Even though the idea that inflammation causes depression is logical, reasonable, and scientifically justifiable, things have a tendency to go off the rails when it comes to popular explanations for why it does, and what should be done about it.
The truth is however, it isn’t always easy or even possible, to make a black and white distinction between metabolic symptoms and causes, and this is relevant to the relationship between inflammatory processes and mood disorders, like depression or anxiety. Is depression a symptom of inflammation, or is inflammation a symptom of depression?
“In humans, there is evidence that different types of psychosocial stressors may stimulate the pro-inflammatory cytokine network, including increases in IL-6 and TNFα…psychosocial stress-induced elevations in pro-inflammatory cytokines orchestrate stress-induced changes in peripheral blood immune cells, inflammatory reactions and neurobehavioral changes.” (Berk M, et al., 2013)
“Biomarkers of inflammation (for example, cytokines and C-reactive protein (CRP)) are reliably elevated in depressed patients. Moreover, administration of inflammatory stimuli reduces neural activity and dopamine release in reward-related brain regions in association with reduced motivation and anhedonia.” (Felger JC, et al., 2016)
Many symptoms (or biochemical changes) resulting from stress or metabolic suppression, go on to promote further interference with metabolism, and because of this, it can sometimes be difficult to know for certain what caused what.
“The result of this study showed that there was a significant relationship between depression and metabolic syndrome….the relationship between two of the variables (depression and metabolic syndrome) was bilateral; this means that metabolic syndrome leads to depression and vice versa…” (Ghanei Gheshlagh R, et al., 2016)
“Magnesium treatment is hypothesized to be effective in treating major depression resulting from intraneuronal magnesium deficits. These magnesium ion neuronal deficits may be induced by stress hormones…” (Eby GA, Eby KL., 2006)
The good news is you don’t necessarily need to know which came first, inflammation or depression. If you take a more holistic approach, and look for the deeper biological processes (capable of driving a number of interrelated problems), it’s possible to see that there are good reasons why inflammation is closely associated with depression, and that there are things that can be done about it.
One recently fashionable suggestion is that an infection of some kind can be responsible for the inflammation, which then leads to depression. Although this is a reasonable hypothesis (and likely true in some cases), it’s worth discussing the elements which could be behind the simultaneous promotion of all three of these things (infection, inflammation, depression), and more.
The proper functioning of thyroid energy system metabolism is a central factor protecting against chronic and systemic inflammation, as well as being a fundamental part of the defense against infection and mood dysregulation.
“OS [oxidative stress] seems to be an important mechanism underlying the progress of inflammation. A vicious circle creates a link between these two conditions. Thyroid hormones can have a protective role, modulating antioxidant levels; on the other side, a tissue hypothyroidism can worsen OS.” (Mancini A, et al, 2016)
“…experimental as well as clinical studies indicate that the inflammatory cytokine network plays a central role in the genesis of the low T3 syndrome. IL-6 decreases the mRNA of liver type 5′-deiodinase (DI) as well as of thyroid type 5′-DI and these and other mechanisms are implicated in the low T3 induced by bacterial endotoxins…” (Enia G, et al., 2007)
Exposure to stress causes blood sugar to be used up at an increased rate, and this is particularly relevant when metabolism is already under functioning. When blood sugar runs low, the stress hormones cortisol and adrenaline, increase to assist in providing needed alternative energy.
High cortisol has been shown to be involved in the etiology of depression, and other varieties of mood disorder.
“The stress responsive hypothalamic pituitary adrenal (HPA) axis has been implicated in the pathophysiology of anxiety and depression as well as cognitive functioning…Upwards of 40-60% of depressed patients experience hypercortisolemia or other disturbances of the HPA system…” (Keller J, et al., 2017)
“…distinct pattern of cortisol secretion for a community sample of depressed individuals involving a larger CAR (cortisol awakening response) and higher average cortisol across the day….support for the prediction that the at-risk group would have greater waking cortisol when compared to controls…” (Dienes KA, et al., 2013)
Stress and hypoglycemia, play a significant role in the promotion of thyroid dysfunction and depression, and high cortisol and hypothyroidism often fuel each other. Cortisol can promote inflammation, and inflammation can also promote cortisol.
