Antioxidant Therapies Address Common Underpinnings of These Chronic Conditions
There is not a day that goes by that healthcare practitioners don’t face challenges. Attending to many complex patients stacked back-to-back, communicating bad news to a patient, working with insurance to cover labs—most physicians encounter at least one of these, if not all three, each and every day. One of the additional challenges we face with complex patients is addressing a long list of diagnoses; as integrative providers, we often find ourselves trying to treat not just one, but often three or four health concerns in a single visit. With our broad education and tolle totum (treat the whole person) vision, it is difficult to avoid this tendency.
Fortunately, there are many nutritional therapies that address conditions we commonly see coexisting. Here, we look at factors in a set of conditions that commonly overlap: chronic fatigue syndrome, depression, and insomnia. More importantly, we discuss some shared solutions that will help the integrative practitioner support patients with these difficulties.
Common Underpinnings
The overlapping issues of chronic fatigue syndrome (CFS), depression, and insomnia are at times so deeply intertwined that it may be difficult to tease out which one is the primary diagnosis, as each can be symptoms of the others. Approximately 2/3 of patients with CFS experience a mood disorder, while many have poor sleep quality;[1],[2] up to 80% of individuals who are depressed experience insomnia;[3] and approximately half of patients with insomnia have a psychiatric disorder, while they often experience fatigue (as anyone might) after many sleepless nights.[4]
Although each of these may have a unique aetiology, there is evidence of common underpinnings in oxidative and nitrosative stress, the immune response, and the depletion of antioxidant defenses.[5],[6] In both CFS and depression, we see an elevation of numerous inflammatory cytokines,[7] possibly triggered by viral infections,[8] psychological stress,[9] translocation of lipopolysaccharide (LPS) from the gastrointestinal tract,[10],[11] or an autoimmune response.[12] The alternate naming of CFS, myalgic encephalomyelitis, reflects the state of central nervous system inflammation, and the severity of neuropsychological symptoms has been demonstrated to be associated with the amount of neuroinflammation that exists.[13]
In individuals with CFS, concomitant depression is associated with higher levels of pro-inflammatory cytokines and evening cortisol, the latter of which has even been shown to predict greater depressive symptoms.[14] Multiple studies have shown an increase in pro-inflammatory cytokines, including interleukin (IL)-1, IL-2, IL-6, and tumour necrosis factor alpha (TNFα), in individuals with both CFS and depression.[15],[16] An autoimmune response directed at serotonin (5-HT) has been observed in both CFS and depression, with one study showing a higher incidence of anti-5-HT antibody activity in 54.1% of depressed patients versus 5.7% of controls.[17],[18] Higher amounts of TNFα, IL-1, and somatic symptoms (including malaise and cognitive dysfunction) were associated with the presence of 5-HT antibodies. Activated glial cells in the brain release not only some of these inflammatory cytokines but also glutamate, superoxide, and nitric oxide (NO), contributing to a hyperexcitable state and oxidative and nitrosative stress.[19]
More often than not, insomnia and/or poor sleep quality comes along with CFS and depression. Poor sleep quality in individuals with CFS is associated with higher levels of IL-1β, IL-6, and TNFα.[20] Sleep deprivation contributes to altered immune system function and increases in TFNα, IL-1β, IL-6, IL-17A, and C-reactive protein, with many of these increases persisting even after two days of recovery sleep.[21],[22],[23] With the increase in inflammatory mediators, the permeability of the blood–brain barrier also is increased with chronic sleep loss.[24],[25]
Increased levels of inflammation and oxidative stress may further contribute to mitochondrial dysfunction, which affects energy production and may worsen symptoms of fatigue.[26] Mitochondrial dysfunction is not unique to CFS; it has also been noted in depression—again, possibly due to the increased oxidative stress.[27] Healthy levels of functioning mitochondria are necessary for normal neuron dendrite development and neuroplasticity.
A Common Solution?
