« Go back to issue 48(2) summary

Diet and depressive disorders

Mariane Lutz1, Camila Vargas1, Jana Stojanova1, Marcelo Arancibia1,2

1 Center of Interdisciplinary Studies in Health - CIESAL and Faculty of Medicine, Universidad de Valparaiso, Valparaiso, Chile

2 Grupo de Investigación en Resiliencia, Adversidad y Reparación (GIRAR), CIESAL and Faculty of Medicine, Universidad de Valparaiso, Valparaiso, Chile

 

Received: 26/11/2019 – Accepted: 07/08/2020

DOI: 10.15761/0101-60830000000290

Abstract

Background: The importance of foods or food constituents in mental health is increasingly recognized, and “nutritional psychiatry” is a growing discipline. Objective: This narrative review aims to present work supporting associations between food or food constituents and mental health, specifically depressive disorders. Methods: The data presented is derived from preclinical and clinical work, including in vitro and in vivo assays, as well as observational studies and randomized clinical trials of dietary interventions. The focus of the review is the mediation of inflammatory processes and oxidative stress by dietary constituents that are an integral part of a healthy diet, such as the Mediterranean diet and similar. Results and Discussion: We present evidence for the role of the diet in prevention and management of depressive disorders, beyond the effect of individual nutrients. The findings indicate that among the dietary components with higher degree of evidence to influence depressive disorders are long chain n-3 polyunsaturated fatty acids (EPA and DHA), and various dietary bioactive compounds, especially plant-derived secondary metabolites represented by polyphenols such as flavonoids and resveratrol. Conclusion: Diet exerts an important role on mental health, and evidence indicates that some dietary constituents contribute to the prevention of depressive disorders.

Lutz M / Arch Clin Psychiatry. 2021;48(2):117-122

Keywords

Diet; Mental health; Depressive disorders; Phenolic compounds; Polyunsaturated fatty acids

Introduction

In ancient Greece, medical treatises already pointed to the dietary intake of fruits, vegetables, nuts, herbs and spices as prescriptions to relieve various ailments at a time when boundaries between the categories ‘drugs’ and ‘foods’ were diffuse [1]. Based on this knowledge, Islamic medicine emphasized the influence of mind states and emotions on the genesis of numerous illnesses, proposing diet as the primary means for healing and recuperating the body’s equilibrium [2]. The study of the potential impact of an adequate diet on the brain has advanced to the degree that “nutritional psychiatry” has emerged as a research field in its own right [3]. It focuses on the intake of dietary constituents and their effect on mood alterations, mainly depressive disorders (DD) and anxiety disorders [4-6]. Numerous antidepressants are widely available [7] and have an important therapeutic role. However, they cannot ameliorate the spectrum of alterations that occur in DD and are unlikely to be a long-term solution over a lifetime. Further, there are individuals for whom antidepressants are not an option due to troubling side-effects, or therapeutic failure.

DD are common, recurrent disorders, affecting over 300 million people worldwide [8]. Lifestyle choices may constitute an alternative to manage DD, offering an option for individuals that are unable to access to pharmacological therapy or psychotherapy, as well as for those exhibiting mild disorders [9]. Indeed, healthy lifestyle habits should be considered in any medical prescription. Diet is a major environmental health determinant that is susceptible to being modified. Adequate nutrition in all age stages exerts fundamental roles in mental health, since the brain requires macro- and micronutrients to function optimally [10-13]. Inadequate nutrition may augment the risk of developing mood and cognitive alterations by affecting physiological processes including levels of neurotransmitters, function of cell membranes and function of vascular tissue, among others [14]. Although relationships between diet and the development of mood impairment may occur in different scenarios, in the present review we will focus on those affecting inflammatory processes and oxidative stress, as well as the effect of gut microbiota.

Diet and the Central Nervous System

Among the most studied dietary components associated with neurodevelopment, brain function and its impact on DD and anxiety are classical nutrients (tryptophan [15]), certain vitamins (B12 and folic acid [16-18], D [19]), minerals (magnesium [20], zinc [21,22]), taurine [23], and fatty acids [24-26]). More recently, the list has included bioactive compounds that are not necessarily categorized as nutrients, such as phenolic compounds.

