This review provides an overview of the efficacy, safety, and mechanisms of action in the treatment of depression.
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, Ï-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 Ï-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 Ï-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 Ï-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 Ï-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 Ï-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 Ï-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 Ï-3 fatty acids in red blood cell membranes is a possible risk factor for suicide attempt. Lower levels of total Ï-3 fatty acids (compared with the general adult population) were also found in women with postpartum depression. In community studies, percentages of Ï-3 polyunsaturated fatty acids and ratios of Ï-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 Ï-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 Ï-3 polyunsaturated fatty acids has been further supported by studies in animals. Carlezon and colleagues first reported that Ï-3 fatty acids alone or combined with uridine had an antidepressant effect in rats. The combination of fluoxetine and Ï-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 Ï-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 Ï-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 Ï-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 Ï-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 Ï-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, Ï-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 Ï-3 polyunsaturated fatty acids may be promising in the treatment of pregnant women with depression. We reported the first successful use of Ï-3 polyunsaturated fatty acids as monotherapy in a pregnant woman with major depression. In our recent 8-week intervention trial, Ï-3 polyunsaturated fatty acid monotherapy significantly improved depressive symptoms compared with placebo.45 Ï-3 Polyunsaturated fatty acids were well tolerated, and there were no adverse effects on the mothers or newborns.[45-47] However, a study using Ï-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 Ï-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 Ï-3 polyunsaturated fatty acids in pregnant women with depression are needed before we can suggest Ï-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 Ï-3 fatty acids. Ï-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, Ï-3 polyunsaturated fatty acids reduced felony-level violent offenses in prisoners by 37%. In addition to the antidepressant effects, Ï-3 fatty acids may have broader therapeutic effects, including improvements in adverse impulse control and aggression.
Safety Profile of Omega-3 Polyunsaturated Fatty Acids
Ï-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 Ï-3 polyunsaturated fatty acids may theoretically increase the risk of bleeding. Clinical trials have shown the consumption of high-dose Ï-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 Ï-3 polyunsaturated fatty acid supplementation for patients with a high risk of bleeding (n = 4397), the risk of clinically significant bleeding was “virtually nonexistent.”
Oxidation of Ï-3 polyunsaturated fatty acid preparations is a potential problem, because it may lead to rancidity or toxicity. Adding vitamin E, an antioxidant, to Ï-3 polyunsaturated fatty acids is a common way to reduce rancidity, to maintain freshness, and to increase shelf life. The concurrent use of vitamin E with Ï-3 polyunsaturated fatty acids may also overcome the potential risk of oxidative stress.[56-58] However, even without the addition of vitamin E, Ï-3 polyunsaturated fatty acids have been found to decrease oxidative stress and increase levels of vitamin E.[59,60]
Theoretically, large amounts of fish consumption may also result in suboptimal fetal development because of the potential presence of environmental toxins such as mercury, polychlorinated biphenyls, dioxins, and other contaminants. These risks of exposure to environmental toxins are substantially reduced through purification processes used to concentrate fish oil supplements.[52,53] In addition, the nutritional benefits of maternal seafood consumption to fetal neuro-development appear to be significantly greater than the theoretical contaminant risks, even when mothers exceeded the 12 oz per week recommendation. Inadequate consumption of EPA and DHA appears to be detrimental to fetal neurodevelopment.
Since Ï-3 polyunsaturated fatty acids may have antidepressant effects, another possible adverse effect is drug-induced mania. Until now, there has only been one formal case report to show Ï-3 polyunsaturated fatty acid–induced hypomania. Further research is needed to clarify whether treatment with Ï-3 polyunsaturated fatty acids increases the risk for mania or hypomania.
Mechanisms of Antidepressant Effects
At the cellular level, Ï-3 fatty acids are incorporated into all cell membranes, but those of the retina, brain, and myocardium are particularly enriched. Furthermore, these fatty acids perform a plethora of duties, including facilitating the conformational changes of rhodopsin, assisting in nerve cell signaling and neurodevelopment, modulating the activities of cardiac ion-channel proteins, and modifying gene expression.
The anti-inflammatory effects of Ï-3 fatty acids are mediated by their interference with arachidonic acid metabolism. Arachidonic acid serves as the precursor to cellular mediators such as thromboxanes, prostaglandins, and leukotrienes. They compete with arachidonic acid for rate-limiting enzymes and for incorporation into cell membranes. At the molecular level, Ï-3 fatty acids can affect gene and protein expression, modulate membrane protein activity, and serve as a reservoir for bioactive molecules.
Several mechanisms have been proposed for the antidepressant effects of Ï-3 polyunsaturated fatty acids:
• First, Ï-3 polyunsaturated fatty acids regulate serotonergic and dopaminergic neurotransmitters in signal transduction.[66-68]
• Second, Ï-3 polyunsaturated fatty acids play an important role in mood stabilization by targeting parts of the “arachidonic acid cascade,” which has been identified as one of the mechanisms of mood stabilizers. The arachidonic acid cascade hypothesis in mood disorders has been supported by a number of findings, including higher levels of arachidonic acid and hyperactivity of its major metabolic enzyme phospholipase A2 (PLA2) in patients with mood disorders, the inhibitory effect on PLA2 activity of mood stabilizers, and the therapeutic effect of Ï-3 polyunsaturated fatty acids on persons with mood disorders.
