Commonalities Between Chronic Fatigue Syndrome, Depression, and Insomnia

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Unraveling the Truth About Antioxidants: ROS and disease: finding the right balance.

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]


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.


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