A number of studies have found decreased omega-3 content in the blood of depressed patients. Omega-3 fatty acids play a critical role in the development and function of the central nervous system.
Emerging research is establishing an association between omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and major depressive disorder.
This article includes the effects of eicosapentaenoic acid (EPA) in depressive symptoms, premenstrual syndrome, anorexia nervosa syndrome, bipolar depression, borderline personality disorder and agoraphobia.
Evidence from epidemiological [population], laboratory and clinical studies suggest that dietary lipids [fats] and other associated nutritional factors may influence vulnerability and outcome in depressive disorders. Research in this area is growing at a rapid pace.
The goal of this report is to integrate various branches of research in order to update mental health professionals.
Major depressive disorder (MDD) is a recurrent, debilitating, and potentially life threatening illness. Over the last 100 years, the age of onset of major depression has decreased, and its overall incidence has increased in Western countries.
The increases in depression, up to 20-fold higher post 1945, cannot be fully explained by changes in attitudes of health professionals or society, diagnostic criteria, reporting bias, institutional or other artifacts.
Despite advances in pharmacotherapy, and the increasing sophistication of cognitive/behavioural interventions, there are many patients with major depressive disorder who remain treatment resistant.
Depression is undoubtedly an extremely complex and heterogeneous condition. This is reflected by the non-universal results obtained using cognitive-behavior and antidepressant medications.
As research continues to mount, it is becoming clear that neurobiology/physiology, genetics, life stressors, and environmental factors can all contribute to vulnerability to depression.
While much attention has been given to genetics and life stressors, only a small group of international researchers have focused on nutritional influences on depressive symptoms.
Collectively, the results of this relatively small body of research indicate that nutritional influences on major depressive disorder are currently underestimated. (Note: Since this review a great deal of studies on nutritional influences, such as omega-3 fish oils, have confirmed the role of nutrition in depression).
Omega-3 fatty acids in particular represent an exciting area of research, with eicosapentaenoic acid (EPA) emerging as a new potential agent in the treatment of depression.
Dietary fish and seafood provide varying amounts of pre-formed EPA and DHA.
Science Daily reported in February 2006 that Dr. Cunnane, a metabolic physiologist at the University of Sherbrooke in Quebec, stated that something had to start the process of brain expansion and he thinks it was early humans eating clams, frogs, bird eggs and fish from shoreline environments. â€œThis is what created the necessary physiological conditions for explosive brain growth,” says Dr. Cunnane. Her study of fossil material excavated from numerous Homo habilis sites in eastern Africa revealed a bevy of chewed fish bones, particularly catfish. (Science Daily 22/2/2006).
The dietary intake of omega-3 fatty acids has dramatically declined in Western countries over the last century. The North American diet currently has omega-6 fats outnumbering omega-3 by a ratio of up to 20:1. There are a number of reasons for this skewed ratio, most notably the mass introduction of omega-6 rich oils into the food supply, either directly or through animal rearing practices
The ideal dietary ratio of omega-6 to omega-3 has been recommended by an international panel of lipid experts to be approximately 2:1 . Given that approximately 20% of the dry weight of the brain is made up of polyunsaturated fatty acids (PUFA) and that one out of every three fatty acids in the central nervous system are PUFA, the importance of these fats cannot be argued.
Considering that highly-consumed vegetable oils have significant omega-6 to omega-3 ratios, it is quite plausible that, for some individuals, inadequate intake of omega-3 fatty acids may have neuropsychiatric consequences.
A number of epidemiological (population) studies support a connection between dietary fish/seafood consumption and a lower prevalence of depression. Significant negative correlations have been reported between worldwide fish consumption and rates of depression.
Examination of fish/seafood consumption throughout nations has also been correlated with protection against post-partum depression, bipolar disorder and seasonal affective disorder.
Separate research involving a random sample within a nation confirms the global findings, as frequent fish consumption in the general population is associated with a decreased risk of depression and suicidal ideation.
In addition, a cross-sectional study from New Zealand found that fish consumption is significantly associated with higher self-reported mental health status.
The epidemiological (population) studies which support a connection between dietary fish and depression clearly do not prove causation. There are a number of cultural, economic and social factors which may confound the results.
