Motivation and emotion/Book/2020/Omega-3 fatty acids and mood

Overview
Even as young kids, our parents instilled into our brains that if we eat healthy, nutrient-rich food, we will become strong, or be able to see in the dark, or we will become extremely smart. But did we ever understand what certain foods could do for our mental health and mood. Many dietitians will tell you that it is important to consume carbohydrates, proteins, vitamins and minerals, but there is an overarching consensus that omega-3 intake is just as important as the others. Omega-3 fatty acids are an extremely important part of the human diet, as they possess anti-inflammatory properties in the brain and central nervous system (Polokowski et al., 2020). The health benefits from omega-3 fatty acids are extensive, with eye health, cognitive functioning, mental well-being and organ functioning being some of the many (Swanson et al., 2012). These specific polyunsaturated fatty acids have received substantial attention as being relevant to mental health disorders, particularly anxiety and depression. Omega-3 fatty acids reduce inflammation in the endocannabinoid system, the hypothalamic-pituitary-adrenal axis, and the central nervous system. The processes that take place within these systems, surprisingly have a lot to do with the prevalence of depressive and anxious symptoms. The preventative role of omega-3 fatty acids in anxious and depressive disorders may also depend on other factors, including diet quality, medication use and social environments (Grosso et al., 2014).

Focus questions:
 * What are omega-3 fatty acids?
 * What are mood disorders?
 * What is the relationship between omega-3 fatty acids and mood?
 * How can we increase our omega-3 intake?

What are omega-3 fatty acids?
Polyunsaturated fatty acids (PUFA) are acids "that contain two or more carbon-carbon double bonds not saturated with hydrogen atoms at various locations within the molecule", as stated by Grosso and colleagues (2014). They are classified into groups by their chemical structure in omega-3 and omega-6 fatty acids (Grosso et al., 2014). Omega-3 fatty acids refers to a group of polyunsaturated fatty acids in which the first double bond is 3 carbons from the end carbon atom of the molecule (Grosso et al., 2014).

Omega-3 fatty acids are a fundamental component of the human diet, as it is a necessity for healthy brain function and the development of the central nervous system (CNS) (Polokowski et al., 2020). The dietary fats have an array of health benefits for your body, including cognitive functioning and mental well-being, organ function, and physical well-being (Swanson et al., 2012). They are known to signal molecules that regulate inflammation and neuroinflammation, meaning they possess anti-inflammatory, antiarrhythmic, and anti-thrombotic properties (Covington, 2004; Swanson et al., 2012; Larrieu & Laye, 2018). Omega-3 fatty acids are essential as the body does not synthesise them, meaning humans need to obtain them through diet and supplementation (Covington, 2004).

Omega-3 fatty acids are one of the two main elemental components to long chain PUFAs, that are grouped into three main acids important to human functioning (Giles et al., 2013; Polokowski et al., 2020).

Omega-3 PUFA are synthesised by dietary shorter-chained omega-3 fatty acid ALA to form important long-chain omega-3 fatty acids. These are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Grosso et al., 2014).

Alpha-linolenic acid


Alpha-linolenic acid (ALA) is an essential omega-3 fatty acid, that can not be metabolised by the body. ALA has been demonstrated to provide anti-inflammatory and antidepressant properties (Blondeau et al., 2015).

Alpha-linolenic acid can be acquired from plant-based ingredients, such as seeds, nuts, and leafy vegetables. However, ALA generally is metabolised into eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (Polokowski et al., 2020).

Eicosapentaenoic acid and docosahexaenoic acid
Among the omega-3 polyunsaturated fatty acids are docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which are synthesised from alpha-linolenic acid (ALA) (Simopoulos, 2002; Giles et al., 2014). DHA and EPA play important roles in the development and function of healthy cognitive functioning and memory, and are precursors of several metabolites that are potent lipid mediators (Swanson et al., 2012).

