Fish Oils: Ethyl Ester versus Triglyceride forms

Low strength natural fish oils are in triglyceride (TG) form, as are most natural oils. To purify the oils by removing impurities and less desirable fatty acids and to concentrate the EPA and DHA fatty acid components, molecular distillation is used.  This process allows the oil to vaporize at low temperatures under pressure and is also known as vacuum distillation. The resulting vapor is collected and cooled, stratifying into distinct layers of fatty acids. This allows a purer esterified oil (called an ethyl ester form, or EE) with higher levels of EPA-DHA than crude fish oils and removal of triglycerides and cholesterol as well as other undesirable components. 

Some companies like to add triglycerides back in; this dilutes the fish oil concentrate by about 20% and the process also introduces mono- and di-glycerides, which don’t exist in natural fish oils to a significant degree but are thought responsible for higher absorption levels of this reconverted triglyceride form (rTG) oil over natural triglyceride and ethyl ester forms. If no triglycerides are added back, the body’s own store of triglycerides will be used to bond to the fatty acids after absorption, potentially lowering serum triglycerides more than an rTG oil. 

Absorption from our guts is always in the form of free fatty acids, so the oil’s original triglycerides are typically discarded during digestion and reattached later from body stores. This lowers the potential of the TG or rTG oils to lower triglycerides already in our bodies since they introduce additional triglycerides, which may be absorbed either into the body (adding more triglycerides into the liver) or into fiber or other materials that carry cholesterol out through the stool (potentially reducing the removal of cholesterol by competitive absorption). 

The prescription fish oils are in the ethyl ester form, not triglyceride form, because of the higher purity and higher strength of EE fish oils over TG or rTG forms resulting in better study outcomes on cardiovascular health measures. 

Krill oil is distinct because of its phospholipid matrix that greatly enhances omega-3 absorption more than the EE, TG, or rTG forms of fish oil.

The Facts About Omega-3 Fatty Acids and Increased Prostate Cancer Risk

A study released this week, “Plasma Phospholipid Fatty Acids and Prostate Cancer Risk in the SELECT Trial,” published in the Journal of the National Cancer Institute (JNCI)) suggests that the omega-3 essential fatty acids EPA, DPA, and DHA - but not the omega-3 fatty acid ALA, found in flax, chia, hemp seeds, and nuts that have repeatedly been shown to lower prostate cancer rates - are somehow associated with increased risks of high-grade prostate cancer. At the same time, higher amounts of normally harmful trans fats in these subjects were associated with lower rates of advanced prostate cancer. [1] Because of the known limitations of this particular kind of study, all of these reported results were completely unproven, highly questionable, and highly unlikely to be true.

What kind of study was this? It is data mining of a previously published population study in which important variables and endpoints for fish oil's relationship to prostate cancer were not controlled, nor any cause and effect demonstrated. Because it is a secondary analysis of a largely epidemiological (population) study, it represents the lowest level of evidence in human studies because most relevant variables, confounding factors, and clinical endpoints are not systematically collected for proper analysis as they would be in an actual controlled clinical trial. Instead, the limited goal was to look for possible associations that were admittedly not rigorous enough to be considered as actual evidence of a causal relationship. As a preliminary study, it was consciously designed only to raise questions, rather than to provide answers, and it did accomplish that goal but also created a messy splash of misleading and over-emphatic headlines inaccurately suggesting that this one study somehow trumps many more robust clinical trials. So much for the media knowing of and respecting the Scientific Method. [2]

Dr Marilyn Glenville PhD, the UK’s leading nutritionist specializing in women’s health and former President of the Food and Health Forum at the Royal Society of Medicine, has noted some deficiencies in the current JNCI report; some examples: [3]

• “This is not a randomised controlled trial but a trial comparing Omega 3 levels in men with prostate cancer with healthy men. The men with prostate cancer had higher levels of Omega 3. But you cannot extrapolate cause and effect from this finding. It is like saying that if the majority of men with prostate cancer played tennis compared to healthy controls then tennis could trigger prostate cancer.”
• In 2009 the Harvard School of Public Health reported that “Omega 3 deficient diets cause up to 96,000 preventable deaths a year in the US. The researchers estimated the number of deaths resulting from 12 preventable causes and Omega 3 deficiency ranked as the sixth highest killer of Americans. A deficiency in these fats was classed as a bigger killer than high intake of trans fats.” [4]
• “…there are many cultures such as the Japanese who eat high amounts of oily fish containing Omega 3 fatty acids and yet have one of the lowest prostate cancer death rates in the world.”