“…studies all taken together suggest a physiologic feedback loop where lower thyroid function increases cortisol…in the case of primary hypothyroidism (elevated TSH) cortisol is elevated…” (Walter KN, et al., 2012)
“This study examined how prolonged, exhaustive exercise affects: (1) thyroid hormones, and (2) the interrelationship of cortisol…to such exercise on thyroid hormones…Exhaustive exercise; (1) decreases select thyroid hormones by 24 hours into recovery, (2) cortisol responses are inversely related to these thyroid reductions…” (Hackney AC, Dobridge JD., 2009)
“Elevated levels of inflammation-related cytokines, including interleukin-6 (IL-6), have been associated with increased levels of chronic and acute stress and anxiety levels… pro-inflammatory cytokines stimulate activity in the HPA axis, leading to increases in cortisol, but cortisol and other glucocorticoids (GCs) typically act as immuno-suppressants…However, recent research has increasingly found that GCs are immuno-modulatory, rather than simply immunosuppressive…Although in the short-term, cortisol acts as an immuno-suppressant…long-term chronic activation of the HPA axis has been hypothesized to contribute to inflammation” (DeSantis AS, et al., 2012)
Stress promotes adrenaline, and adrenaline increases the release of stored polyunsaturated fats (PUFAs) into the blood stream, causing thyroid energy system suppression and inflammation. The breakdown products of the polyunsaturated fats, have been associated with depression, and are one of the main things behind chronic blood sugar dysregulation issues.
“This meta-analysis suggests an association between increased lipid peroxidation in peripheral blood samples and the presence of MDD [major depressive disorder]. This finding is consistent with a general increase in oxidative stress in those with depressive symptoms and provides evidence for a specific elevation of lipid peroxidation.” (Mazereeuw G, et al., 2015)
“When patients with depression were compared with healthy controls, depression was associated with higher oxidative stress MDA [malondialdehyde…a breakdown product of PUFA] levels…” (Jiménez-Fernández S, et al., 2015)
“MDA status is used as biomarker for oxidative stress…MDA levels have been found to be increased in depression…we found significantly increased levels of MDA in patients of major depressive disorder…which suggests an extremely significant relationship. Increased MDA levels implicate increased lipid peroxidation products in major depressive disorder.” (Bajpai A, et al., 2014)
“…depression is associated with increased IL-6 trans-signaling and lipid peroxidation. Severity of depression, number of episodes and suicidal attempts are associated with activated I&O [immune & oxidative] pathways…” (Sowa-Kućma M, 2018)
Stress can promote hypoglycemia as well as hyperglycemia, and things related to both low and high blood sugar, can potentially lead to an increased susceptibility to infection.
Infection is known to promote increases in cortisol and inflammation, and an energy metabolism suppressed, inflammatory state, is far more susceptible to infectious disease.
“In community-acquired pneumonia (CAP), the cortisol level on admission can be a useful biomarker for prognosis…Compared to patients with an uneventful recovery, cortisol on presentation was significantly higher in patients with an adverse outcome…and also remained significantly higher throughout the course of disease…” (Remmelts HH, et al., 2012)
When stress, blood sugar dysregulation, and the release of PUFAs, exacerbate thyroid energy dysfunction, digestion often becomes sluggish. Ineffective digestion increases the tendency for bacteria and fungi to grow in number, and move up into the small intestine, where they encourage the release of potentially harmful and inflammatory substances, such as bacterial endotoxin (LPS).
Increased endotoxin exposure, has been shown to be connected to many metabolic factors related to stress and depression, as well as many other kinds of inflammation related illnesses.
“Endotoxin-administration in human subjects…induces specific dose-dependent symptoms: At higher doses…flu-like symptoms such as fever, chills, myalgias, headache, and nausea predominate, while at lower doses…symptoms such as loss of fatigue, reduced appetite, and cognitive impairment occur…These symptoms are similar to symptoms seen in idiopathic depression.” (DellaGioia N, Hannestad J., 2010)
“Evidence indicates that major depression is accompanied by increased translocation of gut commensal Gram-negative bacteria (leaky gut) and consequent activation of oxidative and nitrosative (O&NS) pathways.” (Gomes C, et al., 2018)
“Results revealed that subjects exposed to endotoxin versus placebo showed greater increases in self-reported and observer-rated depressed mood…alterations in reward-related neural circuitry represent an important avenue for understanding inflammatory-associated depression.” (Eisenberger NI, et al., 2010)
“Endotoxin administration induced pronounced transient increases in plasma levels of TNF-α, IL-1ra, IL-6, IL-10, and cortisol. Positive mood was decreased and state anxiety increased…These findings may have implications for the putative role of inflammatory processes in the pathophysiology of depression.” (Kullmann JS, 2013)
Endotoxin can directly promote infection, as well as causing levels of the stress substances, such as serotonin and nitric oxide, to rise. Serotonin, nitric oxide, and endotoxin, can all foster inflammation throughout the intestine (as well as systemically), and can cause interference with mitochondrial energy systems, leading to more exposure to endotoxin, stress, and inflammation.
