Oxidation of ω-3 polyunsaturated fatty acid preparations is a potential problem, because it may lead to rancidity or toxicity. Adding vitamin E, an antioxidant, to ω-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 ω-3 polyunsaturated fatty acids may also overcome the potential risk of oxidative stress.[56-58] However, even without the addition of vitamin E, ω-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 ω-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 ω-3 polyunsaturated fatty acid–induced hypomania. Further research is needed to clarify whether treatment with ω-3 polyunsaturated fatty acids increases the risk for mania or hypomania.
Mechanisms of Antidepressant Effects
At the cellular level, ω-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 ω-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, ω-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 ω-3 polyunsaturated fatty acids:
• First, ω-3 polyunsaturated fatty acids regulate serotonergic and dopaminergic neurotransmitters in signal transduction.[66-68]
• Second, ω-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 ω-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 ω-3 polyunsaturated fatty acids for depression. While it is still too early to recommend ω-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 ω-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 ω-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 ω-3 fatty acid supplementation. In patients with refractory depression, persistent suicidal ideation, and/or impulsive behavior, ω-3 polyunsaturated fatty acids may be considered as adjunctive therapy.[29,30,50,51,74] Despite the limited number of studies, findings indicate that ω-3 polyunsaturated fatty acids may benefit people who have attempted suicide or those with recurrent self-harming behavior.[16,50]
ω-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 ω-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 ω-3 polyunsaturated fatty acids is considered necessary for optimal development of the fetal brain and CNS during pregnancy. Hence, ω-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 ω-3 polyunsaturated fatty acids has yet to be elucidated, monotherapy for patients with acute manic episodes may not be recommended. However, ω-3 fatty acids may be considered as adjunctive therapy in patients with bipolar depression.
In addition to the general adult population, ω-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 ω-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 ω-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 ω-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 ω-3 fatty acid supplementation. For pregnant women, with careful monitoring, ω-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 ω-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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