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Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature

Child and Adolescent Psychiatry Research Centre, Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric University Hospital, University of Zurich, CH-8032 Zurich, Switzerland
Division of Clinical Chemistry and Biochemistry, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland
Children’s Research Center, University Children’s Hospital Zurich, CH-8032 Zurich, Switzerland
Center for Integrative Human Physiology, University of Zurich, CH-8057 Zurich, Switzerland
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2021, 22(9), 4393;
Received: 7 April 2021 / Revised: 20 April 2021 / Accepted: 20 April 2021 / Published: 22 April 2021
(This article belongs to the Special Issue Enzymes and Mammalian Fatty Acid Metabolism)


Major depressive disorders (MDDs) are often associated with a deficiency in long-chain omega-3 polyunsaturated fatty acids (ω-3 PUFAs), as well as signs of low-grade inflammation. Epidemiological and dietary studies suggest that a high intake of fish, the major source of ω-3 PUFAs, is associated with lower rates of MDDs. Meta-analyses of randomized placebo-controlled ω-3 PUFAs intervention-trials suggest that primarily eicosapentaenoic acid (EPA), but not docosahexaenoic acid (DHA), is responsible for the proposed antidepressant effect. In this review, we dissect the current biological knowledge on EPA and DHA and their bioactive lipid metabolites to search for a pharmacological explanation of this, to date, unexplained clinical observation. Through enzymatic conversion by cyclooxygenase (COX), lipoxygenase (ALOX), and cytochrome P-450 monooxygenase (CYP), EPA and DHA are metabolized to major anti-inflammatory and pro-resolving lipid mediators. In addition, both ω-3 PUFAs are precursors for endocannabinoids, with known effects on immunomodulation, neuroinflammation, food intake and mood. Finally, both ω-3 PUFAs are crucial for the structure and organization of membranes and lipid rafts. While most biological effects are shared by these two ω-3 PUFAs, some distinct features could be identified: (1) The preferential CYP monooxygenase pathway for EPA and EPA derived eicosanoids; (2) The high CB2 receptor affinities of EPA-derived EPEA and its epoxy-metabolite 17,18-EEQ-EA, while the DHA-derived endocannabinoids lack such receptor affinities; (3) The competition of EPA but not DHA with arachidonic acid (AA) for particular glycerophospholipids. EPA and AA are preferentially incorporated into phosphatidylinositols, while DHA is mainly incorporated into phosphatidyl-ethanolamine, -serine and -choline. We propose that these distinct features may explain the superior antidepressant activity of EPA rich ω-3 PUFAs and that these are potential novel targets for future antidepressant drugs.

1. Introduction

Epidemiological studies report an inverse association between intake of oily fish and the prevalence [1,2,3,4,5,6] and incidence of major depressive disorders (MDDs)* [7,8,9]. Greater seafood consumption also predicts lower prevalence rates for postpartum depression [10] and lower lifetime prevalence rates for bipolar I disorder, bipolar II disorder, and bipolar spectrum disorders [11]. A recent meta-analysis of 26 studies involving 150,278 participants found that high versus low fish intake protects against depression with a pooled relative risk of 0.83 [12].
In line with the lower seafood consumption, lower ω-3 PUFA levels have been measured in erythrocyte cell membranes or plasma of adult MDD patients [13], as well as in mothers with postpartum depression [14]. A meta-analytic review including 684 patients with MDD and 2670 healthy controls [15] found significantly lower levels of ω-3 PUFAs in the erythrocyte-membranes of MDD patients (Effect Size [ES] = −0.51, p < 0.0001), in particular of EPA (ES = −0.18, p = 0.004) and DHA (ES = −0.35, p = 0.0002). Lower levels of ω-3 PUFAs lead to increased ω-6/ω-3 ratios frequently reported in adult MDD [16,17,18,19], as well as in drug-naive pediatric MDD [20]. In addition, independent groups reported inverse associations between membrane ω-3 PUFAs and the number of suicide attempts [2,21,22].
The epidemiological inverse association between fish intake and depression, as well as the observation of low ω-3 PUFAs in erythrocyte membranes of patients with MDD, triggered a range of ω-3 PUFAs intervention trials. Most of these studies were of a small scale; however, in most of these randomized placebo-controlled trials (RCTs) a beneficial effect of ω-3 PUFAs on depressive symptoms was corroborated across the lifespan. In recent years, these small-scale RCTs have been evaluated in several meta-analyses, [23,24,25,26,27,28,29,30], which, however, differed in their inclusion criteria (e.g., combining clinical with non-clinical populations, see Table 1). Beneficial effects of ω-3 PUFAs on MDD were observed in all but one meta-analyses [29] and yielded standardized mean differences (SMD) of 0.22–0.56 for primary and secondary depression [23,24,25]. The one meta-analysis that did not observe a beneficial effect of ω-3 PUFAs on MDD [29] included RCTs, in which the criteria for clinical depression were not met. It is likely that the unrestricted Bloch and Hannestad meta-analysis was confounded by a single large study [31], which investigated the antidepressant effects of ω-3 PUFAs on mild depressive symptoms in a large non-clinical population. Indeed, when the same authors restricted their meta-analysis to RCTs only including patients meeting criteria for MDD, they observed a moderate beneficial effect for ω-3 PUFAs with a SMD of 0.42 [29].
Furthermore, ω-3 PUFA composition and doses varied substantially between RCTs included in previous meta-analyses [23,24,25,26], increasing the risk for a negative overall effect in case that only one particular ω-3 PUFA has an antidepressant effect [23,24,25,27,28,29,30]. While 21 studies, using supplements containing greater than 50% EPA or pure ethyl-EPA, observed a significant reduction in depressive symptoms [23], studies using purified DHA or PUFA compositions containing more than 50% DHA showed no beneficial effect [32,97,98]. Two more recent meta-analyses [24,26] confirmed this early finding. Hence, the results from the available RCTs suggest that EPA-rich, rather than DHA-rich formulations have an antidepressant effect, particularly in primary MDD [23,24,25,26]. In this review, we, therefore, investigate the current knowledge about the biology of EPA, DHA, and of their metabolites in order to find a pharmacological explanation for the proposed superior antidepressant effects of EPA. (* A list of abbreviations is provided at the end of the article.)

2. Omega-3 PUFAs and Immunomodulation

2.1. Anti-Inflammatory Effects of EPA and DHA

Several lines of evidence support an altered immune-status in depression, with pro-inflammatory cytokines in both plasma and cerebrospinal fluid influencing the progression and severity of depressive disorders [99,100,101,102,103,104,105,106,107]. While ω-3 PUFAs have been shown to reduce the secretion of pro-inflammatory cytokines in several cellular and animal models [108], there is also increasing support for a similar effect in humans. Two RCTs in conditions with chronic inflammation and depression demonstrated a protective effect of ω-3 PUFAs against the development of depressive symptoms, which correlated with a decrease in pro-inflammatory mediators [109,110]. These associations of reduced inflammation with better clinical outcome were further substantiated by an RCT showing that MDD patients with higher levels of inflammatory markers benefitted more from ω-3 PUFAs, than patients with no signs of low-grade inflammation [33]. This finding suggests that at least some of the pharmacological effects of the ω-3 PUFAs in MDD may be mediated through an anti-inflammatory mechanism.
EPA and DHA share a number of pharmacological properties that contribute to the suppression of inflammation [108,111,112]. They both act as competitive antagonists at the Toll-like receptor-4 (TLR4), which mediates the pro-inflammatory activity of saturated fatty acids [113] and lipopolysaccharides [114], and they activate the transcription factor PPARγ [115]. The latter suppresses the activity of the pro-inflammatory NFκB signaling-cascade [116]. DHA seems to be more potent in inhibiting NFκB signaling [108,115,117], as well as in enhancing intracellular levels of glutathione, reducing nitric-oxide production [118], and reducing the expression of COX2 [119], while EPA seems to be more powerful in reducing the expression of IL-1β and the chemokine MCP-1 [119]. The mechanism leading to IL-1β secretion is a well-controlled mechanism, where cells recognize the presence of danger signals [120,121] and respond by mounting an immune response. This immune response is initiated by the formation of a multi-protein complex called inflammasome, and results in the production and secretion of active IL-1β (reviewed by [121]).
In case macrophages or microglia are confronted with a danger signal (e.g., stress reaction, viral infections), they assemble an inflammasome called NLRP3, whereas neurons generate an inflammasome with a slightly different composition, called NLRP1 [122,123]. Alcocer-Gómez et al. [124] observed increased gene expression of NLRP3 and caspase-1 in blood cells, and increased serum levels of IL-1β and IL-18 in non-treated patients with adult MDD, whilst IL-1β and IL-18 correlated with the Beck Depression Inventory scores [124]. In addition, in a recent study including 299 depressed Vietnam War veterans [125], carriers of the NLRP12 polymorphisms (rs34436714) were associated with a higher DASS21 Score for depression (p = 0.037).
It has been shown that saturated fatty acids induce inflammasomes [121] and support inflammation [126], whereas DHA and EPA suppress the generation of inflammasomes, probably through G protein-coupled receptor signaling (GPR120 and GPR40), ultimately inhibiting the IL-1β secretion [126].
Reactive oxygen species (ROS) represent another trigger for the induction of inflammasomes [127] and there is indication from cell culture experiments that ω-3 PUFAs reduce ROS formation [128,129]. Proton magnetic resonance spectroscopy enables measurement of the intracellular antioxidant glutathione in the living human brain [130] that protects cells from the oxidative damage associated with increased ROS formation. Adults at risk of depression showed an attenuated glutathione/creatinine ratio that inversely correlated with an increase in depressive symptom severity [131]. In another study in first-episode psychosis patients, twelve weeks treatment with ethyl-EPA supplementation led to a marked increase in glutathione of more than 20% that closely correlated with an improvement in negative symptoms [132]. The modulation of the intracellular redox balance by ω-3 PUFAs may, therefore, be one potential mechanism of how ω-3 PUFAs modulate inflammation and promote neuroprotection [133], possibly by inhibiting the production of the generation of NLRP3 inflammasomes via Redox Balance Modulation [134].
In summary, there is compelling evidence that ω-3 PUFAs, in particular, EPA and DHA, suppress pro-inflammatory and promote anti-inflammatory pathways. Both ω-3 PUFAs suppress NFκB signaling, inhibit inflammasome formation, down-regulate cyclooxygenase-2 transcription and counteract redox misbalances. Although both ω-3 PUFAs have preferences in their affinity with particular inflammatory signaling cascades, EPA seems to be more potent in reducing IL-1β and chemokine MCP-1 production and, therefore, inhibiting inflammasome production. However, at this stage, it would be premature to balance these differential effects against each other and to classify either DHA or EPA as the stronger anti-inflammatory effector.

2.2. Pro- and Anti-Inflammatory Oxidation Products from EPA and DHA

2.2.1. Prostaglandins and Leukotrienes

The released PUFAs form a pool of precursors that are metabolized to distinct bioactive lipid mediators by three major pathways: the cyclooxygenase (COX) pathway, the lipoxygenase pathway (ALOX), and the cytochrome P-450 monooxygenase (CYP) pathway (Figure 1; for an extensive review, see [135]). The products from PUFAs of the ω-6 and ω-3 families are also called oxylipins. The exact profile and balance of bioactive products derived from this PUFA pool depends on cell and tissue type and is determined by environmental and physiological contexts.
The enzymatic oxidation of AA, EPA and DHA by these three major pathways gives rise to a wide spectrum of bioactive lipid mediators, which are called “eicosanoids” when metabolized from AA and EPA and docosanoids when derived from DHA. At the beginning of inflammation, the COX and the ALOX5 enzymes, respectively, generate pro-inflammatory 2-series prostaglandins (PG…2) and the 4-series leukotrienes (LT…4) from AA. This enzymatic conversion is competitively inhibited by both EPA and DHA, which limits the inflammatory effect of the AA derived eicosanoids. Notably, EPA is itself metabolized by the COX and ALOX5 enzymes to generate the 3-series prostaglandins and 5-series leukotrienes. These EPA-derived 3-series prostaglandins and 5-series leukotrienes were shown to be partial agonists of the same receptors triggered by the AA-derived 2-series prostaglandins and 4-series leukotrienes, and it is thought that they competitively suppress the pro-inflammatory triggering of the AA-derived eicosanoids. For example, the AA-derived LTB4 is a potent chemo-attractant for neutrophils, eosinophils and macrophages, whereas the EPA-derived LTB5 analogue acts as partial agonist only [136,137,138]. While both ω-3 PUFAs inhibit the conversion of AA to the mainly pro-inflammatory eicosanoids, only EPA gives rise to metabolites, which are weak agonists at certain receptors that mediate pro-inflammatory responses of AA derived 2-series prostaglandins and 4-series leukotrienes [115].

