A Flavonoid Rich Meal -- with Tuna for Omega-3!

Flavonoids are compounds found in plants.  Their functions include providing pigmentation — especially yellow, red and blue tones — and also protecting against the attacks of insects and microbes.  Remarkably, they have numerous beneficial effects on the human body and mind as well.  A recent study in the American Journal of Epidemiology (Letenneur et al. 2007) demonstrated that flavonoids may be beneficial for the brain.  It measured cognitive decline in the elderly over ten years, and divided the subjects into three groups based on their estimated flavonoid intake.  Interestingly, there was a significant negative correlation between flavonoid intake and rate of cognitive decline: those who ate the most flavonoid-rich foods had the lowest rates of cognitive decline, and vice versa.  The USDA Database for the Flavonoid Content of Select Foods is probably the most comprehensive resource out there for determining the flavonoid content of the foods you eat.  It’s technical, but well worth the effort to digest!

Several randomized controlled trials have been performed utilizing omega-3 fatty acids as a monotherapy for depression, or as augmentation therapy (added to an antidepressant for major depressive disorder.)  Two recent meta-analyses aggregated these data, and found that there is evidence for an anti-depressant effect of omega-3 fatty acids when used in conjunction with anti-depressant medications for depression; however, there was evidence of publication bias in favor of positive studies.  That is, a normal distribution of the effect sizes showed an absence of small, negative studies that have been published.  The available evidence from randomized controlled trials is modest, but does support a role for omega-3 fatty acids as an augmentation therapy for depression.  However, randomized controlled trials do not at this time support a role for omega-3 fatty acids in monotherapy for major depressive disorder, nor for boosting “subclinical depression” (which is to say depressed mood that does not meet the criteria for major depressive disorder.)

Problem with Randomized Controlled Trials

All of these studies involve very short time courses (e.g. supplementation over the course of approximately twelve weeks.)  The epidemiological data suggests that it is the overall consumption of omega-3 fatty acids over years to a lifetime that has a protective effect.  None of our randomized controlled trials are done over a long enough time period to determine the full effect of omega-3 fatty acids on mood.

Conclusion: Omega-3 Fatty Acids Have a Protective Effect

It is important to aggregate the evidence across a range of different types of studies, including epidemiological, cellular and molecular in addition to randomized controlled trials.  When that is done, the potential effect of Omega-3 fatty acids on depression and other mood disorders looks to be far greater than the available evidence from randomized, controlled trials.  As the Committee on Research on Psychiatric Treatments of the American Psychiatric Association recently concluded, “The preponderance of epidemiologic and tissue compositional studies supports a protective effect of omega-3 EFA intake, particularly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).”

Correlation Between Fish Consumption and Major Depression

In this classic article to the Lancet, JR Hibbeln demonstrated that there was an inverse correlation between annual fish consumption in a country, and that country’s incidence of depression (Hibbeln, 1998.)  As you can see from the graph, those countries that consumed the most fish per capita, such as Japan, had the lowest rates of depression.  Vice versa, those countries where people consumed the lowest amount of fish, such as the United States, had the highest rates of depression per capita.  Of course, correlation is not causation – the fact that two things are linked does not mean one causes the other.  For that reason, epidemiological studies such as this one must be confirmed by other methodologies: mechanistic studies in cell cultures, animal models of illness, and randomized clinical trials.  Research on why fish consumption might help prevent depression has focused on omega-3 fatty acids.  Cellular studies have confirmed that Omega-3 fatty acids, found mostly in certain kinds of fish, but also in walnuts, soybeans, flaxseed, and some other plants, are integral components of the cell membrane of brain cells.  Without adequate omega-3’s, membrane dysfunction may lead to cellular dysfunction, and from cellular dysfunction to conditions such as depression.

Next week: what randomized clinical trials show about omega-3 consumption and depression!

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We recently had a patient at the hospital where I work who became psychotic, or lost touch with reality, believing that the CIA wanted to assasinate him, and hearing voices whispering death threats through the hallways.  The only cause that could be found was vitamin B12 deficiency.  Once we gave him injections of vitamin B12, he slowly improved and could once again tell the difference between reality and what only existed in his mind.

Vitamin B12 is one of the crucial dietary nutrients that our bodies, and especially our brains, needs to survive.  This vitamin is involved in basic DNA replication, and it also helps to breaks down certain fatty acids that are toxic to the protective sheath around brain cells.  Deficiencies of vitamin B12 can result from a variety of causes.  Some of the most common are alcoholism, autoimmune disease, inflammatory bowel disease, and even eating a strictly vegan diet that excludes all animal products.  The reason for the latter is that the active form of vitamin B12 has only been found in animal sources, or alternatively, grown in some strains of yeast, which many vegans consider to be off-limits.  Unfortunately, tempeh, seaweed, miso, and other plant foods do not contain the form of B12 that the human body can utilize.  Without some form of supplementation in the vegan diet, vegans could begin to suffer from the symptoms of vitamin B12 deficiency, including anemia and fatigue, decreased sensation in the extremities, coordination difficulties, memory loss, dementia, depression, or even psychosis.  That is why it is critical, if you eat a purely vegan diet to take a vitamin B12 supplement.  If you have any of the above symptoms, make sure to see your doctor, as vitamin B12 deficiency might be a reversible cause.

But how well was the study done? A close review of the figures showed several inconsistencies. It appeared that there was actually evidence of a viral protein DNA in several of the “normal” controls, that was not counted in the final results. One of the experiments in which they tried to show that the virus produced an infection in a new cell did not seem to show the positive conclusions they derived. Additionally, there were typos and unclear descriptions of methodology, raising questions about how well the work was done. There were other worrying signs. After the paper was published, the senior author said that there was evidence of viral infection in 95% of patients, a much larger percentage than reported in the actual paper. Given the seemingly arbitrary way in which some of the experiments were called “positive” and others “negative”, this claim is hard to believe, and it is possible that the increased numbers reflect poor methodology that yields false positive results.

Despite all of these uncertainties, the question for a chronic fatigue syndrome patient, many of whom have suffered for years, is, “Could this possibly be helpful for me?” If, for example, XMRV were actually a causative agent in chronic fatigue syndrome, and a patient tested positive for the virus, an anti-viral medication might theoretically be able to decrease viral replication and thus improve symptoms. However, there are serious side-effects to anti-viral medications that make their utilization potentially dangerous, and any such usage would be “off-label”, opening up physicians who prescribed them for chronic fatigue syndrome to a wide range of lawsuits. As the benefit is unclear, there is cause for caution, for both patients and physicians. Additionally, as the detection method for the virus is not yet standardized, it is possible that the laboratory doing the testing might do so sloppily, and provide a positive result when the patient is actually negative, or vice versa.

At this stage, there is both promise and peril in the testing of XMRV. The true impact of the discovery of XMRV in chronic fatigue syndrome will not be known until many more studies – of independent authorship from the original group — are completed.