Although seeking and addressing possible underlying contributors such as chronic viral infections or gastrointestinal pathogens is important in achieving long-term resolution, therapies that help reduce inflammation and/or restore balance to antioxidant systems may also be effective. Unsurprisingly, some of our big-hitter antioxidants such as vitamins C and E, N-acetylcysteine, CoQ10, lipoic acid, and the hormone melatonin (discussed at length in “Catching Zzzzz’s” in the Fall 2018 issue of FOCUS[28]) may be of benefit for fatigue and depression, likely due to their intersection with these common disease underpinnings. Interestingly, the more we study the mechanisms of pharmaceutical antidepressants, the more we learn that they, too, have anti-inflammatory, antioxidative, and anti-apoptotic effects and may even improve mitochondrial dysfunction.[29],[30]
Vitamin C
Vitamin C is not only an antioxidant, but also an important cofactor for the synthesis of several hormones and neurotransmitters.[31] It is found at high levels in the adrenal glands where many of these substances are made.[32] In human studies, vitamin C has been shown to have a modulatory effect on cortisol, increasing it in settings of medication-induced suppression and decreasing post-exertion increases.[33],[34] Vitamin C has been shown to decrease depression and anxiety scores[35],[36],[37] and reduce fatigue in healthy office workers as well as individuals following a hypocaloric diet.[38],[39]
Vitamin E
Vitamin E is an important antioxidant for cellular membrane protection, and is present at high levels in the inner mitochondrial and other cellular membranes.[40] Of the many forms of vitamin E, alpha-tocopherol has been most widely studied; thus, when the form is unspecified in research studies, alpha-tocopherol can be assumed. In vitro, alpha tocopherol has been shown to reduce microglial production of NO, IL‐1α, and TNFα, improving neuronal cell survival;[41] vitamin E has also been shown to have neuroprotective effects in human studies.[42] Although there are limited clinical studies assessing the effectivity of vitamin E as a treatment for CFS and depression, significantly lower levels of vitamin E have been shown in individuals with major depression as well as those with CFS.[43],[44] Perhaps even more indicative of an association with CFS, the same CFS patients were shown to have significantly higher levels of alpha-tocopherol when their symptoms were in remission.
N-Acetylcysteine (NAC)
NAC is biologically important as an antioxidant and source of cysteine, the rate-limiting amino acid for glutathione formation.[45] Supplementation with NAC has been shown to replenish intracellular glutathione levels and effectively treat deficiency.[46] In addition to restoring antioxidant balance, NAC has been shown in animal models of aging and chronic stress to improve mitochondrial function in the brain and reduce neuroinflammation.[47],[48]
NAC has been broadly studied in mental health settings with positive clinical findings in the treatment of addiction, obsessive compulsive disorder, and depression.[49],[50] A 2016 systemic review and meta-analysis of the use of NAC for the treatment of depressive symptoms concluded that NAC ameliorated depressive symptoms, improved functionality, and was well tolerated.[51] Human studies have shown that NAC positively impacts muscular and exercise-related fatigue as well as fatigue in the setting of autoimmunity.[52],[53],[54] Because studies have shown muscle dysfunction in response to exercise in individuals with CFS (in addition to aspects of autoimmunity previously discussed), NAC may also prove to be helpful for these individuals.[55]
Coenzyme Q10 (CoQ10)
CoQ10 is an important consideration for conditions associated with mitochondrial dysfunction, as it is a key player in their production of energy and it protects the mitochondrial membranes from oxidative damage. In animals, administration of CoQ10 has been shown to increase the concentration of mitochondria in the brain and protect the brain from various damaging insults.[56] Significantly lower levels of CoQ10 have been demonstrated in patients with depression, and levels were even lower in those with CFS or treatment-resistant depression.[57] In patients with bipolar disorder or multiple sclerosis, CoQ10 supplementation reduced depressive symptoms.[58],[59] Supplementation with CoQ10 has also been shown to decrease fatigue symptoms in fibromyalgia and CFS, as well as fatigue in healthy people.[60],[61],[62]
Lipoic Acid
Much like CoQ10, the antioxidant lipoic acid is important for mitochondrial function and has neuroprotective effects.[63] Lipoic acid helps to regenerate other antioxidants, particularly vitamin C, vitamin E, and glutathione, in part by activation of nuclear factor erythroid 2-related factor 2 (Nrf2)–dependent antioxidant transcription.[64] In experimental models, lipoic acid reduces the autoimmune response directed at the central nervous system.[65],[66] Treatment of macrophages with lipoic acid has been shown to reduce LPS-induced production of TNFα and NO as well as further immune system activation.[67]