Duffy MacKay, N.D., vice president, scientific and regulatory affairs of the Council for Responsible Nutrition, also noted some concerns with the report: [5]

• “Hundreds of studies over the past two decades have shown omega-3 fatty acids to have positive effects associated with cardiovascular health, perinatal health, inflammation, cognitive function, or cancer. Collectively, this body of research serves as the basis for numerous recommendations from respected organizations, scientific boards and healthcare practitioners that Americans get omega-3 fatty acids in their diets.”
• “While we encourage researchers to continue to study omega-3 fatty acids with an open mind, it is counterproductive when studying nutrition for researchers to promote their study as if it were the only piece of research that counts. In this case in particular, it is especially disingenuous for the researchers to make the kinds of assertions we've seen in the press, given their results are in stark contrast to previous epidemiologic studies that not only demonstrate no correlation between omega-3 consumption through fish and/or supplementation and the risk of prostate cancer, but in many cases also showed a protective effect against prostate cancer.”
• “One should also consider whether this study could have simply been measuring a biomarker reflecting recent intake of fish or fish oil supplements in a group of high risk cancer patients that had been told to increase their EPA and DHA levels, as compared to a group of non-cancer patients that had not been told to consume more EPA and DHA. Plasma levels of EPA and DHA reflect very recent intake and are considered a poor biomarker of long term omega-3 intake especially when compared to red blood cell levels, which reflect medium term intake. A single fish oil dose (or hearty serving of fish at lunch) results in >100 percent increase in plasma omega-3 levels. So looking at plasma levels in healthy and sick people may only provide insight into the recent habits of these individuals.”
• “The American Heart Association, the World Health Organization (WHO), the U.S. Institute of Medicine’s Food Nutrition Board (IOM FNB) and the 2010 Dietary Guidelines all have current policies advising Americans to eat more fatty fish to get the benefits of omega-3 fish oils. It is highly unlikely this one study will change that advice. Omega-3s can also be obtained by taking one of the many supplement products on the market. For those consumers who have concerns about prostate cancer or other questions about omega-3 fatty acids, we recommend speaking with your doctor or other healthcare practitioner.”

If you are a man and believe this report, then you’ll probably want to eat partially hydrogenated artificial trans fats instead of omega-3 fats for prostate health; though that change would greatly increase your risk of suffering far deadlier cardiovascular diseases, based on evidence from many clinical trials. But that would be ridiculous. In fact, many cultures around the world consume far more fish oil than Americans without having increased risks of aggressive prostate cancer; these include the Inuit people ("Eskimos"), Scandinavians, Southeast Asians, Pacific Islanders, Japanese, Filipinos, and others. 

In any case, in the absence of proper controls or any evidence of causation, we actually can’t know what these study results really mean. For example:

• Were DHA levels related to diet, supplementation, or both?
• Were fish and/or fish oils perhaps consumed as a deliberate health choice because of prior knowledge of prostate issues, rather than actually causing or aggravating those issues? In other words, could the consumption represent an attempt to improve a pre-existing condition by improving one’s nutritional status and be unrelated to the disease itself? Perhaps even suggested by medical teams as potentially helpful for patients' diet?
• If they had been collected, what would key inflammatory and oxidative markers, that are much likelier to be related to prostate health problems than long-chain omega-3 fatty acids such as DHA, have told us about these men’s state of health and disease?
• Where is the biochemical evidence that DHA itself may negatively contribute to prostate concerns? None is presented, even theoretically.

The Global Organization for EPA and DHA Omega-3s (GOED) also criticized these and numerous other some aspects of the JNCI report, among them these important points: [6]

• “The difference in mean blood plasma phospholipid fatty acids blood level for omega-3s was 4.66% in the combined cancer group versus 4.48% in the control. They are basing their results on just ca. 0.2% difference in omega-3 levels.”
• “Plasma phospholipid fatty acids as measured in this study are not a good index of long term intake and are influenced dramatically by a single meal, or even timing of a fish oil dose. A single fish oil dose massively increases LC omega 3 (typically increasing levels by 100% or more) in about 4-12 hours and then washes out around 48 hours.”
• “The study was not designed to look at omega-3 and confounded with selenium and Vitamin E used in the treatment arms.”
• “The test cohort included sick and healthy people. It is possible that sick people were taking fish oil supplements at a higher rate than the healthy individuals.”
• “A recent meta-analysis of fish consumption and prostate cancer by Szymanski et al. (2010) reported a large reduction in late stage or fatal prostate cancer among cohort studies." [7]
• "Several population based studies have shown a benefit of increased omega-3 fatty acid intakes to reducing prostate cancer risk.” [8]^, [9]

As I said earlier, this type of study raises questions about possible associations; but due to its built-in limitations, and results conflicting with most other related studies, provides no real answers.  Unfortunately, its counter-intuitive results generate sensational press coverage rarely accompanied by any true perspective on what this new study really means (not much).