Most significantly, those who do consume more fish may generally have healthier lifestyle habits, including exercise and stress management. Despite the limitations, the epidemiological data certainly justify a closer examination of omega-3 fatty acids in those actually with depression.
A number of studies have found decreased omega-3 content in the blood of depressed patients.
Furthermore, the eicosapentaenoic acid (EPA) content in red blood cell phospholipids is negatively linked with the severity of depression, and the omega-6 to EPA ratio positively correlates with the clinical symptoms of depression.
Relationships between omega-3 status and post-partum depression have also been investigated.
In a cohort of 380 Australian women, blood plasma DHA was investigated at 6 months post-partum. Logistic regression analysis indicated that a 1% increase in plasma docosahexaenoic (DHA) was associated with a 59% reduction in the reporting of depressive symptoms.
It is well known that during pregnancy there is a significant transfer (up to 2.2 g/day) essential fatty acids (EFAs) to the developing fetus. Increased risk of post-partum depressive symptoms has recently been associated with a slower normalization of DHA levels after pregnancy.
Suicide attempts have also been associated with low levels of red blood cell EPA. In a study involving 100 suicide attempt cases in China compared to 100 hospital admission controls, there was an eightfold difference in suicide attempt risk between the lowest and highest red blood cell EPA level quartiles.
The seasonality of depression and suicide has been described by investigators, with more deaths in spring and summer vs. autumn and winter.
Total serum cholesterol has been highly significantly synchronized with the annual rhythms in violent suicide deaths.
Recently, investigators found that EFA levels also vary by season. The authors of this study suggest that the seasonal variation in EPA or DHA may, in part, explain seasonality of violent suicide occurrence.
The overlap between cardiovascular disease and depression has also been noted, with omega-3 status emerging as a common thread.
Major depression in acute coronary syndrome patients is associated with significantly lower plasma levels of omega-3 fatty acids, particularly DHA. In addition, elevated homocysteine levels, a known risk factor for cardiovascular disease, has been associated with the excess omega-6 fatty acids found in the Western diet.
Finally, lowered intake of the parent omega-3 alpha linolenic acid has been associated with depression in 771 Japanese patients with newly diagnosed lung cancer.
It is important to note that not every study supports an association between lowered omega-3 status and depression.
The epidemiological (population) and laboratory studies, along with the research which shows depressed patients appear to have lowered omega-3 status, have naturally led to clinical investigations.
A number of case reports have appeared in the literature, the first of which was over 20 years ago. In this initial series of case reports, flaxseed oil (source of the parent omega-3 ALA) at various dosages, was reported to improve the symptoms of bipolar depression and agoraphobia.
An additional case report documented an improvement in depressive symptoms during pregnancy with the use of 4 g EPA/2 g DHA per day. Interestingly, improvements in symptoms occurred at four weeks, and with the exception of insomnia and anxious thoughts, all symptoms resolved at six weeks.
A series of case reports also suggest that 1-4 g of pure eicosapentaenoic acid (EPA) may be helpful in anorexia nervosa, a condition with the highest risk of morbidity and mortality among psychiatric disorders.
In all six of the cases, EPA was reported to improve mood to varying degrees. For some, discontinuing EPA therapy resulted in deteriorations in mood and other psychiatric symptoms.
An interesting study examined fish oil vs. marine oil extracted from Antarctic krill in premenstrual syndrome.
Krill is similar to fish oil, with the exception that it contains naturally-occurring phospholipids, and contains more EPA per gram than standard fish oil capsules (240 mg/g EPA in krill vs.180 mg/g in standard fish oil).
In the 3-month trial, 70 patients received 2 g of krill oil or 2 g fish oil daily for one month, then for eight days prior to, and two days during, menstruation for the following two months.
Evaluation at 45 days and three months showed that krill oil significantly improved depressive symptoms of premenstrual syndrome. The absence of significant effects of fish oil on mood suggests that the presence of the phospholipids and/or higher amounts of EPA may be responsible for the therapeutic effect of krill oil.
There have been some controlled studies that have examined omega-3 fatty acids and a placebo intervention in depression.
The first small clinical study with 30 participants showed that four months of treatment with 9.6 g of omega-3 fatty acids (6.2 g EPA/3.4 g DHA) was of therapeutic value in bipolar disorder. Specifically, this study showed a highly significant effect in treating depression.