Animal models suggest that lipoic acid may be useful for the treatment of depression.[68] Treatment with lipoic acid also supports healthy levels of brain-derived neurotrophic factor (BDNF), an important mediator of neuroplasticity that is positively associated with clinical improvements in depression.[69],[70] It has been shown in animals and humans to help reduce cognitive dysfunction, which is also a common problem in individuals with depression and CFS.[71],[72]
Melatonin
Like lipoic acid, melatonin also turns on transcription of other antioxidants via the Nrf2 pathway and is a neuroprotective antioxidant itself.[73],[74] Melatonin interacts with the receptors MT1 and MT2, which not only affect sleep but also mood, learning, and memory.[75] Decreased melatonin production has been observed in individuals with depression in several studies.[76],[77] A 2017 review found trends toward an improvement in depressive episodes in individuals with the use of melatonin.[78] In CFS patients with delayed nocturnal onset of melatonin production, treatment with melatonin significantly improved fatigue, concentration, motivation, and activity.[79]
Antioxidant Minerals
In addition to these antioxidants, certain minerals play a very important part in our antioxidant systems and are critical for normal immune system function. Zinc and selenium are two minerals of particular importance for these reasons.
Zinc is a trace mineral with very important antioxidant effects, being necessary for the normal synthesis and function of metallothionein (which plays a role in cellular signaling and the reduction of superoxide and hydroxyl radicals) as well as normal homocysteine metabolism.[80] Both depression and CFS are associated with lower levels of zinc, and lower levels of zinc in individuals with CFS are correlated with inflammation and defects in T cell activation.[81],[82] In healthy humans, long term supplementation of zinc has been shown to have both antioxidative and anti-inflammatory effects, reducing TNFα-induced immune cell activation and LPS-induced TNFα and IL-1β production.[83] Zinc supplementation has been shown to improve depression in a variety of settings, including autoimmunity and obesity, both of which are associated with a pro-inflammatory state.[84],[85],[86]
The trace mineral selenium is critical for the function of several selenoproteins, including five glutathione peroxidase (GPX) enzymes,[87] as well as other enzymes that help reduce reactive oxygen species and regenerate antioxidants.[88] Selenoproteins also play an important role in energy production and are required for thyroid hormone metabolism.[89]
A significantly lower level of GPX activity has been shown in individuals with depression than in normal healthy controls, with GPX activity being inversely and significantly related to depressed mood and autonomic symptoms.[90] Selenium supplementation has been shown to significantly increase glutathione levels in humans, which is not only important for antioxidant protection but also for normal immune system function, particularly the response against viral infections.[91],[92] Selenium intake and supplementation have also been shown to be associated with an improvement in mood and energy levels.[93]
Clearly, many nutritional tools have evidence that they may intercept the inflammatory and oxidative stress state associated with depression and CFS. Although some patients may benefit from these interventions as monotherapies, others may find improvement with a combination that addresses multiple potential contributing factors as well as nutritional deficiencies. Because many individuals with depression and CFS experience these conditions chronically, therapies such as these may be necessary long term and at higher dosages in the setting of increased stress or other challenges.
References
[1] Kruesi MJ, et al. Psychiatric diagnoses in patients who have chronic fatigue syndrome. J Clin Psychiatry. 1989 Feb;50(2):53-6.
[2] Togo F, et al. Sleep structure and sleepiness in chronic fatigue syndrome with or without coexisting fibromyalgia. Arthritis Res Ther. 2008;10(3):R56.
[3] Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res. 2003 Jan-Feb;37(1):9-15.
[4] National Institutes of Health. National Institutes of Health State of the Science Conference statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep. 2005 Sep;28(9):1049-57.
[5] Van Konynenburg RA. Is glutathione depletion an important part of the pathogenesis of chronic fatigue syndrome? Presented: AACFS Seventh International Conference; 2004 Oct 8; Madison, WI.