Healthy Diet

A major behavioral factor for men and women that exerts a protective effect on mental health is intake of fruits and vegetables [27]. The Mediterranean Diet (MedD) is recognized to have numerous health properties, and is characterized by abundant plant-derived foods (e.g. fruits, vegetables, pulses, whole grains, nuts, extra virgin olive oil), moderate intake of fish, poultry, dairy, and a low intake of red meats, refined grains, sugar and processed products. This diet supplies a variety of bioactive compounds, such as polyphenols, carotenoids, sulfur compounds, phytosterols, terpenes, among others, many of which exhibit antioxidant activity. Intake of these food constituents has been associated, among various physiological effects, with optimism in adults [28-30]. With regard to mental health, the MedD is a dietary pattern that has been associated with reduced incidence of Alzheimer disease, cognitive impairment and depression compared to a Western diet [31-41]. The latter is characterized by a high content of saturated fats and n-6 polyunsaturated fatty acids (PUFA), meats and processed foods. Indeed, the intake of processed foods has been associated with DD in observational studies [42]. Opie et al. [43] recommend following a “traditional” dietary pattern (e.g. MedD, Norwegian or Japanese) that favors natural and local produce, and limits intake of processed, convenience and ready-to-eat products, among others, considered non-healthy. The MedD contains a variety of tree nuts (walnuts, almonds, pistachios, pine nuts, Brazil nuts, among others), characterized as healthy due to their macronutrient (fats, proteins with a high proportion of arginine) and micronutrient (minerals, vitamins) content, while also supplying various bioactive phytochemicals with a potential beneficial effect on brain function (phenolic acids, flavonoids, stilbenes, isoflavones, lignans, tannins, proanthocyanidines, carotenoids, alkaloids, cumestans, phytates, among others [10,44,45]).

Phenolic Compounds

A healthy diet supplies a myriad of phenolic compounds (PC) that may affect neural function in multiple ways [46]. PC are capable of interacting with intracellular and glial signaling pathways; they modulate brain flux, protect against neurotoxins and neuroinflammation [47,48]. Some neural cells possess PC, GABA [49,50] and opioid receptors [51,52], which may activate pathways related to plasticity and the synthesis of new synaptic routes. Numerous PC have been assayed in preclinical studies for their potential roles as antidepressants [53-55].

Resveratrol (3,4,5-trihydroxy-trans-stilbene) is a widely studied PC found in red/black grapes, peanuts, and derivatives that exhibits pleiotropic actions [56,57]. In preclinical models, resveratrol exerts anti-inflammatory, antioxidant, anti-polimerizing action on amyloid beta, and modulates the action of various molecular effectors that participate in neuronal survival and death, among others [50,58,60,61]. As an anti-inflammatory agent, resveratrol dampens the expression of inflammatory mediators (e.g. receptors RTL4 [62], ATP/P2X7 [63]; cyclooxygenases COX-1, COX-2; and cytokines including TNFα). It is able to influence expression of intracellular mediators such as SIRT-1 [64,65], AMPK [66], and eNOS [67,68], ultimately impacting transcription factors, including NF-κB. Other effects related to the inflammatory response includereduced synthesis of endothelin-1, a potent vasoconstrictor [69].

PC are generally recognized as antioxidants that primarily act by augmenting the activity of antioxidant enzymes including catalase, glutathione peroxidase, and superoxide dismutase [70-72]. In a chronic stress model primarily designed to investigate antioxidant effects of trans-resveratrol, Yu et al. [73] observed an increment of monoamine neurotransmitters (serotonin, noradrenaline and dopamine) that the authors attribute to inhibition of oxidation induced by monoamine-oxidases. Further, Fahim et al. [74] demonstrated that resveratrol reverted depression associated with testicular dysfunction in rats, likewise related to diminished oxidative stress, inflammation and apoptosis, but also, ultimately, restitution of testicular function and increase of testosterone levels.

There are many examples of PC with potential to exert beneficial effects on mental health. An outstanding example is quercetin, a flavonoid abundant in a variety of fruits and vegetables (e.g. apples and onions). In addition to exerting classical antioxidant effects attributed generally to PC, quercetin can activate the transcription factor Nrf2, which regulates the expression of endogenous antioxidant proteins [75], and can augment the production of heme oxygenase-1, which is also an antioxidant [76]. Another example, frequently promoted in health claims, is that of flavonoid polyphenols derived from cocoa that are present in high amounts in dark chocolate. These PC exhibit high antioxidant and anti-inflammatory properties [77], and have been shown to exert beneficial effects by preventing neurodegeneration and mood impairment [78]. Jackson et al. [79] analyzed the US National Health and Nutrition Examination Survey (NHANES) data of dietary intake during 2007-2008 and 2013-2014, observing that dark chocolate intake associated with reduced depressive symptoms.

Despite the growing body of evidence supporting the potential effects of PC on neuroprotection, there remains a lack of randomized clinical trials to substantiate these primarily preclinical findings.

Polyunsaturated Fatty Acids

The availability of dietary fatty acids is fundamental for growth, development, and maintenance of the nervous system, particularly long chain polyunsaturated fatty acids (LCPUFA) belonging to both n-3 family (derived from a-linolenic acid [ALA, 18:3n-3]) and n-6 family (derived from linoleic acid [AL, 18:2n-6]). Of particular relevance for neuroprotection are n-3 eicosapentaenoic acid [EPA, 20:5n-3] and docosahexaenoic acid [DHA, 22:6n-3], primarily found in fatty fish and seafood [80,81]. The MedD supplies ALA through seeds and nuts, and encourages consumption of seafood [82]. Indeed, low dietary intake of foods supplying LCPUFA has been associated with DD [83,84].