In real life, most Americans and others in Western societies no longer consume the ideal amount or ratio of omega-3 fatty acids in their diet as our ancestors did a century or two ago. This reduction reportedly contributes to the large increase in chronic health problems that plague these societies. It is a public disservice to inappropriately scare people away from healthy foods and supplements, which help balance the diet in these many cases where the lack of essential nutrients is actually causing harm, based solely on such flimsy “evidence”. 

After reviewing this study I, a vegetarian, will continue to take my vegan DHA supplement twice a day with absolutely no concerns that it will negatively affect my own prostate health. Why am I not at all concerned? Because there is still no hard evidence explaining how long-chain omega-3 fatty acids like EPA and DHA may promote prostate cancer. There is still no demonstrated mode of action for this concern, and there are still no plausible explanations of any biological mechanisms that could justify the theory that long-chain omega-3 fatty acids may promote prostate cancer. My lack of concern is evidence based, after carefully reviewing the studies in question. Contrast this with the fear-mongering about fish, fish oil, and omega-3 fatty acids in foods and supplements that is overwhelmingly based on speculation, flimsy data, ignorance (on several levels), and maybe even some bias.

By Neil E. Levin, CCN, DANLA

REFERENCES:

[1] http://www.newswise.com/articles/view/605211/?sc=rssn&utm_source=feedburner&utm_medium=feed&utm_campaign=Feed%3A+NewswiseScinews+%28Newswise%3A+SciNews%29

[2] http://teacher.nsrl.rochester.edu/phy_labs/appendixe/appendixe.html

[3] http://www.hfma.co.uk/docs/Omega_3_and_Prostate_Risk-July2013.pdf

[4] The Preventable Causes of Death in the United States: Comparative Risk Assessment of Dietary, Lifestyle, and Metabolic Risk Factors" study, April 2009, PLoS Medicine

[5] http://www.crnusa.org/CRNPR13-Omega3071113.html

[6] http://us1.campaign-archive1.com/?u=4ae075406cd789efec4e9ff09&id=6f3dc7a018&e=1704ffc192

[7] Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92(5):1223–1233

[8] Terry P, Lichtenstein P, Feychting M, et al. Fatty fish consumption and risk or prostate cancer. Lancet, 2001,357:1764-6.

[9] Lietzman MF, Stampfer MJ, Michaud DS, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of prostate cancer. Am J Clin Nutr 2004;80:204-216.

Fish Oil: Excerpts from a magazine interview with me

The balance of fatty acids in the body can promote inflammatory or non-inflammatory states. Higher amounts of omega-3 fats in the diet have been shown to modulate inflammation and keep it within healthy ranges. The various cellular and tissue damage that can occur from chronic inflammatory states are certainly not healthful. This basic mechanism of action implies a wide-ranging and powerful effect of omega-3 fats to support wellness. Additionally, these fats are part of brain and nerve structures, so they help to maintain the health of those tissues, as well.

Omega-3 and omega-6 fats have been called “essential fatty acids” since the body can’t manufacture them from other fats, as it typically can for other types of fat. The optimal ratio of omega-6 to omega-3 fats is somewhere between 1:1 and 3:1. The common American diet has been estimated to be over 15:1, a marked deviation from a healthy norm.

The benefits of most other non-omega-3 fatty acids in fish oil are not well-defined in the scientific literature. Fish oil naturally contains a range of fats, including cholesterol, triglycerides, and stearic acid. The ones that are considered less desirable, cholesterol and triglycerides, are sometimes removed from fish oils to further concentrate the omega-3 portion and allow higher strengths in fewer capsules.

All natural oils contain various mixtures of fatty acids in varying amounts. Omega-9 fats are best known as being abundant in Olive Oil, and are considered non-inflammatory and especially healthy if substituted for most omega-6 fats that are pro-inflammatory. Some natural oils are fairly well balanced, such as flax and hemp seed oils, or walnut oil. Others, like fish oil, tend to be predominantly omega-3. Most vegetable oils are mostly omega-6 fats and their predominance in the modern diet has been blamed for some of our poor health.

