Heart Disease &
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
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
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
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;
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
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
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
source of nutrients and supplements.
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