2.2.2. Resolvins and Other Poly-Hydroxyl Products

While the prostaglandins and leukotrienes depend on COX and ALOX5 enzymatic activities, other classes of lipid mediators, called specialized pro-resolving lipid mediators (SPMs), like the resolvins, maresins, and neuroprotectins, depend on enzymatic oxygenation by CYP450 and ALOX12/15 [139]. For example, the E-series of the resolvins derive from EPA, which is oxidized to dihydroxy-EPA derivatives (RvE2 and RvE3) [140,141] and a tri-hydroxy-EPA derivative (RvE1) [142]. Similarly, the metabolism of DHA generates several di-hydroxy and tri-hydroxy derivatives, referred to as maresins, neuroprotectin-D and D-series of resolvins (for reviews, see [143,144]).
These SPMs diminish inflammation by reducing the influx of neutrophils to inflamed tissue and promote the resolution of inflammation by increasing the phagocytic activity of monocytes and macrophages [143,145]. Application of these SPMs, such as RvD1 or RvE1, in mouse models of chronic inflammatory diseases consistently induced anti-inflammatory and pro-resolution effects [146]. Intriguingly, RvE1 and RvD1 suppressed inflammation and depression-like behavior in animal depression models [147,148,149,150] and in several animal models of chronic inflammatory diseases that are associated with major depression, like periodontitis, type II diabetes and atherosclerosis [151,152,153]. Nevertheless, judged by data from preclinical experiments, there is little evidence to date for a fundamental distinction between EPA- and DHA-derived mediators [154], although minor differences have been described [155,156,157]. Future research will have to dissect differences in the pharmacology of EPA- and DHA-derived SPMs to address differences in their antidepressant properties.
Microglial cells are the brain’s innate immune cells and contribute to the shaping of neuronal networks during brain development. Rey et al. [158] found that microglial cells in the offspring of pregnant mice fed with deficient, balanced or supplemented ω-3 PUFA diets, displayed distinctive lipid profiles, with higher levels of EPA than DHA. The same group [159] showed that dietary ω-3 PUFA supplementation induced ω-3 PUFA enrichment in the hippocampus which led to an increase in ω-3 PUFA-derived oxylipins and a decrease in ω-6 PUFA-derived oxylipins upon LPS stimulation. In addition, the LPS-induced pro-inflammatory cytokine increase was reduced by dietary ω-3 PUFA supplementation. These results indicate that brain ω-3 PUFAs promote the synthesis of anti-inflammatory oxylipins.

2.2.3. CYP Metabolism of Double Bonds or the Terminal Carbon Atom

The third oxidation pathway leading to bioactive eicosanoids and docosanoids is mediated by certain cytochrome P450 isoenzymes (CYPs), including CYP1A1, CYP2E1, CYP4A1 and CYP4A12a. These CYPs hydroxylate AA at its terminal ω1-carbon forming 20-HETE, which has pro-inflammatory, vasoconstrictive and hypertensive properties [160,161]. The same isoenzymes, however, generate an epoxide at the ω-3 double bond of EPA and DHA [162,163,164], producing 17,18-EEQ and 19,20-EDP, respectively, which display vasodilatory and anti-inflammatory activities in the cardiovascular system, the bronchi, kidney and the nervous system [165,166]. The receptor for 20-HETE has recently been identified as GPR75, but it has not been investigated whether the two ω-3 PUFA-derived lipid mediators, 17,18-EEQ and 19,20-EDP, compete for binding to GPR75 [167]. This may become interesting because ω-3 PUFA supplementation has a pronounced effect on cellular AA levels [164,168,169], shifts the CYP mediated lipid mediators from predominantly AA-metabolites to EPA- and DHA-derived metabolites, and increases the plasma and tissue levels of 17,18-EEQ and 19,20-EDP [168]. There is indication that this ω-3 PUFA supplementation-mediated shift in the CYP-metabolome mainly produces EPA-metabolites, and that this increase is more pronounced than for the COX- and ALOX-metabolomes [168].

2.2.4. Epoxidation of Endocannabinoids

Both series of PUFAs are also substrates for the endogenous production of endocannabinoids. The endocannabinoid system is known to be involved in numerous functions such as appetite control, food intake, energy balance, neuroprotection, neurodegenerative diseases, mood disorders, modulation of pain, and inflammatory responses [170]. The best-known endogenous ligands for the two main cannabinoid-receptors CB1 and CB2 are the AA-derived anandamide (arachidonic acid-ethanolamide; AEA) and 2-arachidonyl-glycerol [171,172]. However, also EPA and DHA are metabolized to ethanolamides, resulting in compounds known as EPEA and DHEA, respectively [173,174]. All endocannabinoids are further metabolized by COX2, ALOX and CYPs, resulting in diverse active bioactive lipid metabolites with different selectivities for the different cannabinoid-receptors [174,175,176]. For example, CYP mediated epoxidation of the potent and selective CB1 agonist anandamide [174,177], and generates the selective CB2 receptor agonist 5,6-EET-EA [175]. In contrast to the AA-derived anandamide, the EPA metabolite EPEA displays high affinity for both cannabinoid receptors, while epoxidation of the susceptible ω-3 double bond yields 17,18-EEQ-EA with weak CB1 affinity, but still high CB2 affinity [174]. The DHA-derived endocannabinoid DHEA and its ω-3 epoxide metabolite lack relevant affinities for either cannabinoid receptor CB1 or CB2 [166,174,178,179]. Thus, there are differences between the different PUFA-derived endocannabinoids and their epoxy-metabolites in terms of CB-receptor selectivity. In particular, EPA-derived EPEA is a general agonist for both CB-receptors and epoxidation changes it to a specific CB2 agonist, while the DHA-derived endocannabionoids lack relevant receptor affinities. This may be significant, since supplementation with ω-3 PUFAs resulted in increased levels of EPEA and DHEA in rat brain at the expense of anandamide [180,181] and because the CB2 receptor is thought to signal anti-inflammatory effects in both peripheral and CNS immune cells [182].

3. Omega-3 PUFAs, Membrane Structure and Organization

3.1. Differential Effects of EPA and DHA on Lipid Raft Formation

Cellular membranes are not just homogenous mixtures of lipids and proteins but their properties vary in patches. Preclinical findings suggest a crucial role of membrane organization and the associated assembly of signaling proteins in the induction of depression- and anxiety-related behaviors [183]. One kind of patch in the cellular membrane is membrane regions called “lipid-rafts”, which are crucial for cell signaling because key transduction proteins are enriched in these membrane patches [184,185]. For example, the above-mentioned TLR4 is localized in these lipid-rafts and disruption of the latter interferes with TLR4 signaling [185,186]. Preclinical studies provide evidence that the disruption of the TLR4 pathway by PUFA supplementation is not due to changes in gene expression of mediator proteins, but originates at the membrane level [186]. Interestingly, both ω-3 PUFAs EPA and DHA are incorporated in the cellular membrane, but modulate these lipid rafts differently. DHA was shown to increase the size of lipid rafts, presumably through its hairpin-like structure. This is thought to lead to a dispersion of effector molecules such as the TLR4 and its cofactor CD14, which hinders their signal transduction leading to a reduced pro-inflammatory cytokine secretion [185]. In contrast, EPA causes a profound restructuring of both the raft and non-raft membranes [187], but its effect on raft reorganization has not been extensively studied to date. While these experiments were done in macrophages, similar effects presumably occur in microglia and other immune cells [188]. Whether this differential effect of ω-3 PUFAs on the size and lipid composition of the lipid rafts is directly relevant for the pathogenesis of MDDs is, however, currently not known.

3.2. Preferential Incorporation of EPA and DHA into Different Types of Glycerophospholipids

When GPCR-agonists, growth factors or cytokines bind to their receptors, they can activate several phospholipase A2 isoenzymes acting on membrane phospholipids to release ω-6 and ω-3 PUFAs [189]. These phospholipases display preferences for certain PUFAs, which possibly depends on the preferential integration of PUFAs into different phospholipids. For example in brain cells, EPA is preferentially incorporated at the SN2 position of phosphatidyl-inositol phospholipids and is released by several phospholipase A2 isoenzymes, amongst which the cPLA2-IVA isoform is quantitatively most abundant [190,191]. In contrast, DHA is incorporated at the SN2 position of phosphatidyl-ethanolamine, phosphatidylserine and phosphatidylcholine, and is released by the A2-phospholipases, iPLA2β and iPLA2γ [192,193,194]. There is evidence that EPA itself enhances the expression of cPLA2 in MDD patients [195] and preclinical animal models suggest that stress and inflammation also lead to increased expression of cPLA2 [196,197]. Hence, it may well be that risk factors like stress and inflammation preferentially promote the release of EPA.

4. Discussion

Over fifty controlled studies (see Table 1) investigated the antidepressant effects of ω-3 fatty acids in a range of human conditions, with over a dozen studies focusing on primary MDD. These studies showed that, in particular, patients with moderate to severe depression seem to benefit from ω-3 fatty acids rich in EPA. Rather unexpectedly, controlled studies using DHA-enriched fish-oil preparations or purified DHA failed to demonstrate major antidepressant actions.
This is even more remarkable considering that the mammalian brain has a unique fatty acid composition with high levels of AA and DHA, but remarkably low levels of EPA (see Table 2). In rat brain, for instance, the levels of EPA are 300-fold lower than those of DHA [198]. Since depressive symptoms are assumed to be of central origin, it seems paradoxical that EPA is a more effective antidepressant than DHA with its purported centrally mediated effects on the HPA axis and the neurotropic effects on brain development. In principle, the results from the intervention studies imply that the antidepressant activity of EPA is independent of such mechanisms. Studying the molecular differences that distinguish EPA from DHA (see Table 2) identified three metabolic pathways that may explain the preferential EPA-derived effects. These are the distinct membrane integration and release of EPA by cPLA2, the preferential enrichment of the EPA-derived CYP-metabolome after ω-3 PUFA supplementation, and the higher CB2 receptor affinities of the endocannabinoid EPEA and its epoxy-metabolite 17,18-EEQ-EA.
The first difference between the two ω-3 PUFAs is observed in the integration of EPA and DHA into different phospholipid species in the cellular membrane. After crossing the blood-brain barrier, PUFAs are mainly incorporated into membrane phospholipids. DHA is predominantly inserted at the SN2 position of phosphatidylethanolamine (PE), phosphatidylserine (PS) and phosphatidylcholine (PC) [199,200], whereas EPA is preferentially incorporated at the SN2 position of phosphatidylinositol (PI) [199]. At the same SN2 position of PI, AA is also incorporated. It now seems that EPA competes with its analogous C20-ω-6 fatty acid AA for PI incorporation [201] and that, depending on the PUFA integrated in PI, the downstream signaling events of the specific cell is changed.
For signaling, the PUFAs have to be released from the SN2 position of the phospholipids. EPA has been shown to compete with AA for its release from PI by the PLA2 enzymes and there is an indication that the most abundant PLA2 isoenzyme releasing AA and EPA in brain, cPLA2, is increased by several risk factors for MDD like stress, inflammation and hypertension. This argues for the competition of EPA with AA for eicosanoid production and for the preferential release of EPA from membranes by certain risk factors for MDD upon EPA supplementation. In light of the rather pro-inflammatory eicosanoids produced from AA by the COX, ALOX and the CYP pathways, such a competitive suppression of AA eicosanoids by EPA may well add an additional level of anti-inflammation compared to DHA, and could provide a partial explanation for the “EPA-paradox” mentioned above.
Table 2. List of functional differences between EPA and DHA.
Table 2. List of functional differences between EPA and DHA.
Last step of DHA synthesis (not EPA synthesis) is in peroxisome[108,112]
Rate-limiting step in DHA biosynthesis is between EPA and DHA[202,203,204]
Brain levels of DHA are kept high, while EPA levels are kept low[193,194,205,206]
Size of lipid rafts is increased by DHA and unaltered by EPA[185]
DHA is inserted in PE1, PS and PC, while EPA is inserted in PI[199]
EPA and DHA are released from lipids by different PLA2 isoenzymes[191,192]
COX and ALOX5 metabolize EPA and AA, not DHA[108,112]
EPA-derived resolvins and DHA-derived resolvins in some cases activate distinct G-protein coupled receptors[207]
RvE1 reduces, while RvD1 increases platelet aggregation[157]
EPA, not DHA activates PPARα[208]
EPA, not DHA increases expression of cPLA2[195]
EPA, not DHA improves depression[23,24,25,33]
EPA, not DHA ameliorates cardiac illness[209]
EPEA and its epoxide, but not DHEA or its epoxide are highly potent CB2 receptor agonists[174]
Abbreviations. PE: phosphatidylethanolamine, PC: phosphatidylcholine, PS: phosphatidylserine, PI: phosphatidylinositol, PLA2: phospholipase A2, RvE1: Resolvin E1, RvD1: Resolvin D1, PPAR: peroxisome proliferator-activated receptor, EPEA: EPA-ethanolamine, DHEA: DHA-ethanolamine.
The enzymatic metabolism of the ω-3 and ω-6 PUFAs leads to the formation of the wide spectrum of eicosanoids and docosanoids. Different groups have investigated the effect of dietary supplementation with EPA/DHA on the production of these eicosanoids and docosanoids. These studies showed that fish oil supplementation in humans resulted in a large increase in EPA-derived CYP-derivatives and a smaller increase in EPA- and DHA-derived LOX-dependent metabolites in plasma and tissue [168]. The levels of the hydroxy-, epoxy- and dihydroxy-derivatives correlated to the parent PUFA in erythrocytes with a particularly strong correlation between EPA levels in erythrocytes and the concentrations of EPA-derived CYP-metabolites, including 17,18-EEQ [169]. The authors also calculated that the CYP-enzymes metabolize EPA 8-fold more efficiently, and DHA twice as efficiently as AA [168], suggesting that changes upon fish oil supplementation may come from the preferential metabolism of EPA by CYP-isoenzymes. However, whether these EPA- and DHA-derived CYP lipid mediators are also differentially produced in the brain has not been investigated.
Both series of PUFAs are also metabolized to endogenous endocannabinoids involved in appetite control, food intake, energy balance, and several neurological and mood disorders [170]. These endocannabinoids signal through a series of different receptors with the main receptors identified as the endocannabinoid receptors CB1 and CB2. EPA-derived and DHA-derived endocannabinoids were shown to have different affinities for these two endocannabinoid receptors. While the EPA-derived endocannabinoid 17,18-EEQ-EA is a specific CB2 agonist, the DHA-endocannabinoid 19,20-EDP-EA lacks a relevant affinity for CB2-receptors [174]. This seems of interest because the CB2 receptor has emerged as a potential anti-inflammatory target to reduce neuroinflammation [177] and chronic inflammatory diseases [210]. The CB2 receptor is expressed on monocytes, macrophages, dendritic cells, and microglia cells [172,176] and CB2 agonists have been shown to reduce neutrophil, monocyte and macrophage infiltration, to reduce microglia activation and migration, and to inhibit the release of inflammatory cytokines, chemokines, reactive oxygen species and nitric oxide [172,176,177,211]. Since dietary supplementation with EPA and DHA results in an increase in EPEA- and DHEA-levels at the expense of the AA-derived AEA (reviewed by [174]), the formation of, especially, the EPA-derived endocannabinoids and their epoxy-metabolites may alter the level of CB2-receptor stimulation. Such a mechanism may also contribute to the preferential anti-inflammatory and antidepressant profile seen for EPA.