EPA and DHA incorporate in phospholipids and cholesterol esters embedded in neuronal membranes [85], including myelin and synaptosomes [86], with high amounts of DHA, in particular, in the synaptic, mitochondrial and endoplasmic membranes. Both participate directly in synaptogenesis and synaptic functions, activation of ion channels, modulation of cell signaling mechanisms, including dopaminergic and serotoninergic pathways, neural cell development and remodeling [87-90]. Non-esterified DHA participates in cognition and visual processes [91], through the regulation of gene expression [92].

In their systematic review and meta-analysis, Goldsmith et al. [93] confirm that severe mental illnesses, including major DD and schizophrenia, are associated with higher levels of inflammatory peripheral and systemic biomarkers. DHA modulates inflammation by acting on a variety of transcription factors involved in metabolic pathways [94-96]. Further, EPA and DHA are precursors for a variety of molecules with potent anti-inflammatory effect, including resolvins and neuroprotectins [97-99]. The multiplicity of roles on brain function has led to work evaluating DHA supplementation on neuropsychiatric disorders, including DD, as well as age-related diseases such as Alzheimer’s [100-103]. Numerous studies of diverse epidemiological designs, including randomized controlled trials, support the intake of EPA and DHA to improve mood disorders, among which DD predominates [104-107]. There is currently clinical evidence that n-3 LCPUFA may reduce symptoms of DD [108-113]. Interest on the subject is rapidly rising, as evidenced by a recent increment in research on the topic. Initial clinical trials have evaluated dietary LCPUFA intake with severe DD [114-116] and systematic reviews of observational studies, some with controversial results [117-121], indicate that LCPUFA may exert at least a preventive effect, and might even have a therapeutic role in severe DD [122]. Whether this is definitively attributable to reduction of inflammation is not established [123].

Gut Microbiota

Obesity is highly prevalent in the population globally, and is bidirectionally associated with DD [124,125], with an inflammatory component underlying both pathologies [126], and obesity-associated neuroinflammatory processes have been described [127]. The gut microbiota–brain axis has emerged as a major determinant for the modulation of obesity [128] as well as cognition and behavior [129], including social behaviors and managing stress [130]. Depletion of the microbiota profoundly alters the underlying [130]. Among recent evidence, Huang et al. [131] describe a significant shift of microbial diversity in patients with DD compared to healthy individuals, exhibiting a higher content of pro-inflammatory bacterial genera. In DD, as in all stress-related disorders, hypothalamic-pituitary-adrenal alterations are common, including elevated plasma cortisol, elevated corticotropin releasing factor levels in cerebrospinal fluid and high concentrations of pro-inflammatory cytokines [132]. The persistence of low-grade immune-inflammatory processes are an integral part of the pathophysiology of DD [133], and the role of the gut microbiota-brain axis in these pathophysiological mechanisms is increasingly recognized [134]. Studies involving the manipulation of gut microbiota with probiotics for the prevention and treatment of DD and associated comorbidities are being profusely published [135]; however, the topic is beyond the scope of the present review.

Conclusion

This review addresses the increasing recognition of the relationship between diet and mood disorders, mainly depression. DD affect individuals of all age groups worldwide, and the medical community is increasingly recognizing that the approach to this illness should be more holistic, in contrast to current strategies based primarily on pharmacotherapy. We present evidence for the role of the diet in prevention and management, beyond the effect of individual nutrients. Increasing evidence indicates that dietary constituents exerting beneficial effects on DD include various bioactive compounds with antioxidant and anti-inflammatory effects, including phenolic compounds, and n-3 fatty acids, namely EPA and DHA. These are an integral part of a healthy diet, exemplified by the MedD and similar. The role of the gut-brain axis is briefly covered, though it is noteworthy that healthy diets include constituents that positively affect the amount and diversity of intestinal microbiota; this is an additional argument to emphasize the importance of adequately choosing the foods we eat.

Disclosure Statement

The authors have no conflicts of interest to declare.

Funding Sources

This research received no external funding.

