Neurobehavioral Aspects of Omega-3 Fatty Acids:
Possible Mechanisms and Therapeutic Value
in Major Depression

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:    Frankp@chiro.org

FROM:   Alternative Medicine Review 2003 (Nov); 8 (4): 410–425 ~ FULL TEXT

Logan AC

CAM Research Consulting,
13 Stonewall Court,
Mahwah New Jersey 07430, USA.
aclnd@cfs-fm.org

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Omega-3 fatty acids have been the subject of volumes of international research, the results of which indicate these substances may have therapeutic value in a number of medical conditions. An emerging area of research is examining the neurobehavioral aspects of omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and the critical role of these essential fats in the functioning of the central nervous system. Investigations have linked omega-3 fatty acids to a number of neuropsychiatric disorders, including depression. The purpose of this article is to examine the possible mechanisms of action and potential clinical value of omega-3 fatty acids in major depression. A novel mechanism involving omega-3 modulation of cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) is proposed.

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Introduction

Omega-3 fatty acids are long chain, polyunsaturated fatty acids (PUFA) of plant and marine origin. Because these essential fatty acids (EFAs) cannot be synthesized in the human body, they must be derived from dietary sources. Flaxseed, hemp, canola, and walnuts are generally rich sources of the omega-3 PUFA alpha-linolenic acid (ALA). Fish provide varying amounts of omega-3 fatty acids in the form of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). ALA can be metabolized into the longer chain EPA and DHA (Figure 1). [1] The role played by EFAs in the human body has been the subject of volumes of international research, particularly in recent years. The results indicate that omega-3 fatty acids may be of value in the treatment of various medical conditions. [2]

The brain contains a high concentration of PUFA (approximately 20 percent of dry weight) and, in the nervous system, one out of every three fatty acids (FAs) belong to the PUFA group. [3, 4] Given the high concentration of EFAs in the nervous system, it is not surprising that investigators have focused on the role of omega-3 fatty acids in brain function. Recent research underscores the important role of these fatty acids in central nervous system (CNS) function, and the potential EFAs have in the treatment of various neuropsychiatric disorders. While beneficial effects of omega-3 fatty acids have been linked to Alzheimer’s disease, [5] attention deficit hyperactivity disorder, [6] autism, [7] schizophrenia, [8] hostility, [9] anxiety, [10] and bipolar disorder, [11] the focus of this article will be the role of omega-3 fatty acids in the neurobiology and treatment of major depressive disorder.

Major Depression on the Rise

Mood disorders, including major depression, are recurrent, debilitating, and potentially life-threatening illnesses. In the last 100 years, the age of onset of major depression has decreased and its overall incidence has increased in Western countries. For example, severe forms of major depression affect up to five percent of the population in the United States, while up to 20 percent present with milder forms and another two percent have bipolar disorder. [12] This increase cannot be explained merely by changes in attitude of health professionals or society, diagnostic criteria, reporting bias, or institutional or other artifacts. [13, 14] Despite advances in pharmacotherapy, a significant proportion of depressed patients are considered treatment-resistant. [15] Poor compliance, side effects, or lack of desired effects are not uncommon with antidepressant medications. Selective serotonin reuptake inhibitor (SSRI) treatment produces a 50-percent improvement in only about half of those who maintain therapy, while about 30 percent of depressed patients discontinue medications before six-weeks are complete. [16, 17] Such lack of desired results encourages the continued search for improvements in current pharmacotherapy and novel treatments.

In contrast to the increased incidence of depression, the dietary intake of omega-3 fatty acids has dramatically declined in Western countries over the last 100 years. The ideal ratio of omega-3 to omega-6 EFAs is approximately 1:1, according to the conclusion of an international panel of lipid experts published in the Journal of the American College of Nutrition. [18] The North American diet currently has omega-6 fats outnumbering omega-3 fats by a ratio of 20:1, largely as a result of the ubiquitous supply of various omega- 6-rich oils (corn, sunflower, safflower, cottonseed) added directly to the food supply or through animal rearing. [19] It is reported that corn oil has an omega-6:3 ratio of 60:1 and safflower a ratio of 77:1 (Tables 1 and 2). [20] The following research indicates these dietary fatty acid alterations and the indiscriminate 20-year-old message that all fat is harmful have not been without neurophysiological and neurobiological consequences.

