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The Role of Omega-3 Fatty Acids in Psychiatric and Neurological Disorders

                Dietary factors may be at least partially responsible for the increase in the incidence of depression and other psychiatric illnesses in Western societies in the past few decades. One factor that may be particularly important is the level of consumption of omega-6 essential fatty acids compared with omega-3 essential fatty acids. The ratio of omega-6 to omega-3 fatty acids in the diet of the general population has risen over the past 150 years from around 1:1 to more than 10:1.¹ Both omega-3 and omega-6 are long-chain polyunsaturated fatty acids. They are called essential fatty acids because we have to get them from dietary sources; they are not synthesized by the human body. Omega-3 fatty acids come from fish and some plant sources, while omega-6 fatty acids come mostly from vegetable oils.

                Omega-3 fatty acids are important in the make-up of brain and nerve cell membranes, in the development of the nervous system, and in the functioning of neurotransmitters. Optimal intake of omega-3 fatty acids may improve cardiovascular health, decrease the risk of some cancers, and prevent gastrointestinal, bone, and respiratory illnesses.² A lack of omega-3 fatty acids in the diet could be a cause of mood and neurological disorders, like depression or Alzheimer's disease. Along those lines, increasing consumption of omega-3 fatty acids might prevent these illnesses or play a role in their treatment.

Epidemiological studies

                Studies comparing prevalence rates of mood disorders cross-nationally find that countries with lower consumption of fish per capita have 30- to 60-fold higher rates of major depression, postpartum depression, and bipolar disorder.² Most studies analyzing populations within individual countries also find a higher incidence of depressive symptoms associated with lower fish consumption. In addition, some countries with high per capita seafood consumption---for example, Iceland (225 lb/person per year) and Japan (147 lb/person per year)---have lower prevalence rates of seasonal affective disorder than countries at the same latitude, which get more winter sunlight but have average annual fish intakes of only 50 to 70 lb/person.³

Tissue studies

                Several studies have found lower levels of omega-3 fatty acids in the blood or fat tissue of subjects with major depressive disorder than in controls.² While this suggests an association between the two conditions, this kind of study cannot determine whether the low levels occurred before or after a person became depressed nor what caused them. Having a psychiatric disorder may influence how a person eats and therefore cause low levels of omega-3 fatty acids through dietary choices. Also, genetic factors may influence how fatty acids are metabolized, degraded, or oxidized in patients with psychotic or affective disorders. Smoking may also lower omega-3 fatty acids levels. Smokers have lower levels of omega-3 fatty acids than nonsmokers, and there is a higher incidence of smoking among patients with psychiatric disorders than in the general population. The severity of psychiatric symptoms may influence diet, smoking, and self-care. Conversely, poor nutrition may contribute to the worsening of symptoms.

Mechanism of action

                The two main marine-based omega-3 fatty acids are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Some sources of EPA and DHA are salmon, mackerel, halibut, sardines, herrings, anchovies, tuna, oyster, and lobster.⁴ Alpha-linolenic acid (ALA) comes from plant sources and can be converted by the body to EPA and DHA (although this is an inefficient process). Some sources of ALA are flaxseeds, flaxseed oil, canola oil, soybeans, soybean oil, pumpkin seeds, walnuts, and perilla seed oil. Omega-3 fatty acids are concentrated in the membranes of synaptic nerve cells and retinal photoreceptors. They help regulate vascular and immune functions that affect the central nervous system. A biologically active lipid mediator compound derived from DHA regulates a gene-expression program that protects stressed human brain cells from inflammation and cell death.⁵

                The most common omega-6 fatty acid is arachidonic acid (AA). It competes with EPA and DHA for membrane space and is converted to inflammatory eicosanoids. The change in the ratio of omega-6 to omega-3 fatty acids in Western diets has led to a higher proportion of AA in the cell membranes of most tissues, rather than EPA. This leads to a high proportion of inflammatory eicosanoids, which can worsen dysfunctions of the immune, cardiovascular, renal, bone, and central nervous systems. The products of EPA metabolism, on the other hand, are anti-inflammatory.

