Linking Omega-3 Fatty Acids and Depression

C H A P T E R

13 Linking Omega-3 Fatty Acids and Depression Justyna Godos⁎, Sabrina Castellano†, Fabio Galvano⁎, Giuseppe Grosso⁎ ⁎

Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy † Department of Educational Sciences, University of Catania, Catania, Italy

INTRODUCTION Polyunsaturated fatty acids (PUFAs) are fatty acids with two or more double bonds between carbon atoms. PUFAs can be classified primarily as omega-3 or omega-6, depending on the position of the first double bond from the methyl end in the carbon chain. Omega-3 (also called as ω-3 fatty acids or n-3 fatty acids) refers to a group of PUFAs, in which the first double bond is found between the third and the fourth carbon atom from the methyl end of the molecule. The omega-6 (also called as ω-6 fatty acids or n-6 fatty acids) is a family of PUFAs, in which the first double bond is between the sixth and the seventh carbon atom, counting from the methyl end.1 Omega-3 PUFAs include α-linolenic acid (ALA), stearidonic acid (SDA), eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA). The initial rate-limiting step of omega-3 PUFAs synthesis involves desaturation of ALA (18:3n-3) by ∆6-desaturase to SDA (18:4n-3), followed by an elongation to eicosatetraenoic acid (20:4n-3). Next, ∆5-desaturase catalyzes a second desaturation to form EPA (20:5n-3). EPA is then further elongated by elongase, first to DPA (22:5n-3) and then to tetracosapentaenoic acid (24:5n-3). Tetracosapentaenoic acid then undergoes a second ∆6 desaturation to form tetracosahexaenoic acid (24:6n-3). The initial steps occur in the endoplasmic reticulum. Nonetheless, the final stage of DHA synthesis occurs in the peroxisome following the translocation. In the peroxisome, during single cycle of β-oxidation, tetracosahexaenoic acid is shortened to DHA (22:6n-3) and then translocated back to the endoplasmic reticulum for subsequent esterification into aminophospholipids.1 On the other hand, omega-6 PUFAs derive from linoleic acid (LA, 18:2n-6), which can be converted into gamma linolenic acid (GLA, 18:3n-6), ­dihomo-gamma-linolenic acid (DGLA, 20:3n-6), and arachidonic acid (AA, 20:4n-6). Both LA