“…endotoxin may aid the prolongation of…infection and therefore infection chronicity. On the other hand, this contrasts with acute infection…where overt inflammation contributes to pathology…” (Moran AP., 2010)
“Intriguingly, low levels of circulating Gram-negative bacterial endotoxin lipopolysaccharide (LPS) appear to be one of the key culprits in provoking a non-resolving low-grade inflammation.” (Glaros TG, et al., 2013)
Suppression of energy metabolism can result in a reduction in intestinal barrier capability, allowing for bacterial endotoxin to be released in greater amounts into the system, leading to an increasingly generalized inflammatory state, and chronic interference with thyroid and immune system function.
“LPS molecules are potent inflammagens…and may be both cytotoxic and/or neurotoxic…They are known to induce the production of a variety of pro-inflammatory cytokines…Indeed, cytokine production…is central to the development of inflammation…” (Etheresia Pretorius, et al., 2016)
Eventually, a vicious circle type stress situation can be created, involving continuously increasing levels of inflammatory materials, including endotoxin, the polyunsaturated free fatty acids, the prostaglandins and cytokines, iron dysregulation, and rising exposure to the stress substances (like estrogen, nitric oxide and serotonin), all increasing the risk of depression.
“…risk factor for developing postinfective IBS …Adverse life events…depression…Clinical conditions with an inflammatory basis…characterised by excess postprandial serotonin release…Several studies report evidence of low-grade inflammation in IBS…” (Spiller R., 2007)
“…we demonstrate that feeding of HFD [high fat diet] results in…an increased capacity to produce 5-HT which has previously been shown to…be a potent stimulator of inflammation.” (Hernandez LL, et al., 2012)
“Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression…Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors.” (Gądek-Michalska A, et al., 2013)
“Selected sex hormone parameters were significantly different in overweight and obese compared to normal weight males and certain differences could be seen between younger and older males. Depressive symptomatology was associated with increased estradiol levels in younger men, regardless of BMI.” (Stanikova D, et al., 2018)
All of these types of defensive metabolic changes, can feed into the creation of a chronically blood sugar dysregulated high stress state, increasing susceptibility to many different (but related) kinds of inflammatory illness.
Depression is in many ways an energy deficient, hypothermic, hibernation-like state, and although the common belief that more serotonin leads to more happiness is extremely popular and profitable, experimental evidence suggests that high serotonin is a driver of mood instability (including anxiety and depression) as well as inflammation.
“Here we show that 5-HT [serotonin] from the dorsal raphe nucleus…enhances fear and anxiety…results…provide a potential mechanistic explanation for the clinical observation of early adverse events to SSRI treatment in some patients with anxiety disorders.” (Marcinkiewcz CA, et al., 2016)
Misinterpretations (as well as misrepresentations) regarding the significance of a few important biochemical stress related processes (like for instance viewing serotonin or nitric oxide as something you want to increase rather than decrease), can be enough to prevent the pieces of the puzzle from falling into place.
“The reigning paradigm conceptualizes depression as a state of reduced serotonin transmission…we have reviewed a large body of evidence indicating that the opposite appears to be true. For the depressive phenotypes we have considered—sickness behavior, starvation depression, and melancholia—serotonin transmission to multiple brain regions appears to be elevated…” (Andrews PW, et al., 2015)
“Several recent studies have implicated nitric oxide (NO) as a critical regulator of neuroinflammation, thus suggesting a possible role in the pathophysiology of MDD [Major depressive disorder]…Increased concentrations of NO enhance the production of reactive nitrogen species (RNS) and reactive oxygen species (ROS), which are associated with an increase in pro-inflammatory cytokines….evidences suggest that abnormalities in NO signaling may constitute a trait-marker related to MDD pathophysiology…” (Kudlow P, et al., 2016)
Science is now showing that many popular antidepressants designed to increase serotonin levels, are not only often ineffective in the treatment of depression, they can be responsible for a significant worsening of symptoms, as well as the promotion of inflammatory disease conditions.