                There are many different biological mechanisms through which omega-3 fatty acids may have an effect on psychiatric disorders. These include an increase in serotonergic neurotransmission, changes in dopaminergic function, suppression of some second messenger activity, a decrease in heart rate variability, an increase in nerve cell growth, the prevention of nerve cell death, improved blood flow in the brain, regulation of gene expression, and competition of EPA with AA for enzymatic action and a resulting decrease in the inflammatory response.²

Treatment studies

                A subcommittee of the American Psychiatric Association (APA), chaired by University of Arizona Associate Professor of Psychiatry, Obstetrics/Gynecology, and Nutritional Sciences, Marlene Freeman, MD, recently reviewed the scientific literature to evaluate the evidence base for the therapeutic use of omega-3 fatty acids in the treatment of psychiatric disorders.² Three double-blind, placebo-controlled studies of EPA or a combination of EPA and DHA as adjunctive treatment for antidepressant-refractory major depressive disorder found positive results.^6-8 Treatment response occurred quickly: significant differences were observed within 2 weeks in some cases. No serious adverse side effects were associated with the treatment. One of the studies that compared different doses of EPA found a better effect with 1 gram than with higher doses, suggesting that omega-3 fatty acids may have a maximally effective dose beyond which higher doses do not provide greater benefit.⁶

                In bipolar disorder, two of three double-blind, placebo-controlled trials reported benefits from EPA or the combination of EPA and DHA used as adjuncts or monotherapy.^9,10 The third found no significant difference from placebo.¹¹ The APA subcommittee pooled all studies of omega-3 fatty acids in bipolar and unipolar depression into one meta-analysis. Differences in the design and execution of each study (including different doses and combinations of omega-3 fatty acids used) produced widely different results, but omega-3 fatty acids produced a statistically significant improvement under both the best-case (P = .02) and the worst-case scenarios (P = .03).

                Omega-3 fatty acids have been studied for the treatment of depression in women both during and following pregnancy. The body's stores of omega-3 fatty acids decrease during pregnancy because DHA is selectively transferred to the fetus.² In the United States, pregnant women consume only 20% to 60% of the recommended levels of omega-3 fatty acids, possibly due in part to warnings that the mercury content in some fish could cause central nervous system problems in babies. But omega-3 fatty acids are necessary for optimal fetal brain and nervous system development, and inadequate intake increases the risk of intrauterine growth retardation and visual problems among children. One study found that EPA and DHA supplementation was superior to placebo at lengthening gestational age at delivery.¹² There is some evidence that adding omega-3 fatty acids to formula for preterm infants improves visual attention and cognitive development.¹³

                Results of studies in pregnant women have been mixed. In one small, open-label trial, a combined EPA and DHA supplement during pregnancy was associated with about a 40% reduction in scores on a postnatal depression scale.¹⁴ In a double-blind, randomized, dose-ranging trial in women with postpartum depression, depression scale scores were decreased by approximately 50% in those who took omega-3 fatty acids for 8 weeks.¹⁵ Two other studies found negative results: In an open-label prevention trial of seven pregnant women with a history of postpartum depression, EPA and DHA supplementation in the third trimester did not prevent postpartum depression.¹⁶ In a larger trial involving 138 breastfeeding mothers, the depression scores of women who took low-dose DHA supplements for 4 months after childbirth were not significantly different from those in women who received placebo.¹⁷

                Several studies have found benefit from adjunctive treatment with omega-3 fatty acids in schizophrenia. EPA was found to be significantly superior to DHA or placebo as an adjunctive medication in one study, and it significantly lowered scores on the Positive and Negative Syndrome Scale (PANSS) in another study where it was used as monotherapy.¹⁸ In a dose-ranging study, patients with schizophrenia who were taking clozapine (Clozaril and others) showed improvement with EPA augmentation, but those taking other antipsychotic medications did not. When the data from all published studies were pooled by the APA subcommittee, various analyses showed that, overall, omega-3 fatty acids fail to improve schizophrenic symptoms.²