5. Conclusions

In conclusion, whilst a satisfactory explanation for the lacking anti-depressant activity of DHA remains obscure, there is a body of indirect evidence that EPA improves depression at least partially by acting as a pro-drug through competition with AA for integration and release from membranes, by its abundant CYP-mediated metabolome, and by the high CB2 receptor affinities of its endocannabinoid EPEA and its epoxy-metabolite 17,18-EEQ-EA. Future research should explore these distinct EPA features as potential novel drug targets for antidepressant drug development.

Author Contributions

Conceptualization, H.O.K. and G.E.B.; resources, S.W.; writing—original draft preparation, H.O.K.; writing—review and editing, H.O.K., M.H., G.E.B.; visualization, G.E.B.; supervision, G.E.B. All authors have read and agreed to the published version of the manuscript.


The Swiss National Science Foundation has funded work by G.E.B., S.W. and M.H. (Omega- 3 pMDD Projekt 33IC30_166826, Project 173088 and Sinergia 177225).

Conflicts of Interest

G.E.B. received speaker honoraria at the annual nutritional conference sponsored by Burgerstein Switzerland. H.O.K., M.H. and S.W. declare no potential conflict of interest. The funders had no role in any aspect of the manuscript.


AAarachidonic acid
AEAarachidonic acid-ethanolamide
ALOXarachidonate lipoxygenase
CB1cannabis receptor-1
CD14cluster of differentiation-14
CYPcytochrome P450
DASS21 scorea 21-item rating scale to quantify depression anxiety and stress
DHAdocosahexaenoic acid
DHEAdocosahexaenoic acid-ethanolamine
EPAeicosapentaenoic acid
EPEAeicosapentaenoic acid-ethanolamine
17,18-EEQ-EAethanolamine derivative of EPA, where the omega-3 bond is oxidized to an epoxide
ESeffect size
GPR or GPCRG-protein-coupled receptor
20-HETE20-hydroxy-tetraenoic acid
MCP1monocyte chemoattractive protein-1
MDDmajor depressive disorder
NLRPacronym for NACHT, LRR and PYD domains-containing protein
NFκBnuclear factor-κB
OCDobsessive-compulsive disorder
PLA2phospholipase A2
PPARperoxisome proliferator-activated receptor
PUFApolyunsaturated fatty acid
RCTrandomized controlled trial
RvE1Resolvin E1
RvD1Resolvin D1
ROSreactive oxygen species
SMDstandardized mean differences
SPMspecialized pro-resolving mediators
TLRToll-like receptor


