipids. This finding suggests that lithium and antimanic anticonvulsants act by targeting parts of the arachidonic acid cascade, which may be functionally hyperactive in mania.[26,27]
Omega-3 fatty Acids as Antidepressants
Several randomized, double-blind, placebo-controlled studies have been conducted to test the antidepressant effects of ω-3 polyunsaturated fatty acids in patients with major depressive disorder. Most of the studies have found beneficial effects of EPA or an EPA/DHA combination, although one study using DHA monotherapy in depression and another in subclinical depression showed no therapeutic effects.[28-32] In a dose-exploring study, supplementation with 1g daily of EPA seemed to be more efficacious than 2 or 4 g daily.29 Recently, EPA was found to be as effective as fluoxetine in controlling depressive symptoms, while an EPA/fluoxetine combination was significantly better than either EPA or fluoxetine alone, which suggests a synergistic effect.
The antidepressant effects of ω-3 polyunsaturated fatty acids have been supported by 2 recent meta-analyses of patients with unipolar and bipolar depression pooled for analysis.[34-35] Although another meta-analysis found efficacy when participants with confirmed depression were included, it did not support the antidepressant effects of ω-3 fatty acids when heterogeneous populations (eg, community samples) were included. This negative finding needs to be interpreted with caution because of a few limitations, such as pooling heterogeneous populations, using different mood assessments, and implementing different intervention methods.[36-37]
Patients with bipolar disorder benefited from ω-3 fatty acids in a 4-month, double-blind, randomized controlled trial. The improvement, however, may have been a consequence of antidepressant, but not antimanic, effects. The hypothesis that ω-3 fatty acids are not beneficial for the manic phase of bipolar disorder is supported by our preliminary double-blind, randomized controlled trial. In addition, ω-3 polyunsaturated fatty acid supplementation was shown to be effective in patients with bipolar depression in other studies.[41,42] Another double-blind, randomized, placebo-controlled study, however, did not find evidence of efficacy for the adjunctive treatment of EPA 6 g daily in patients with bipolar depression or rapid cycling bipolar disorder.
Monotherapy with ω-3 polyunsaturated fatty acids may be promising in the treatment of pregnant women with depression. We reported the first successful use of ω-3 polyunsaturated fatty acids as monotherapy in a pregnant woman with major depression. In our recent 8-week intervention trial, ω-3 polyunsaturated fatty acid monotherapy significantly improved depressive symptoms compared with placebo.45 ω-3 Polyunsaturated fatty acids were well tolerated, and there were no adverse effects on the mothers or newborns.[45-47] However, a study using ω-3 polyunsaturated fatty acids on a heterogeneous sample of pregnant (n = 12) and postnatal (n = 14) patients showed no positive effects. Furthermore, results from a study that combined ω-3 polyunsaturated fatty acids or placebo with supportive psychotherapy were also negative. Future studies using larger sample sizes with a broader dosage regimen and varying compositions of ω-3 polyunsaturated fatty acids in pregnant women with depression are needed before we can suggest ω-3 polyunsaturated fatty acids as a first-line treatment for depressive disorders in pregnancy.
There is considerable evidence in support of the antidepressant effects of ω-3 fatty acids. ω-3 Polyunsaturated fatty acids were found to have highly significant effects on depressive symptoms with no clinically relevant adverse effects in children (aged 6 to 12 years) who were depressed. Furthermore, in patients with recurrent self-harm, thegroup that received supplementation had significantly improved scores for depression, suicidality, and daily stress. Moreover, diminished aggression and severity of depressive symptoms were observed in women with borderline personality disorder. In conjunction with multivitamins and minerals, ω-3 polyunsaturated fatty acids reduced felony-level violent offenses in prisoners by 37%. In addition to the antidepressant effects, ω-3 fatty acids may have broader therapeutic effects, including improvements in adverse impulse control and aggression.
Safety Profile of Omega-3 Polyunsaturated Fatty Acids
ω-3 Polyunsaturated fatty acids have been shown in numerous clinical studies to be well tolerated by patients with chronic medical illness or mental disorders and by pregnant women. In these studies, adverse events were rare.
It has been suggested that the potential antithrombotic effect of ω-3 polyunsaturated fatty acids may theoretically increase the risk of bleeding. Clinical trials have shown the consumption of high-dose ω-3 polyunsaturated fatty acids to be safe, even when concurrently administered with other agents that may increase bleeding, such as aspirin and warfarin. According to Harris’s systematic review of 19 clinical trials with ω-3 polyunsaturated fatty acid supplementation for patients with a high risk of bleeding (n = 4397), the risk of clinically significant bleeding was “virtually nonexistent.”
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