References

  1. Totelin L. When foods become remedies in ancient Greece: The curious case of garlic and other substances. J Ethnopharmacol 2015;167:30-7.
  2. Carnevali R, Masillo A. Brief history of psychiatry in the Islamic world. J Int Soc Hist Islamic Med 2007;6:97–101.
  3. Jacka FN. Nutritional Psychiatry: Where to Next? EBioMed 2017;17:24–9.
  4. Murakami K, Sasaki S. Dietary intake and depressive symptoms: a systematic review of observational studies. Mol Nutr Food Res 2010;54:471-88.
  5. Sánchez-Villegas A, Martínez-González MA. Diet, a new target to prevent depression? BMC Med 2013;11:3.
  6. Opie RS, O’Neil A, Itsiopoulos C, Jacka FN. The impact of whole-of-diet interventions on depression and anxiety: a systematic review of randomised controlled trials. Public Health Nutr 2015;18:2047–209.
  7. Chávez-Castillo M, Núñez V, Nava M, Ortega A, Rojas M, Bermudez V, et al. Depression as a neuroendocrine disorder: Emerging neuropsychopharmacological approaches beyond monoamines. Adv Pharmacol Sci 2019;2019:201.
  8. World Health Organization, WHO: Depression and Other Common Mental Disorders, Global Health Estimates. Publication WHO/MSD/MER/2017.2, Geneve, 2017.
  9. García-Toro M, Ibarra O, Gili M, Serrano MJ, Oliván B, Vicens E, et al. Four hygienic– dietary recommendations as add-on treatment in depression: a randomized-controlled trial. J Affect Disord 2012;140:200–3.
  10. Gómez-Pinilla F. Brain foods: the effects of nutrients on brain function. Nature 2008;9:568-78.
  11. Goyal MS, Iannotti LL, Raichle ME. Brain Nutrition: A life span approach. Annu Rev Nutr 2018;38:381–99.
  12. Moore K, Hughes CF, Ward M, Hoey L, McNulty H. Diet, nutrition and the ageing brain: current evidence and new directions. Proc Nutr Soc 2018;77:152-63.
  13. Harbottle L. The effect of nutrition on older people’s mental health. Brit J Commun Nurs 2019;24(Suppl 7):S12-6.
  14. Jacka FN, Pasco JA, Mykletun A, Williams LJ, Hodge AM, O’Reilly SL, et al. Association of Western and traditional diets with depression and anxiety in women. Am J Psychiatry 2010;167:305–11.
  15. Shaw K, Turner J, Del Mar C. Are tryptophan and 5-hydroxytryptophan effective treatments for depression? A meta-analysis.  Aust N Z J Psych 2002;36:488-91.
  16. Sachdev PS, Parslow RA, Lux O, Salonikas C, Wen W, Naidoo D, et al. Relationship of homocysteine, folic acid and vitamin B12 with depression in a middle-aged community sample. Psychol Med 2005;35:529-38.
  17. Sánchez-Villegas A, Doreste J, Schlatter J, Pla J, Bes-Rastrollo M, Martínez-González MA. Association between folate, vitamin B(6) and vitamin B(12) intake and depression in the SUN cohort study. J Hum Nutr Diet 2009;22:122–33.
  18. Skarupski KA, Tangney C, Li H, Ouyang B, Evans DA, Morris MC. Longitudinal association of vitamin B-6, folate, and vitamin B-12 with depressive symptoms among older adults over time. Am J Clin Nutr 2010;92:330-5.
  19. Cuomo A, Giordano N, Goracci A, Fagiolini A. Depression and vitamin D deficiency: Causality, assessment, and clinical practice implications. Neuropsychiatry (London) 2012;7:606–14.
  20. Derom ML, Sayon-Orea C, Martinez-Ortega JM, Martinez-Gonzalez MA. Magnesium and depression: a systematic review. Nutr Neurosci 2013;16:191-206.
  21. Yari T, Aazami S. Dietary intake of zinc was inversely associated with depression. Biol Trace Elem Res 2012;145:286-90.
  22. Lai J, Moxey A, Nowak G, Vashum K, Bailey K, McEvoy M. The efficacy of zinc supplementation in depression: systematic review of randomised controlled trials. J Affect Disord 2012;136:e31–9.
  23. Jakaria M, Azam S, Haque E, Jo S-H, Uddin S, Kim I-S, et al. Taurine and its analogs in neurological disorders: Focus on therapeutic potential and molecular mechanisms. Redox Biol 2019;24:101223.
  24. McNamara RK, Carlson SE. Role of omega-3 fatty acids in brain development and function: potential implications for the pathogenesis and prevention of psychopathology. Prostagl Leukot Essent Fatty Acids 2006;75:329–49.
  25. Hibbeln JR. Depression, suicide and deficiencies of omega-3 essential fatty acids in modern diets. World Rev Nutr Diet 2009;99:17-30.
  26. Payne M. Nutrition and late-life depression: etiological considerations. Aging Health 2010;6:133–43.
  27. Rooney C, McKinley MC, Woodside JV. The potential role of fruit and vegetables in aspects of psychological well-being: a review of the literature and future directions. Proc Nutr Soc 2013;72:420–32.
  28. White BA, Horwath CC, Conner TS. Many apples a day keep the blues away—daily experiences of negative and positive affect and food consumption in young adults. Br J Health Psychol 2013;18:782–98.