Docosahexaenoic acid (DHA) is critical for the development and function of a healthy brain, and although it is abundant in the brain, it can be difficult for it to travel through the blood-brain barrier. Different mechanisms facilitate the uptake the two types of DHA, nonesterified DHA and LPC-DHA, through the blood-brain barrier (Polokowski et al., 2020). The uptake of DHA is a highly complex system with no specific mechanism assisting the transmission of DHA to the brain.

Eicosapentaenoic acid (EPA) is released in the brain to compete with arachidonic acid (AA), which belongs to the omega-6 polyunsaturated fatty acid group and obtained through meat, poultry, and eggs, for enzymatic metabolism which ultimately induces the production of less inflammatory derivatives (Simopoulos, 2002).

DHA and EPA are biologically more potent than alpha-linolenic acid (ALA), and are primarily obtained through seafood sources, such as fish and fish oil supplements (Simopoulos, 2002; Swanson et al., 2012).

Mood
Mood is an affective state, that can either be negative or positive.

What is meant by mood in this chapter?
When talking about mood, and omega-3 fatty acids' relationship with mood, we are referring to depressive and anxious symptoms. This is mainly due to majority of the emotional effects of omega-3 fatty acids being focused on depression and depressive symptoms, or anxiety and stress. There is little research looking into omega-3 fatty acids' influence on mood disorders more broadly.

Mood disorders
Mood disorders are disorders that involve prolonged emotional disturbances. These disturbances can be depression and/or mania. The Diagnostic and Statistical Manual of Mental Disorders 5th Edition (DSM-5) identifies disruptive mood dysregulation disorder, persistent depressive disorder and bipolar disorders as mood disorders (Parker, 2014). Research primarily focuses on depression in multiple forms when studying the influence of omega-3 fatty acids on mood.

Depression
Depression is a mental disorder characterised by "sadness, loss of interest in activities, and decreased energy" (Grosso et al., 2014). They are a plethora of other depressive symptoms, such as loss of confidence and self-esteem, diminished concentration, disturbances of sleep and/or appetite, and thoughts of death and suicide (Grosso et al., 2014). A person can suffer from multiple variations of depression and/or depressive symptoms. Two common variations are (1) depressive episodes, involving common depression symptoms such as depressed mood, loss of interest, and increased fatigability, or (2) bipolar affective disorders, which consists of inconsistent mood variations between depressive episodes and manic episodes.

Endocannabinoid system
The endocannabinoid system is a neuromodulatory system that is composed of endogenous cannabinoids and cannabinoid receptors (Lu & Mackie, 2016). It plays an important role in the central nervous system and its development, as well as neuroplasticity, food lipids and behaviours (Lu & Mackie, 2016; Larrieu & Laye, 2018). Endogenous cannabinoids (endocannabinoids) are endogenous lipids that engage CB1 or CB2 cannabinoid receptors (Lu & Mackie, 2016; Bosch-Bouju & Laye, 2016). The most abundant receptor is the CB1 cannabinoid receptor (Lu & Mackie, 2016). Endocannabinoids (eCBS) include the fatty acids, anandamide (AEA), N-docosahexaenoyl ethanolamide (DHEA), oleylethanolamide and palmitoylethanolamide. AEA and 2-AG, are AA-derived metabolites, and DHEA is derived from DHA, oleylethanolamide and palmitoylethanolamide from EPA (Lu & Mackie, 2016; Bosch-Bouju & Laye, 2016). However, the two main omega-3 PUFAs in literature are the ethanolamides derived from DHA, known as DHEA, and from EPA, EPEA (Bosch-Bouju & Laye, 2016). Endocannabinoids are made on-demand and are rapidly degraded back into polyunsaturated fatty acids or oxidised into active metabolites (Bosch-Bouju & Laye, 2016).

The role of the endocannabinoid system in the regulation of mood, anxiety and depressive disorders has been increasingly researched in clinical studies. These disorders are associated with low content of omega-3 intake in the diet, and low omega-3 levels in the blood and brain. Similarly, it has been established that those with anxious or depressive disorders have lower levels of endocannabinoids in their blood (Bosch-Bouju & Laye, 2016). There is evidence of nutritional polyunsaturated fatty acids intake influencing endocannabinoid levels. Therefore, normalising omega-3 PUFAs in the brain and blood and can normalise endocannabinoid levels, further possibly influencing mood, anxiety and depressive disorders (Larrieu & Laye, 2016).