Epidemiological Data

If omega-3 fatty acids play a role in depressive disorders, then it would be expected that countries consuming greater amounts of these fatty acids (primarily through fish intake) would have a lower prevalence of depression. In his research published in Lancet, Joseph Hibbeln of the National Institutes of Health found a significant negative correlation between worldwide fish consumption and prevalence of depression. [21] In research involving a random sample within a nation, frequent fish consumption in the general population is associated with a decreased risk of depression and suicidal ideation. [22] A recent cross-sectional study conducted in New Zealand found fish consumption is significantly associated with higher self-reported mental health status. [23] Hibbeln recently found a similar negative correlation between total seafood (including shellfish) consumption and the prevalence of postpartum depression in 22 countries. Higher concentrations of DHA in mother’s milk and greater seafood consumption both predicted lower prevalence of post-partum depression. [24] National per capita fish consumption has also been correlated with protection against seasonal affective disorder. [25] While this does not prove causation, and cultural, social, and economic factors are possible confounding factors, it does provide support to the notion omega-3 fatty acids might play a role in depression.

Omega-3 Fatty Acid Status and Depression

One method to determine EFA status is to examine levels in the plasma and red blood cell (RBC) membranes. While not identical, significant correlations exist between blood and brain phospholipids. [26] A number of investigations have found a decreased omega-3 content in the blood of depressed patients. [27-30] In fact, EPA content in RBC phospholipids is negatively correlated with the severity of depression, while the omega-6 FA arachidonic acid to EPA ratio positively correlates with the clinical symptoms of depression. [27] In addition, a negative correlation between adipose tissue DHA and depression has been observed. Mildly depressed subjects had 34.6-percent less DHA in adipose tissue than non-depressed subjects. Examining adipose tissue FAs is important because it is more reflective of long-term (1-3 year) intake. [31]

Individuals with depression are more likely to have atopic diseases, a possible indicator of decreased FA intake and/or metabolism. [32] Those with atopic disorder have been shown to have low plasma and RBC omega-3 levels. [33] Histamine may also be playing a significant role in the connection between atopy and depression. [34] In addition, women with depression are more likely to have spontaneous pre-term births, [35] and research indicates omega-3 fatty acids can delay pre-term delivery, [36, 37] an interesting connection warranting further exploration. The overlap between cardiovascular disease and depression has also been noted, with some investigators suggesting omega- 3 status is a common thread. [38]

Depression, Omega-3 Fatty Acids, and CNS Function

In order to appreciate the potential role of omega-3 fatty acids in mental health, some of the neurobiological alterations that exist in depression must first be examined. While the exact mechanisms involved in the pathogenesis of depression remain obscure, there is a growing body of research indicating involvement of the frontal cortex and limbic system, including the hippocampus and the nucleus accumbens (NA). [39]

The chance discovery of antidepressant medications has led to 50 years of research focusing on monoamines and depression. With the efficacy of modern antidepressants, the involvement of serotonin, norepinephrine, and dopamine in the antidepressant activity of medications and the pathophysiology of depression seems clear. Indeed, a large body of research suggests altered neurotransmission in major depression. However, the relationship between depression and neurobiology is extremely complex and cannot be fully explained by this “monoaminergic hypothesis.” Those receiving antidepressants demonstrate an immediate increase in the availability of various neurotransmitters, yet mood elevation can take months of pharmacotherapy, indicating an adaptation or drug-induced plasticity is taking place. Also, the monoaminergic theory does not account for the large number of depressed patients who do not respond to current antidepressants. [39, 40]

Animal models of depression have resulted in valuable insights into potential biological mechanisms and/or consequences of depression. Research shows decreased levels of dopamine turnover in the prefrontal cortex and dopamine levels that are up to six-fold higher in the NA. [41, 42] Conversely, agents that are NAdopamine receptor agonists have antidepressant activity. [43] The NA is involved in learning, reward, and motivation, and abnormalities in this area have been linked to major depression. [44-46] Neurochemical activity in the NA is extremely complex and, while overall increases in total dopamine may be observed, functionality may be altered.

