Heart Disease & Depression:
by  A.S. Gissen

It was an unsolved medical mystery: Why did studies examining the effect of lowering serum cholesterol on cardiovascular disease show an increase in overall mortality from suicide, homicide, and accidents? This connection between lower cholesterol levels and these adverse events seems like a contradiction. Yet, other researchers have found an association between low serum cholesterol and increased depression. But does lowering cholesterol in heart disease patients really affect mood? Other studies, after all, have shown no relationship between depression and heart disease.

An excellent explanation of these conflicting results is the difference in polyunsaturated fatty acid intake between the different groups. For instance, in one study conducted in Finland, lower serum cholesterol was associated with lower mortality due to accidents and violence in coastal, fish-eating residents, but not among inland residents. Coldwater fish are an excellent source of long-chain polyunsaturated fatty acids like docosahexaenoic acid (DHA).

Historically, post-evolutionary human beings consumed a diet that achieved a balance between omega-6 and omega-3 fatty acids. Today, however, the average individual consuming a Western diet is deficient in omega-3 fatty acids due to excessive intake of corn, sunflower, safflower, cottonseed, and soybean oils rich in omega-6 fatty acids and decreased consumption of omega-3 rich foods such as salmon and tuna.

The imbalance between omega-6 and omega-3 fatty acids seen today is one explanation for the fact that lower cholesterol levels can be associated with depression in heart disease patients. Other research has shown increased aggression in primates fed a diet that lowered serum cholesterol. The ratios of n-6 to n-3 essential fatty acids increased from 6:1 on a high-fat diet to 33:1 on a low-fat, cholesterol-lowering diet. In humans, violent impulsive offenders have been shown to have a similar increase in n-6 polyunsaturates and decrease in n-3 polyunsaturates in their serum compared to diet-matched control subjects. While much has been published about the relative cardiovascular effects of cholesterol and dietary fats, the research showing the relationship between dietary fat consumption and brain functioning has received little attention.

Now, a fascinating article has been published in the American Journal of Clinical Nutrition titled, 'Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy.' The article reviewed the evidence that long-chain polyunsaturated fatty acids, particularly docosahexaenoic acid (DHA), can be ingested in the diet or synthesized in the body from essential fatty acid precursors. As the authors state, 'Unsaturated fatty acid composition is a major physiological determinant of the biophysical properties of membranes and DHA seems highly specialized for neuronal membrane function.' The important fact is that during deficiency states, DHA within cell membranes and their components will be replaced by n-6 fatty acids whose biophysical properties are different.

The Historical Link Between Depression and Fat Consumption
During the last century the incidence of depression has increased dramatically as the amounts of n-6 fatty acids consumed has increased. During the same period, n-3 fatty acid consumption has decreased. It is well documented that there has been a dramatic increase in the lifetime prevalence of depression during this century. While many stresses of modern life probably contribute to this effect, deficiencies of n-3 fatty acids may play a major role. During human evolution, ratios of n-6 to n-3 fatty acids were approximately 1:1, but are now estimated to be between 10:1 to 25:1.

The use of infant formula, which is devoid of DHA in contrast with human milk, has also steadily increased during this century. Formula devoid of the fatty acids has been shown to result in reduced brain concentrations of DHA. Additionally, these formula-fed children have been documented to have decreased intelligence quotients at 7 years of age. Because of this, formula in most industrialized countries besides the United States is now fortified with n-3 fatty acids.

'Just as increased consumption of saturated fat and the altered ratio of n-6 to n-3 intake is believed to have increased the incidence of atherosclerosis in the last century,' noted the study authors, 'it is suggested here that decreasing n-3 essential fatty acid intake may also affect the nervous system in early development or adulthood, to increase vulnerability to depression.'

Interestingly, societies that consume large amounts of fish containing n-3 fatty acids have lower rates of depression. Because a low n-3 fatty acid diet is known to contribute to coronary heart disease, there should be a relationship between heart disease and depression if there is a link between fatty acids and depression. In one meta-analysis of 83 studies, a consistent highly significant positive association between depression and coronary heart disease and myocardial infarction was found. In fact, depression was more strongly linked with coronary heart disease than any other personality variable, including type A personality. In another review of 30 years of research it was shown that depression accurately predicts coronary artery disease and poor survival outcome. These studies suggest a strong epidemiological link between n-3 fatty acid consumption, heart disease, and depression.