• Third, EPA is important in balancing immune and neuronal functions by antagonizing membrane arachidonic acid, thereby reducing prostaglandin E2 (PGE2) synthesis. For example, animals fed a high–arachidonic acid diet or treated with PGE2 demonstrated behaviors, such as anorexia, low activity, and changes in sleep pattern and attention, that are similar to somatic symptoms of depression in humans.
• Fourth, EPA may have a beneficial effect on hypothalamic-pituitary-adrenal axis dysfunction, treatment-resistant depression, and multidrug resistance through the action of P-glycoprotein, which transports many substrates, including steroids and SSRIs.[25,72]
Prescribing Omega-3 Fatty Acids for Depression
As a result of more reports in the media and scientific journals, psychiatrists are facing increased inquiries from patients and their families about the use of Ï-3 polyunsaturated fatty acids for depression. While it is still too early to recommend Ï-3 polyunsaturated fatty acids as a primary treatment for depressive or other psychiatric disorders, their use as adjunctive therapy is recommended.
The Omega-3 Fatty Acids Subcommittee, assembled by the Committee on Research on Psychiatric Treatments of the American Psychiatric Association, has provided a list of clinical recommendations (Table 1). These serve as an endorsement of the guidelines of the American Heart Association. Hence, they do not include precise recommendations for specific depressive disorders. The committee noted that patients with psychiatric disorders are at disproportionate risk for cardiovascular and metabolic disorders. One example of a preventive strategy is the 22% reduction of the hypertriglyceridemia induced by clozapine when patients were given Ï-3 fatty acids. Concentrated EPA and DHA are now available by prescription for lowering triglycerides, and preparations include Lovaza at dosages of 2 to 4 g daily.
The evidence for using Ï-3 polyunsaturated fatty acids as adjunctive treatment in a special population of patients with mood disorders and comments on their use in clinical practice are presented in Table 2. In general, it is not recommended that patients with a psychiatric disorder stop their current pharmacological and/or psychosocial treatments while receiving Ï-3 fatty acid supplementation. In patients with refractory depression, persistent suicidal ideation, and/or impulsive behavior, Ï-3 polyunsaturated fatty acids may be considered as adjunctive therapy.[29,30,50,51,74] Despite the limited number of studies, findings indicate that Ï-3 polyunsaturated fatty acids may benefit people who have attempted suicide or those with recurrent self-harming behavior.[16,50]
Ï-3 Fatty acids may have a role in treating depression in pregnant women. The FDA has not approved any antidepressant for use in pregnancy, and although current antidepressants have not been proved to have adverse effects, recent data have raised the concern that pregnant women taking SSRIs during the third trimester may be at considerably increased risk for perinatal complications.[75,76] A profound decrease in maternal levels of Ï-3 polyunsaturated fatty acids during pregnancy is because of a higher demand of the fetus during development.[77,78] This depletion in the mother may precipitate the occurrence of depression.
Adequate maternal intake of Ï-3 polyunsaturated fatty acids is considered necessary for optimal development of the fetal brain and CNS during pregnancy. Hence, Ï-3 polyunsaturated fatty acid monotherapy, along with close monitoring of mental status and suicide risk, may be highly beneficial for pregnant women with mild or moderate depression.
Since the antimanic effect of Ï-3 polyunsaturated fatty acids has yet to be elucidated, monotherapy for patients with acute manic episodes may not be recommended. However, Ï-3 fatty acids may be considered as adjunctive therapy in patients with bipolar depression.
In addition to the general adult population, Ï-3 fatty acids may be considered as adjunctive therapy for depression in children, adolescents, and the elderly, especially those with a comorbid physical illness. In patients with a tendency for severe bleeding, bleeding time should be monitored.
Since most clinical trials of Ï-3 polyunsaturated fatty acids used different combinations (EPA, DHA alone, or a combination) and different dosages (less than 1g to 9.6 g daily), it is still not possible to recommend an optimal dose.[29,30,38] It is recommended that patients start at 1 g of EPA and/or DHA per day. Patients who frequently consume fish typically have higher tissue levels of Ï-3 polyunsaturated fatty acids; therefore, a higher initial dose of 2 to 4 g daily may be required in those who do not eat fish regularly. As with antidepressants, the therapeutic effects may not appear until after 4 weeks, but it may take longer in pregnant women.[30,45] For patients who have a partial response by 4 weeks, we recommend doubling the dose; for patients with little or no response, switching to or combining with other antidepressants is recommended.
The Ï-3 fatty acids may be useful adjunctive therapy for depression. In general, we do not recommend that patients stop their current pharmacological and/or psychosocial treatments while receiving Ï-3 fatty acid supplementation. For pregnant women, with careful monitoring, Ï-3 fatty acids may be considered as monotherapy. There are still some remaining questions in clinical applications, such as the appropriate dosage or the optimal ratio of EPA to DHA. More large-scale studies for the efficacy and safety of Ï-3 fatty acids in specific populations, such as children and the elderly, are needed before further recommendations can be made.
[Editor's note: The above article was published as a Category 1-CME in the August 2008 issue of Psychiatric Times (2008;25(9):76-80). The activity is now expired].
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