Flaming Depression!

MraaaEven though the idea that inflammation causes depression is reasonable and 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 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.

“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.”

“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.”

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.

“Examination of metabolic disorders in treatment-refractory depression identified an unexpectedly large proportion of patients with potentially treatable abnormalities.”

“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…”

“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…”

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 is responsible for the inflammation, which then leads to depression. Although this is likely a valid argument, 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 potentially being an essential 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.”

“…subclinical hypo-thyroidism patients have increased inflammatory markers…Level of inflammatory markers increases in patients as disease progress if left untreated.”

“…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…”

Exposure to stress causes blood sugar to be used up at an increased rate, and this is more so the case when metabolism is already under functioning. When blood sugar runs low, the stress hormones cortisol and adrenalin, 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.

“…we revealed a high-risk subtype…demarcated by both high depressive symptoms and elevated cortisol levels…”

“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…”

“…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…”

Stress and hypoglycemia play a significant role in the promotion of thyroid dysfunction and depression, and high cortisol and hypothyroidism often fuel eachother. 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…”

“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…”

“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”

Stress promotes adrenalin, and adrenalin increases the release of stored polyunsaturated fats (PUFAs) into the blood stream, causing thyroid 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.”

“When patients with depression were compared with healthy controls, depression was associated with higher oxidative stress MDA [malondialdehyde…a breakdown product of PUFA] levels…”

“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.”

“…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…”

Stress can promote hypoglycemia as well as hyperglycemia, and both low and high blood sugar can potentially lead to an increased susceptibility to infection.

“…stress-induced hyperglycemia…has been described as a significant contributor to posttraumatic infectious complications…”

“…hypoglycemia is significantly associated with 30-day mortality for patients hospitalized with pneumonia…”

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…”

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).

“…hypothyroidism is associated with bacterial overgrowth development. Excess bacteria could influence clinical gastrointestinal manifestations…”

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.”

“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.”

“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.”

“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.”

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…”

“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.”

“…in response to lipopolysaccharide [endotoxin], human monocytes secrete IL-1β independently of classical inflammasome stimuli.”

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…”

Eventually, this can create a vicious circle type stress situation, 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 including estrogen, nitric oxide and serotonin, all potentially promoting depression.

“…higher body iron was found to be associated with higher depressive symptoms among young adult males…”

“…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…”

“…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.”

“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.”

“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.”

All of these kinds of metabolic changes can potentially feed into 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 popular 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.

“This study demonstrates that mild hypothermia affects the balance of cytokines produced by monocytes, leading to a pro-inflammatory state.”

“Whole-body hyperthermia holds promise as a safe, rapid-acting, antidepressant modality with a prolonged therapeutic benefit.”

“Here we show that 5-HT [serotonin] from the dorsal raphe nucleusenhances 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.”

Misinterpretations (as well as misrepresentations) regarding the significance of a few important biochemical 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…”

“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…”

Science is now showing that popular antidepressants which 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 promoting inflammatory disease in general.

Aspirin is known to protect against many of the diseases of stress and inflammation, and has also been demonstrated to have potential anti-depressant, anxiolytic, even antipsychotic effects.

“Our results suggest that aspirin can serve as a potential antidepressant both individually and as adjuvant agent in the treatment of depression.”

A failure to distinguish between the temporary reduction of inflammatory symptoms via immune system suppression, and a genuinely anti-inflammatory effect resulting from improvements in metabolic function, makes it likely that ineffective and counter-productive treatment methodologies for depression, continue to be 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.”

Misconceptions regarding the biological significance of a variety of substances, add weight to flawed arguments, such as those claiming that sugar promotes inflammation and mood dysfunction, and that fish oil is a beneficial, anti-inflammatory ‘medicine’, useful in the treatment of depression. Because whole fields of biological experimentation are largely ignored for political and financial (and other) reasons, this means important information remains unknown to many 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…”

Sugar (in the context of a metabolically supportive diet) promotes thyroid energy production and digestive function, and directly lowers 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 mood disorders.

Continuously high levels of stress, and interference with thyroid energy systems, can 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 chemical toxins and poisons in the environment, social isolation, authoritarian school and workplace cultures and other things – all have a part to play in relation to 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 many different biochemical byproducts of suppressed metabolism) can be involved in inflammatory disease promotion in general, 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 stress.

That way it’s then likely to become more obvious that the treatment of one metabolic issue, will also usually become a part of the treatment of metabolic issues in general.

It isn’t that inflammation and infection do not fuel depression. I would say they all feed each other in a circular fashion, and that’s one reason why they can be challenging to fix. The one thing they all do have in common is metabolism, because metabolic function impacts upon the whole system.

And so 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 opposing forces, potentially limiting recovery.

A diet avoiding PUFAs, and restricting difficult to digest grains, seeds, nut, legumes and under cooked vegetable matter, with enough protein from milk, cheese and gelatinous meat, and plenty of sugar from sweet fruit, fruit juice and white sugar, is one way to go about moving metabolism in the right direction.