Some consumers do know about various sources of fish oil, and some have advantages or disadvantages. For example salmon is a favored source of omega-3 fats, though salmon oil typically contains less than other common fish oils. Traditional fish sources may be better accepted by those who won’t or can’t eat shellfish. The fisheries in Norway and Peru are among the best managed traditional fisheries on earth.

Krill, a small crustacean shellfish, is a unique source of omega-3 fats since krill also naturally bonds the fatty acids to phospholipids, which are essential for cell membranes and which enhance the bioavailability of the oil. Krill oil also contains the powerful antioxidant pigment astaxanthin, which is responsible for the color of shrimp and salmon. Krill is considered the best managed fishery in the world, with trained observers on each boat monitoring the harvest. The krill harvest limit can be rapidly adjusted to support a healthy population, and the total world harvest (most of which goes into pet foods) is only a fraction of the allowable sustainable harvest level.

My Interview on Memory and Brain Health for a trade magazine

The brain must be intact and healthy in order for it to perform normal functions like thought and memory. There is evidence that chronic or acute inflammation, or other insults to brain cells/tissues from chemicals or other damaging agents, can provoke negative health effects. In essence, the brain is literally under attack on a daily basis, requiring a constant infusion of supporting protective nutrients to maintain proper brain health and functionality.

Antioxidants and magnesium are key nutrients needed to protect the brain from chemicals called excitotoxins, such as MSG, which are damaging to brain cells when levels of various nutrients are insufficient to control them. The physical damage to brain cells that can be caused by oxidation, sometimes in the form of a bio-electrical spark causing a chain reaction that rips electrons from a string of innocent cells until an antioxidant ‘electron donor’ puts an end to it, can be prevented or stopped by antioxidants. Antioxidants also protect fats from oxidizing (going rancid), and since the brain is nearly half fat it is dependent on both fatty acids and antioxidants to protect its structural integrity.

While it is normally not necessary to see a physician before taking a brain/memory support dietary supplement, people on medications should always check if there are known interactions before using any new supplement and it is wise to always bring a list of your supplements to share with your doctor at your annual check-up. Those with known memory problems should request a medical evaluation to set a baseline level in order to maintain their mental assets and be able to compare future mental performance.

To aid this preservation of our mental faculties, it is obviously best to consume adequate levels of relevant protective nutrients for many years, rather than waiting until the senility of old age creeps up on us and then trying to regain lost abilities. Otherwise, careful eating and appropriate supplementation may be started ‘too little, too late.’

The best mental/brain support nutrients include some surprisingly ordinary ingredients: Lecithin, Vitamins A-E, and Antioxidants. Lecithin provides essential phospholipids for the brain, nerves, and cell membranes; including Choline, Serine, and other brain nutrients that directly support neurotransmitter production and memory. Lecithin’s Phosphatidyl Choline (PC) is a precursor of the neurotransmitter acetylcholine; in the central nervous system acetylcholine is involved in learning, memory, and mood. Phosphatidylserine (PS) also affects the levels of neurotransmitters in the brain related to mood, memory, and mental function.

Lecithin, which is a highly processed extract of soybean oil, does not in itself contain protein (allergens) or genetic material (GMOs), which the original soybeans may have contained. Some Lecithin products are derived from certified non-GMO soybeans or even sunflower seeds.

Another way to get Lecithin’s benefits is in the form of Krill Oil. Krill has its Omega-3 fatty acids bonded to phospholipids similar to those found in soy or egg lecithin. So krill not only supplies EPA, DHA, and phospholipids for brain, nerve, and membrane health but also enhances their bioavailability and access to the brain due to the ability of phospholipids to cross the blood-brain barrier better than ordinary fish oils. Fish Oils providing EPA and DHA should also be considered brain nutrients, as DHA is a significant physical component of the brain.

Vitamin E and its related compounds (the tocotrienols) have been shown to protect neurons (brain and nerve cells) from being damaged or even killed off by excitotoxic chemicals. The antioxidant benefits of this essential vitamin’s “family” of compounds also help to prevent oxidative reactions that can damage brain tissues. Look for gamma-tocopherol along with the usual alpha-tocopherol plus higher amounts of gamma- and delta- form tocotrienols.

Vitamin C directly pumps excitotoxins from neurons, protecting the brain and nerve cells from being damaged by these potentially toxic chemicals. There are several populations with impaired ascorbate absorption; including those with poor insulin sensitivity, those with gut inflammation, those who take aspirin, and those on low sodium diets; all situations where normal vitamin C uptake and utilization is often suboptimal.