Modern brain imaging technology has allowed investigators to examine cerebral blood flow and glucose utilization in patients with major depression. The findings have been fairly consistent, with researchers reporting that in major depression there are blood flow abnormalities, including hypoperfusion in the limbic system and prefrontal cortex. In addition, depressed patients have decreased glucose metabolism in a number of brain regions and this hypometabolic state correlates negatively with severity of depression. [47, 48]

A number of investigators have examined the role of proinflammatory cytokines in the pathophysiology of depression. A growing body of research indicates that depression is associated with excessive production of proinflammatory cytokines. These cytokines, including interleukin-1beta (IL-1ß), -2, and -6, interferon-gamma, and tumor necrosis factor- alpha (TNF-a), can have direct and indirect effects on the CNS. For example, they may lower neurotransmitter precursor availability, activate the hypothalamic- pituitary axis, and alter the metabolism of neurotransmitters and neurotransmitter transporter mRNA. [49] Researchers have found elevations in IL- 1ß and TNF-a are associated with severity of depression. [50] Psychological stress, infection, trauma, allergies, toxins, and various other factors can be responsible for a rise in these cytokines (Figure 2). [49] Interestingly, various tricyclic and serotonin re-uptake inhibiting antidepressant medications can inhibit the release of the above-mentioned cytokines. [49, 51]

Research shows major depression is associated with neuronal atrophy in the hippocampus [52] and prefrontal cortex. [53] Antidepressant treatment can lead to the activation of intracellular cascades that regulate gene expression and ultimately control neuronal survival and structural plasticity. Until recently, the notion that neurogenesis takes place in adult humans was not even considered. Now, however, researchers suggest depression may inhibit neurogenesis in the hippocampus, [52] an idea supported by the findings that antidepressants can promote neurogenesis. [40] Chronic, but not acute, administration of antidepressants can cause an increase in nerve growth factors, particularly brain-derived neurotrophic factor (BDNF), and these nerve growth factors can play a role in the plasticity and survival of the developed, adult nervous system. Serum BDNF has been found to be negatively correlated with the severity of depressive symptoms. [54] Enhancing the cyclic AMP (cAMP) signal-transduction cascade increases the activity and expression of cAMP response element-binding protein (CREB), which in turn increases BDNF. [39] Novel ways to increase BDNF include enhancing cAMP by inhibiting the phosphodiesterases(PDE), specifically PDE4, that break down cAMP. PDE4 inhibitors have antidepressant activity but are not in use due to intolerable side effects. [40] BDNF expression can be inhibited by physical and psychological stress, [55] and a diet high in saturated fat and sucrose. [56, 57] On the other hand, expression may be enhanced by voluntary exercise, learning activities and, as mentioned, antidepressants. [55]

Omega-3 fatty acids are an essential component of CNS membrane phospholipid-acyl chains and, as such, are critical to the dynamic structure of neuronal membranes. 3 DHA is continuously secreted by astrocytes, bathing the neuron in omega-3 fatty acid. [58] The binding of serotonin to the astroglial 5HT2A receptor can mobilize DHA to supply the neuron. [59] Alterations in membrane lipids can alter function by changing fluidity. Proteins are embedded in the lipid bi-layer and the conformation or quaternary structure of these proteins appears to be sensitive to the lipid microenvironment. The proteins in the bi-layer have critical cellular functions, acting as receptors, enzymes, and transporters. [60-64] In addition, EFAs can act as sources for second messengers within and between neurons. [65] An optimal fluidity is required for neurotransmitter binding and the signaling within the cell. [66] Omega-3 fatty acids can alter neuronal fluidity by displacing cholesterol from the membrane. [67]