  1. Bountziouka, V.; Polychronopoulos, E.; Zeimbekis, A.; Papavenetiou, E.; Ladoukaki, E.; Papairakleous, N.; Gotsis, E.; Metallinos, G.; Lionis, C.; Panagiotakos, D. Long-term fish intake is associated with less severe depressive symptoms among elderly men and women: The MEDIS (MEDiterranean ISlands Elderly) epidemiological study. J. Aging Health 2009, 21, 864–880. [Google Scholar] [CrossRef] [PubMed]
  2. Tanskanen, A.; Hibbeln, J.R.; Hintikka, J.; Haatainen, K.; Honkalampi, K.; Viinamaki, H. Fish consumption, depression, and suicidality in a general population. Arch. Gen. Psychiatry 2001, 58, 512–513. [Google Scholar] [CrossRef]
  3. Timonen, M.; Horrobin, D.; Jokelainen, J.; Laitinen, J.; Herva, A.; Rasanen, P. Fish consumption and depression: The Northern Finland 1966 birth cohort study. J. Affect. Disord. 2004, 82, 447–452. [Google Scholar] [CrossRef] [PubMed]
  4. Suominen-Taipale, A.L.; Partonen, T.; Turunen, A.W.; Mannisto, S.; Jula, A.; Verkasalo, P.K. Fish consumption and omega-3 polyunsaturated fatty acids in relation to depressive episodes: A cross-sectional analysis. PLoS ONE 2010, 5, e10530. [Google Scholar] [CrossRef][Green Version]
  5. Appleton, K.M.; Woodside, J.V.; Yarnell, J.W.; Arveiler, D.; Haas, B.; Amouyel, P.; Montaye, M.; Ferrieres, J.; Ruidavets, J.B.; Ducimetiere, P.; et al. Depressed mood and dietary fish intake: Direct relationship or indirect relationship as a result of diet and lifestyle? J. Affect. Disord. 2007, 104, 217–223. [Google Scholar] [CrossRef] [PubMed]
  6. Murakami, K.; Miyake, Y.; Sasaki, S.; Tanaka, K.; Arakawa, M. Fish and n-3 polyunsaturated fatty acid intake and depressive symptoms: Ryukyus Child Health Study. Pediatrics 2010, 126, e623–e630. [Google Scholar] [CrossRef]
  7. Li, Y.; Dai, Q.; Ekperi, L.I.; Dehal, A.; Zhang, J. Fish consumption and severely depressed mood, findings from the first national nutrition follow-up study. Psychiatry Res. 2011, 190, 103–109. [Google Scholar] [CrossRef]
  8. Sanchez-Villegas, A.; Henriquez, P.; Figueiras, A.; Ortuno, F.; Lahortiga, F.; Martinez-Gonzalez, M.A. Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. Eur. J. Nutr. 2007, 46, 337–346. [Google Scholar] [CrossRef]
  9. Astorg, P.; Couthouis, A.; Bertrais, S.; Arnault, N.; Meneton, P.; Guesnet, P.; Alessandri, J.M.; Galan, P.; Hercberg, S. Association of fish and long-chain n-3 polyunsaturated fatty acid intakes with the occurrence of depressive episodes in middle-aged French men and women. Prostaglandins Leukot. Essent. Fatty Acids 2008, 78, 171–182. [Google Scholar] [CrossRef]
  10. Hibbeln, J.R. Fish consumption and major depression. Lancet 1998, 351, 1213. [Google Scholar] [CrossRef]
  11. Noaghiul, S.; Hibbeln, J.R. Cross-national comparisons of seafood consumption and rates of bipolar disorders. Am. J. Psychiatry 2003, 160, 2222–2227. [Google Scholar] [CrossRef]
  12. Li, F.; Liu, X.; Zhang, D. Fish consumption and risk of depression: A meta-analysis. J. Epidemiol. Commun. Health 2016, 70, 299–304. [Google Scholar] [CrossRef] [PubMed]
  13. Su, K.P.; Matsuoka, Y.; Pae, C.U. Omega-3 polyunsaturated fatty acids in prevention of mood and anxiety disorders. Clin. Psychopharmacol. Neurosci. 2015, 13, 129–137. [Google Scholar] [CrossRef][Green Version]
  14. De Vriese, S.R.; Christophe, A.B.; Maes, M. Lowered serum n-3 polyunsaturated fatty acid (PUFA) levels predict the occurrence of postpartum depression: Further evidence that lowered n-PUFAs are related to major depression. Life Sci. 2003, 73, 3181–3187. [Google Scholar] [CrossRef]
  15. Lin, P.Y.; Huang, S.Y.; Su, K.P. A meta-analytic review of polyunsaturated fatty acid compositions in patients with depression. Biol. Psychiatry 2010, 68, 140–147. [Google Scholar] [CrossRef] [PubMed]
  16. Adams, P.B.; Lawson, S.; Sanigorski, A.; Sinclair, A.J. Arachidonic acid to eicosapentaenoic acid ratio in blood correlates positively with clinical symptoms of depression. Lipids 1996, 31, S157–S161. [Google Scholar] [CrossRef]
  17. Maes, M.; Smith, R.; Christophe, A.; Cosyns, P.; Desnyder, R.; Meltzer, H. Fatty acid composition in major depression: Decreased omega 3 fractions in cholesteryl esters and increased C20: 4 omega 6/C20:5 omega 3 ratio in cholesteryl esters and phospholipids. J. Affect. Disord. 1996, 38, 35–46. [Google Scholar] [CrossRef]
  18. Edwards, R.; Peet, M.; Shay, J.; Horrobin, D. Omega-3 polyunsaturated fatty acid levels in the diet and in red blood cell membranes of depressed patients. J. Affect. Disord. 1998, 48, 149–155. [Google Scholar] [CrossRef]
  19. Frasure-Smith, N.; Lesperance, F.; Julien, P. Major depression is associated with lower omega-3 fatty acid levels in patients with recent acute coronary syndromes. Biol. Psychiatry 2004, 55, 891–896. [Google Scholar] [CrossRef] [PubMed]
  20. Pottala, J.V.; Talley, J.A.; Churchill, S.W.; Lynch, D.A.; von Schacky, C.; Harris, W.S. Red blood cell fatty acids are associated with depression in a case-control study of adolescents. Prostaglandins Leukot. Essent. Fatty Acids 2012, 86, 161–165. [Google Scholar] [CrossRef]
  21. Huan, M.; Hamazaki, K.; Sun, Y.; Itomura, M.; Liu, H.; Kang, W.; Watanabe, S.; Terasawa, K.; Hamazaki, T. Suicide attempt and n-3 fatty acid levels in red blood cells: A case control study in China. Biol. Psychiatry 2004, 56, 490–496. [Google Scholar] [CrossRef]
  22. Sublette, M.E.; Hibbeln, J.R.; Galfalvy, H.; Oquendo, M.A.; Mann, J.J. Omega-3 polyunsaturated essential fatty acid status as a predictor of future suicide risk. Am. J. Psychiatry 2006, 163, 1100–1102. [Google Scholar] [CrossRef] [PubMed]
  23. Martins, J.G. EPA but not DHA appears to be responsible for the efficacy of omega-3 long chain polyunsaturated fatty acid supplementation in depression: Evidence from a meta-analysis of randomized controlled trials. J. Am. Coll. Nutr. 2009, 28, 525–542. [Google Scholar] [CrossRef]
  24. Sublette, M.E.; Ellis, S.P.; Geant, A.L.; Mann, J.J. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J. Clin. Psychiatry 2011, 72, 1577–1584. [Google Scholar] [CrossRef] [PubMed][Green Version]
  25. Grosso, G.; Pajak, A.; Marventano, S.; Castellano, S.; Galvano, F.; Bucolo, C.; Drago, F.; Caraci, F. Role of omega-3 fatty acids in the treatment of depressive disorders: A comprehensive meta-analysis of randomized clinical trials. PLoS ONE 2014, 9, e96905. [Google Scholar] [CrossRef][Green Version]
  26. Mocking, R.J.; Harmsen, I.; Assies, J.; Koeter, M.W.; Ruhe, H.G.; Schene, A.H. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl. Psychiatry 2016, 6, e756. [Google Scholar] [CrossRef]
  27. Parker, G.; Gibson, N.A.; Brotchie, H.; Heruc, G.; Rees, A.M.; Hadzi-Pavlovic, D. Omega-3 fatty acids and mood disorders. Am. J. Psychiatry 2006, 163, 969–978. [Google Scholar] [CrossRef]
  28. Freeman, M.P.; Fava, M.; Lake, J.; Trivedi, M.H.; Wisner, K.L.; Mischoulon, D. Complementary and alternative medicine in major depressive disorder: The American Psychiatric Association Task Force report. J. Clin. Psychiatry 2010, 71, 669–681. [Google Scholar] [CrossRef]
  29. Bloch, M.H.; Hannestad, J. Omega-3 fatty acids for the treatment of depression: Systematic review and meta-analysis. Mol. Psychiatry 2012, 17, 1272–1282. [Google Scholar] [CrossRef] [PubMed]
  30. Lin, P.Y.; Mischoulon, D.; Freeman, M.P.; Matsuoka, Y.; Hibbeln, J.; Belmaker, R.H.; Su, K.P. Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. Mol. Psychiatry 2012, 17, 1161–1167. [Google Scholar] [CrossRef]
  31. Rogers, P.J.; Appleton, K.M.; Kessler, D.; Peters, T.J.; Gunnell, D.; Hayward, R.C.; Heatherley, S.V.; Christian, L.M.; McNaughton, S.A.; Ness, A.R. No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: A randomised controlled trial. Br. J. Nutr. 2008, 99, 421–431. [Google Scholar] [CrossRef] [PubMed][Green Version]
  32. Marangell, L.B.; Martinez, J.M.; Zboyan, H.A.; Kertz, B.; Kim, H.F.; Puryear, L.J. A double-blind, placebo-controlled study of the omega-3 fatty acid docosahexaenoic acid in the treatment of major depression. Am. J. Psychiatry 2003, 160, 996–998. [Google Scholar] [CrossRef]
  33. Rapaport, M.H.; Nierenberg, A.A.; Schettler, P.J.; Kinkead, B.; Cardoos, A.; Walker, R.; Mischoulon, D. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: A proof-of-concept study. Mol. Psychiatry 2016, 21, 71–79. [Google Scholar] [CrossRef]
  34. Peet, M.; Horrobin, D.F. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch. Gen. Psychol. 2002, 59, 913–919. [Google Scholar] [CrossRef]
  35. Nemets, B.; Stahl, Z.; Belmaker, R.H. Addition of omega-3 fatty acid to maintenance medication treatment for recurrent unipolar depressive disorder. Am. J. Psychiatry 2002, 159, 477–479. [Google Scholar] [CrossRef] [PubMed]
  36. Su, K.P.; Huang, S.Y.; Chiu, C.C.; Shen, W.W. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur. Neuropsychopharmacol. 2003, 13, 267–271. [Google Scholar] [CrossRef]
  37. Silvers, K.M.; Woolley, C.C.; Hamilton, F.C.; Watts, P.M.; Watson, R.A. Randomised double-blind placebo-controlled trial of fish oil in the treatment of depression. Prostaglandins Leukot. Essent. Fatty Acids 2005, 72, 211–218. [Google Scholar] [CrossRef] [PubMed]
  38. Nemets, H.; Nemets, B.; Apter, A.; Bracha, Z.; Belmaker, R.H. Omega-3 treatment of childhood depression: A controlled, double-blind pilot study. Am. J. Psychiatry 2006, 163, 1098–1100. [Google Scholar] [CrossRef]
  39. Grenyer, B.F.; Crowe, T.; Meyer, B.; Owen, A.J.; Grigonis-Deane, E.M.; Caputi, P.; Howe, P.R. Fish oil supplementation in the treatment of major depression: A randomised double-blind placebo-controlled trial. Prog. Neuropsychopharmacol. Biol. Psychiatry 2007, 31, 1393–1396. [Google Scholar] [CrossRef] [PubMed]
  40. Jazayeri, S.; Tehrani-Doost, M.; Keshavarz, S.A.; Hosseini, M.; Djazayery, A.; Amini, H.; Jalali, M.; Peet, M. Comparison of therapeutic effects of omega-3 fatty acid eicosapentaenoic acid and fluoxetine, separately and in combination, in major depressive disorder. Aust. N. Z. J. Psychiatry 2008, 42, 192–198. [Google Scholar] [CrossRef]
  41. Mischoulon, D.; Papakostas, G.I.; Dording, C.M.; Farabaugh, A.H.; Sonawalla, S.B.; Agoston, A.M.; Smith, J.; Beaumont, E.C.; Dahan, L.E.; Alpert, J.E.; et al. A double-blind, randomized controlled trial of ethyl-eicosapentaenoate for major depressive disorder. J. Clin. Psychiatry 2009, 70, 1636–1644. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Rondanelli, M.; Giacosa, A.; Opizzi, A.; Pelucchi, C.; La Vecchia, C.; Montorfano, G.; Negroni, M.; Berra, B.; Politi, P.; Rizzo, A.M. Effect of omega-3 fatty acids supplementation on depressive symptoms and on health-related quality of life in the treatment of elderly women with depression: A double-blind, placebo-controlled, randomized clinical trial. J. Am. Coll. Nutr. 2010, 29, 55–64. [Google Scholar] [CrossRef] [PubMed]
  43. Rondanelli, M.; Giacosa, A.; Opizzi, A.; Pelucchi, C.; La Vecchia, C.; Montorfano, G.; Negroni, M.; Berra, B.; Politi, P.; Rizzo, A.M. Long chain omega 3 polyunsaturated fatty acids supplementation in the treatment of elderly depression: Effects on depressive symptoms, on phospholipids fatty acids profile and on health-related quality of life. J. Nutr. Health Aging 2011, 15, 37–44. [Google Scholar] [CrossRef] [PubMed]
  44. Lesperance, F.; Frasure-Smith, N.; St-Andre, E.; Turecki, G.; Lesperance, P.; Wisniewski, S.R. The efficacy of omega-3 supplementation for major depression: A randomized controlled trial. J. Clin. Psychiatry 2011, 72, 1054–1062. [Google Scholar] [CrossRef]