Endocannabinoids instability can induce homosynaptic and heterosynaptic long-term depression (Larrieu & Laye, 2018). According to Bosch-Bouju and Laye (2016), in the brain, omega-3 and omega-6 polyunsaturated fatty acids and endocannabinoids derived from omega-3 and omega-6 present in physiological concentrations. There is an imbalance between omega-6 and omega-3, favouring omega-6, in conditions such as mood disorders or neurodegenerative diseases (Bosch-Bouju & Laye, 2016). When dietary supplementations of omega-3 PUFAs are taken, the omega-6 and omega-3 imbalance reduces. This normalisation of polyunsaturated fatty acid levels could normalise endocannabinoids derived from omega-3 fatty acids, and ultimately contribute to the prevention and treatment of the disorder (Bosch-Bouju & Laye, 2016).

In the investigation of interactions between endocannabinoids and omega-3 PUFAs in mood and depressive disorders, we need to also consider the hypothalamic-pituitary-adrenal axis (HPA) (Bosch-Bouju & Laye, 2016).

Hypothalamic-pituitary-adrenal axis
Dietary polyunsaturated fatty acids are significant modulators of the hypothalamic-pituitary-adrenal axis. The function of endocannabinoids is also related to the HPA axis (Bosch-Bouju & Laye, 2016).

Stress activates the hypothalamic-pituitary-adrenal axis (HPA), and increases proinflammatory cytokine production (Giles et al., 2014). Depression has been associated with higher level of cortisol in the blood due to the hyperactivity of the HPA axis, majorly due to the hypersecretion of corticotropin-releasing hormone (CRH) (Grosso et al., 2014). Whilst the study of the relationship between omega-3 fatty acid deficiency and emotional behaviour/mood is underdeveloped, this idea that increased hypothalamic corticotropin-releasing hormone release has been linked to hypothalamic-pituitary-adrenal axis hyperactivity and increased omega-3 PUFAs intake (Larrieu & Laye, 2018). When stressed, the HPA axis is activated, stimulating the release of corticotropin-releasing hormone. If too much of the CRH is released, anxiety can be heightened along with depressive symptoms, sleep disturbances and more (Slominski, 2009). Grosso and colleagues (2014) suggested that, from animal studies, it has been reported that the response to stress can be regulated by omega-3 fatty acid intake, further supporting the idea that omega-3 deficiency influence anxious and depressive symptoms.

Furthermore, studies suggest that glucocorticoids can activate the release of endocannabinoids, specifically AEA and 2-AG. As discussed before, the normalisation of endocannabinoids, through omega-3 PUFA dietary intake can stabilise any PUFAs imbalance, contributing to the reduction of anxious or depressive symptoms. Endocannabinoids, when stable, can efficiently act to regulate the stress response (Larrieu & Laye, 2018).

Glucocorticoids suppress inflammatory signalling pathways, including inhibiting the stress-related outflow pathways, such as the corticotropin-releasing hormone, the hypothalamic-pituitary-adrenal axis, and the sympathetic nervous system (‘fight or flight’ response) (Grosso et al., 2014). Failure of glucocorticoids to inhibit inflammatory responses could potentially contribute to the worsening of neuropsychiatric disorders, however, the connection is not yet known (Grosso et al., 2014).

Both stress and depression increase the risk of prolonged infectious episodes, which, again, enhances proinflammatory cytokine production (Giles et al., 2014). Proinflammatory cytokines enhance and stimulate the inflammatory response in the brain (Zhang & An, 2007). The corticotropin-releasing hormone release, from the hypothalamic-pituitary-adrenal axis, is considered the primary mechanism by which cytokines stimulate glucocorticoid release (Giles et al., 2014). If any of these mechanisms are unstable, the possibility of inflammatory properties enhancing the deterioration of emotional behaviour, stress and depression is relevant.