It is not surprising there are functional consequences when animals are fed a diet deficient in omega-3 fatty acids (Table 3). Reduction in omega-3 intake (in the form of ALA) results in a reduction of omega-3 content throughout the brain cells and organelles along with a compensatory rise in omega-6 fatty acid content. This alteration is accompanied by a 40 percent reduction in the Na+K+ ATPase of nerve terminals, an enzyme that controls ion transport produced by nerve transmission and that consumes half the energy used by the brain. [63] There is also a 20-percent reduction in 5’- nucleotidase activity, a decrease in fluidity in the surface polar part of the membrane, [63] and a significant reduction in the cell body size of the hippocampal CA1 pyramidal neuron. [68] A 30-percent reduction in the average densities of synaptic vesicles in the terminals of the hippocampal CA1 region has also been observed as a result of an omega-3 deficiency combined with a learning task. [69] Deficiency of omega-3s also results in a 30-35 percent reduction in phosphatidylserine (PS) in the rat brain cortex, brain mitochondria, and olfactory bulb. [70] On the other hand, fish oil supplemented to rats can increase PS composition of the cerebral membrane. [71] This is an interesting finding, given research showing that PS has antidepressant activity in adults. [72, 73] PS can activate various enzymes, including protein kinase C, Na+K+ ATPase, and tyrosine hydroxylase, as well as regulating calcium uptake. It is therefore suggested that altering PS in cerebral membranes can alter neurotransmission. [71]

A number of studies have specifically examined the effect of an omega-3 deficient diet on dopamine and serotonin levels in animals. Animals on such a diet have a reduction in the dopaminergic vesicle pool [74] along with a 40-60 percent decrease in the amount of dopamine in the frontal cortex and an increase in the NA, [75, 76] alterations strikingly similar to the animal models of depression described above. Although overall dopamine levels in the NA are higher in an omega-3 deficiency and the animal model of depression, function of the NA-dopaminergic system appears to be abnormal in both. In an omega-3 deficiency, the release of dopamine from the vesicular storage pool under tyramine stimulation is 90-percent lower than in rats receiving an adequate omega-3 intake. [74] In the animal model of depression, although overall NA-dopamine levels are higher, the extracellular levels of dopamine in the NA are lower than normal controls and do not respond to normal serotonin stimulation. [77]

The increase in dopamine in the NA of omega-3 deficient rats is thought to be a result of loss of normal inhibitory control by reductions in frontal cortex dopamine input. [78] The frontal cortex dopamine reductions may be due to abnormalities of storage within the presynaptic terminal. The vesicular monoamine transporter (VMAT2) is present on the presynaptic vesicle membrane and allows for dopamine entry and storage in the vesicle. In omega-3 deficient rats, the levels of VMAT2 are significantly decreased in the frontal cortex. In addition, the pre- and post-synaptic dopamine receptor D2R is decreased in the frontal cortex and dramatically increased in the NA, alterations reflective of protein and mRNA expression. [79] These findings have tremendous implications in the area of nutritional neuroscience, particularly that related to genetic transcription as influenced by dietary modifications. Interestingly, fish oil supplementation in rats leads to a 40-percent increase in dopamine levels in the frontal cortex as well as an increase in binding to the D2 receptor. In addition, fish oil supplementation (15 times greater than previously suggested minimum requirements [80]) caused a decrease in activity of monoamine-oxidase B, an enzyme responsible for breaking down dopamine. [71]