  45. Tajalizadekhoob, Y.; Sharifi, F.; Fakhrzadeh, H.; Mirarefin, M.; Ghaderpanahi, M.; Badamchizade, Z.; Azimipour, S. The effect of low-dose omega 3 fatty acids on the treatment of mild to moderate depression in the elderly: A double-blind, randomized, placebo-controlled study. Eur. Arch. Psychiatry Clin. Neurosci. 2011, 261, 539–549. [Google Scholar] [CrossRef] [PubMed]
  46. Sinn, N.; Milte, C.M.; Street, S.J.; Buckley, J.D.; Coates, A.M.; Petkov, J.; Howe, P.R. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: A 6-month randomised controlled trial. Br. J. Nutr. 2012, 107, 1682–1693. [Google Scholar] [CrossRef][Green Version]
  47. Gertsik, L.; Poland, R.E.; Bresee, C.; Rapaport, M.H. Omega-3 fatty acid augmentation of citalopram treatment for patients with major depressive disorder. J. Clin. Psychopharmacol. 2012, 32, 61–64. [Google Scholar] [CrossRef][Green Version]
  48. Rizzo, A.M.; Corsetto, P.A.; Montorfano, G.; Opizzi, A.; Faliva, M.; Giacosa, A.; Ricevuti, G.; Pelucchi, C.; Berra, B.; Rondanelli, M. Comparison between the AA/EPA ratio in depressed and non depressed elderly females: Omega-3 fatty acid supplementation correlates with improved symptoms but does not change immunological parameters. Nutr. J. 2012, 11, 82. [Google Scholar] [CrossRef] [PubMed][Green Version]
  49. Mozaffari-Khosravi, H.; Yassini-Ardakani, M.; Karamati, M.; Shariati-Bafghi, S.-E. Eicosapentaenoic acid versus docosahexaenoic acid in mild-to-moderate depression: A randomized, double-blind, placebo-controlled trial. Eur. Neuropsychopharmacol. 2013, 23, 636–644. [Google Scholar] [CrossRef]
  50. Mischoulon, D.; Nierenberg, A.A.; Schettler, P.J.; Kinkead, B.L.; Fehling, K.; Martinson, M.A.; Rapaport, M.H. A double-blind, randomized controlled clinical trial comparing eicosapentaenoic acid versus docosahexaenoic acid for depression. J. Clin. Psychiatry 2014, 76, 54–61. [Google Scholar] [CrossRef]
  51. Park, Y.; Park, Y.-S.; Kim, S.H.; Oh, D.H.; Park, Y.-C. Supplementation of n-3 polyunsaturated fatty acids for major depressive disorder: A randomized, double-blind, 12-week, placebo-controlled trial in Korea. Ann. Nutr. Metab. 2015, 66, 141–148. [Google Scholar] [CrossRef]
  52. Ginty, A.T.; Conklin, S.M. Short-term supplementation of acute long-chain omega-3 polyunsaturated fatty acids may alter depression status and decrease symptomology among young adults with depression: A preliminary randomized and placebo controlled trial. Psychiatry Res. 2015, 229, 485–489. [Google Scholar] [CrossRef]
  53. Young, A.S.; Arnold, L.E.; Wolfson, H.L.; Fristad, M.A. Psychoeducational psychotherapy and omega-3 supplementation improve co-occurring behavioral problems in youth with depression: Results from a pilot RCT. J. Abnorm. Child Psychol. 2017, 45, 1025–1037. [Google Scholar] [CrossRef]
  54. Gabbay, V.; Freed, R.D.; Alonso, C.M.; Senger, S.; Stadterman, J.; Davison, B.A.; Klein, R.G. A double-blind placebo-controlled trial of omega-3 fatty acids as a monotherapy for adolescent depression. J. Clin. Psychiatry 2018, 79, 11596. [Google Scholar] [CrossRef] [PubMed]
  55. Trebatická, J.; Hradečná, Z.; Böhmer, F.; Vaváková, M.; Waczulíková, I.; Garaiova, I.; Luha, J.; Škodáček, I.; Šuba, J.; Ďuračková, Z. Emulsified omega-3 fatty-acids modulate the symptoms of depressive disorder in children and adolescents: A pilot study. Child Adolesc. Psychiatry Ment. Health 2017, 11, 1–10. [Google Scholar] [CrossRef][Green Version]
  56. Jahangard, L.; Sadeghi, A.; Ahmadpanah, M.; Holsboer-Trachsler, E.; Bahmani, D.S.; Haghighi, M.; Brand, S. Influence of adjuvant omega-3-polyunsaturated fatty acids on depression, sleep, and emotion regulation among outpatients with major depressive disorders-Results from a double-blind, randomized and placebo-controlled clinical trial. J. Psychiatr. Res. 2018, 107, 48–56. [Google Scholar] [CrossRef] [PubMed]
  57. Tayama, J.; Ogawa, S.; Nakaya, N.; Sone, T.; Hamaguchi, T.; Takeoka, A.; Hamazaki, K.; Okamura, H.; Yajima, J.; Kobayashi, M. Omega-3 polyunsaturated fatty acids and psychological intervention for workers with mild to moderate depression: A double-blind randomized controlled trial. J. Affect. Disord. 2019, 245, 364–370. [Google Scholar] [CrossRef] [PubMed]
  58. Fristad, M.A.; Vesco, A.T.; Young, A.S.; Healy, K.Z.; Nader, E.S.; Gardner, W.; Seidenfeld, A.M.; Wolfson, H.L.; Arnold, L.E. Pilot randomized controlled trial of omega-3 and individual–family psychoeducational psychotherapy for children and adolescents with depression. J. Clin. Child Adolesc. Psychol. 2019, 48, S105–S118. [Google Scholar] [CrossRef]
  59. Trebatická, J.; Hradečná, Z.; Surovcová, A.; Katrenčíková, B.; Gushina, I.; Waczulíková, I.; Sušienková, K.; Garaiova, I.; Šuba, J.; Ďuračková, Z. Omega-3 fatty-acids modulate symptoms of depressive disorder, serum levels of omega-3 fatty acids and omega-6/omega-3 ratio in children. A randomized, double-blind and controlled trial. Psychiatry Res. 2020, 287, 112911. [Google Scholar] [CrossRef]
  60. Stoll, A.L.; Severus, W.E.; Freeman, M.P.; Rueter, S.; Zboyan, H.A.; Diamond, E.; Cress, K.K.; Marangell, L.B. Omega 3 fatty acids in bipolar disorder: A preliminary double-blind, placebo-controlled trial. Arch. Gen. Psychol. 1999, 56, 407–412. [Google Scholar] [CrossRef] [PubMed]
  61. Hirashima, F.; Parow, A.M.; Stoll, A.L.; Demopulos, C.M.; Damico, K.E.; Rohan, M.L.; Eskesen, J.G.; Zuo, C.S.; Cohen, B.M.; Renshaw, P.F. Omega-3 fatty acid treatment and T(2) whole brain relaxation times in bipolar disorder. Am. J. Psychiatry 2004, 161, 1922–1924. [Google Scholar] [CrossRef]
  62. Chiu, C.C.; Huang, S.Y.; Chen, C.C.; Su, K.P. Omega-3 fatty acids are more beneficial in the depressive phase than in the manic phase in patients with bipolar I disorder. J. Clin. Psychiatry 2005, 66, 1613–1614. [Google Scholar] [CrossRef][Green Version]
  63. Frangou, S.; Lewis, M.; McCrone, P. Efficacy of ethyl-eicosapentaenoic acid in bipolar depression: Randomised double-blind placebo-controlled study. Br. J. Psychiatry J. Ment. Sci. 2006, 188, 46–50. [Google Scholar] [CrossRef][Green Version]
  64. Keck, P.E., Jr.; Mintz, J.; McElroy, S.L.; Freeman, M.P.; Suppes, T.; Frye, M.A.; Altshuler, L.L.; Kupka, R.; Nolen, W.A.; Leverich, G.S.; et al. Double-blind, randomized, placebo-controlled trials of ethyl-eicosapentanoate in the treatment of bipolar depression and rapid cycling bipolar disorder. Biol. Psychiatry 2006, 60, 1020–1022. [Google Scholar] [CrossRef] [PubMed]
  65. Frangou, S.; Lewis, M.; Wollard, J.; Simmons, A. Preliminary in vivo evidence of increased N-acetyl-aspartate following eicosapentanoic acid treatment in patients with bipolar disorder. J. Psychopharmacol. 2007, 21, 435–439. [Google Scholar] [CrossRef]
  66. Murphy, B.L.; Stoll, A.L.; Harris, P.Q.; Ravichandran, C.; Babb, S.M.; Carlezon, W.A., Jr.; Cohen, B.M. Omega-3 fatty acid treatment, with or without cytidine, fails to show therapeutic properties in bipolar disorder: A double-blind, randomized add-on clinical trial. J. Clin. Psychopharmacol. 2012, 32, 699–703. [Google Scholar] [CrossRef] [PubMed]
  67. McNamara, R.K.; Strawn, J.R.; Tallman, M.J.; Welge, J.A.; Patino, L.R.; Blom, T.J.; DelBello, M.P. Effects of fish oil monotherapy on depression and prefrontal neurochemistry in adolescents at high risk for bipolar I disorder: A 12-week placebo-controlled proton magnetic resonance spectroscopy trial. J. Child Adolesc. Psychopharmacol. 2020, 30, 293–305. [Google Scholar] [CrossRef][Green Version]
  68. Freeman, M.P.; Davis, M.; Sinha, P.; Wisner, K.L.; Hibbeln, J.R.; Gelenberg, A.J. Omega-3 fatty acids and supportive psychotherapy for perinatal depression: A randomized placebo-controlled study. J. Affect. Disord. 2008, 110, 142–148. [Google Scholar] [CrossRef] [PubMed][Green Version]
  69. Rees, A.M.; Austin, M.P.; Parker, G.B. Omega-3 fatty acids as a treatment for perinatal depression: Randomized double-blind placebo-controlled trial. Aust. N. Z. J. Psychiatry 2008, 42, 199–205. [Google Scholar] [CrossRef] [PubMed]
  70. Nishi, D.; Su, K.-P.; Usuda, K.; Chang, J.P.-C.; Hamazaki, K.; Ishima, T.; Sano, Y.; Ito, H.; Isaka, K.; Tachibana, Y.; et al. Plasma estradiol levels and antidepressant effects of omega-3 fatty acids in pregnant women. Brain Behav. Immun. 2020, 85, 29–34. [Google Scholar] [CrossRef]
  71. Lucas, M.; Asselin, G.; Merette, C.; Poulin, M.J.; Dodin, S. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: A double-blind, placebo-controlled, randomized clinical trial. Am. J. Clin. Nutr. 2009, 89, 641–651. [Google Scholar] [CrossRef][Green Version]
  72. Antypa, N.; Smelt, A.H.; Strengholt, A.; Van der Does, A.J. Effects of omega-3 fatty acid supplementation on mood and emotional information processing in recovered depressed individuals. J. Psychopharmacol. 2012, 26, 738–743. [Google Scholar] [CrossRef]
  73. Sohrabi, N.; Kashanian, M.; Ghafoori, S.S.; Malakouti, S.K. Evaluation of the effect of omega-3 fatty acids in the treatment of premenstrual syndrome: “A pilot trial”. Complement. Ther. Med. 2013, 21, 141–146. [Google Scholar] [CrossRef] [PubMed]
  74. Behan, P.O.; Behan, W.M.; Horrobin, D.F. Effect of high doses of essential fatty acids on the postviral fatigue syndrome. Acta Neurol. Scand. 1990, 82, 209–216. [Google Scholar] [CrossRef] [PubMed]
  75. Warren, G.; McKendrick, M.; Peet, M. The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA. Acta Neurol. Scand. 1999, 99, 112–116. [Google Scholar] [CrossRef]
  76. Zanarini, M.C.; Frankenburg, F.R. omega-3 Fatty acid treatment of women with borderline personality disorder: A double-blind, placebo-controlled pilot study. Am. J. Psychiatry 2003, 160, 167–169. [Google Scholar] [CrossRef][Green Version]
  77. Fux, M.; Benjamin, J.; Nemets, B. A placebo-controlled cross-over trial of adjunctive EPA in OCD. J. Psychiatr. Res. 2004, 38, 323–325. [Google Scholar] [CrossRef]
  78. Hallahan, B.; Hibbeln, J.R.; Davis, J.M.; Garland, M.R. Omega-3 fatty acid supplementation in patients with recurrent self-harm. Single-centre double-blind randomised controlled trial. Br. J. Psychiatry J. Ment. Sci. 2007, 190, 118–122. [Google Scholar] [CrossRef][Green Version]
  79. Peet, M.; Horrobin, D.F. A dose-ranging exploratory study of the effects of ethyl-eicosapentaenoate in patients with persistent schizophrenic symptoms. J. Psychiatr. Res. 2002, 36, 7–18. [Google Scholar] [CrossRef]
  80. Fenton, W.S.; Dickerson, F.; Boronow, J.; Hibbeln, J.R.; Knable, M. A placebo-controlled trial of omega-3 fatty acid (ethyl eicosapentaenoic acid) supplementation for residual symptoms and cognitive impairment in schizophrenia. Am. J. Psychiatry 2001, 158, 2071–2074. [Google Scholar] [CrossRef]
  81. Qiao, Y.; Mei, Y.; Han, H.; Liu, F.; Yang, X.M.; Shao, Y.; Xie, B.; Long, B. Effects of Omega-3 in the treatment of violent schizophrenia patients. Schizophr. Res. 2018, 195, 283–285. [Google Scholar] [CrossRef]
  82. Chiu, C.C.; Su, K.P.; Cheng, T.C.; Liu, H.C.; Chang, C.J.; Dewey, M.E.; Stewart, R.; Huang, S.Y. The effects of omega-3 fatty acids monotherapy in Alzheimer’s disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study. Prog. Neuropsychopharmacol. Biol. Psychiatry 2008, 32, 1538–1544. [Google Scholar] [CrossRef] [PubMed]
  83. Freund-Levi, Y.; Basun, H.; Cederholm, T.; Faxen-Irving, G.; Garlind, A.; Grut, M.; Vedin, I.; Palmblad, J.; Wahlund, L.O.; Eriksdotter-Jonhagen, M. Omega-3 supplementation in mild to moderate Alzheimer’s disease: Effects on neuropsychiatric symptoms. Int. J. Geriatr. Psychiatry 2008, 23, 161–169. [Google Scholar] [CrossRef] [PubMed]