Other antioxidants of benefit for brain health include Alpha Lipoic Acid, various carotenoids including Astaxanthin (also found in Krill oil), and Pycnogenol®. In addition to supplementation, it always helps to consume a variety of antioxidants from fruits and vegetables to maintain a good level and balance of antioxidants.

The formation of abnormal structures in the brain may in part be due to oxidative damage that perhaps can be kept within normal acceptable ranges by having a variety of antioxidant nutrients available. Genes in the subject cells are controlled by “switches,” that are in turn modulated by environmental “triggers.” The presence of various protective nutrients helps to maintain proper cellular health; whereas the deficiency of adequate protective nutrients can allow potentially damaging effects, leading to cell death and the subsequent formation of abnormal brain structures.

The presence of excessive amounts of saturated fats in the diet, especially if from an excess of processed foods, inevitably reduces the amount of available long-chain fatty acids EPA and DHA (DHA can be made from EPA) that are essential for brain and nerve health. The deficit of these two fatty acids increases the likelihood of uncontrolled inflammatory processes in the body, as an imbalance of beneficial dietary fats like EPA, DHA and GLA that can reduce the fatty acids needed to make prostaglandins responsible for maintaining a healthy inflammatory response. The fact that EPA is needed for healthy membranes throughout the body and DHA is an important constituent of the brain itself also testify to the importance of these fatty acids for healthy brain structures and functions, including memory.

• Natural antioxidant vitamins Beta-Carotene, C, and E are protective of brain tissues and are available in antioxidant formulas and multiple vitamins..

• Alpha GPC is a form of choline that is bioavailable to the brain; an acetylcholine precursor, it supports memory and cognitive acuity.

• DMAE is a naturally occurring amino metabolite known primarily as a precursor to choline and acetylcholine, chemicals in the brain responsible for nerve transmissions and cognitive function; DMAE has been used most predominantly to improve memory and focus while stimulating neural activity.

• NADH is a metabolite of niacin (vitamin B3) that is directly involved in neurotransmitter production to support mental alertness.

• Ginkgo biloba extract is thought to improve memory and quality of life, and is available in various strengths.

• Acetyl-L-Carnitine is a form of an important amino acid, which in short-term studies has improved memory in older adults.

• Vitamin B1 deficiencies have been associated with confusion and memory loss in seniors deficient in that nutrient.

• High strength fish oils and Krill oil supply the omega-3 fatty acids DHA and EPA that are important brain and nerve components often deficient in the general population.

• Genistein, a phytoestrogen found in Soy Protein Isolates and Soy Isoflavones, has been shown to act as an antioxidant to preserve brain cell integrity.

• Ashwagandha has been shown to be protective of brain cells in non-clinical laboratory experiments.

Essential fatty Acids (EFAs) interview, Natural Products Marketplace magazine, January, 2011

The awareness of EFAs, especially the Omega-3 fatty acids EPA and DHA, is large and growing larger. The accumulating mountain of evidence and the endorsement by popular health “gurus” assures continued growth in this important product category. As the benefits of specific fatty acids for regulation of various healthy body functions – such as inflammatory processes, hormonal health, and maintaining brain/nerve/cellular structures – becomes even more well known, more and more people recognize the potential for EFAs to positively affect their health.

While there are combination products that deliver Omega-3, Omega-6, and Omega-9 fatty acids together, the focus has been more on specific sources such as fish or flax, along with some more unusual ones. Of course, natural oil sources are not comprised of a single fatty acid. For example, natural fish oil can not only supply EPA and DHA but also originally supplies ALA, cholesterol, triglycerides, and other fatty acids; though many of these components can be removed during processing to provide purer and stronger materials that are richer in EPA and DHA to require far fewer capsules to reach desired levels of these two fractions. Flax oil is best known as a vegetarian source of the omega-3 fatty acid ALA (alpha-linolenic acid), but ALA levels are only about 55% of the total; flax oil also contains about 19% omega-9 as oleic acid, 14% omega-6 as linoleic acid, and 12% saturated fats. The conversion of ALA to EPA is a significant metabolic hurdle. Women do this conversion better than men; people who consume the most omega-6 in their diets have a more difficult time converting ALA to EPA. Typically between 5% and 15% of ALA converts to EPA and about 2% to 5% of ALA converts to DHA, making flax a much more dilute and less certain source of EPA-DHA.