[6] Moylan S, et al. Oxidative & nitrosative stress in depression: why so much stress? Neurosci Biobehav Rev. 2014 Sep;45:46-62.
[7] Maes M. An intriguing and hitherto unexplained co-occurrence: Depression and chronic fatigue syndrome are manifestations of shared inflammatory, oxidative and nitrosative (IO&NS) pathways. Prog Neuropsychopharmacol Biol Psychiatry. 2011 Apr 29;35(3):784-94.
[8] Maes M. Inflammatory and oxidative and nitrosative stress pathways underpinning chronic fatigue, somatization and psychosomatic symptoms. Curr Opin Psychiatry. 2009 Jan;22(1):75-83.
[9] Iwata M, et al. The inflammasome: pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun. 2013 Jul;31:105-14.
[10] Maes M, et al. Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability. J Affect Disord. 2007 Apr;99(1-3):237-40.
[11] Maes M, et al. Increased IgA and IgM responses against gut commensals in chronic depression: further evidence for increased bacterial translocation or leaky gut. J Affect Disord. 2012 Dec 1;141(1):55-62.
[12] Sotzny F, et al. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Jun;17(6):601-9.
[13] Nakatomi Y, et al. [Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome]. Brain Nerve. 2018 Jan;70(1):19-25.
[14] Milrad SF, et al. Depression, evening salivary cortisol and inflammation in chronic fatigue syndrome: A psychoneuroendocrinological structural regression model. Int J Psychophysiol. 2018 Sep;131:124-30.
[15] Maes M, et al. Inflammatory and cell-mediated immune biomarkers in myalgic encephalomyelitis/chronic fatigue syndrome and depression: inflammatory markers are higher in myalgic encephalomyelitis/chronic fatigue syndrome than in depression. Psychother Psychosom. 2012;81(5):286-95.
[16] Maes M, et al. Activation of cell-mediated immunity in depression: association with inflammation, melancholia, clinical staging and the fatigue and somatic symptom cluster of depression. Prog Neuropsychopharmacol Biol Psychiatry. 2012 Jan 10;36(1):169-75.
[17] Klein R, Berg PA. High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res. 1995 Oct 16;1(1):21-6.
[18] Maes M, et al. Increased autoimmune activity against 5-HT: a key component of depression that is associated with inflammation and activation of cell-mediated immunity, and with severity and staging of depression. J Affect Disord. 2012 Feb;136(3):386-92.
[19] Glassford JA. The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Front Physiol. 2017 Feb 17;8:88.
[20] Milrad SF, et al. Poor sleep quality is associated with greater circulating pro-inflammatory cytokines and severity and frequency of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) symptoms in women. J Neuroimmunol. 2017 Feb 15;303:43-50.
[21] Ruiz FS, et al. Immune alterations after selective rapid eye movement or total sleep deprivation in healthy male volunteers. Innate Immun. 2012 Feb;18(1):44-54.
[22] van Leeuwen WM, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One. 2009;4(2):e4589.
[23] Chennaoui M, et al. Effect of one night of sleep loss on changes in tumor necrosis factor alpha (TNF-α) levels in healthy men. Cytokine. 2011 Nov;56(2):318-24.
[24] He J, et al. Sleep restriction impairs blood-brain barrier function. J Neurosci. 2014 Oct 29;34(44):14697-706.
[25] Hurtado-Alvarado G, et al. Blood-Brain Barrier Disruption Induced by Chronic Sleep Loss: Low-Grade Inflammation May Be the Link. J Immunol Res. 2016;2016:4576012.
[26] Morris G, Maes M. Mitochondrial dysfunctions in myalgic encephalomyelitis/chronic fatigue syndrome explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways. Metab Brain Dis. 2014 Mar;29(1):19-36.
[27] Streck EL, et al. Mitochondria and the central nervous system: searching for a pathophysiological basis of psychiatric disorders. Braz J Psychiatry. 2014 Apr-Jun;36(2):156-67.
[28] Allergy Research Group. Catching Zzzzz’s. FOCUS Newsletter. Fall 2018:8-11.
