According to the World Health Organization, it is estimated that by the year 2020, depression will account for the second greatest increase in morbidity following cardiovascular disease, presenting a significant socioeconomic burden.1 Investigators of the Global Burden of Disease Study indicated that "the findings reinforce the importance of treating depressive disorders as a public-health priority and of implementing cost-effective interventions to reduce their ubiquitous burden."2
"Omega-3 fatty acids has emerged as the Holy Grail of neuronutrients in treating depression."9
Depression is a complex and heterogeneous disorder that has a negative impact on the quality of life, morbidity/mortality, and cognitive function. As an intricate mental health disorder, depression consists of a spectrum of clinical depression that ranges from mild to moderate depression, which is characterized by symptoms that include low self-worth, depressed moods, disturbed sleep, anxiety, low energy, and poor concentration, to the more severe clinical major depressive disorder that involves feelings of deep despair that lead to thoughts of suicide.3 In the United
States alone, an estimated 1 in 10 adults reports depression, although some studies indicate these figures to be higher.2 According to a recent report by the Centers for Disease Control and Prevention's National Center for Health Statistics, approximately 11% of Americans 12 years or older take antidepressant drugs, including many (>68%) who have not seen a mental health care professional in the past year. This report also indicates that the rate of antidepressant drug use in the United States has increased by a remarkable 400% since 1988, a paradox in itself considering the medical literature continues to document the limitations, adverse effects, and withdrawal symptoms associated with antidepressant medications, as well as their potential for precipitating suicidal thoughts and feelings.4,5
In view of the complexity of mental health disorders, such as depression, anxiety, and insomnia, which are common comorbid psychiatric conditions, it would appear that a holistic treatment model that incorporates a complementary and integrative therapy approach within the framework of conventional health care would most effectively support optimal healing. This concept of an integrative healing model of treatment is evidenced by a growing body of practitioners who support the use of complementary and integrative health therapies such as neuronutritional science to enhance the outcomes of treatment in mood disorders.6-8 For those in clinical practice, omega-3 polyunsaturated fatty acids (PUFAs) have emerged as the Holy Grail of neuronutrients in treating depression.9
INFLAMMATION
Its role in depression
There is an extensive body of clinical evidence that associates chronic systemic low-grade inflammation to a broad spectrum of health problems that include cardiovascular disease, rheumatoid arthritis, and autism.10-14 Inflammatory processes have also been shown to induce symptoms of depression, anxiety, and other mental health disorders.8,10
Although acute inflammatory reactions are generally protective and a component of the normal innate immune response, uncontrolled chronic inflammatory processes are detrimental and precipitate disease.15 Inflammation is the manifestation of an activated immune system that protects against invading pathogens, irritation, and toxins. When mobilized in response to foreign substances, inflammation catalyzes a cascade of events through the release of white blood cells and chemicals known as cytokines (cyto, derived from Greek, meaning "cell"; kines, from Greek, meaning movement). As signaling molecules of the immune system, cytokines function as a protective mechanism by producing controlled amounts of inflammation. However, when the intrinsic balance of the immune system is disrupted, the resulting secondary reactions can precipitate chronic systemic low-grade inflammation.
Inflammatory mechanisms have been implicated in the pathophysiology of depression. It has been clearly demonstrated that both depression and anxiety have the ability to enhance the production of proinflammatory cytokines.16-18 A variety of factors seems to increase the risk for the development of depression, which appear to be associated with systemic inflammation; these factors include but are not limited to psychosocial stressors, poor diet and lifestyle, obesity, alterations in gut permeability, and sleep, and vitamin D deficiency.19
This article explores the role of inflammation and the environmental risk factor of psychosocial stressors as it relates to the development of depression.
Inflammatory risk factors
Psychosocial stressors
There is significant evidence that psychosocial stressors, such as psychological trauma, subchronic stressors, and early childhood trauma, increase the risk for the development of clinical depression and other mood disorders, while impacting neuroimmune circuits.
In human models, studies indicate that different types of psychosocial stressors may increase the proinflammatory cytokine network, including interleukin-6 and tumor necrosis factor [alpha]. 20 These findings indicate that psychosocial stress-induced elevations in proinflammatory cytokines coordinate stress-induced changes in peripheral blood immune cells, inflammatory reactions, and changes in neurobehavior.
