Neurobehavioral aspects of omega-3 fatty acids: possible mechanisms and therapeutic value in major depression

Alternative Medicine Review, Nov, 2003 by Alan C. Logan

Abstract

Omega-3 fatty acids have been the subject of volumes of international research, the results of which indicate these substances may have therapeutic value in a number of medical conditions. An emerging area of research is examining the neurobehavioral aspects of omega-3 fatty acids (alpha-linolenic, eicosapentaenoic, docosahexaenoic) and the critical role of these essential fats in the functioning of the central nervous system. Investigations have linked omega-3 fatty acids to a number of neuropsychiatric disorders, including depression. The purpose of this article is to examine the possible mechanisms of action and potential clinical value of omega3 fatty acids in major depression. A novel mechanism involving omega-3 modulation of cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) is proposed.

(Altern Med Rev 2003;8(4):410-425)

Introduction

Omega-3 fatty acids are long chain, polyunsaturated fatty acids (PUFA) of plant and marine origin. Because these essential fatty acids (EFAs) cannot be synthesized in the human body, they must be derived from dietary sources. Flaxseed, hemp, canola, and walnuts are generally rich sources of the omega-3 PUFA alpha-linolenic acid (ALA). Fish provide varying amounts of omega3 fatty acids in the form of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). ALA can be metabolized into the longer chain EPA and DHA (Figure 1). (1) The role played by EFAs in the human body has been the subject of volumes of international research, particularly in recent years. The results indicate that omega-3 fatty acids may be of value in the treatment of various medical conditions. (2)

[FIGURE 1 OMITTED]

The brain contains a high concentration of PUFA (approximately 20 percent of dry weight) and, in the nervous system, one out of every three fatty acids (FAs) belong to the PUFA group. (3,4) Given the high concentration of EFAs in the nervous system, it is not surprising that investigators have focused on the role of omega-3 fatty acids in brain function. Recent research underscores the important role of these fatty acids in central nervous system (CNS) function, and the potential EFAs have in the treatment of various neuropsychiatric disorders. While beneficial effects of omega-3 fatty acids have been linked to Alzheimer's disease, (5) attention deficit hyperactivity disorder, (6) autism, (7) schizophrenia, (8) hostility, (9) anxiety, (10) and bipolar disorder, (11) the focus of this article will be the role of omega-3 fatty acids in the neurobiology and treatment of major depressive disorder.

Major Depression on the Rise

Mood disorders, including major depression, are recurrent, debilitating, and potentially life-threatening illnesses. In the last 100 years, the age of onset of major depression has decreased and its overall incidence has increased in Western countries. For example, severe forms of major depression affect up to five percent of the population in the United States, while up to 20 percent present with milder forms and another two percent have bipolar disorder. (12) This increase cannot be explained merely by changes in attitude of health professionals or society, diagnostic criteria, reporting bias, or institutional or other artifacts. (13,14) Despite advances in pharmacotherapy, a significant proportion of depressed patients are considered treatment-resistant. (15) Poor compliance, side effects, or lack of desired effects are not uncommon with antidepressant medications. Selective serotonin reuptake inhibitor (SSRI) treatment produces a 50-percent improvement in only about half of those who maintain therapy, while about 30 percent of depressed patients discontinue medications before six-weeks are complete. (16,17) Such lack of desired results encourages the continued search for improvements in current pharmacotherapy and novel treatments.

In contrast to the increased incidence of depression, the dietary intake of omega-3 fatty acids has dramatically declined in Western countries over the last 100 years. The ideal ratio of omega-3 to omega-6 EFAs is approximately 1:1, according to the conclusion of an international panel of lipid experts published in the Journal of the American College of Nutrition. (18) The North American diet currently has omega-6 fats outnumbering omega-3 fats by a ratio of 20:1, largely as a result of the ubiquitous supply of various omega-6-rich oils (corn, sunflower, safflower, cottonseed) added directly to the food supply or through animal rearing. (19) It is reported that corn oil has an omega-6:3 ratio of 60:1 and safflower a ratio of 77:1 (Tables 1 and 2). (20) The following research indicates these dietary fatty acid alterations and the indiscriminate 20-year-old message that all fat is harmful have not been without neurophysiological and neurobiological consequences.

Epidemiological Data

If omega-3 fatty acids play a role in depressive disorders, then it would be expected that countries consuming greater amounts of these fatty acids (primarily through fish intake) would have a lower prevalence of depression. In his research published in Lancet, Joseph Hibbeln of the National Institutes of Health found a significant negative correlation between worldwide fish consumption and prevalence of depression. (21) In research involving a random sample within a nation, frequent fish consumption in the general population is associated with a decreased risk of depression and suicidal ideation. (22) A recent cross-sectional study conducted in New Zealand found fish consumption is significantly associated with higher self-reported mental health status. (23)