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

Abstract

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.

Review of the Midbrain Ascending Arousal Network Nuclei and Implications for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), Gulf War Illness (GWI) and Postexertional Malaise (PEM)

“…In contrast, cluster headaches, which are uncommon in ME/CFS and GWI, may be interpreted as exteroceptive pain with the arousal of sympathetic fight-flight reactions, motor agitation, and restlessness. The molecular mechanisms of sickness behaviors are complex but may involve IL6, IL1-beta, INF-alpha, and other cytokines as well as modulation of arachidonic acid cytochrome P450 metabolites and phosphatidylinositol derivatives by eicosapentaenoic acid (EPA) and effects on cannabinoid CB2 receptors [ 135 , 136 , 137 , 138 ]. EPA may have some benefits for treating anxiety [ 139 ] and PTSD [ 140 , 141 ] but has small non-clinical effects compared to placebo in depression [ 142 ].…”

Biological Role of Nutrients, Food and Dietary Patterns in the Prevention and Clinical Management of Major Depressive Disorder

“…Fish and especially oily fishes as well as fish oil are rich in ω-3 PUFA, particularly docosahexaenoic acid (DHA; 22:6 ω-3) and eicosapentaenoic acid (EPA; 20:5 ω-3), proving multiple antidepressant effects [ 79 ]. Despite DHA and EPA sharing multiple biological actions, there are some disparities in their molecular activities explaining their differential role as antidepressants [ 80 ]. A meta-analysis of randomized control trials claimed that EPA, but not DHA, was responsible for the most antidepressant effects of ꞷ-3 PUFA [ 81 ].…”

Exploring the Role of Nutraceuticals in Major Depressive Disorder (MDD): Rationale, State of the Art and Future Prospects

“…Kalkman et al [ 97 ] checked that EPA also denotes more antidepressant effects because its lipid metabolites have endocannabinoid behavior now that they find affinity in cannabinoid receptor-2 (CB2). These derived metabolites imply effects on immunomodulation, neuroinflammation, food intake and mood.…”