DHA Deficiency Decreases Dopamine Levels
The authors of the aforementioned review use this evidence to present a hypothesis that they titled, 'Diet-induced membrane disorder and disruption of multiple neurotransmitter systems: a biophysical hypothesis.' According to this theory, the lack of sufficient intake of certain long-chain polyunsaturated fatty acids, especially DHA, results in alterations of neuronal membranes that cause changes of brain functioning. Membrane essential fatty acids may influence functions including neurotransmitter production, degradation release reuptake, and binding.

While research in this area is just beginning, compelling animal evidence suggests this theory has merit. Rats fed a diet deficient in n-3 fatty acids showed the expected decrease in n-3 acids, and their replacement with n-6 fatty acids, in the brain. Amazingly, this was accompanied by a 55% decrease in brain dopamine concentration and a 13% decrease in dopamine receptor binding. This suggests that n-6 fatty acids may not mimic the biophysical properties of n-3 fatty acids like DHA.

The finding that diet could so significantly alter brain functioning through membrane-induced changes is certainly a dramatic and significant discovery. The authors contend that, 'Therefore, many aspects of biogenic amine neurotransmission, including its metabolism, release, uptake, and receptor function, appear to be influenced by dietary fatty acyl composition and the resulting changes in membrane lipid composition and biophysical properties. The high concentrations of long-chain n-3 fatty acids in synaptic membranes, with their unique but not well-understood biophysical properties, indicate they may have a critical role in synaptic neurotransmission.'

While the exact functioning of DHA and DHA-containing membrane components isnt well understood, evidence is accumulating to suggest several fundamental roles in membrane dynamics. Depression is a common clinical symptom of hypocalcaemia and one of the common findings in depressed patients is an increase in intracellular calcium. DHA has been shown to lower stimulated increases in intracellular calcium, and further, calcium channel blockers have been found to be effective in certain mental disorders. This is possibly due to their masking the negative effects of membrane DHA depletion on calcium metabolism.

Because derangements of calcium metabolism have been implicated in cardiovascular disease, senility, and aging, the potential role of DHA in membrane-www.ed calcium homeostasis is one proposed mechanism of action that links several of the proposed influences of DHA on health.

Human depression is a cycling and recurrent illness that is modeled in animals by a process known as kindling. One of the more interesting mechanisms that could explain how decreased brain DHA influences depression is by promoting the development of kindling.

Heres how kindling works. In humans, periods of stress are often followed by depressions. It has been hypothesized that repeated stresses may predispose some individuals to cycles of depression. This has been demonstrated in animal models of depression where animals repeatedly receive electrical or chemical stimulation. Even when these stimulations are below the threshold that the animals can stand, seizures and stereotypic behaviors soon emerge and become self-propagating even in the absence of any stimulus. This has been considered analogous to human depression, and is known as kindling. This process is considered dependent on the stimulation of protein kinase C and other membrane-dependent second messengers. Protein kinase is one of several enzymes that are part of the immune reaction. They are activated by cytokines and control cellular processes.

It has been demonstrated that DHA has unique, specialized effects on protein kinase C, and the membrane content of DHA may facilitate the optimal functioning of protein kinase C. Interestingly, lithium not only attenuates protein kinase C membrane translocation, but also increases brain membrane DHA content. Lithium is widely used for affective cycling and depression. As the authors state, 'Thus, a small increase of neural DHA, www.ed either by diet or lithium, may lead to a more optimal environment for NMDA-protein kinase C signal transduction and thus may dampen development of depressive cycles in response to stress.'

Although much evidence has accumulated suggesting a role of n-3 fatty acids in depression, it is surprising they have not been the subject of extensive clinical tests. This is in spite of the fact that more than 300 years ago a diet consisting of brains, an excellent source of these fatty acids, was recommended as a treatment for severe depression.

Additionally, there has been much scientific excitement about a product derived from brain called bovine cortex phosphatidylserine (BC-PS). This product was mentioned in the review because BC-PS contains 29% of its fatty acids as DHA. The DHA contained in the BC-PS molecule is considered important to the functioning of BC-PS, a well-researched compound developed over the last two decades that is undergoing clinical testing for its positive effects on mental functioning and depression. The authors reference an article that found PS derived from bovine brain cortex, which is rich in DHA, effective at increasing dopamine, norepinephrine, and epinephrine concentrations, while PS derived from soybeans, with very low DHA levels, did not affect catecholamine levels.

This led the authors to conclude that the DHA portion of the PS molecule was necessary for its unique physiological effects. Not surprisingly, BC-PS has been found effective in improving depressive symptomatology in elderly patients. BC-PS is currently available only as a pharmaceutical in Europe and especially Italy, the country where it was developed. (Editors Note: since this article was written there is new evidence to suggest soy-derived phosphatidylserine is effective. See later article in Vitamin Research News).