In animal research, an omega- 3 deficiency results in as much as a 46-percent increase in serotonin receptor (5HT2) density in the frontal cortex. 75 This finding is thought to reflect an adaptation to reduced serotonin function and similar observations have been made regarding 5HT2 receptors in suicide victims. [81] In healthy adults, higher concentrations of plasma DHA predict higher cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5- HIAA), a metabolite that reflects serotonin turnover, particularly in the frontal cortex. [82] Numerous studies link low CSF 5-HIAA with psychiatric conditions, including violent suicide attempts during depression. [83]

When an animal diet is omega-3 FA deficient, widespread reductions in DHA levels are observed, although reductions are particularly pronounced in the frontal cortex (40% reduction). Another area with a marked DHA reduction is the olfactory bulb (35% reduction), which may also have behavioral consequences. [84] Olfactory bulbectomy in the rat causes serotonergic- and dopaminergic-associated, depression- related behavioral changes. [85, 86] In addition, dietary omega-3 deficiency can affect nerve growth factor in different areas of the rat brain, [87] while research indicates DHA can promote neurite outgrowth of cells induced by nerve growth factor. [88] These findings have important implications, given the research on BDNF and depression. An omega-3 deficiency has also been shown to decrease glucose uptake of brain cells by 30 percent and decrease cytochrome oxidase activity by up to 40 percent. [89] Glucose uptake and cytochrome oxidase activity are indicators of neuronal functional activity. An omega-3 deficiency can also alter the delivery of amino acids and sucrose across the blood-brain barrier. [90] It has also been shown that an omega-3 deficiency may compromise normal cerebral microperfusion, whereas supplementation may improve cognitive abnormalities related to cerebral hypoperfusion. [91, 92] Finally, omega-3 fatty acids are welldocumented inhibitors of proinflammatory cytokines, particularly TNF-a and IL-1ß, [93] although the precise mechanism remains unclear. It is possible the omega-3 induced suppression of prostaglandin E2 (PGE2), thromboxane A2, and histamine are involved in anti-inflammatory effects [94-96] and therefore, alleviation of depressive symptoms (Figure 3). It has been shown that, in addition to elevated cytokines, patients with major depression are more likely to have high levels of plasma and salivary PGE2. [97-99] Recently it was shown that PGE2, histamine, and IL-1ß might, under certain circumstances, up-regulate PDE4 activity.100-102 If this is the case in the CNS, then omega-3 fatty acids may actually trigger the cAMP cascade, leading to expression of CREB and BDNF. An investigation into the effects of omega- 3 fatty acids on the cAMP cascade warrants investigation

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Conclusion

Limited clinical data, combined with rapidly growing support of laboratory and epidemiological studies, suggest omega-3 fatty acids may play a role in the prevention and management of depression. Fish oil supplements are usually well tolerated, with an impressive longterm safety record at doses of 1 g daily. [114, 115] EFA supplements rich in omega-3 fatty acids are also generally inexpensive, making them attractive as an adjuvant or alternative to standard pharmacotherapy. At this time, however, there is no established clinically appropriate dose of omega-3 fatty acids for depression. In addition, it is unclear whether the most clinically active component is EPA, DHA, or a combination of the two. [26, 116] Supplementation with marine extracts that contain EPA, DHA, and phospholipids is an area warranting further investigation. For now, the bulk of clinical evidence indicates the EPA component of fish oils may be most important in mood stability, and that relatively low levels are required (1 g daily) for successful outcomes. It should be noted that administration of omega-3 fatty acids, most often via high doses of flaxseed oil, may induce hypomania, mania, or other behavioral changes in a small percentage (less than 3%) of individuals. [104, 117] Further research is necessary before firm conclusions can be drawn regarding the neurobiological influences of omega-3 fatty acids and their clinical value in the treatment of depression. It is anticipated that additional research will shed further light on the neuropsychological aspects of dietary lipids. In the meantime, given the current excess intake of dietary omega-6 fatty acids and the available evidence pertaining to omega-3 fatty acids and brain function, clinicians should ensure adequate intake of omega-3 fatty acids, particularly in patients with mood disorders such as depression.

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