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and ALA are considered essential fatty acids as mammalian cells are incapable of synthesizing these fatty acids from simpler precursors.2 The major dietary sources of PUFAs are aquatic organisms, vegetable oils (i.e., flaxseed, walnut, canola, soybean) and seeds (i.e., chia, hemp, flaxseed).3 High amounts of ALA, the precursor of other omega-3 PUFAs, are mainly found in plant-based foods, including flaxseed, chia seeds, soybeans, and walnuts. Instead, the primary sources of EPA and DHA comprise liver of lean white fish such as cod and halibut, the body of oily fish such as salmon and mackerel, the blubber of marine mammals such as seals and whales, and marine algae.4 Finally, similar to ALA, the precursor of omega-6 PUFAs may be found mostly in crop seeds and vegetables oils, including canola, soybean, and sunflower oil.5 In fact, a joint expert consultation of the United Nations Food and Agriculture Organization (FAO) and the World Health Organization (WHO) recommend an intake of 1–2 servings of fish per week, considering that each serving is providing 200–500 mg DHA and EPA.6 Moreover, the data support the inclusion of vegetable oils and food sources high in ALA, especially in a vegetarian diet. It has been established that dietary ALA and LA play a crucial role in maintaining tissue omega-3 and omega-6 long-chain PUFAs (LC-PUFAs) levels, which are important components of cell membrane phospholipids. LC-PUFAs contribute not only to the membrane structure but also to membrane fluidity, functionality of membrane receptors, and cell signal transduction. Additionally, LA and ALA are critically responsible for producing various classes of pro-inflammatory and anti-inflammatory eicosanoids. Eicosanoids are signaling lipids that include prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs), and hydroxyeicosatetraenoic acids (HETEs), which have been previously linked to various pathological processes such as inflammation. Omega-3-derived eicosanoids mostly promote anti-inflammatory response, while omega-6-derived eicosanoids are pro-inflammatory. Nonetheless, the synthesis of AA-derived eicosanoids depends on the concentration of DGLA, as DGLA competes with AA for cyclooxygenase (COX) and lipoxygenase (LOX), enzymes implicated in LC-PUFAs metabolism. The excess of DGLA inhibits the synthesis of AA-derived eicosanoids due to its higher affinity for the COX and LOX enzymes.7 Taking into account above-mentioned mechanisms, an adequate and balanced intake of omega-3 and omega-6 should be considered in order to maintain homeostasis. Over the last century, extreme nutritional changes, particularly in industrialized countries, caused a substantial decrease in dietary intake of omega-3 PUFAs.8 Extensive refining and processing of foods, as well as cultural dietary choices have led to an increase in omega-6 PUFAs intake (i.e., associated with Western diet increased consumption of vegetable oils). Nowadays, fatty acids represent 30%–40% of total energy consumed by European populations, whereas, in ancestral nutrition, fatty acid consumption was limited to approximately 20%–30% of total energy intake. The ancestors, who ate a diet richer in omega-3 fatty acids, had an estimated ratio of omega-6:omega-3 of 1.5:1. However, according to the nutritional changes in the Western diet, this ratio has now increased, and the estimated range is from 10:1 to 20:1.9,10 Dietary omega-3 PUFAs have been considered of particular interest due to the association with human health.11 In particular, many epidemiological and experimental studies emphasized their possible role in the prevention and treatment of depressive disorders. Due to evidence from animal and human studies reporting that omega-3 deficiency may lead to

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impaired neuronal function and altered inflammatory status, the biological plausibility of the effects of the omega-3 PUFAs raised several hypotheses, although merely speculative.12 The aim of this chapter is to review the current evidence regarding the association between omega-3 PUFAs and depression, taking into account both epidemiological and clinical studies. Finally, proposed molecular mechanisms underlying the beneficial effect of omega-3 PUFAs toward depression will be pointed out.

BURDEN OF DEPRESSION Depression is a mental disorder characterized by sadness, lack of interest in activities, and anhedonia. Other symptoms include loss of confidence and self-esteem, inappropriate feeling of guilt or worthlessness, diminished concentration, disturbance of sleep and appetite, suicidal thoughts, and sometimes attempted or actual suicide.13 Depending on the number and severity of symptoms, a depressive episode can be categorized as mild, moderate, or severe. There are different types of depression, including: (i) recurrent depressive disorder that involves repeated depressive episodes, during which, the person may experience depressed mood, loss of interest and enjoyment, reduced energy leading to diminished activity, anxiety symptoms, disturbed sleep and appetite, feeling of guilt or low self-worth, or poor concentration; (ii) bipolar affective disorders that typically consist of both manic and depressive episodes separated by periods of normal mood, manic episodes may involve elevated or irritable mood, over-activity, inflated self-esteem, and a decreased need for sleep.13 The Diagnostic and Statistical Manual of Mental Disorders (DSMV) defines major depressive disorder (MDD) diagnosis based on the presence of primarily symptoms, either depressed mood or loss of interest or pleasure, during the 2-week period. In addition, the diagnostic criteria require the presence of at least five items listed in DSMV, among which are (i) depressed mood, (ii) markedly diminished interest or pleasure in activities, (iii) significant weight loss when not dieting or weight gain, (iv) insomnia or hypersomnia, (v) psychomotor agitation or retardation, (vi) fatigue or loss of energy, (vii) feelings of worthlessness or excessive or inappropriate guilt, (viii) diminished ability to think or concentrate, or indecisiveness, (ix) recurrent thoughts of death, recurrent suicidal ideation, or a suicide attempt.14 The course of MDD is quite variable, some individuals may experience remission (rarely), while others may experience many years with few or no symptoms between discrete episodes. The risk of recurrence becomes progressively lower over time as the duration of remission increases, however, with higher rates in individuals whose preceding episode was severe, in younger individuals, and in individuals who have already experienced multiple episodes. The persistence of even mild depressive symptoms during remission is a powerful predictor of recurrence.14 Depression is a significant contributor to the global burden of disease and affects people in all communities across the world. According to the recent report of the Global Burden of Disease Study, MDD is the third leading cause of global disability.15 By 2020, depression is projected to be the second leading cause of disease burden worldwide after heart disease. Currently, depression is estimated to affect 350 million people. The World Mental Health Survey conducted in 17 countries found that on average about 1 in 20 people reported having an episode of depression in the previous year. Nonetheless, despite the high prevalence of