A soy-derived PS product has recently become available in the United States. Because it is derived from soy, it should be low in DHA. Therefore, it has questionable effectiveness pending independent research confirming its biochemical effects are equivalent to BC-PS. While the research on phosphatidylserine is impressive, it has all been conducted using BC-PS. If BC-PS works because of its DHA content, than the potential for DHA may be equally impressive.

The Importance of Supplementation
With the significance that n-3 fatty acids play in our health, both neuronal and cardiovascular, the necessity of adequate intake is clear. Ideally, that would include numerous servings of n-3 fatty acid rich fish. It appears that our intake of n-3 fatty acids is especially important for those of us on low-fat diets, or diets high in vegetable oils and other sources of n-6 fatty acids. Because DHA seems to be the most important dietary n-3 fatty acid, fish oil supplements are a reasonable means of increasing our intake. Fish oil is primarily eicosapentaenoic acid (EPA), rather than DHA. However, it does contain a significant amount of DHA. VRP offers EthylEPA, which contains 300 mg EPA and 200 mg DHA. VRP also offers DHA supplements containing 135 mg of DHA per gel.

With the emerging importance of n-3 fatty acids in the functioning of the nervous system, it seems likely that research will increase in the coming years. The necessity of DHA for infants, and the fact that based on this research most other industrialized counties now require n-3s addition to infant formula, should behoove the FDA to quickly move to require their use in the United States. The idea that our intake of n-3 fatty acids can influence both our cardiovascular and nervous systems should be reason for all of us to ensure we are consuming an adequate amount of these important dietary fats.

Reference: J.R. Hibbeln and N. Salem Jr. Am J Chin Nutr. 1995; 62:1-9.

Fish Oil and DHA
As you can now imagine after reading this months article on DHA, the old belief that a fish oils potency is measured by its EPA content may only be half the story. This is because DHA, the other fatty acid found with EPA in fish oil, also has independent and profound biological effects.

One of the major areas of development for DHA supplements has been infant formula. DHA has been shown to be important for retina and brain development in infants, and is found in relative abundance in human milk. Cow milk is not a significant source.

Because research has shown that infants have a reduced ability to synthesize DHA, and that supplemental DHA can improve retina and brain development, DHA has been developed as a formula additive in many parts of the world. During this research it was found that large supplements of EPA can reduce the growth rate of infants, so pure DHA sources were developed. Unfortunately, this increased the price dramatically when compared to fish oil. This is a problem that only appears in rapidly growing infants given large supplements of fish oil that contain EPA and DHA, and fish oil is still a good source of DHA for adults. In societies where both children and adults eat large amounts of EPA and DHA containing fish, the benefits of both EPA and DHA are seen.

In terms of chemical composition, not all fish oil supplements are created equal. Most supplements have their EPA and DHA in the triglyceride form. Additionally, these triglyceride-form fish oil supplements usually contain cholesterol. A unique kind of supplemental EPA and DHA that has been clinically used in Japan is called the ethyl esters of EPA and DHA. This ethyl ester fish oil supplement is refined to remove the triglycerides, and converts the EPA and DHA to their purer ester form. The two major differences between ethyl ester and triglyceride forms of EPA and DHA is their apparent potency (ethyl esters have been shown to be better absorbed and utilized), and their differing effects on oxidation in the body (ethyl esters have been shown to increase resistance to oxidation, as opposed to the triglyceride form). This last point is especially important, as traditional fish oil supplements have been shown to increase lipid peroxidation. The ethyl esters of EPA and DHA appear to not have this drawback and are featured in VRPs EthylEPA.

Unfortunately, most studies of fish oil supplementation have examined effects on blood clotting, a proposed mechanism of the association of fish with a lower risk of cardiovascular disease. The doses used in most of these studies has been quite large, as this is necessary to significantly change blood clotting. Epidemiological studies, however, have shown that relatively moderate amounts of dietary fish oil have a positive effect on both cardiovascular disease and depression. Additionally, studies have shown that supplementation with small amounts of the ethyl esters of EPA and DHA can significantly raise the level of these fatty acids in cellular membranes. Therefore, for most of us, a capsule or two of EthylEPA should be adequate in the absence of significant dietary sources of DHA. Regular consumers of EPA- and DHA-rich foods (3 or more servings weekly) probably don't require supplementation. People with clinical disorders that may be responsive to DHA supplementation will likely require larger doses taken under a physicians supervision.

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