                Data on the role of omega-3 fatty acids in the prevention or treatment of dementia are inconclusive at this time. A decreased level of plasma DHA seems to be common in cognitive impairment with aging, and the concentration of DHA in membrane phospholipids at synapses is decreased in the brains of people with Alzheimer's disease.⁴ In several animal studies, high DHA consumption has been associated with reduced risk of Alzheimer's disease.⁴ A prospective cohort study of 815 people, aged 65 to 94 years, who were followed for an average of 3.9 years, found that eating fish at least once a week lowered the risk of developing Alzheimer's disease by 60% compared with people who rarely or never ate fish.¹⁹ On the other hand, the Rotterdam Study, a prospective, cohort study that followed over 5,000 subjects for a mean of 6 years, did not show a protective effect of omega-3 fatty acid intake.²⁰ A recent, randomized, double-blind, placebo-controlled trial of dietary supplementation with DHA and EPA in 204 patients with mild to moderate Alzheimer's disease, with a mean age of 74 years, found no differences between groups after 6 months of treatment.²¹ In a small subgroup of patients with very mild cognitive dysfunction, however, supplementation did slow down cognitive decline.

                In children with attention-deficit hyperactivity disorder (ADHD), several studies have found depletions in omega-3 fatty acids in red blood cell membranes or plasma compared with controls.² The lowest levels of DHA were associated with more severe symptoms. Two placebo-controlled trials of adjunctive DHA treatment in ADHD found lack of benefit.^22,23 However, three other studies involving 208 children showed therapeutic benefit in children with behavior and learning difficulties from combined omega-3 and omega-6 fatty acid supplements.^24-26 Compared with placebo, there were improvements in teacher-rated attention, parent-rated conduct, reading and spelling progress, and teacher-rated ADHD symptoms, as well as fewer children who met clinical criteria for oppositional defiant disorder.

Conclusions

                From the epidemiologic and treatment studies that they reviewed, the APA subcommittee concluded that modest evidence supports the use of EPA or a combination of EPA and DHA as adjunctive treatment for several conditions, including mood disorders, schizophrenia, and ADHD. They support the recommendations of the American Heart Association, which state that adults should eat fish at least twice weekly, and patients with coronary heart disease should consume 1 g total of EPA plus DHA per day. The subcommittee does not recommend using supplementation with omega-3 fatty acids in place of established psychiatric treatment options.

                Even if further research finds that omega-3 fatty acids do not have direct benefits for mood disorders or other psychiatric illnesses, it is clear that they do for cardiovascular disease, which often occurs in conjunction with depression and worsens prognosis. In addition, many people with a mental illness smoke, which lowers omega-3 fatty acids in the body. For overall general health, following the guidelines of the American Heart Association makes sense. In addition, fish oil supplements do not appear to contain worrisome levels of mercury or other environmental contaminants, so they appear to be safe for use in pregnancy.

References

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3.             Cott J, Hibbeln JR: Lack of seasonal mood change in Icelanders. Am J Psychiatry 2001;158:328.
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22.           Bekaroglu M, Aslan Y, Gedik Y, Deger O, Mocan H, Erduran E, Karahan C: Relationships between serum free fatty acids and zinc, and attention deficit hyperactivity disorder: A research note. J Child Psychol Psychiatry 1996;37:225-227.
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24.           Stevens L, Zhang W, Peck L, Kuczek T, Grevstad N, Mahon A, Zentall SS, Arnold LE, Burgess JR: EFA supplementation in children with inattention, hyperactivity, and other disruptive behaviors. Lipids 2003;38:1007-1021.
25.           Richardson AJ, Montgomery P: The Oxford-Durham study: A randomized controlled trial of dietary supplementation with fatty acids in children with developmental coordination disorder. Pediatrics 2005;115:1360-1366.