Fish oil is subject to environmental concerns related to both sustainability and contaminants. Manufacturers audit their suppliers and set strict identity/safety specifications to assure the quality of products.

Most fish oils are molecularly distilled to remove contaminants, manufactured under strict quality assurance standards, and screened to be free of potentially harmful levels of contaminants and heavy metals, such as mercury, PCB’s, dioxins, and others.

Other types of EFAs include Flax seed oil, Evening Primrose Oil, Pumpkin seed oil, Black Currant seed oil, Wheat Germ oil, Castor Oil, and Virgin Coconut Oil.

Purity, potency, and freshness are always the challenges with EFAs.

The trend is toward more concentrated products of higher purity that allow people to get their EPA and DHA with smaller quantities of capsules or less volume of liquid. Liquids and smaller capsule sizes allow more children and seniors to enjoy the benefits of fish oils, while high strength capsules better hit the main demographic in between.

All fish oil supplements are typically hundreds of times safer than eating a serving of fish in relation to environmental factors; and typical esterified products have the added benefit of being free of cholesterol and triglycerides, which are undesirable food components for those with high cholesterol. By far, most of the studies proving the health benefits of supplemental fish oils have been with the esterified (ethyl ester) form, rather than the triglyceride form found in cold water fatty fish. There is very strong science supporting the use of this form.

Esterified fish oils also have been shown to sustain human serum levels better than the triglyceride form, over both a 24-hour period and a one-month period, which better supports a healthy heart rhythm. Notably, the most concentrated products are available only as esterified fatty acids. The ability of a consumer to get the 1-3 grams daily of EPA + DHA recommended by many health experts is enhanced by modern formulas that concentrate these essential fatty acids into fewer capsules and smaller serving sizes with fewer undesirable components, thus increasing customer compliance with a healthy nutritional protocol.

Both triglyceride and esterified ethyl ester fish oils are available in the marketplace, and both forms have their advocates. In the body, both forms must first be digested, stripping off the triglycerides or ethyl esters and leaving only free fatty acids that can be readily absorbed. These free fatty acids are then combined with triglycerides present in the liver before entering general circulation; so the circulating form will actually be the triglyceride form, no matter which form of fish oil one consumes. Both forms provide great value and important nutrients for the consumer; but the triglyceride form has no more proven value than the ethyl ester form, despite some excessive marketing claims.

Omega-3 fats, depression and mood disorders

Studies do show the potential benefits, and also evidence the good tolerability, of omega-3 fats in mood disorders. While these nutrients may not be a "cure" or even a drug-like treatment, their protective effects in these patient groups has been fairly well established: "Biological marker studies indicate deficits in omega-3 fatty acids in people with depressive disorders, while several treatment studies indicate therapeutic benefits from omega-3 supplementation. A similar contribution of omega-3 fatty acids to coronary artery disease may explain the well-described links between coronary artery disease and depression." Parker G, et al. Omega-3 fatty acids and mood disorders. Am J Psychiatry. 2006 Jun;163(6):969-78. Review. Erratum in: Am J Psychiatry. 2006 Oct;163(10):1842. PMID: 16741195 "Five of six double-blind, placebo-controlled trials in schizophrenia, and four of six such trials in depression, have reported therapeutic benefit from omega-3 fatty acids in either the primary or secondary statistical analysis, particularly when EPA is added on to existing psychotropic medication. Individual clinical trials have suggested benefits of EPA treatment in borderline personality disorder and of combined omega-3 and omega-6 fatty acid treatment for attention-deficit hyperactivity disorder. The evidence to date supports the adjunctive use of omega-3 fatty acids in the management of treatment unresponsive depression and schizophrenia." Peet M, Stokes C. Omega-3 fatty acids in the treatment of psychiatric disorders. Drugs. 2005;65(8):1051-9. Review. PMID: 15907142 "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), in mood disorders. Meta-analyses of randomized controlled trials demonstrate a statistically significant benefit in unipolar and bipolar depression (p = .02). The results were highly heterogeneous, indicating that it is important to examine the characteristics of each individual study to note the differences in design and execution. There is less evidence of benefit in schizophrenia. EPA and DHA appear to have negligible risks and some potential benefit in major depressive disorder and bipolar disorder, but results remain inconclusive in most areas of interest in psychiatry...Health benefits of omega-3 EFA may be especially important in patients with psychiatric disorders, due to high prevalence rates of smoking and obesity and the metabolic side effects of some psychotropic medications." Freeman MP, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry. 2006 Dec;67(12):1954-67. Review. PMID: 17194275