The implication that psychosocial stressors regulate the production of proinflammatory cytokines versus anti-inflammatory compounds has important significance for stress-related disorders, including depression, anxiety, and posttraumatic stress disorder. In summary, psychosocial stressors, such as abuse, trauma, and other negative life events often precede the onset of clinical depression. In translational research models, results show that proinflammatory cytokines can cause depression and anxiety. These mechanisms may offer insight in how psychosocial stressors and psychological trauma may elicit mood disorders in vulnerable individuals with poor functioning immune, endocrine, and nervous systems. Recent research studies have corroborated these findings.
A multidisciplinary health and development study in New Zealand that followed 1000 participants from birth to 32 years of age demonstrated that individuals who experienced stressors in childhood that resulted from abuse, poor treatment, and economic hardship had a 2-fold probability to suffer chronic inflammation.21 The negative impact of stressors on health in adulthood has also been demonstrated in US populations. In one study, it was found that adversity experienced during childhood shortened the lifespan by 7 to 15 years, citing evidence that early acute stressors can result in an inflammatory response that leads to premature aging, when compared with individuals without exogenous environmental stressors.22 There is supportive evidence that early childhood stress can result in persistent effects over a prolonged period of time, resulting in an increased vulnerability to inflammatory disease and psychiatric illness later in adult life.
Research continues to support the association between psychosocial stressors and inflammation in adulthood and has become an instrumental risk factor for disease onset. Studies have shown that the manner in which individuals respond to psychosocial stressors, such as job strain, may contribute to the level of intensity of inflammatory activity. Stress-related job strain is a known risk factor for inflammation, and for other inflammatory diseases, such as cardiovascular disease, and more recently has been shown to be strongly associated with an increased risk of depression.23 Through the identification of risk factors related to stress, and by understanding the inflammatory response and its deleterious cascade of events, inflammatory diseases such as depressive disorders can be prevented and effectively treated.
OMEGA-3 FATTY ACIDS
Research has established that long-chain omega-3 PUFA plays a fundamental role in brain structure and function. Epidemiological and cross-sectional studies have also identified a role for long-chain omega-3 fatty acids (PUFAs), which include docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in the etiology of depression.
Anti-inflammatory properties
Both depression and anxiety have demonstrated the ability to enhance the production of proinflammatory cytokines.16-18 Inflammatory mechanisms have been implicated in the pathophysiology of depression. Furthermore, stressful experiences that often precipitate depression can increase proinflammatory cytokine production.17 The antidepressant properties of omega-3 fatty acids are related to their ability to reduce inflammatory responses.24,25
Omega-3 fatty acids and omega-6 PUFA consumption have a direct influence on inflammation. Arachidonic acid, an omega-6 fatty acid, increases proinflammatory cytokine production.24 In contrast, the eicosanoids derived from omega-3 PUFAs decrease the production of arachidonic acid-derived eicosanoids.26 A high omega-6 to omega-3 fatty acid ratio has been demonstrated to have an inflammatory effect, whereas a higher intake of omega-3 fatty acids in the form of EPA and DHA regulates the production of inflammatory cytokines.27
Effects on depression
An accumulating body of evidence has implicated a deficiency in dietary omega-3 fatty acids, EPA and DHA, in the pathophysiology of several mood disorders, including depression, bipolar disorder, and seasonal affective disorder.28-31 The highest quantity of omega-3 fatty acids found in the brain is DHA, which is highly concentrated at nerve synapses and therefore of vital importance for neural cell signaling and neurotransmitter processes.25,26 Observational studies have linked lower omega-3 PUFAs and higher omega-6 PUFAs with inflammation, depression, and anxiety.6 Although additional research may be warranted to confirm and extend these findings, the body of evidence strongly suggests that low omega-3 fatty acid status has beneficial effects on different mood disorders, including depression and anxiety. Furthermore, this evidence presents compelling evidence that low omega-3 PUFA levels may represent a modifiable risk factor for mechanisms implicated in the progression of mood disorders.
SUMMARY
Chronic systemic low-grade inflammation has been linked to a broad spectrum of health conditions that include cardiovascular disease, stroke, rheumatoid arthritis, and mood disorders such as depression and anxiety. Deficits in omega-3 fatty acids have been identified as a contributing factor in mood disorders and offer a potential rational treatment approach.32
REFERENCES