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depression, the mental health budgets of the majority of countries represent <1% of their total health expenditures. >40% of countries have no mental health policy and over 30% have no mental health programs.16 Moreover, both direct economic costs of depression in terms of cost of treatment and indirect costs through lost days of work and reduced productivity, represent a major issue for public health.17

EPIDEMIOLOGICAL EVIDENCE Mental, physical, and social health represents fundamental elements of the general well-being of a person. These factors are closely interwoven and deeply interdependent. For instance, the increased prevalence of depression over the last decades in Western countries has been accompanied by increased prevalence of cardiovascular diseases (CVDs) and fundamental changes in dietary habits.17,18 Based on the epidemiological evidence, several studies suggested that depression may share common pathophysiologic mechanisms with CVDs and their risk factors,19 including increased production of pro-inflammatory cytokines,20 endothelial dysfunction,21 elevated plasma homocysteine levels,22 blood flow abnormalities (i.e., in depression, hypoperfusion in the limbic system and prefrontal cortex),23 and impaired glucose metabolism (i.e., low glucose utilization in a number of brain regions correlating negatively with severity of depression).24 Consequently, it has been hypothesized that besides environmental, behavioral, and genetic factors,25 nutritional factors could significantly contribute to the increase in prevalence of both depression and CVDs. Indeed, significant shift over the last century in the dietary intake of long-chain PUFAs toward an increased intake of saturated fats and change in the ratio of omega-6 to omega-3 fatty acids intake was annotated.26 The first observation of an inverse association between per capita fish consumption and national annual prevalence of major depression was reported about 15 years ago.27 Since then, several epidemiological studies demonstrated a significant inverse association between dietary intake of oily fish and prevalence28–33 and incidence34–36 of depression and bipolar disorder,37 setting a threshold of vulnerability of about 650 mg/day. Interestingly, regarding the Mediterranean countries, several studies reported a decreased prevalence38 and incidence39–41 of depression and/or depressive symptoms in subjects more adherent to the Mediterranean dietary pattern, which is characterized by a high consumption of fish. The favorable effects of the Mediterranean diet on mental health may depend on the synergic beneficial properties of a variety of foods with a high content of omega-3 PUFAs, such as oily fish, but also olive oil and varieties of nuts.42 Such positive effects on mental health of long-chain fatty acids contained in the Mediterranean diet may also explain the evidence supporting protective effects of Mediterranean diet toward CVDs.43 However, these conclusions are still not definitive, as other components of the Mediterranean dietary pattern may exert considerable positive effects on the brain function, and thereby undermining the evidence regarding omega-3 fatty acids.44 Recently, the association between dietary omega-3 PUFAs and EPA/DHA intake and depression was explored using meta-analytical approach. The study reported significant reduced risk of depression, when considering the highest versus the lowest category of dietary omega-3 PUFAs intake, even though several of the individual studies reported nonsignificant results and the amount of omega-3 PUFAs estimated across included studies varied to a great extent.