[29] Caiaffo V, et al. Anti-inflammatory, antiapoptotic, and antioxidant activity of fluoxetine. Pharmacol Res Perspect. 2016 Apr 7;4(3):e00231.
[30] Adzic M, et al. Antidepressant Action on Mitochondrial Dysfunction in Psychiatric Disorders. Drug Dev Res. 2016 Nov;77(7):400-6.
[31] May JM, et al. Ascorbic acid efficiently enhances neuronal synthesis of norepinephrine from dopamine. Brain Res Bull. 2013 Jan;90:35-42.
[32] Patak P, et al. Vitamin C is an important cofactor for both adrenal cortex and adrenal medulla. Endocr Res. 2004 Nov;30(4):871-5.
[33] Das D, et al. Effect of Vitamin C on adrenal suppression by etomidate induction in patients undergoing cardiac surgery: A randomized controlled trial. Ann Card Anaesth. 2016 Jul-Sep;19(3):410-7.
[34] Peters EM, et al. Vitamin C supplementation attenuates the increases in circulating cortisol, adrenaline and anti-inflammatory polypeptides following ultramarathon running. Int J Sports Med. 2001 Oct;22(7):537-43.
[35] Mazloom Z, et al. Efficacy of supplementary vitamins C and E on anxiety, depression and stress in type 2 diabetic patients: a randomized, single-blind, placebo-controlled trial. Pak J Biol Sci. 2013 Nov 15;16(22):1597-600.
[36] Brody S. High-dose ascorbic acid increases intercourse frequency and improves mood: a randomized controlled clinical trial. Biol Psychiatry. 2002 Aug 15;52(4):371-4.
[37] de Oliveira IJ, et al. Effects of Oral Vitamin C Supplementation on Anxiety in Students: A Double-Blind, Randomized, Placebo-Controlled Trial. Pak J Biol Sci. 2015 Jan;18(1):11-8.
[38] Suh SY, et al. Intravenous vitamin C administration reduces fatigue in office workers: a double-blind randomized controlled trial. Nutr J. 2012 Jan 20;11:7.
[39] Huck CJ, et al. Vitamin C status and perception of effort during exercise in obese adults adhering to a calorie-reduced diet. Nutrition. 2013 Jan;29(1):42-5.
[40] Ibrahim WH, et al. Dietary coenzyme Q10 and vitamin E alter the status of these compounds in rat tissues and mitochondria. J Nutr. 2000 Sep;130(9):2343-8.
[41] Li Y, et al. Vitamin E suppression of microglial activation is neuroprotective. J Neurosci Res. 2001 Oct 15;66(2):163-70.
[42] Argyriou AA, et al. Vitamin E for prophylaxis against chemotherapy-induced neuropathy: a randomized controlled trial. Neurology. 2005 Jan 11;64(1):26-31.
[43] Maes M, et al. Lower serum vitamin E concentrations in major depression. Another marker of lowered antioxidant defenses in that illness. J Affect Disord. 2000 Jun;58(3):241-6.
[44] Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010 Jul;25(4):319-23.
[45] Elbini Dhouib I, et al. A minireview on N-acetylcysteine: An old drug with new approaches. Life Sci. 2016 Apr 15;151:359-63.
[46] Atkuri KR, et al. N-Acetylcysteine–a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007 Aug;7(4):355-9.
[47] Cocco T, et al. Tissue-specific changes of mitochondrial functions in aged rats: effect of a long-term dietary treatment with N-acetylcysteine. Free Radic Biol Med. 2005 Mar 15;38(6):796-805.
[48] Fernandes J, Gupta GL. N-acetylcysteine attenuates neuroinflammation associated depressive behavior induced by chronic unpredictable mild stress in rat. Behav Brain Res. 2019 May 17;364:356-65.
[49] Nocito Echevarria MA, et al. N-acetylcysteine for treating cocaine addiction – A systematic review. Psychiatry Res. 2017 May;251:197-203.
[50] Couto JP, Moreira R. Oral N-acetylcysteine in the treatment of obsessive-compulsive disorder: A systematic review of the clinical evidence. Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:245-54.