  84. Da Silva, T.M.; Munhoz, R.P.; Alvarez, C.; Naliwaiko, K.; Kiss, A.; Andreatini, R.; Ferraz, A.C. Depression in Parkinson’s disease: A double-blind, randomized, placebo-controlled pilot study of omega-3 fatty-acid supplementation. J. Affect. Disord. 2008, 111, 351–359. [Google Scholar] [CrossRef] [PubMed]
  85. Carney, R.M.; Freedland, K.E.; Rubin, E.H.; Rich, M.W.; Steinmeyer, B.C.; Harris, W.S. Omega-3 augmentation of sertraline in treatment of depression in patients with coronary heart disease: A randomized controlled trial. JAMA J. Am. Med. Assoc. 2009, 302, 1651–1657. [Google Scholar] [CrossRef][Green Version]
  86. Bot, M.; Pouwer, F.; Assies, J.; Jansen, E.H.; Diamant, M.; Snoek, F.J.; Beekman, A.T.; de Jonge, P. Eicosapentaenoic acid as an add-on to antidepressant medication for co-morbid major depression in patients with diabetes mellitus: A randomized, double-blind placebo-controlled study. J. Affect. Disord. 2010, 126, 282–286. [Google Scholar] [CrossRef][Green Version]
  87. Giltay, E.J.; Geleijnse, J.M.; Kromhout, D. Effects of n-3 fatty acids on depressive symptoms and dispositional optimism after myocardial infarction. Am. J. Clin. Nutr. 2011, 94, 1442–1450. [Google Scholar] [CrossRef][Green Version]
  88. Bot, M.; Pouwer, F.; Assies, J.; Jansen, E.H.; Beekman, A.T.; de Jonge, P. Supplementation with eicosapentaenoic omega-3 fatty acid does not influence serum brain-derived neurotrophic factor in diabetes mellitus patients with major depression: A randomized controlled pilot study. Neuropsychobiology 2011, 63, 219–223. [Google Scholar] [CrossRef] [PubMed]
  89. Andreeva, V.A.; Galan, P.; Torres, M.; Julia, C.; Hercberg, S.; Kesse-Guyot, E. Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: Ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial. Am. J. Clin. Nutr. 2012, 96, 208–214. [Google Scholar] [CrossRef][Green Version]
  90. Fontani, G.; Corradeschi, F.; Felici, A.; Alfatti, F.; Migliorini, S.; Lodi, L. Cognitive and physiological effects of Omega-3 polyunsaturated fatty acid supplementation in healthy subjects. Eur. J. Clin. Investig. 2005, 35, 691–699. [Google Scholar] [CrossRef]
  91. van de Rest, O.; Geleijnse, J.M.; Kok, F.J.; van Staveren, W.A.; Hoefnagels, W.H.; Beekman, A.T.; de Groot, L.C. Effect of fish-oil supplementation on mental well-being in older subjects: A randomized, double-blind, placebo-controlled trial. Am. J. Clin. Nutr. 2008, 88, 706–713. [Google Scholar] [CrossRef][Green Version]
  92. Antypa, N.; Van der Does, A.J.; Smelt, A.H.; Rogers, R.D. Omega-3 fatty acids (fish-oil) and depression-related cognition in healthy volunteers. J. Psychopharmacol. 2009, 23, 831–840. [Google Scholar] [CrossRef] [PubMed]
  93. Kiecolt-Glaser, J.K.; Belury, M.A.; Andridge, R.; Malarkey, W.B.; Glaser, R. Omega-3 supplementation lowers inflammation and anxiety in medical students: A randomized controlled trial. Brain Behav. Immun. 2011, 25, 1725–1734. [Google Scholar] [CrossRef][Green Version]
  94. DeFina, L.F.; Marcoux, L.G.; Devers, S.M.; Cleaver, J.P.; Willis, B.L. Effects of omega-3 supplementation in combination with diet and exercise on weight loss and body composition. Am. J. Clin. Nutr. 2011, 93, 455–462. [Google Scholar] [CrossRef][Green Version]
  95. Kiecolt-Glaser, J.K.; Belury, M.A.; Andridge, R.; Malarkey, W.B.; Hwang, B.S.; Glaser, R. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: A randomized controlled trial. Brain Behav. Immun. 2012, 26, 988–995. [Google Scholar] [CrossRef] [PubMed][Green Version]
  96. Van der Wurff, I.; Von Schacky, C.; Bergeland, T.; Leontjevas, R.; Zeegers, M.P.; Kirschner, P.; de Groot, R. Effect of one year krill oil supplementation on depressive symptoms and self-esteem of Dutch adolescents: A randomized controlled trial. Prostaglandin Leukot. Essent. Fatty Acids 2020, 163, 102208. [Google Scholar] [CrossRef] [PubMed]
  97. Chiu, C.C.; Huang, S.Y.; Su, K.P. Omega-3 polyunsaturated fatty acids for postpartum depression. Am. J. Obstet. Gynecol. 2004, 190, 582–583. [Google Scholar] [CrossRef]
  98. Chiu, C.C.; Huang, S.Y.; Shen, W.W.; Su, K.P. Omega-3 fatty acids for depression in pregnancy. Am. J. Psychiatry 2003, 160, 385. [Google Scholar] [CrossRef]
  99. Leonard, B.; Maes, M. Mechanistic explanations how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci. Biobehav. Rev. 2012, 36, 764–785. [Google Scholar] [CrossRef]
  100. Lang, U.E.; Borgwardt, S. Molecular mechanisms of depression: Perspectives on new treatment strategies. Cell. Physiol. Biochem. 2013, 31, 761–777. [Google Scholar] [CrossRef]
  101. Rosenblat, J.D.; Cha, D.S.; Mansur, R.B.; McIntyre, R.S. Inflamed moods: A review of the interactions between inflammation and mood disorders. Prog. Neuropsychopharmacol. Biol. Psychiatry 2014, 53, 23–34. [Google Scholar] [CrossRef]
  102. Lotrich, F.E. Inflammatory cytokine-associated depression. Brain Res. 2015, 1617, 113–125. [Google Scholar] [CrossRef] [PubMed][Green Version]
  103. Goldsmith, D.R.; Rapaport, M.H.; Miller, B.J. A meta-analysis of blood cytokine network alterations in psychiatric patients: Comparisons between schizophrenia, bipolar disorder and depression. Mol. Psychiatry 2016, 21, 1696–1709. [Google Scholar] [CrossRef]
  104. Kopschina Feltes, P.; Doorduin, J.; Klein, H.C.; Juarez-Orozco, L.E.; Dierckx, R.A.; Moriguchi-Jeckel, C.M.; de Vries, E.F. Anti-inflammatory treatment for major depressive disorder: Implications for patients with an elevated immune profile and non-responders to standard antidepressant therapy. J. Psychopharmacol. 2017, 31, 1149–1165. [Google Scholar] [CrossRef] [PubMed][Green Version]
  105. Kalkman, H.O.; Feuerbach, D. Antidepressant therapies inhibit inflammation and microglial M1-polarization. Pharmacol. Ther. 2016, 163, 82–93. [Google Scholar] [CrossRef] [PubMed]
  106. Young, J.J.; Bruno, D.; Pomara, N. A review of the relationship between proinflammatory cytokines and major depressive disorder. J. Affect. Disord. 2014, 169, 15–20. [Google Scholar] [CrossRef] [PubMed]
  107. Kalkman, H.O. The association between vascular inflammation and depressive disorder. Causality, biomarkers and targeted treatment. Pharmaceuticals 2020, 13, 92. [Google Scholar] [CrossRef] [PubMed]
  108. Calder, P.C. Omega-3 polyunsaturated fatty acids and inflammatory processes: Nutrition or pharmacology? Br. J. Clin. Pharmacol. 2013, 75, 645–662. [Google Scholar] [CrossRef] [PubMed][Green Version]
  109. Gharekhani, A.; Khatami, M.R.; Dashti-Khavidaki, S.; Razeghi, E.; Noorbala, A.A.; Hashemi-Nazari, S.S.; Mansournia, M.A. The effect of omega-3 fatty acids on depressive symptoms and inflammatory markers in maintenance hemodialysis patients: A randomized, placebo-controlled clinical trial. Eur. J. Clin. Pharmacol. 2014, 70, 655–665. [Google Scholar] [CrossRef]
  110. Su, K.P.; Lai, H.C.; Yang, H.T.; Su, W.P.; Peng, C.Y.; Chang, J.P.; Chang, H.C.; Pariante, C.M. Omega-3 fatty acids in the prevention of interferon-alpha-induced depression: Results from a randomized, controlled trial. Biol. Psychiatry 2014, 76, 559–566. [Google Scholar] [CrossRef] [PubMed]
  111. Cipollina, C. Endogenous generation and signaling actions of omega-3 fatty acid electrophilic derivatives. Biomed. Res. Int. 2015, 2015, 501792. [Google Scholar] [CrossRef][Green Version]
  112. Dyall, S.C. Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Front. Aging Neurosci. 2015, 7, 52. [Google Scholar] [CrossRef] [PubMed][Green Version]
  113. Lee, J.Y.; Sohn, K.H.; Rhee, S.H.; Hwang, D. Saturated fatty acids, but not unsaturated fatty acids, induce the expression of cyclooxygenase-2 mediated through Toll-like receptor 4. J. Biol. Chem. 2001, 276, 16683–16689. [Google Scholar] [CrossRef][Green Version]
  114. Shi, H.; Kokoeva, M.V.; Inouye, K.; Tzameli, I.; Yin, H.; Flier, J.S. TLR4 links innate immunity and fatty acid-induced insulin resistance. J. Clin. Investig. 2006, 116, 3015–3025. [Google Scholar] [CrossRef] [PubMed]
  115. Russell, F.D.; Burgin-Maunder, C.S. Distinguishing health benefits of eicosapentaenoic and docosahexaenoic acids. Mar. Drugs 2012, 10, 2535–2559. [Google Scholar] [CrossRef] [PubMed][Green Version]
  116. Zhao, G.; Etherton, T.D.; Martin, K.R.; Vanden Heuvel, J.P.; Gillies, P.J.; West, S.G.; Kris-Etherton, P.M. Anti-inflammatory effects of polyunsaturated fatty acids in THP-1 cells. Biochem. Biophys. Res. Commun. 2005, 336, 909–917. [Google Scholar] [CrossRef]
  117. Weldon, S.M.; Mullen, A.C.; Loscher, C.E.; Hurley, L.A.; Roche, H.M. Docosahexaenoic acid induces an anti-inflammatory profile in lipopolysaccharide-stimulated human THP-1 macrophages more effectively than eicosapentaenoic acid. J. Nutr. Biochem. 2007, 18, 250–258. [Google Scholar] [CrossRef] [PubMed]
  118. Komatsu, H.; Hoshino, A.; Funayama, M.; Kawahara, K.; Obata, F. Oxidative modulation of the glutathione-redox couple enhances lipopolysaccharide-induced interleukin 12 P40 production by a mouse macrophage cell line, J774A.1. Free Radic. Res. 2003, 37, 293–299. [Google Scholar] [CrossRef]
  119. Allam-Ndoul, B.; Guenard, F.; Barbier, O.; Vohl, M.C. Effect of n-3 fatty acids on the expression of inflammatory genes in THP-1 macrophages. Lipids Health Dis. 2016, 15, 69. [Google Scholar] [CrossRef][Green Version]
  120. Mogensen, T.H. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 2009, 22, 240–273. [Google Scholar] [CrossRef] [PubMed][Green Version]
  121. Guo, H.; Callaway, J.B.; Ting, J.P. Inflammasomes: Mechanism of action, role in disease, and therapeutics. Nat. Med. 2015, 21, 677–687. [Google Scholar] [CrossRef] [PubMed][Green Version]
  122. Zhang, B.; Zhang, Y.; Xu, T.; Yin, Y.; Huang, R.; Wang, Y.; Zhang, J.; Huang, D.; Li, W. Chronic dexamethasone treatment results in hippocampal neurons injury due to activate NLRP1 inflammasome in vitro. Int. Immunopharmacol. 2017, 49, 222–230. [Google Scholar] [CrossRef]
  123. Iwata, M.; Ota, K.T.; Duman, R.S. The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses. Brain Behav. Immun. 2013, 31, 105–114. [Google Scholar] [CrossRef] [PubMed][Green Version]
  124. Alcocer-Gomez, E.; de Miguel, M.; Casas-Barquero, N.; Nunez-Vasco, J.; Sanchez-Alcazar, J.A.; Fernandez-Rodriguez, A.; Cordero, M.D. NLRP3 inflammasome is activated in mononuclear blood cells from patients with major depressive disorder. Brain Behav. Immun. 2014, 36, 111–117. [Google Scholar] [CrossRef]
  125. Akosile, W.; Voisey, J.; Lawford, B.; Colquhounc, D.; Young, R.M.; Mehta, D. The inflammasome NLRP12 is associated with both depression and coronary artery disease in Vietnam veterans. Psychiatry Res. 2018, 270, 775–779. [Google Scholar] [CrossRef][Green Version]
  126. Yan, Y.; Jiang, W.; Spinetti, T.; Tardivel, A.; Castillo, R.; Bourquin, C.; Guarda, G.; Tian, Z.; Tschopp, J.; Zhou, R. Omega-3 fatty acids prevent inflammation and metabolic disorder through inhibition of NLRP3 inflammasome activation. Immunity 2013, 38, 1154–1163. [Google Scholar] [CrossRef][Green Version]
  127. Zhou, R.; Tardivel, A.; Thorens, B.; Choi, I.; Tschopp, J. Thioredoxin-interacting protein links oxidative stress to inflammasome activation. Nat. Immunol. 2010, 11, 136–140. [Google Scholar] [CrossRef] [PubMed]
  128. Zhang, Y.; Jiang, L.; Hu, W.; Zheng, Q.; Xiang, W. Mitochondrial dysfunction during in vitro hepatocyte steatosis is reversed by omega-3 fatty acid-induced up-regulation of mitofusin 2. Metabolism 2011, 60, 767–775. [Google Scholar] [CrossRef]