Examination: Bosch-Bouju and Laye (2016) conducted a study to demonstrate the variations in dietary omega-3 polyunsaturated fatty acids and their impact on the hypothalamic-pituitary-adrenal axis.

One group of mice were fed with an omega-3 polyunsaturated fatty acid deficient diet. The other group of mice were fed with a docosahexaenoic acid (DHA) rich diet.

Results: Mice fed with an omega-3 PUFA deficient diet exhibited higher levels of corticosterone, while mice fed with a DHA-rich diet exhibited controlled levels of corticosterone, and those levels were not influenced by social defeat stress.

Again, the direct interaction between omega-3 fatty acids and the hypothalamic-pituitary-adrenal axis, in regards to the stress response and inflammatory properties, is still a grey area that needs further exploration. However, Bosch-Bouju and Laye (2016) state that animal studies are showing promising results for omega-3 rich diets and its influence on emotional behaviour.

The central nervous system
The central nervous system (CNS) is made up of the brain and spinal cord, and is the core to most functions within our bodies. The CNS has the second highest concentration of lipids in the organism (50-60% of dry weight in the brain). These lipids are ravenous for omega-3 fatty acids (Larrieu & Laye, 2018). Polyunsaturated fatty acids are released in the CNS via neurotransmitter stimulation and metabolised to active compounds (Giles et al., 2014). Despite both omega-6 and omega-3 PUFAs being necessary for cells to maintain their normal structure and function, the ratio of omega-3 to omega-6 fatty acids is important to these cellular processes (Giles et al., 2014).

The anti-inflammatory properties of omega-3 PUFAs act as therapeutic agents against neurodegenerative diseases, and influence brain plasticity (Wysoczanki et al., 2016). As the central nervous system controls most of the functions of our body and mind, the anti-inflammatory properties of omega-3 fatty acids will influence the central nervous system’s function.

Omega-3 fatty acids play a significant role in the development and function of the central nervous system. Essential PUFAs are metabolised. This means that linolenic acid (LA), an omega-6 PUFA, and alpha-linolenic acid (ALA), an omega-3 PUFA, compete for conversion into their specific forms, arachidonic acid (AA) and docosahexaenoic acid (DHA), for entry into the brain (Larrieu & Laye, 2018). DHA accounts for 10-15% of fatty acids in the brain. The conversion of ALA into DHA desaturates the strength of the fatty acid, leading to the recommendation of omega-3 dietary intake (Larrieu & Laye, 2018).

Western diet influence on omega-3 intake
Over time, the expansion and development of Western countries has been associated with the significant changes in the omega-3 and omega-6 polyunsaturated fatty acid content of the diet (Giles et al., 2014; Larrieu & Laye, 2018). This expansion has seen an increase in total fat and saturated fat content, and an excessive amount of omega-6 PUFA content, resulting in an imbalance of omega-3 and omega-6 fatty acid ratio (Grosso et al., 2014).

Omega-6 fatty acids account for majority of the polyunsaturated fatty acids in, predominantly, the Western diet. We have shifted towards foods higher in saturated fats from domestic animals and omega-6 PUFA-rich food from vegetable oils, and away from omega-3 PUFA-rich foods, such as fish and fish oil, wheat germ, walnuts and plants (Giles et al., 2014). Recently, recommendations from dietary professionals to replace saturated fats, like butter, with polyunsaturated fatty acid oils that are plant-based. These oils are high in linolenic acid (LA) and are low in alpha-linolenic acid (ALA). This is reflected in larger quantities of omega-6 and smaller quantities of omega-3 intake, resulting in the Western diet becoming insufficient in omega-3 PUFAs (Larrieu & Laye, 2018).