[51] Fernandes BS, et al. N-Acetylcysteine in depressive symptoms and functionality: a systematic review and meta-analysis. J Clin Psychiatry. 2016 Apr;77(4):e457-66.
[52] McKenna MJ, et al. N-acetylcysteine attenuates the decline in muscle Na+,K+-pump activity and delays fatigue during prolonged exercise in humans. J Physiol. 2006 Oct 1;576(Pt 1):279-88.
[53] Cobley JN, et al. N-Acetylcysteine’s attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations. Int J Sport Nutr Exerc Metab. 2011 Dec;21(6):451-61.
[54] Lai ZW, et al. N-acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2012 Sep;64(9):2937-46.
[55] Jammes Y, et al. Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise. J Intern Med. 2005 Mar;257(3):299-310.
[56] Matthews RT, et al. Coenzyme Q10 administration increases brain mitochondrial concentrations and exerts neuroprotective effects. Proc Natl Acad Sci U S A. 1998 Jul 21;95(15):8892-7.
[57] Maes M, et al. Lower plasma Coenzyme Q10 in depression: a marker for treatment resistance and chronic fatigue in depression and a risk factor to cardiovascular disorder in that illness. Neuro Endocrinol Lett. 2009;30(4):462-9.
[58] Mehrpooya M, et al. Evaluating the effect of coenzyme Q10 Augmentation on treatment of bipolar depression: a double-blind controlled clinical trial. J Clin Pharmacol. 2018 Oct 1;38(5):460-6.
[59] Sanoobar M, et al. Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial. Nutri Neurosci. 2016 Mar 15;19(3):138-43.
[60] Mizuno K, et al. Antifatigue effects of coenzyme Q10 during physical fatigue. Nutrition. 2008 Apr 1;24(4):293-9.
[61] Castro-Marrero J, et al. Does oral coenzyme Q10 plus NADH supplementation improve fatigue and biochemical parameters in chronic fatigue syndrome? Antioxid Redox Signal. 2015 Mar 10;22(8):679-85.
[62] Miyamae T, et al. Increased oxidative stress and coenzyme Q10 deficiency in juvenile fibromyalgia: amelioration of hypercholesterolemia and fatigue by ubiquinol-10 supplementation. Redox Report. 2013 Jan 1;18(1):12-9.
[63] Seifar F, et al. α-Lipoic acid, functional fatty acid, as a novel therapeutic alternative for central nervous system diseases: A review. Nutr Neurosci. 2019 May;22(5):306-16.
[64] Suh JH, et al. Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc Natl Acad Sci U S A. 2004 Mar 9;101(10):3381-6.
[65] Morini M, et al. Alpha-lipoic acid is effective in prevention and treatment of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2004 Mar;148(1-2):146-53.
[66] Chaudhary P, et al. Lipoic acid decreases inflammation and confers neuroprotection in experimental autoimmune optic neuritis. J Neuroimmunol. 2011 Apr;233(1-2):90-6.
[67] Kiemer AK, et al. Inhibition of LPS-induced nitric oxide and TNF-alpha production by alpha-lipoic acid in rat Kupffer cells and in RAW 264.7 murine macrophages. Immunol Cell Biol. 2002 Dec;80(6):550-7.
[68] Silva MC, et al. Augmentation therapy with alpha-lipoic acid and desvenlafaxine: a future target for treatment of depression? Naunyn Schmiedebergs Arch Pharmacol. 2013 Aug;386(8):685-95.
[69] de Sousa CN, et al. Reversal of corticosterone-induced BDNF alterations by the natural antioxidant alpha-lipoic acid alone and combined with desvenlafaxine: Emphasis on the neurotrophic hypothesis of depression. Psychiatry Res. 2015 Dec 15;230(2):211-9.
[70] Brunoni AR, et al. A systematic review and meta-analysis of clinical studies on major depression and BDNF levels: implications for the role of neuroplasticity in depression. Int J Neuropsychopharmacol. 2008 Dec;11(8):1169-80.
[71] Manda K, et al. Radiation-induced cognitive dysfunction and cerebellar oxidative stress in mice: protective effect of alpha-lipoic acid. Behav Brain Res. 2007 Feb 12;177(1):7-14.