  129. Lepretti, M.; Martucciello, S.; Burgos Aceves, M.A.; Putti, R.; Lionetti, L. Omega-3 fatty acids and insulin resistance: Focus on the regulation of mitochondria and endoplasmic reticulum stress. Nutrients 2018, 10, 350. [Google Scholar] [CrossRef] [PubMed][Green Version]
  130. Rae, C.D.; Williams, S.R. Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy. Anal. Biochem. 2017, 529, 127–143. [Google Scholar] [CrossRef] [PubMed]
  131. Duffy, S.L.; Lagopoulos, J.; Cockayne, N.; Lewis, S.J.; Hickie, I.B.; Hermens, D.F.; Naismith, S.L. The effect of 12-wk omega-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients “at risk” for major depression. Nutrition 2015, 31, 1247–1254. [Google Scholar] [CrossRef] [PubMed]
  132. Berger, G.E.; Wood, S.J.; Wellard, R.M.; Proffitt, T.M.; McConchie, M.; Amminger, G.P.; Jackson, G.D.; Velakoulis, D.; Pantelis, C.; McGorry, P.D. Ethyl-eicosapentaenoic acid in first-episode psychosis. A 1H-MRS study. Neuropsychopharmacology 2008, 33, 2467–2473. [Google Scholar] [CrossRef][Green Version]
  133. Liu, Q.; Wu, D.; Ni, N.; Ren, H.; Luo, C.; He, C.; Kang, J.X.; Wan, J.B.; Su, H. Omega-3 polyunsaturated fatty acids protect neural progenitor cells against oxidative injury. Mar. Drugs 2014, 12, 2341–2356. [Google Scholar] [CrossRef][Green Version]
  134. Cai, S.M.; Yang, R.Q.; Li, Y.; Ning, Z.W.; Zhang, L.L.; Zhou, G.S.; Luo, W.; Li, D.H.; Chen, Y.; Pan, M.X.; et al. Angiotensin-(1-7) Improves Liver Fibrosis by Regulating the NLRP3 Inflammasome via Redox Balance Modulation. Antioxid. Redox Signal. 2016, 24, 795–812. [Google Scholar] [CrossRef]
  135. Gabbs, M.; Leng, S.; Devassy, J.G.; Monirujjaman, M.; Aukema, H.M. Advances in our understanding of oxylipins derived from dietary PUFAs. Adv. Nutr. 2015, 6, 513–540. [Google Scholar] [CrossRef][Green Version]
  136. Goldman, D.W.; Pickett, W.C.; Goetzl, E.J. Human neutrophil chemotactic and degranulating activities of leukotriene B5 (LTB5) derived from eicosapentaenoic acid. Biochem. Biophys. Res. Commun. 1983, 117, 282–288. [Google Scholar] [CrossRef]
  137. Strasser, T.; Fischer, S.; Weber, P.C. Leukotriene B5 is formed in human neutrophils after dietary supplementation with icosapentaenoic acid. Proc. Natl. Acad. Sci. USA 1985, 82, 1540–1543. [Google Scholar] [CrossRef][Green Version]
  138. Nieves, D.; Moreno, J.J. Effect of arachidonic and eicosapentaenoic acid metabolism on RAW 264.7 macrophage proliferation. J. Cell Physiol. 2006, 208, 428–434. [Google Scholar] [CrossRef]
  139. Serhan, C.N.; Chiang, N.; Van Dyke, T.E. Resolving inflammation: Dual anti-inflammatory and pro-resolution lipid mediators. Nat. Rev. Immunol. 2008, 8, 349–361. [Google Scholar] [CrossRef] [PubMed][Green Version]
  140. Oh, S.F.; Dona, M.; Fredman, G.; Krishnamoorthy, S.; Irimia, D.; Serhan, C.N. Resolvin E2 formation and impact in inflammation resolution. J. Immunol. 2012, 188, 4527–4534. [Google Scholar] [CrossRef][Green Version]
  141. Isobe, Y.; Arita, M.; Matsueda, S.; Iwamoto, R.; Fujihara, T.; Nakanishi, H.; Taguchi, R.; Masuda, K.; Sasaki, K.; Urabe, D.; et al. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. J. Biol. Chem. 2012, 287, 10525–10534. [Google Scholar] [CrossRef][Green Version]
  142. Arita, M.; Bianchini, F.; Aliberti, J.; Sher, A.; Chiang, N.; Hong, S.; Yang, R.; Petasis, N.A.; Serhan, C.N. Stereochemical assignment, antiinflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 2005, 201, 713–722. [Google Scholar] [CrossRef]
  143. Chiang, N.; Serhan, C.N. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol. Aspects Med. 2017, 58, 114–129. [Google Scholar] [CrossRef]
  144. Serhan, C.N. Treating inflammation and infection in the 21st century: New hints from decoding resolution mediators and mechanisms. FASEB J. 2017, 31, 1273–1288. [Google Scholar] [CrossRef][Green Version]
  145. Colgan, S.P.; Serhan, C.N.; Parkos, C.A.; Delp-Archer, C.; Madara, J.L. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J. Clin. Investig. 1993, 92, 75–82. [Google Scholar] [CrossRef][Green Version]
  146. Serhan, C.N. Pro-resolving lipid mediators are leads for resolution physiology. Nature 2014, 510, 92–101. [Google Scholar] [CrossRef][Green Version]
  147. Gilbert, K.; Bernier, J.; Godbout, R.; Rousseau, G. Resolvin D1, a metabolite of omega-3 polyunsaturated fatty acid, decreases post-myocardial infarct depression. Mar. Drugs 2014, 12, 5396–5407. [Google Scholar] [CrossRef][Green Version]
  148. Deyama, S.; Ishikawa, Y.; Yoshikawa, K.; Shimoda, K.; Ide, S.; Satoh, M.; Minami, M. Resolvin D1 and D2 reverse lipopolysaccharide-induced depression-like behaviors through the mTORC1 signaling pathway. Int. J. Neuropsychopharmacol. 2017, 20, 575–584. [Google Scholar] [CrossRef][Green Version]
  149. Deyama, S.; Shimoda, K.; Suzuki, H.; Ishikawa, Y.; Ishimura, K.; Fukuda, H.; Hitora-Imamura, N.; Ide, S.; Satoh, M.; Kaneda, K.; et al. Resolvin E1/E2 ameliorate lipopolysaccharide-induced depression-like behaviors via ChemR23. Psychopharmacology 2018, 235, 329–336. [Google Scholar] [CrossRef]
  150. Ishikawa, Y.; Deyama, S.; Shimoda, K.; Yoshikawa, K.; Ide, S.; Satoh, M.; Minami, M. Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model. Behav. Brain Res. 2017, 332, 233–236. [Google Scholar] [CrossRef]
  151. Hasturk, H.; Abdallah, R.; Kantarci, A.; Nguyen, D.; Giordano, N.; Hamilton, J.; Van Dyke, T.E. Resolvin E1 (RvE1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis. Arterioscler. Thromb. Vasc. Biol. 2015, 35, 1123–1133. [Google Scholar] [CrossRef] [PubMed][Green Version]
  152. Salic, K.; Morrison, M.C.; Verschuren, L.; Wielinga, P.Y.; Wu, L.; Kleemann, R.; Gjorstrup, P.; Kooistra, T. Resolvin E1 attenuates atherosclerosis in absence of cholesterol-lowering effects and on top of atorvastatin. Atherosclerosis 2016, 250, 158–165. [Google Scholar] [CrossRef] [PubMed][Green Version]
  153. Sima, C.; Montero, E.; Nguyen, D.; Freire, M.; Norris, P.; Serhan, C.N.; Van Dyke, T.E. ERV1 overexpression in myeloid cells protects against high fat diet induced obesity and glucose intolerance. Sci. Rep. 2017, 7, 12848. [Google Scholar] [CrossRef]
  154. Buckley, C.D.; Gilroy, D.W.; Serhan, C.N. Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 2014, 40, 315–327. [Google Scholar] [CrossRef][Green Version]
  155. Herova, M.; Schmid, M.; Gemperle, C.; Hersberger, M. ChemR23, the receptor for chemerin and resolvin E1, is expressed and functional on M1 but not on M2 macrophages. J. Immunol. 2015, 194, 2330–2337. [Google Scholar] [CrossRef][Green Version]
  156. Schmid, M.; Gemperle, C.; Rimann, N.; Hersberger, M. Resolvin D1 Polarizes primary human macrophages toward a proresolution phenotype through GPR32. J. Immunol. 2016, 196, 3429–3437. [Google Scholar] [CrossRef][Green Version]
  157. Lannan, K.L.; Spinelli, S.L.; Blumberg, N.; Phipps, R.P. Maresin 1 induces a novel pro-resolving phenotype in human platelets. J. Thromb. Haemost. 2017, 15, 802–813. [Google Scholar] [CrossRef] [PubMed]
  158. Rey, C.; Nadjar, A.; Joffre, F.; Amadieu, C.; Aubert, A.; Vaysse, C.; Pallet, V.; Laye, S.; Joffre, C. Maternal n-3 polyunsaturated fatty acid dietary supply modulates microglia lipid content in the offspring. Prostaglandins Leukot. Essent. Fatty Acids 2018, 133, 1–7. [Google Scholar] [CrossRef]
  159. Rey, C.; Delpech, J.C.; Madore, C.; Nadjar, A.; Greenhalgh, A.D.; Amadieu, C.; Aubert, A.; Pallet, V.; Vaysse, C.; Laye, S.; et al. Dietary n-3 long chain PUFA supplementation promotes a pro-resolving oxylipin profile in the brain. Brain Behav. Immun. 2019, 76, 17–27. [Google Scholar] [CrossRef] [PubMed]
  160. Waldman, M.; Peterson, S.J.; Arad, M.; Hochhauser, E. The role of 20-HETE in cardiovascular diseases and its risk factors. Prostaglandins Lipid Mediat. 2016, 125, 108–117. [Google Scholar] [CrossRef] [PubMed]
  161. Elshenawy, O.H.; Shoieb, S.M.; Mohamed, A.; El-Kadi, A.O. Clinical Implications of 20-Hydroxyeicosatetraenoic acid in the kidney, liver, lung and brain: An emerging therapeutic target. Pharmaceutics 2017, 9, 9. [Google Scholar] [CrossRef]
  162. Arnold, C.; Konkel, A.; Fischer, R.; Schunck, W.H. Cytochrome P450-dependent metabolism of omega-6 and omega-3 long-chain polyunsaturated fatty acids. Pharmacol. Rep. 2010, 62, 536–547. [Google Scholar] [CrossRef]
  163. Konkel, A.; Schunck, W.H. Role of cytochrome P450 enzymes in the bioactivation of polyunsaturated fatty acids. Biochim. Biophys. Acta 2011, 1814, 210–222. [Google Scholar] [CrossRef]
  164. Schunck, W.H.; Konkel, A.; Fischer, R.; Weylandt, K.H. Therapeutic potential of omega-3 fatty acid-derived epoxyeicosanoids in cardiovascular and inflammatory diseases. Pharmacol. Ther. 2018, 183, 177–204. [Google Scholar] [CrossRef]
  165. Ulu, A.; Harris, T.R.; Morisseau, C.; Miyabe, C.; Inoue, H.; Schuster, G.; Dong, H.; Iosif, A.M.; Liu, J.Y.; Weiss, R.H.; et al. Anti-inflammatory effects of omega-3 polyunsaturated fatty acids and soluble epoxide hydrolase inhibitors in angiotensin-II-dependent hypertension. J. Cardiovasc. Pharmacol. 2013, 62, 285–297. [Google Scholar] [CrossRef] [PubMed][Green Version]
  166. Spector, A.A.; Kim, H.Y. Cytochrome P450 epoxygenase pathway of polyunsaturated fatty acid metabolism. Biochim. Biophys. Acta 2015, 1851, 356–365. [Google Scholar] [CrossRef] [PubMed][Green Version]
  167. Garcia, V.; Gilani, A.; Shkolnik, B.; Pandey, V.; Zhang, F.F.; Dakarapu, R.; Gandham, S.K.; Reddy, N.R.; Graves, J.P.; Gruzdev, A.; et al. 20-HETE signals through g-protein-coupled receptor GPR75 (Gq) to affect vascular function and trigger hypertension. Circ. Res. 2017, 120, 1776–1788. [Google Scholar] [CrossRef][Green Version]
  168. Fischer, R.; Konkel, A.; Mehling, H.; Blossey, K.; Gapelyuk, A.; Wessel, N.; von Schacky, C.; Dechend, R.; Muller, D.N.; Rothe, M.; et al. Dietary omega-3 fatty acids modulate the eicosanoid profile in man primarily via the CYP-epoxygenase pathway. J. Lipid Res. 2014, 55, 1150–1164. [Google Scholar] [CrossRef] [PubMed][Green Version]
  169. Schuchardt, J.P.; Schmidt, S.; Kressel, G.; Willenberg, I.; Hammock, B.D.; Hahn, A.; Schebb, N.H. Modulation of blood oxylipin levels by long-chain omega-3 fatty acid supplementation in hyper- and normolipidemic men. Prostaglandins Leukot. Essent. Fatty Acids 2014, 90, 27–37. [Google Scholar] [CrossRef][Green Version]
  170. Freitas, H.R.; Isaac, A.R.; Malcher-Lopes, R.; Diaz, B.L.; Trevenzoli, I.H.; De Melo Reis, R.A. Polyunsaturated fatty acids and endocannabinoids in health and disease. Nutr. Neurosci. 2018, 21, 695–714. [Google Scholar] [CrossRef]
  171. Smaga, I.; Bystrowska, B.; Gawlinski, D.; Przegalinski, E.; Filip, M. The endocannabinoid/endovanilloid system and depression. Curr. Neuropharmacol. 2014, 12, 462–474. [Google Scholar] [CrossRef][Green Version]
  172. Turcotte, C.; Blanchet, M.R.; Laviolette, M.; Flamand, N. The CB2 receptor and its role as a regulator of inflammation. Cell. Mol. Life Sci. 2016, 73, 4449–4470. [Google Scholar] [CrossRef][Green Version]
  173. Balvers, M.G.; Verhoeckx, K.C.; Plastina, P.; Wortelboer, H.M.; Meijerink, J.; Witkamp, R.F. Docosahexaenoic acid and eicosapentaenoic acid are converted by 3T3-L1 adipocytes to N-acyl ethanolamines with anti-inflammatory properties. Biochim. Biophys. Acta 2010, 1801, 1107–1114. [Google Scholar] [CrossRef]
  174. McDougle, D.R.; Watson, J.E.; Abdeen, A.A.; Adili, R.; Caputo, M.P.; Krapf, J.E.; Johnson, R.W.; Kilian, K.A.; Holinstat, M.; Das, A. Anti-inflammatory omega-3 endocannabinoid epoxides. Proc. Natl. Acad. Sci. USA 2017, 114, E6034–E6043. [Google Scholar] [CrossRef][Green Version]