  29. Blanchflower DG, Oswald AJ, Stewart-Brown S. Is psychological wellbeing linked to the consumption of fruit and vegetables? Soc Indic Res 2013;114:785–801.
  30. Boehm JK, Williams DR, Rimm EB, Ryff C, Kubzansky LD. Association between optimism and serum antioxidants in the midlife in the United States study. Psychosom Med 2013;75:2–10.
  31. Scarmeas N, Stern Y, Tang MX, Mayeux R, Luchsinger JA. Mediterranean diet and risk for Alzheimer’s disease. Ann Neurol 2006;6:912–21.
  32. Valls-Pedret C, Lamuela-Raventós RM, Medina-Remón A, Quintana M, Corella D, Pintó X, et al. Polyphenol-rich foods in the Mediterranean diet are associated with better cognitive function in elderly subjects at high cardiovascular risk. J Alzheimers Dis 2012;29:773Y782.
  33. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N. Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol 2013;74:580–91.
  34. Skarupski KA, Tangney CC, Li H, Evansm DA, Morris MC. Mediterranean diet and depressive symptoms among older adults over time. J Nutr Health Aging 2013;17:441–5.
  35. Trichopoulou A, Kyrozis A, Rossi M, Katsoulis M, Trichopoulos D, La Vecchia C, et al. Mediterranean diet and cognitive decline over time in an elderly Mediterranean population. Eur J Nutr 2015;54:1311Y1321.
  36. Baumgart M, Snyderm HM, Carrillo MC, Fazio S, Kim H, Johns H. Summary of the evidence on modifiable risk factors for cognitive decline and dementia: a population-based perspective. Alzheimers Dement 2015;11:718–26.
  37. Valls-Pedret C, Sala-Vila A, Serra-Mir M, Corella D, de la Torre R, Martínez-González MÁ, et al.  Mediterranean diet and age-related cognitive decline: a randomized clinical trial. JAMA Intern Med 2015;175:1094– 103.
  38. Khalid S, Williams CM, Reynolds SA. Is there an association between diet and depression in children and adolescents? A systematic review. Br J Nutr. 2016;116:2097-108.
  39. Li Y, Lv MR, Wei YJ, Sun L, Zhang JX, Zhang HG, et al. Dietary patterns and depression risk: A meta-analysis. Psychiatry Res 2017;253:373-82.
  40. Wu L, Sun D. Adherence to Mediterranean diet and risk of developing cognitive disorders: an updated systematic review and meta-analysis of prospective cohort studies. Sci Rep 2017;7:41317.
  41. Molendijk M, Molero P, Ortuno Sanchez‐Pedreno F, Van der Does W, Martinez‐Gonzalez MA. Diet quality and depression risk: A systematic review and dose‐response meta‐analysis of prospective studies. J Affective Dis 2018;226:346–54.
  42. Rosso G, Estruch R. Nut consumption and age-related disease. Maturitas 2016;84:11–6.
  43. Opie R, Itsiopoulos C, Parletta N, Sanchez-Villegas A, Akbaraly TN, Ruusunen A, et al. Dietary recommendations for the prevention of depression. Nutr Neurosci 2017;20:161-71.
  44. Alasalvar C, Shahidi F. Tree Nuts: Composition, Phytochemicals, and Health Effects. In Alasalvar C, Shahidi F (Eds.) CRC Press, Boca Raton, FL, USA, 2008.
  45. Gorji N, Moeini R, Memariani Z. Almond, hazelnut and walnut, three nuts for neuroprotection in Alzheimer’s disease: A neuropharmacological review of their bioactive constituents. Pharmacol Res 2018;129:115-27.
  46. Lamport DJ, Saunders C, Butler LT, Spencer JPE. Fruits, vegetables, 100% juices, and cognitive function. Nutr Rev. 2014;72:774–89.
  47. Spencer JPE. The impact of flavonoids on memory: physiological and molecular considerations. Chem Soc Rev 2009;38:1152–61.
  48. Fraga CG, Galleano M, Verstraeten SV, Oteiza PI. Basic biochemical mechanisms behind health benefits of polyphenols. Mol Aspects Med 2010;31:435–45.
  49. Adachi N, Tomonaga S, Tachibana T, Denbow DM, Furuse M. (−)-Epigallocatechin gallate attenuates acute stress response through GABAergic system in the brain. Eur J Pharmacol 2006;531:171–5.
  50. Hanrahan JR, Chebib M, Johnston GAR. Flavonoid modulation of GABA(A) receptors. Br J Pharmacol 2011;163:234–45.
  51. Katavic PL, Lamb K, Navarro H, Prisinzano TE. Flavonoids as opioid receptor ligands: identification and preliminary structure-activity relationships. J Nat Prod 2007;70:1278–82.
  52. Panneerselvam M, Tsutsumi YM, Bonds JA, Horikawa YT, Saldana M, Dalton ND, et al. Dark chocolate receptors: epicatechin-induced cardiac protection is dependent on delta-opioid receptor stimulation. Am J Physiol Heart Circ Physiol 2010;299:H1604–9.
  53. Ebrahimi A, Schluesener H. Natural polyphenols against neurodegenerative disorders: potentials and pitfalls. Ageing Res Rev. 2012;11:329–45.