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Clinical Evidence

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The dose–response analysis demonstrated a J-shaped decreased risk of depression up to 1.8 g/ day of omega-3 PUFAs intake. Accordingly, dose–response calculated for studies on EPA/DHA showed significant decreased risk of depression up to 0.6 g/day of EPA/DHA intake, despite nonsignificant decreased risk was evident also for further increment in dietary intake.45 Nonetheless, the clarity and reliability of the results obtained from epidemiological studies on omega-3 PUFAs consumption and prevalence and incidence of depression may depend on the limitations characteristic for this type of studies. Indeed, in cross-sectional studies it is difficult to determine whether the outcome followed exposure in time or exposure resulted from the outcome. On the other hand, prospective studies may be affected by the misclassification of exposure, if dietary intake of omega-3 PUFAs is assumed to be constant over the entire follow-up period. Finally, in both types of studies, the use of food frequency questionnaires (FFQs) for the estimation of habitual dietary intake of omega-3 PUFAs may lead to recall bias.

CLINICAL EVIDENCE Although epidemiological evidence supports an inverse association between omega-3 PUFAs and depression, the validity of the findings from clinical research is limited due to the methodological issues. Up to date, several meta-analyses on clinical studies have been conducted regarding the effect of omega-3 PUFAs toward depression, mostly demonstrating benefits of the administration in ameliorating symptoms of depression.46–48 Nonetheless, inconsistent results have been reported in other systematic revisions of literature and meta-analysis.49,50 Systematic reviews and meta-analyses can provide evidence relevant to many aspects of human health; however, the conclusions are less clear and reliable when the included studies have differing results reflected in high heterogeneity. There are several factors that can account for the high heterogeneity across the studies, such as publication bias, unstandardized diagnosis (reliability of outcome measures), variability in treatment dose, and timing or duration of the trial. Other factors include features of the population such as severity of illness, comorbidities, age, and gender.51 In fact, among the limitations of pooled analysis, were study eligibility criteria, differences in omega-3 PUFAs dose, timing and duration of the trial, and overall quality of the study. However, it seems that unstandardized depression assessment (i.e., clinical diagnosis of MDD vs. self-reported depressive symptoms) and comorbidities (CVD, Alzheimer, and schizophrenia), were notably affecting the efficacy of the treatment with omega-3 PUFAs in these pooled analyses, as different mechanisms may underlie the pathophysiology of depression.52 Certain meta-analyses focused on the type of fatty acid used, resulting in a positive effect on depressive symptoms of EPA rather than DHA content of the regime.53,54 Particularly, supplements containing EPA ≥ 60% of total EPA + DHA, in a dose range of 200–2200 mg/day of EPA in excess of DHA, were effective against primary depression.55 It has been also reported that the more severe was the depression, the more likely omega-3 PUFAs supplementation would reduce depressive symptoms. In summary, omega-3 PUFAs may exert antidepressant effects in patients with MDD but not “mood-improving” effects in individuals with only self-reported depressive symptoms, and however, the efficacy strongly depends on the origin of depression.

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MOLECULAR MECHANISMS UNDERLYING POSSIBLE EFFECTS OF OMEGA-3 PUFAS Susceptibility to depression is influenced by a variety of genetic, epigenetic, endocrine, e­ nvironmental, and dietary risk factors. It has been established, that dysregulation of the ­hypothalamic–pituitary–adrenal (HPA) axis, and abnormal release of neurotrophic factors, sex steroids, metabolic, and/or inflammatory cytokines can lead to alterations in neurotransmitters, intracellular signaling, gene transcription, and epigenetic changes that in turn can contribute to short-term and long-lasting imbalances of neuronal function and behavior.56 Therefore, the suggested preventive and therapeutic effects of omega-3 PUFAs toward depression could be underlined by the alteration of one or more of the above-mentioned mechanisms.