[72] Hager K, et al. Alpha-lipoic acid as a new treatment option for Azheimer type dementia. Arch Gerontol Geriatr. 2001;32(3):275-82.
[73] Tuli HS, et al. Molecular aspects of melatonin (MLT)‐mediated therapeutic effects. Life Sci. 2015;135:147-57.
[74] Reiter RJ, et al. Free radical-mediated molecular damage. Mechanisms for the protective actions of melatonin in the central nervous system. Ann N Y Acad Sci. 2001 Jun;939:200-15.
[75] Liu J, et al. MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol. 2016;56:361-83.
[76] Nair NP, et al. Circadian rhythm of plasma melatonin in endogenous depression. Prog Neuropsychopharmacol Biol Psychiatry. 1984;8(4-6):715-8.
[77] Claustrat B, et al. A chronobiological study of melatonin and cortisol secretion in depressed subjects: plasma melatonin, a biochemical marker in major depression. Biol Psychiatry. 1984 Aug;19(8):1215-28.
[78] De Crescenzo F, et al. Melatonin as a treatment for mood disorders: a systematic review. Acta Psychiatrica Scandinavica. 2017 Dec;136(6):549-58.
[79] Van Heukelom RO, et al. Influence of melatonin on fatigue severity in patients with chronic fatigue syndrome and late melatonin secretion. Eu J Neurol. 2006 Jan;13(1):55-60.
[80] Formigari A, et al. Zinc, antioxidant systems and metallothionein in metal mediated-apoptosis: biochemical and cytochemical aspects. Comp Biochem Physiol C Toxicol Pharmacol. 2007 Nov;146(4):443-59.
[81] Swardfager W, et al. Zinc in depression: a meta-analysis. Biol Psychiatry. 2013 Dec 15;74(12):872-8.
[82] Maes M, et al. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006 Feb;90(2-3):141-7.
[83] Prasad AS, et al. Antioxidant effect of zinc in humans. Free Radic Biol Med. 2004 Oct 15;37(8):1182-90.
[84] Ranjbar E, et al. Effects of zinc supplementation on efficacy of antidepressant therapy, inflammatory cytokines, and brain-derived neurotrophic factor in patients with major depression. Nutr Neurosci. 2014 Feb;17(2):65-71.
[85] Solati Z, et al. Zinc monotherapy increases serum brain-derived neurotrophic factor (BDNF) levels and decreases depressive symptoms in overweight or obese subjects: a double-blind, randomized, placebo-controlled trial. Nutr Neurosci. 2015 May;18(4):162-8.
[86] Salari S, et al. Zinc sulphate: A reasonable choice for depression management in patients with multiple sclerosis: A randomized, double-blind, placebo-controlled clinical trial. Pharmacol Rep. 2015 Jun;67(3):606-9.
[87] Rotruck JT, et al. Selenium: biochemical role as a component of glutathione peroxidase. Science. 1973 Feb 9;179(4073):588-90.
[88] Arnér ES. Focus on mammalian thioredoxin reductases–important selenoproteins with versatile functions. Biochim Biophys Acta. 2009 Jun;1790(6):495-526.
[89] Arthur JR, et al. Selenium deficiency, thyroid hormone metabolism, and thyroid hormone deiodinases. Am J Clin Nutr. 1993 Feb;57(2 Suppl):236S-9S.
[90] Maes M, et al. Lower whole blood glutathione peroxidase (GPX) activity in depression, but not in myalgic encephalomyelitis / chronic fatigue syndrome: another pathway that may be associated with coronary artery disease and neuroprogression in depression. Neuro Endocrinol Lett. 2011;32(2):133-40.
[91] El-Bayoumy K, et al. Influence of selenium-enriched yeast supplementation on biomarkers of oxidative damage and hormone status in healthy adult males: a clinical pilot study. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1459-65.
[92] Broome CS, et al. An increase in selenium intake improves immune function and poliovirus handling in adults with marginal selenium status. Am J Clin Nutr. 2004 Jul;80(1):154-62.
[93] Benton D, Cook R. The impact of selenium supplementation on mood. Biol Psychiatry. 1991 Jun 1;29(11):1092-8.