  54. Pathak L, Agrawal Y, Dhir A. Natural polyphenols in the management of major depression. Exp Opin Investig Drugs 2013;22:863–80.
  55. Godos J, Castellano S, Ray S, Grosso G, Galvano F. Dietary polyphenol intake and depression: Results from the Mediterranean healthy eating, lifestyle and aging (MEAL) study. Molecules 2018;23:1–15.
  56. Xu Y, Wang Z, You W, Zhang X, Li S, Barish PA, et al. Antidepressant-like effect of trans-resveratrol: Involvement of serotonin and noradrenaline system. Eur Neuropsychopharmacol 2010;20:405–13.
  57. Ogle WO, Speisman RB, Ormerod BK. Potential of treating age-related depression and cognitive decline with nutraceutical approaches: a mini-review. Gerontology 2013;59:23–31.
  58. Bastianetto S, Ménard C, Quirion R. Neuroprotective action of resveratrol. Biochem Biophys Acta 2015;1852:1195-201.
  59. Moller Poulsen M, Fjeldborg K, Ornstrup MJ, Nordstrøm Kjær TN, Nøhr MK, Bønløkke Pedersen S. Resveratrol and inflammation: Challenges in translating pre-clinical findings to improved patient outcomes. Biochem Biophys Acta 2015;1852:1124–36.
  60. Kuršvietienė L, Stanevičienė I, Mongirdienė A, Bernatonienė J. Multiplicity of effects and health benefits of resveratrol. Medicina 2016;52:148 – 55.
  61. Rahimifard M, Maqbool F, Moeini-Nodeh S, Niaz K, Abdollahi M, Braidy N, et al. Targeting the TLR4 signaling pathway by polyphenols: A novel therapeutic strategy for neuroinflammation. Ageing Res Rev 2017;36:11–9.
  62. Nuka E, Ohnishi K, Terao J, Kawai Y. ATP/P2X7 receptor signaling as a potential anti-inflammatory target of natural polyphenols. PLoS One 2018;13:1–19.
  63. Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem 2009;110:1445-56.
  64. Alcaín FJ, Villalba JM. Sirtuin activators. Exp Op Therap Patents 2009;19:403-14.
  65. Baur JA, Pearson KJ, Price NL, Jamieson HA, Lerin C, Kalra A, et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature 2006;444:337–42.
  66. Dasgupta B, Milbrandt J. Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci USA 2007;104:7217–22.
  67. Xia N, Forstermann U, Li H. Resveratrol and endothelial nitric oxide. Molecules 2014;19:16102–21.
  68. Xia N, Forstermann U, Li H. Effects of resveratrol on eNOS in the endothelium and the perivascular adipose tissue. Ann NY Acad Sci 2017;1403:132–41.
  69. Li H, Xia N, Hasselwander S, Daiber A. Resveratrol and vascular function. Int J Mol Sci 2019;20:2155.
  70. Robb EL, Page MM, Wiens BE, Stuart JA. Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD. Biochem Biophys Res Commun 2008;367:406–12.
  71. Zhang F, Liu J, Shi JS. Anti-inflammatory activities of resveratrol in the brain: Role of resveratrol in microglial activation. Europ J Pharmacol 2010;636:1–7.
  72. Barreca D, Bellocco E, D’Onofrio G, Nabavi SF, Daglia M, Rastrelli L, et al. Neuroprotective effects of quercetin: From chemistry to medicine. CNS Neurol Disord Drug Targets 2016;15: 964–75.
  73. Yu Y, Wang R, Chen C,  Du X, Ruan L, Sun J, et al. Antidepressant-like effect of trans-resveratrol in chronic stress model: Behavioral and neurochemical evidences. J Psychiat Res 2013;47: 315e322.
  74. Fahim AT, Abd El-Fattah AA, Sadik NAH, Ali BM. Resveratrol and dimethyl fumarate ameliorate testicular dysfunction caused by chronic unpredictable mild stress-induced depression in rats. Arch Biochem Biophys 2019;665:152-65.
  75. Granado-Serrano AB, Martin MA, Bravo L, Goya L, Ramos S. Quercetin modulates Nrf2 and glutathione-related defenses in HepG2 cells: Involvement of p38. Chem Biol Interact 2012;195:154–64.
  76. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, et al. Quercetin attenuates inflammatory responses in BV-2 microglial cells: Role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 2015;10:e0141509.
  77. Minihane AM, Vinoy S, Russell WR, Baka A, Roche HM, Tuohy KM, et al. Low‐grade inflammation, diet composition and health: Current research evidence and its translation. Br J Nutr 2015;114:999–1012.
  78. Scholey A, Owen L. Effects of chocolate on cognitive function and mood: A systematic review. Nutr Rev 2013;71: 665–81.
  79. Jackson SE, Smith L, Firth J, Grabovac I, Soysal P, Koyanagi A, et al. Is there a relationship between chocolate consumption and symptoms of depression? A cross-sectional survey of 13,626 US adults. Depress Anxiety DOI 10.1002/da.22950
  80. Hibbeln JR, Salem Jr N. Dietary polyunsaturated fatty acids and depression: when cholesterol does not satisfy. Am J Clin Nutr 1995;62:1–9.
  81. Hibbeln R. Fish consumption and major depression (letter). Lancet 1998;351:1213.
  82. Estruch R. Anti-inflammatory effects of the Mediterranean diet: the experience of the PREDIMED study. Proc Nutr Soc 2010;69:333–40.