Neuro-Inflammation A growing body of scientific evidence indicates that depression is associated with e­ xcessive production of pro-inflammatory cytokines such as interleukin-1beta (IL-1β), ­interleukin-12 (IL-12), and interferon-gamma (IFN-γ),57 and reduced levels of anti-inflammatory cytokines, such as interleukin-4 (IL-4), interleukin-10 (IL-10), and tumor growth factor-beta1 (TGF-β1).58,59 In fact, recent meta-analysis of experimental studies reported a significantly higher concentration of the pro-inflammatory cytokines, including tumor necrosis factor-­ alpha (TNF-α) and interleukin-6 (IL-6) in depressed subjects compared to healthy controls.57 Furthermore, several studies have demonstrated a positive correlation between the severity of the symptoms of depression and the increase in the inflammatory status58. Dysregulation of inflammatory balance, partially caused by the activation of microglia in central nervous system (CNS),60 may lower neurotransmitter precursor availability and therefore alter the metabolism of neurotransmitters, reduce synaptic plasticity and hippocampal neurogenesis, as well as elicit both sickness behavior and psychological pain.58 Chronic inflammation has been associated with the promotion of neurodegeneration,61 a process characterized by progressive loss of structure or function of neurons. The key anti-­ inflammatory effect of omega-3 PUFAs has been long recognized to depend on their metabolites, namely eicosanoids. As described previously, eicosanoids are biologically active lipid mediators produced from PUFAs which play an important role in regulation of immune system function.62 Several studies demonstrated the association between the severity of depression and the degree of incorporation of omega-3 PUFAs in erythrocyte membranes, which are decreased in more severe conditions.63–66 Moreover, results from a case–control study conducted on 16 depressed and 22 non-depressed women recruited during the third trimester of pregnancy demonstrated that high DHA, high total omega-3 and a low omega-6:omega-3 ratio were associated with significantly lower odds of depression.67 Similar findings were reported in some studies conducted on depressed patients with post-myocardial infarction68 and acute coronary syndromes69,70 in which, compared to control group, lower levels of longchain omega-3 PUFAs as measured by a ratio of AA/EPA were found. It is well established that depression is associated with immune system dysregulation. Nonetheless, it has not yet been elucidated whether this immune dysregulation plays a role in the pathophysiology of MDD or whether it increases the susceptibility of the depressed ­patient to immune-related diseases.71 The peripheral immune activation observed in

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­ epressed patients, mediated by the release of pro-inflammatory cytokines, is responsible for d the variety of behavioral, neuroendocrine and neurochemical alterations that are associated with the severity of the symptomology.71 Omega-3 PUFAs have been reported to modulate the release of key pro-inflammatory and anti-inflammatory cytokines and growth factors.72 At the cellular level, they have been demonstrated to regulate the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), a key transcription factor involved in cytokine production and cell survival.72 Recent studies have pointed out the possible role of omega-3 PUFAs in inducing an antidepressant-like effect by modulating oxidative stress response and inflammatory cytokine production in microglia and neuronal cells, through decreased expression of TNF-α, IL-6, nitric oxide synthase (NOS), and upregulated expression of (IFN-γ) and heme oxygenase-1 (HO-1).73 However, results of experimental studies on immune system regulation after administration of omega-3 PUFAs are not univocal. For example, long-term administration of omega-3 PUFAs in a rat model increased plasma serotonin concentration and the expression of hippocampus c-AMP response element binding protein (CREB) and reduced release of IL-6, however, a clear dose-dependent effects and significant differences in expressions of IL-1β, TNF-α, brain-derived neurotrophic factors, and phosphorylated CREB were not observed.74 As mentioned above, MDD is characterized by increased levels of pro-inflammatory cytokines and reduced levels of anti-inflammatory cytokines such as IL-10 and TGF-β1.58,75 It has been demonstrated that plasma TGF-β1 levels are reduced in MDD patients and show a significant negative correlation with the Hamilton Depression Rating Scale,59,76,77 and that antidepressant treatment significantly increases TGF-β1 levels.59 In example, SSRI drugs such as sertraline might exert immunomodulatory effects in vivo through a decrease in the release of the pro-inflammatory cytokine IL-12, and an increase in the anti-inflammatory cytokines such as IL-4 and TGF-β1.77 Similarly, venlafaxine was shown to inhibit microglial activation, reduce pro-inflammatory cytokine secretion, and increase the release of TGF-β1 in an in vitro astroglia-microglia coculture model.78 Finally, recent experimental studies suggested that omega-3 PUFAs can increase the synthesis of TGF-β179,80 and, in particular, in pregnant women,81 although no studies have been yet conducted in MDD patients. Taking into consideration recent evidence, it is important to assess whether TGF-β1 signaling pathway is a common target for both omega-3 PUFAs and antidepressant drugs.