In a separate double-blind, placebo-controlled study with 22 participants, the addition of 2 g of pure EPA to standard antidepressant medication enhanced the effectiveness of that medication vs. medication and placebo.
This 3-week study, involving patients with treatment-resistant depression, showed that EPA had an effect on insomnia, depressed mood, and feelings of guilt and worthlessness. There were no clinically relevant side effects noticed.
In a small pilot study involving 30 participants, Harvard researchers found that just 1 g of EPA could reduce aggression and depressive symptom scores among borderline personality disorder patients.
The results of this 2-month, placebo-controlled study are encouraging, given the difficulty in treating borderline personality disorder. It is also of note that 90 percent of participants remained in the study and no clinically relevant side effects were noticed with EPA.
In a double-blind, placebo-controlled trial over two months, high dose fish oil (9.6 g/day) was added to standard antidepressant therapy in 28 patients with major depressive disorder (MDD).
In this study the patients who received the omega-3 fish oil capsules had a significantly decreased score on the HRSD compared to those taking the placebo. Once again, the fish oil, even at this high dose, was well tolerated with no adverse events reported.
Various doses of pure EPA have also been investigated in depression. In a 12-week, randomized, double-blind, placebo-controlled study, 70 patients were given ethyl-EPA at doses of 1g, 2g or 4g.
The patients in this case had experienced persistent depression, despite ongoing standard antidepressant pharmacotherapy at adequate does.
Interestingly, in this study, “less was more.” Those in the 1g per day group had the best outcome. The patients who received 1 g per day of EPA were the only group to show statistically significant improvements. Among the 1 g/day group, 53 percent achieved a 50 percent reduction in HRSD scores.
The 1g EPA led to improvements in depression, anxiety, sleep, lassitude, libido, and suicidal ideation. These findings suggest that omega-3 fatty acids can augment antidepressant pharmacotherapy and/or alleviate depression by entirely different means than standard medications.
To date, the published data on supplementation with pure EPA on major depressive disorder or depressive symptoms have been positive.
With regard to docosahexaenoic (DHA) or a combination of EPA and DHA, there have been three negative reports.
It is important to consider the nutrients which can ultimately influence omega-3 status. Among them, four important dietary factors also relate to major depressive disorder: zinc, selenium, folic acid and dietary antioxidants.
A number of studies have shown that zinc levels are lower among patients with depression and a recent study found that 25 mg zinc supplementation may improve depressive symptoms.
Interestingly, 25 mg of zinc supplemented for two months has also been shown to significantly increase omega-3 status in the plasma phospholipids at the expense of saturated fat.
Lowered levels of selenium have been associated with negative mood scores in at least 5 studies. Selenium plays a significant role in the human antioxidant defence system. In addition, selenium deficiency can interfere with the normal conversion of alpha linolenic acid (ALA) into eicosapentaenoic (EPA) and docosahexaenoic (DHA), and results in an increase in the omega-6:omega-3 ratio.
Regarding folic acid, a growing body of research has documented the low levels of folic acid among patients with depression.
In addition, there are small clinical trials showing a beneficial effect of folic acid in depression, and its ability to enhance the effectiveness of antidepressant medications at just 500 mcg.
It is of relevance here because folic acid has been shown to increase omega-3 status when supplemented, and decrease omega-3 status when it is in deficiency in the animal model.
Given the current excess intake of omega-6 rich oils, and the emerging research on omega-3 fatty acids and major depressive disorder, all mental health professionals should at least ensure adequate intake of omega-3 fatty acids among patients with major depressive disorder.
The current average North American intake of EPA and DHA is approximately 130 mg per day, well short of the minimum 650 mg recommended by the international panel of lipid experts.
While it is not necessary for mental health professionals to become clinical nutritionists, consideration of a patient’s dietary quality may be worthwhile. Hopefully future research will determine if dietary modifications or supplementation can influence the outcome of standard care.
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Depression & Anxiety: MBCT Treatment Part 2
Depression & Anxiety: MBCT Treatment Part 3
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- Depression & Anxiety Treatment With Innovative Therapy – Part 1
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