The deficit in omega-3 PUFAs in the diet has been linked to numerous inflammatory diseases, including depressive disorders and cardiovascular diseases (Grosso et al., 2014). The increased intake of those saturated fatty acids and omega-6 fatty acids, and the reduced intake of foods rich in omega-3 fatty acids, which have been found to exert anti-inflammatory properties, is associated with depressive disorders and could possibly increase the incidence of both depressive and cardiovascular diseases (Grosso et al., 2014). It is becoming increasingly evident that the imbalance of omega-3 and omega-6 polyunsaturated fatty acids in the brain as linked to neuropsychiatric disorders, particularly those with depressive episodes (Grosso et al., 2014).

Study

Larrieu and Laye (2018) examined the dietary intake of omega-3 polyunsaturated fatty acids and the prevalence of depression in Asian and Western countries. Individuals located in countries, such as Japan and Korea, who are the largest fish consumers, suffered relatively little from depressive disorders. On the other hand, individuals from countries, such as New Zealand, Canada, or Germany, who consumed smaller amounts of fish, had a higher prevalence to develop depressive disorders.

This data suggests that fish consumption and omega-3 dietary intake is correlated with depressive disorders. However, Japan has a high rate of suicides within the country, despite the depression rate being reported low.

Despite high fish consumption and omega-3 intake, countries where stressful lifestyles or the condition of the society are influential could counteract the benefits omega-3 has on depressive symptoms.

Alpha-linolenic acid (ALA), an essential omega-3 fatty acid, cannot be metabolised by the body. Therefore, it is converted into docosahexaenoic acid (DHA). However, the bioconversion of ALA into DHA goes through several cycles of elongation and desaturation. This process makes DHA not sufficient enough to cover the needs of brain (Larrieu & Laye, 2018). This discovery led to the recommendation of dietary intake of fish and fish oil, so the brain has a sufficient amount of DHA and EPA in its system (Giles et al., 2014).

Omega-3 fatty acids and their influence on mood
The reduced dietary supply of omega-3 PUFAs to the brain is associated with mental health disorders, including depression and anxiety. People diagnosed with depression or anxiety have displayed significantly low omega-3 fatty acid intake (Larrieu & Laye, 2018). Low omega-3 PUFAs intake may predispose individuals to depressive symptoms, as well as anxiety. In fact, epidemiological studies have linked low omega-3 dietary intake with the prevalence of depression in the general population (Larrieu & Laye, 2018). Other clinical studies have discovered that individuals diagnosed with depression or anxiety have displayed significantly lower omega-3 fatty acids and an imbalance in omega-6 and omega-3 levels in the blood and brain (Larrieu & Laye, 2018).

Inflammation is a key mechanism in the pathophysiology of depression and anxiety (Larrieu & Laye, 2018). Omega-3 polyunsaturated fatty acids, DHA and EPA, are regulators of the inflammatory response, and have recently been discovered to regulate the neuroinflammatory processes as well (Larrieu & Laye, 2018). The concentration of DHA and EPA is decreased in the membrane of erythrocytes in individuals suffering from depression and anxiety disorders (Larrieu & Laye, 2018). The pathophysiology of depression is dominated by the monoamine hypothesis, which states that the core of depression is an imbalance in serotonergic and noradrenergic neurotransmission (Grosso et al., 2014). Besides their anti-inflammatory properties, omega-3 fatty acids have also been found to positively influence the serotoninergic and dopaminergic transmission in the brain (Grosso et al., 2014). Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) can regulate signal transduction by enhancing membrane-bound enzymes. The membrane changing, that is induced by omega-3 PUFA intake can influence different neurotransmitter systems altering the regulation of dopaminergic and serotonergic neurotransmission that is dysfunctional in individuals with depression or anxiety disorders (Grosso et al., 2014). In fact, it has been reported that higher concentrations of DHA predicted an increase in serotonergic transmission in healthy adults (Grosso et al., 2014).