Neurogenesis Neurogenesis is the process by which new neurons are generated from neural stem cells. Adult neurogenesis occurs in two specific regions of the brain, the subventricular zone (SVZ) of the olfactory bulb and the subgranular zone (SGZ) of the hippocampal dentate gyrus.82,83 The rate of neurogenesis and survival of new neurons in adults can be enhanced by many factors, such as, growth factors and neurotransmitters,84 exercise,85 or enriched environment.86 Interestingly, much evidence indicate that neurogenesis underlies specific dynamics and flexible features of learning and memory, and that there is a cross-talk between neurogenesis and synaptic plasticity.87 Noteworthy, increased neurogenesis has been observed in rodents following ischemia,88,89 stroke,90,91 and after seizures,92,93 suggesting implication in brain self-­ repair and possibility that enhancing neurogenesis and the subsequent survival of new neurons may have significant therapeutic potential.83

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Neurogenesis is decreased in the hippocampus of animal models of MDD, and many therapeutic strategies for the disorder, including antidepressant medication and electroconvulsive therapy, increase hippocampal neurogenesis. In recent years, an interesting hypothesis regarding the role of hippocampal neurogenesis in depression has been proposed. Specifically, it has been suggested that insufficient hippocampal neurogenesis causally underlies depression,94 and may be related to glucocorticoids and serotonin levels, which are also associated with a decreased and increased rate of neurogenesis, respectively.95 Nevertheless, the associations are still uncertain. Recent studies demonstrated the ability of DHA to induce the differentiation of neural stem cells into neurons, however, the evidence regarding other omega-3 PUFAs is limited. Several mechanisms may be involved in the induction of adult neurogenesis by DHA, including promotion of the proliferative activity of neural stem cells and increase in the number of newborn neurons. Consequently, it has been demonstrated that DHA effectively promotes the differentiation of neural stem cells into neurons through promoting cell cycle exit and suppressing cell death. Additionally, dietary administration of DHA was shown to significantly increase the number of newborn neurons in the granule cell layer of the dentate gyrus in adult rodents.96 In neural stem cells, neurogenesis is modulated by a large superfamily of transcriptional factors forming basic helix–loop–helix (bHLH).97 Neurogenesis is promoted by activator-like bHLH transcription factors, such as neurogenin, NeuroD, and Ascl1, while Hes1 and Hes5 exert suppressor-like properties, and thereby prevent terminal differentiation and preserve a pool of stem cells. Accordingly, the effect of DHA administration on the expression of bHLH transcription factors in neural stem cells has been investigated. DHA was shown to significantly decrease the expression of Hes1 and increase expression of neurogenin1 and NeuroD. Interestingly, MAP2 expression, a neuron-specific protein involved in microtubule assembly, an essential step in neuritogenesis, was also significantly increased. Taking into consideration that MAP2 is activated by NeuroD and repressed by Hes1, it can be hypothesized that DHA stimulates neuronal differentiation by altering the expression of bHLH transcription factors.98 Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family of growth factors, involved in spatial learning and memory, acts on certain neurons of the CNS and the peripheral nervous system, supporting the survival of existing neurons, as well as the growth and differentiation of new neurons and synapses.99 Interestingly, as demonstrated in in vivo study, PUFAs supplementation was associated with an increase in the volume of hippocampus, increased synaptogenesis and BDNF expression, and subsequent raise in newborn cells in dentate gyrus and possible differentiation into matured neurons.100 The effects of omega-3 PUFAs, in particular DHA, toward adult neurogenesis are promising. Nevertheless, further studies are needed in order to elucidate the retrieved associations.