  83. Freeman MP, Hibbeln JR, Wisner KL, Davis JM, Mischoulon D, Peet M, et al. Omega-3 fatty acids: evidence basis for treatment and future research in psychiatry. J Clin Psychiatry 2006;67:1954-67. 
  84. Appleton KM, Rogers PJ, Ness AR. Updated systematic review and meta-analysis of the effects of n-3 long-chain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr 2010;91:757–70.
  85. Bourre JM, Dumont O, Piciotti M, Clément M, Chaudière J, Bonneil M, et al. Essentiality of omega 3 fatty acids for brain structure and function. World Rev Nutr Diet 1991;66:103–17.
  86. Lutz M, Durand G. Influence of dietary lipids on fatty acid composition of nervous membranes (myelin and synaptosomes) in rats. Nutr Res 1994;14:1365-73.
  87. Uauy R, Dangour AD. Nutrition in brain development and aging: Role of essential fatty acids. Nutr Rev 2006:64 (Suppl 2):S24–S33.
  88. Kawakita E, Hashimoto M, Shido O. Docosahexaenoic acid promotes neurogenesis in vitro and in vivo. Neuroscience 2006;139:991–7.
  89. Innis SM. Dietary (n-3) Fatty acids and brain development. J Nutr 2007;137:855–9.
  90. Dyall SC. 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.
  91. Weiser MJ, Butt CM, Mohajeri MH. Docosahexaenoic acid and cognition throughout the lifespan. Nutrients 2016;8:99.
  92. Kitajka K, Puskas LG, Zvara A, Hackler L, Jr, Barcelo-Coblijn G, Farkas ST. The role of n-3 fatty polyunsaturated fatty acids in brain: modulation of rat brain gene expression by dietary n-3 fatty acids. Proc Natl Acad Sci USA 2002;99:2619–24.
  93. Goldsmith D, Rapaport M, Miller B. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry 2016;21:1696.
  94. Szanto A, Nagy L. The many faces of PPAR gamma: anti-inflammatory by any means? Immunobiol 2008;213:789–803.
  95. Khorsan R, Crawford C, Ives JA, Walter AR. Jonas WB. The effect of Omega-3 fatty acids on biomarkers of inflammation: A rapid evidence assessment of the literature. Military Med 2014;179(Suppl):2-60.
  96. Marion-Letellier R, Savoye G, Ghosh S. Fatty acids, eicosanoids and PPAR gamma. Eur J Pharmacol 2016;785:44–9.
  97. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal anti-inflammatory drugs and transcellular processing. J Exp Med 2000;192:1197–204.
  98. Calder PC. Polyunsaturated fatty acids and inflammation. Prostagl Leukot Essent Fatty Acids 2006;75:197–202.
  99. Demarquoy J, Le Borgne F. Biosynthesis, metabolism and function of protectins and resolvins. Clin Lipidol 2014;9:683–93.
  100. Liu JJ, Green P, John Mann J, Rapoport SI, Sublette ME. Pathways of polyunsaturated fatty acid utilization: implications for brain function in neuropsychiatric health and disease. Brain Res 2015;1597:220–46.
  101. Saunders EF, Ramsden CE, Sherazy MS, Gelenberg AJ, Davis JM, Rapoport SI. Omega-3 and Omega-6 polyunsaturated fatty acids in bipolar disorder: a review of biomarker and treatment studies. J Clin Psychiatry 2016; 77: e1301-8.
  102. Rapaport MH, Nierenberg AA, Schettler PJ, Kinkead B, Cardoos A, Walker R, et al. Inflammation as a predictive biomarker for response to omega-3 fatty acids in major depressive disorder: a proof-of-concept study. Mol Psychiatry 2016;21:71–9.
  103. Spencer SWJ, Korosi A, Layé S, Shukitt-Hale B, Barrientos RM. Food for thought: how nutrition impacts cognition and emotion. Sci Food 2017;1:7.
  104. Sontrop J, Campbell MK. Omega-3 polyunsaturated fatty acids and depression: a review of the evidence and a methodological critique. Prev Med 2006;42:4–13.
  105. Appleton KM, Woodside JV, Yarnell JW, Arveiler D, Haas B, Amouyel 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;104:217–23.
  106. Sánchez-Villegas A, Henríquez P, Figueiras A. Ortuo F, Lahortiga F, Martínez-González M. Long chain omega-3 fatty acids intake, fish consumption and mental disorders in the SUN cohort study. Eur J Nutr 2007;46:337–46.
  107. Sánchez-Villegas A, Verberne L, De Irala J, Ruız-Canela M, Toledo E, Serra-Majem L, et al. Dietary fat intake and the risk of depression: the SUN project. PLoS One 2011;6:e16268.
  108. Colangelo LA, He K, Whooley MA, Daviglus ML, Liu K. Higher dietary intake of long-chain omega-3 polyunsaturated fatty acids is inversely associated with depressive symptoms in women. Nutrition 2009;25:1011–109.
  109. Lucas M, Mirzaei F, O'Reilly EJ, Pan A, Willett WC, Kawachi I, et al. Dietary intake of n-3 and n-6 fatty acids and the risk of clinical depression in women: a 10-y prospective follow-up study. Am J Clin Nutr 2011;93:1337-43.