Stress may be a pathway by which omega-3 PUFAs can regulate depressive symptoms (Giles et al., 2014). As mentioned previously, stress and depression enhance proinflammatory cytokine production with the brain. Proinflammatory cytokines have been linked to influence the production of monoamine neurotransmitters, serotonin and noradrenaline, two major neurotransmitters that are imbalanced in individuals with depression (Giles et al., 2014). Dietary intake of omega-6 fatty acids increases the production of these proinflammatory cytokines, and unfortunately the Western diet consists of higher omega-6 polyunsaturated fatty acid food sources (Giles et al., 2014). Omega-3 fatty acids reduce the activity of omega-6 fatty acid, therefore, decreasing the proinflammatory cytokine activity that influences monoamine neurotransmitters involved in depression (Giles et al., 2014).

Giles and associates (2014) examined a study that found that both EPA- and DHA-rich fish oil supplementation improved depressive symptoms in adults, both healthy and with mild cognitive impairment. Furthermore, three weeks of fish oil supplementation eliminated stress-induced cortisol increase and decreased increases in epinephrine (Giles et al., 2014).

Current therapeutic strategies for depression and depressive symptoms include drugs that aim to enhance serotonergic neurotransmission (i.e., selective serotonin reuptake inhibitors (SSRI)) or noradrenergic neurotransmission (i.e., noradrenergic reuptake inhibitors (NARI)), or even both with tricyclic antidepressants or serotonin noradrenaline reuptake inhibitors (SNRI) (Grosso et al., 2014). Omega-3 intake is suggested to positively enhance the depressive symptoms some individuals may experience, leading to the potential as an intervention. However, there have been contrasting results about the effects of omega-3 fatty acid intake on depression, majorly due to the consideration of other factors, such as diet quality, including alcohol intake and smoking habits, social environment, and physical activity (Grosso et al., 2014). With more research being conducted, the possibility of omega-3 intake being increased, along with antidepressants medication (if needed), could be a potential future intervention.

Dietary recommendations for an omega-3 rich diet
Prevention studies have suggested consuming 50 to 180 milligrams of EPA and DHA, and 150 to 300 milligrams of ALA-rich foods or supplements daily. However, the United Nations Food and Agriculture Organisation (FAO) and the World Health Organisation (WHO) recommend consuming up to two servings of fish per week, which will provide 200 to 500 milligrams a week, along with the inclusion of oils and food sources high in ALA (Grosso et al., 2014).

Take this quiz, curated by the Global Organisation for EPA and DHA omega-3s, to see if you are getting enough omega-3 fatty acids in your diet. Click here.

Alpha-linolenic acids (ALA) is an omega-3 fatty acid that is found in seeds, oils, green leafy vegetables, nuts, and beans.

Table 1.

Food sources high in alpha-linolenic acids (Covington, 2004; Grosso et al., 2014).

Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are present in seafood sources and oil supplements.

Table 2.

Food sources high in eicosapentaenoic acid and docosahexaenoic acid (Covington, 2004; Grosso et al., 2014).

Conclusion
Prolonged emotional disturbances can vary from depressive episodes to episodes of mania, including prolonged high stress levels. Omega-3 polyunsaturated fatty acids are essential components of any human’s diet. They are not only a necessity for healthy brain function, central nervous system development and cognitive functioning, but also can reduce depressive and anxious symptoms. Omega-3 anti-inflammatory properties regulate inflammation and neuroinflammation that can occur within the neurotransmitters and mechanisms that are involved in depression.

However, research of the link between omega-3 fatty acids and depressive symptoms, anxiety, stress and mood is ongoing, with contrasting results. Many questions within this research area still need to be considered. The pathophysiological processes of depressive symptoms involved in major depressive disorder (MDD), or social anxiety disorder, or persistent depressive disorder, are likely to be different from those with depression in other clinical conditions, such as bipolar disorder and postpartum depression (Grosso et al., 2014).

Being aware of our mood and emotional behaviour, and the link to diet, is extremely important as it is an issue that continues to become relevant in our society today. Ensuring we are eating mindfully, and consuming the recommended amount of vitamins, minerals, proteins, carbohydrates, and so on, along with any supplementations suggested, is a step in the right direction to living a happy, healthy lifestyle.

Further recommendations If you would like to read further about the Australian Dietary Guidelines, and omega-3 dietary intake, please click here.