Aspirin is known to be protective against diseases of stress and inflammation, and has also been demonstrated to have potential anti-depressant, anxiolytic, even antipsychotic effects.
A failure to distinguish between a temporary reduction of inflammatory symptoms (due to immune system and metabolism suppression), and a genuinely anti-inflammatory, pro-metabolic effect, means that sub-optimal (even harmful) treatment approaches for depression, remain popular.
“…substantially increasing EPA+DHA intake for 3 months was found not to have beneficial or harmful effects on mood in mild to moderate depression…Adding the present result to a meta-analysis of previous relevant randomised controlled trial results confirmed an overall negligible benefit of n-3 LCPUFA supplementation for depressed mood.” (Rogers PJ, et al., 2008)
Misconceptions regarding the significance of biochemical substances, can add weight to flawed arguments, such as those claiming that sugar promotes inflammation and mood dysfunction, or that fish oil is a beneficial, anti-inflammatory ‘medicine’, useful in the treatment of depression. When good quality biological evidence gets ignored or suppressed for financial (or other) reasons, this means important information can remain largely unknown, even to practitioners.
“Accumulating evidence implicates oxidative stress in the pathogenesis of several neurodegenerative diseases…Acrolein [a breakdown product of fish oil] is approximately 100 times more reactive…” (Lovell MA, et al., 2001)
Sugar (in the context of a metabolically supportive diet) can promote thyroid energy production and digestive function, and can help lower exposure to the inflammatory substances of stress and disease (including bacterial endotoxin, cortisol, estrogen, serotonin, nitric oxide and the polyunsaturated free fatty acids), all of which have been shown to increase susceptibility to depression, and other ‘psychological’ disorders.
Continuously high levels of stress, and interference with thyroid energy systems, increase activation of the sympathetic nervous system (suppressing digestion, impairing proper immune function and promoting mood destabilization), and some see depression as a kind of ‘allergy to modern life’.
Many different kinds of modern day stressors – including high intake of PUFAs, greater amounts of radiation and environmental poisons, social isolation, toxic culture and other harmful things – play a part in relation to rising susceptibility to infection and inflammation, and the high cortisol, high serotonin low energy states, common to depression.
Rather than trying to pinpoint one specific cause, examining the ways that things that inhibit optimal metabolic performance (including the different biochemical byproducts of suppressed metabolism), can be involved in inflammatory disease promotion, can make it possible for better approaches to healing to become known and available.
Looking at the ways that chronic inflammation or infection can cause depression, will be far more powerful and illuminating, in the context of an appreciation of the things that drive energy metabolism, and protect against excessive stress.
It isn’t that inflammation and infection cannot fuel depression. All kinds of metabolic issues can feed into each other in a circular fashion, and i think that’s one of the reasons why depression can be challenging to fix. It helps to know the ways that metabolism can impact upon the whole system, at a basic level.
I’m not a doctor, or health professional, but it makes sense to me, to question whether things proposed for therapy, are working in the same basic metabolic direction (improving thyroid function and energy metabolism), rather than encouraging forces that work against each other, slowing or preventing recovery.
A diet avoiding PUFAs, and limiting difficult to digest grains, seeds, nuts, legumes, and under cooked vegetable matter, with enough protein from milk, cheese and gelatin, and plenty of sugar from sweet fruits, fruit juice and white sugar, is one thing that has been shown to be able to assist with moving metabolism in the right direction.
Some other things that are known to help promote thyroid energy metabolism, and protect against inflammation and depression, include antibiotics (for eg. minocycline), activated charcoal, methylene blue, cyproheptadine, glycine, red light, niacinamide, coffee and caffeine, thyroid hormone, pregnenolone and progesterone, raw carrot fiber, well cooked mushrooms and more.
The way I see it, it doesn’t really matter so much whether an infection caused the inflammation which lead to the depression, or whether the depression was the result of some other form of ongoing stress. It’s all relevant, and can all be helpful information, but reducing exposure to stress and improving metabolism, can help even without knowing the exact reason it’s helping.
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