  110. Sublette ME, Ellis SP, Geant AL, Mann JJ. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry 2011;72:1577–84.
  111. Muldoon MF, Ryan CM, Yao JK, Conklin SM, Manuck SB. Long-chain omega-3 fatty acids and optimization of cognitive performance. Mil Med 2014;179(11 Suppl):95–105.
  112. Pusceddu MM, Kelly P, Stanton C, Cryan JF, Dinan TG. N-3 Polyunsaturated fatty acids through the lifespan: Implication for psychopathology. Int J Neuropsychopharmacol 2016;19:pyw078.
  113. Stoll AL, Severus WE, Freeman MP, Rueter S, Zboyan HA, Diamond E, Cress KK, Marangell LB. Omega 3 fatty acids in bipolar disorder: a preliminary double-blind, placebo-controlled trial. Arch Gen Psychiatry 1999;56:407–12.
  114. Peet M, Horrobin DF. A dose-ranging study of the effects of ethyl-eicosapentaenoate in patients with ongoing depression despite apparently adequate treatment with standard drugs. Arch Gen Psychiatry 2002;59:913-9.
  115. Su KP, Huang SY, Chiu CC, Shen WW. Omega-3 fatty acids in major depressive disorder. A preliminary double-blind, placebo-controlled trial. Eur Neuropsychopharmacol 2003;13:267–71.
  116. Politi P, Rocchetti M, Emanuele E, Rondanelli M, Barale F. Randomized placebo-controlled trials of omega-3 polyunsaturated fatty acids in psychiatric disorders: A review of the current literature.  Curr Drug Discov Technol 2013;10:245-53.
  117. Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with omega-3 fatty acids in psychiatric disorders: a review of literature data. J Clin Med 2016;5:67.
  118. O’Donovan F, Carney S, Kennedy J, Haye JH, Pender N, Boland F, et al. Associations and effects of omega-3 polyunsaturated fatty acids on cognitive function and mood in healthy adults: a protocol for a systematic review of observational and interventional studies. BMJ Open 2019;9:e02716.
  119. Grosso G, Pajak A, Marventano S, Castellano S, Galvano F, Bucolo C, et al. 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.
  120. Mocking RJ, Harmsen I, Assies J, Koeter MW, Ruhé HG, Schene AH. Meta-analysis and meta-regression of omega-3 polyunsaturated fatty acid supplementation for major depressive disorder. Transl Psychiatry 2016;6:e756.
  121. Sarris J, Murphy J, Mischoulon D, Papakostas GI, Fava M, Berk M, et al. Adjunctive nutraceuticals for depression: a systematic review and meta-analyses. Am J Psychiatry 2016;173:575-87.
  122. Hamazaki K, Takamori A, Tsuchida A, Kigawa M, Tanaka T, Ito M, et al. Dietary intake of fish and n-3 polyunsaturated fatty acids and risks of perinatal depression: The Japan Environment and Children's Study (JECS). J Psychiat Res 2018;98:9-16.
  123. Firth J, Veronese N, Cotter J, Shivappa N, Hebert JR, Ee C, et al. What is the role of dietary inflammation in severe mental illness? A review of observational and experimental findings. Front Psychiatry 2019;10:350.
  124. Markowitz S, Friedman MA, Arent SM. Understanding the relation between obesity and depression: Causal mechanisms and implications for treatment. Clin Psychol Sci Pract 2008;15:1–20.
  125. Rajan TM, Menon V. Psychiatric disorders and obesity: A review of association studies. J Postgrad Med 2017;63:182–90.
  126. Schachter J, Martel J, Lin CS, Chang CJ , Wu TR, Lu CC, et al. Effects of obesity on depression: A role for inflammation and the gut microbiota. Brain Behav Immun 2018;69:1–8.
  127. Guillemot-Legris O, Muccioli GG. Obesity-induced neuroinflammation: beyond the hypothalamus. Trends Neurosci 2017;40:237–53.
  128. Khan MJ, Gerasimidis K, Edwards CA, Shaikh MG. Role of gut microbiota in the aetiology of obesity: proposed mechanisms and review of the literature. J Obes 2016;2016:7353642.
  129. Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 2012;13:701–12.
  130. Dinan TG, Stilling RM, Stanton C, Cryan JF. Collective unconscious: How gut microbes shape human behavior. J Psychiatr Res 2015;63:1-9.
  131. Huang TT, Lai JB, Du YL, Xu Y, Ruan LM, Hu SH. Current understanding of gut microbiota in mood disorders: An update of human studies. Front Genet 2019;10:1–12.
  132. O’Brien SM, Scott LV, Dinan TG. Cytokines: abnormalities in major depression and implications for pharmacological treatment. Hum Psychopharmacol 2004;19:397–403.
  133. Lotrich FE. Inflammatory cytokine-associated depression. Brain Res 2015;1617:113–25.
  134. Gomez-Eguilaz M, Ramon-Trapero JL, Perez-Martinez L, Blanco JR. The microbiota-gut-brain axis and its great projections. Rev Neurol 2019;68:111-7.
  135. Nga QX, Peters C, Xian Ho CY, Limd DY, Yeo W-S. A meta-analysis of the use of probiotics to alleviate depressive symptoms. J Affect Dis 2018;228:13-9.