Synaptic Plasticity Synaptic plasticity represents one of the most fundamental and important functions of the brain, which is the ability of the neural activity generated by an experience to modify neural circuit function and thereby modify subsequent thoughts, feelings, and behavior101

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Synaptic plasticity refers to the activity-dependent modification of the strength or efficacy of synaptic transmission at preexisting synapses, and has been proposed to play an essential role in the capacity of the brain to integrate transient experiences into persistent memory traces. Furthermore, synaptic plasticity is thought to play an important role in the early development of neural circuitry, and accumulating evidence suggests that impairments in synaptic plasticity may contribute to pathophysiology of multiple neuropsychiatric disorders, including depression.101 Up to date, the most consistent findings regarding the implication of disrupted synaptic plasticity in depression, include the reduction of volume of the prefrontal cortex (PFC) and hippocampus,102,103 reduced synapse number in PFC,104 atrophy and loss of neurons, and glia in the PFC and hippocampus,105–107 which have been associated with the length of illness, time of treatment, and the severity of depression.101 Several studies explored the potential effects of omega-3 PUFAs, mainly DHA and EPA, on neurite outgrowth and synaptogenesis in diverse in vitro and in vivo models. In vitro, DHA has been shown to promote hippocampal neurite outgrowth through increased individual neurite length and number of branches.108 Although, DHA action was specific, supplementation with other PUFAs, such as AA and DPA, under identical culture conditions did not affect neurite growth.108 Similarly, it has been demonstrated that moderate concentrations of DHA administrated in in  vitro settings improve the cortical neurons survival and outgrowth.109 Interestingly, as demonstrated in in vivo study, DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood.110 Therefore, adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and protection against neurological disorders. In addition to neurite outgrowth, DHA promotes synaptogenesis and increases the levels of pre- and postsynaptic proteins involved in synaptic transmission and long-term potentiation (LTP), and thereby improves synaptic function.111 Finally, a potential neuroprotective effect of EPA in hippocampus was observed, in particular, through the modulation of synaptic plasticity and activation of the PI3-kinase pathway possibly by its direct effects on neurons and glial cells and by its capacity to increase brain DHA.112

CONCLUSIONS In conclusion, the epidemiological and clinical studies demonstrated the potential beneficial role of omega-3 PUFAs toward prevention and treatment of depression. Several molecular mechanisms were hypothesized to be implicated in the neuroprotective effects of omega-3 PUFAs, including regulation of neuro-inflammation, modulation of adult hippocampal neurogenesis, neurite outgrowth, and synaptogenesis. Overall, increasing scientific evidence supports the neuroprotective properties of omega-3 PUFAs, nevertheless there are still some controversies about their efficacy. Therefore, further research is needed in order to elucidate the role of omega-3 PUFAs toward both prevention and treatment of depression. Finally, a better understanding of the effects of omega-3 PUFAs would allow us to confront the difficulty of how to improve their inadequate dietary intake in Westernized dietary pattern, while maintaining low intake of pro-inflammatory omega-6 PUFAs, and develop evidence-based systems innovations and policies to effectively reduce the burden of depression.

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Acknowledgments Justyna Godos is a PhD student of the International PhD Program in Neuroscience at the Università di Catania.

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