  175. Snider, N.T.; Nast, J.A.; Tesmer, L.A.; Hollenberg, P.F. A cytochrome P450-derived epoxygenated metabolite of anandamide is a potent cannabinoid receptor 2-selective agonist. Mol. Pharmacol. 2009, 75, 965–972. [Google Scholar] [CrossRef] [PubMed][Green Version]
  176. Chiurchiu, V.; Battistini, L.; Maccarrone, M. Endocannabinoid signalling in innate and adaptive immunity. Immunology 2015, 144, 352–364. [Google Scholar] [CrossRef] [PubMed]
  177. Roche, M.; Finn, D.P. Brain CB(2) Receptors: Implications for neuropsychiatric disorders. Pharmaceuticals 2010, 3, 2517–2553. [Google Scholar] [CrossRef][Green Version]
  178. Kim, H.Y.; Spector, A.A.; Xiong, Z.M. A synaptogenic amide N-docosahexaenoylethanolamide promotes hippocampal development. Prostaglandins Lipid Mediat. 2011, 96, 114–120. [Google Scholar] [CrossRef] [PubMed][Green Version]
  179. Lee, J.W.; Huang, B.X.; Kwon, H.; Rashid, M.A.; Kharebava, G.; Desai, A.; Patnaik, S.; Marugan, J.; Kim, H.Y. Orphan GPR110 (ADGRF1) targeted by N-docosahexaenoylethanolamine in development of neurons and cognitive function. Nat. Commun. 2016, 7, 13123. [Google Scholar] [CrossRef][Green Version]
  180. Artmann, A.; Petersen, G.; Hellgren, L.I.; Boberg, J.; Skonberg, C.; Nellemann, C.; Hansen, S.H.; Hansen, H.S. Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine. Biochim. Biophys. Acta 2008, 1781, 200–212. [Google Scholar] [CrossRef]
  181. Rossmeisl, M.; Jilkova, Z.M.; Kuda, O.; Jelenik, T.; Medrikova, D.; Stankova, B.; Kristinsson, B.; Haraldsson, G.G.; Svensen, H.; Stoknes, I.; et al. Metabolic effects of n-3 PUFA as phospholipids are superior to triglycerides in mice fed a high-fat diet: Possible role of endocannabinoids. PLoS ONE 2012, 7, e38834. [Google Scholar] [CrossRef][Green Version]
  182. Boorman, E.; Zajkowska, Z.; Ahmed, R.; Pariante, C.M.; Zunszain, P.A. Crosstalk between endocannabinoid and immune systems: A potential dysregulation in depression? Psychopharmacology 2016, 233, 1591–1604. [Google Scholar] [CrossRef][Green Version]
  183. Muller, C.P.; Reichel, M.; Muhle, C.; Rhein, C.; Gulbins, E.; Kornhuber, J. Brain membrane lipids in major depression and anxiety disorders. Biochim. Biophys. Acta 2015, 1851, 1052–1065. [Google Scholar] [CrossRef][Green Version]
  184. Gorjao, R.; Azevedo-Martins, A.K.; Rodrigues, H.G.; Abdulkader, F.; Arcisio-Miranda, M.; Procopio, J.; Curi, R. Comparative effects of DHA and EPA on cell function. Pharmacol. Ther. 2009, 122, 56–64. [Google Scholar] [CrossRef] [PubMed]
  185. McMurray, D.N.; Bonilla, D.L.; Chapkin, R.S. n-3 Fatty acids uniquely affect anti-microbial resistance and immune cell plasma membrane organization. Chem. Phys. Lipids 2011, 164, 626–635. [Google Scholar] [CrossRef][Green Version]
  186. Schoeniger, A.; Fuhrmann, H.; Schumann, J. LPS- or Pseudomonas aeruginosa-mediated activation of the macrophage TLR4 signaling cascade depends on membrane lipid composition. PeerJ 2016, 4, e1663. [Google Scholar] [CrossRef][Green Version]
  187. Hellwing, C.; Tigistu-Sahle, F.; Fuhrmann, H.; Kakela, R.; Schumann, J. Lipid composition of membrane microdomains isolated detergent-free from PUFA supplemented RAW264.7 macrophages. J. Cell. Physiol. 2018, 233, 2602–2612. [Google Scholar] [CrossRef] [PubMed]
  188. Tang, H.L.; Zhang, G.; Ji, N.N.; Du, L.; Chen, B.B.; Hua, R.; Zhang, Y.M. Toll-Like Receptor 4 in Paraventricular Nucleus Mediates Visceral Hypersensitivity Induced by Maternal Separation. Front. Pharmacol. 2017, 8, 309. [Google Scholar] [CrossRef][Green Version]
  189. Liscovitch, M. Crosstalk among multiple signal-activated phospholipases. Trends Biochem. Sci. 1992, 17, 393–399. [Google Scholar] [CrossRef]
  190. Law, M.H.; Cotton, R.G.; Berger, G.E. The role of phospholipases A2 in schizophrenia. Mol. Psychiatry 2006, 11, 547–556. [Google Scholar] [CrossRef][Green Version]
  191. Basselin, M.; Rosa, A.O.; Ramadan, E.; Cheon, Y.; Chang, L.; Chen, M.; Greenstein, D.; Wohltmann, M.; Turk, J.; Rapoport, S.I. Imaging decreased brain docosahexaenoic acid metabolism and signaling in iPLA(2)beta (VIA)-deficient mice. J. Lipid Res. 2010, 51, 3166–3173. [Google Scholar] [CrossRef] [PubMed][Green Version]
  192. Birbes, H.; Pageaux, J.F.; Fayard, J.M.; Lagarde, M.; Laugier, C. Protein kinase C inhibitors stimulate arachidonic and docosahexaenoic acids release from uterine stromal cells through a Ca2+-independent pathway. FEBS Lett. 1998, 432, 219–224. [Google Scholar] [CrossRef][Green Version]
  193. McNamara, R.K.; Carlson, S.E. Role of omega-3 fatty acids in brain development and function: Potential implications for the pathogenesis and prevention of psychopathology. Prostaglandins Leukot. Essent. Fatty Acids 2006, 75, 329–349. [Google Scholar] [CrossRef] [PubMed]
  194. Bazinet, R.P.; Laye, S. Polyunsaturated fatty acids and their metabolites in brain function and disease. Nat. Rev. Neurosci. 2014, 15, 771–785. [Google Scholar] [CrossRef] [PubMed]
  195. Su, K.P.; Yang, H.T.; Chang, J.P.; Shih, Y.H.; Guu, T.W.; Kumaran, S.S.; Galecki, P.; Walczewska, A.; Pariante, C.M. Eicosapentaenoic and docosahexaenoic acids have different effects on peripheral phospholipase A2 gene expressions in acute depressed patients. Prog. Neuropsychopharmacol. Biol. Psychiatry 2018, 80, 227–233. [Google Scholar] [CrossRef][Green Version]
  196. Fordsmann, J.C.; Ko, R.W.; Choi, H.B.; Thomsen, K.; Witgen, B.M.; Mathiesen, C.; Lonstrup, M.; Piilgaard, H.; MacVicar, B.A.; Lauritzen, M. Increased 20-HETE synthesis explains reduced cerebral blood flow but not impaired neurovascular coupling after cortical spreading depression in rat cerebral cortex. J. Neurosci. 2013, 33, 2562–2570. [Google Scholar] [CrossRef][Green Version]
  197. Song, C.; Zhang, X.Y.; Manku, M. Increased phospholipase A2 activity and inflammatory response but decreased nerve growth factor expression in the olfactory bulbectomized rat model of depression: Effects of chronic ethyl-eicosapentaenoate treatment. J. Neurosci. 2009, 29, 14–22. [Google Scholar] [CrossRef][Green Version]
  198. Chen, C.T.; Domenichiello, A.F.; Trepanier, M.O.; Liu, Z.; Masoodi, M.; Bazinet, R.P. The low levels of eicosapentaenoic acid in rat brain phospholipids are maintained via multiple redundant mechanisms. J. Lipid Res. 2013, 54, 2410–2422. [Google Scholar] [CrossRef][Green Version]
  199. Lee, C.H.; Hajra, A.K. Molecular species of diacylglycerols and phosphoglycerides and the postmortem changes in the molecular species of diacylglycerols in rat brains. J. Neurochem. 1991, 56, 370–379. [Google Scholar] [CrossRef][Green Version]
  200. Soderberg, M.; Edlund, C.; Kristensson, K.; Dallner, G. Fatty acid composition of brain phospholipids in aging and in Alzheimer’s disease. Lipids 1991, 26, 421–425. [Google Scholar] [CrossRef]
  201. Tanaka, T.; Iwawaki, D.; Sakamoto, M.; Takai, Y.; Morishige, J.; Murakami, K.; Satouchi, K. Mechanisms of accumulation of arachidonate in phosphatidylinositol in yellowtail. A comparative study of acylation systems of phospholipids in rat and the fish species Seriola quinqueradiata. Eur. J. Biochem. 2003, 270, 1466–1473. [Google Scholar] [CrossRef] [PubMed]
  202. Kew, S.; Mesa, M.D.; Tricon, S.; Buckley, R.; Minihane, A.M.; Yaqoob, P. Effects of oils rich in eicosapentaenoic and docosahexaenoic acids on immune cell composition and function in healthy humans. Am. J. Clin. Nutr. 2004, 79, 674–681. [Google Scholar] [CrossRef] [PubMed]
  203. Arterburn, L.M.; Hall, E.B.; Oken, H. Distribution, interconversion, and dose response of n-3 fatty acids in humans. Am. J. Clin. Nutr. 2006, 83, 1467S–1476S. [Google Scholar] [CrossRef] [PubMed]
  204. Kaur, G.; Cameron-Smith, D.; Garg, M.; Sinclair, A.J. Docosapentaenoic acid (22:5n-3): A review of its biological effects. Prog. Lipid Res. 2011, 50, 28–34. [Google Scholar] [CrossRef] [PubMed][Green Version]
  205. DeMar, J.C., Jr.; Ma, K.; Bell, J.M.; Rapoport, S.I. Half-lives of docosahexaenoic acid in rat brain phospholipids are prolonged by 15 weeks of nutritional deprivation of n-3 polyunsaturated fatty acids. J. Neurochem. 2004, 91, 1125–1137. [Google Scholar] [CrossRef]
  206. Liu, J.J.; Green, P.; John Mann, J.; Rapoport, S.I.; Sublette, M.E. Pathways of polyunsaturated fatty acid utilization: Implications for brain function in neuropsychiatric health and disease. Brain Res. 2015, 1597, 220–246. [Google Scholar] [CrossRef][Green Version]
  207. Recchiuti, A. Resolvin D1 and its GPCRs in resolution circuits of inflammation. Prostaglandins Lipid Mediat. 2013, 107, 64–76. [Google Scholar] [CrossRef]
  208. Pawar, A.; Jump, D.B. Unsaturated fatty acid regulation of peroxisome proliferator-activated receptor alpha activity in rat primary hepatocytes. J. Biol. Chem. 2003, 278, 35931–35939. [Google Scholar] [CrossRef][Green Version]
  209. Mozaffarian, D.; Wu, J.H. (n-3) fatty acids and cardiovascular health: Are effects of EPA and DHA shared or complementary? J. Nutr. 2012, 142, 614S–625S. [Google Scholar] [CrossRef][Green Version]
  210. Di Marzo, V. New approaches and challenges to targeting the endocannabinoid system. Nat. Rev. Drug Discov. 2018, 17, 623–639. [Google Scholar] [CrossRef]
  211. Correa, F.; Hernangomez, M.; Mestre, L.; Loria, F.; Spagnolo, A.; Docagne, F.; Di Marzo, V.; Guaza, C. Anandamide enhances IL-10 production in activated microglia by targeting CB(2) receptors: Roles of ERK1/2, JNK, and NF-kappaB. Glia 2010, 58, 135–147. [Google Scholar] [CrossRef] [PubMed]
Figure 1. Omega-3/omega-6 PUFA pathways and their bioactive lipid metabolites.
Figure 1. Omega-3/omega-6 PUFA pathways and their bioactive lipid metabolites.
Ijms 22 04393 g001
Table 1. Omega-3 RCTs in depression.
Table 1. Omega-3 RCTs in depression.
Major depressive disorders (MDD)[32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59]
Depressive episodes in bipolar affective disorders[60,61,62,63,64,65,66,67]
Depression during or post pregnancy[68,69,70]
Depression in non-MDD mood disorders (e.g., premenstrual syndrome, dysthymia)[31,45,49,71,72,73]
Depression in other psychiatric conditions (e.g., borderline personality, self-harm, OCD)[74,75,76,77,78]
Depression in established schizophrenia[79,80,81]
Depression in Alzheimer’s dementia/mild cognitive impairment[46,82,83]
Depression in Parkinson’s disease[84]
Depression in medical conditions (cerebrovascular and metabolic diseases or cancer)[85,86,87,88,89]
Depressive features in healthy individuals[90,91,92,93,94,95,96]
Abbreviations: RCT: randomized controlled trial; OCD: obsessive-compulsive disorder.
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Kalkman, H.O.; Hersberger, M.; Walitza, S.; Berger, G.E. Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature. Int. J. Mol. Sci. 2021, 22, 4393.

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Kalkman HO, Hersberger M, Walitza S, Berger GE. Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature. International Journal of Molecular Sciences. 2021; 22(9):4393.

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Kalkman, Hans O., Martin Hersberger, Suzanne Walitza, and Gregor E. Berger. 2021. "Disentangling the Molecular Mechanisms of the Antidepressant Activity of Omega-3 Polyunsaturated Fatty Acid: A Comprehensive Review of the Literature" International Journal of Molecular Sciences 22, no. 9: 4393.

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