Some other things that can help promote energy metabolism and protect against inflammation and depression, include antibiotics (like 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.

I’m no expert, but 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 improving metabolism can work, without necessarily knowing the exact reasons why.

See More Here

Changes in Gut Microbiota Control Metabolic Endotoxemia-Induced Inflammation in High-Fat Diet–Induced Obesity and Diabetes in Mice

Thyroid Hormones, Oxidative Stress, and Inflammation

Depression, anxiety disorders, and metabolic syndrome in a population at risk for type 2 diabetes mellitus

Association between hypothyroidism and small intestinal bacterial overgrowth.

Mild hypothermia promotes pro-inflammatory cytokine production in monocytes.

Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia.

The role of endotoxin in infection: Helicobacter pylori and Campylobacter jejuni.

Effects of aspirin on immobile behavior and endocrine and immune changes in the forced swimming test: comparison to fluoxetine and imipramine.

Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness

Prostaglandins mediate depressive-like behaviour induced by endotoxin in mice.

Role of serotonin in intestinal inflammation: knockout of serotonin reuptake transporter exacerbates 2,4,6-trinitrobenzene sulfonic acid colitis in mice.

In vivo serotonin release and learned helplessness.

Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems.

Serotonin, inflammation, and IBS: fitting the jigsaw together?

Serotonin engages an anxiety and fear-promoting circuit in the extended amygdala

Increased Root Canal Endotoxin Levels are Associated with Chronic Apical Periodontitis, Increased Oxidative and Nitrosative Stress, Major Depression, Severity of Depression, and a Lowered Quality of Life.

Beneficial effect of aspirin against interferon-α-2b-induced depressive behavior in Sprague Dawley rats.

Are there differences in lipid peroxidation and immune biomarkers between major depression and bipolar disorder: Effects of melancholia, atypical depression, severity of illness, episode number, suicidal ideation and prior suicide attempts.

Oxidative Stress and Antioxidant Parameters in Patients With Major Depressive Disorder Compared to Healthy Controls Before and After Antidepressant Treatment: Results From a Meta-Analysis

Nitric Oxide and Major Depressive Disorder: Pathophysiology and Treatment Implications.

High Fat Diet Alters Lactation Outcomes: Possible Involvement of Inflammatory and Serotonergic Pathways

Acute induction of anomalous and amyloidogenic blood clotting by molecular amplification of highly substoichiometric levels of bacterial lipopolysaccharide

Causes and consequences of low grade endotoxemia and inflammatory diseases.

Increased estrogen level can be associated with depression in males.

JNK1 controls adult hippocampal neurogenesis and imposes cell-autonomous control of anxiety behaviour from the neurogenic niche

Elevated morning cortisol is a stratified population- level biomarker for major depression in boys only with high depressive symptoms

Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial.

Is serotonin an upper or a downer? The evolution of the serotonergic system and its role in depression and the antidepressant response

Rapid recovery from major depression using magnesium treatment.

Neurometabolic Disorders: Potentially Treatable Abnormalities in Patients With Treatment-Refractory Depression and Suicidal Behavior

Serotonin Synthesis and Reuptake in Social Anxiety Disorder

Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression

A meta-analysis of lipid peroxidation markers in major depression

Opposing Effects of Fasting Metabolism on Tissue Tolerance in Bacterial and Viral Inflammation.

Whole-Body Hyperthermia for the Treatment of Major Depressive Disorder: A Randomized Clinical Trial.

Depression and sickness behavior are Janus-faced responses to shared inflammatory pathways

alpha-Tocopherol administration produces an antidepressant-like effect in predictive animal models of depression.

Changes in serum cortisol levels during community-acquired pneumonia: the influence of dexamethasone.

Higher Body Iron Is Associated with Greater Depression Symptoms among Young Adult Men but not Women: Observational Data from the Daily Life Study

Cortisol Secretion in Depressed and At-Risk Adults

Antidepressant-like effect of α-tocopherol in a mouse model of depressive-like behavior induced by TNF-α.

Maternal Inflammation Disrupts Fetal Neurodevelopment via Increased Placental Output of Serotonin to the Fetal Brain

Subclinical hypothyroidism is linked to micro-inflammation and predicts death in continuous ambulatory peritoneal dialysis

Prostaglandin-mediated inhibition of serotonin signaling controls the affective component of inflammatory pain

Relationship of Hyperglycemia and Surgical-Site Infection in Orthopaedic Surgery

Inflammatory responses and inflammation-associated diseases in organs

Oxidative Stress and Major Depression

Association of Hypoglycemia with Mortality for Subjects Hospitalized with Pneumonia

Inflammatory markers in patients with hypothyroidism and diabetes mellitus type 1.

The antiviral effector IFITM3 disrupts intracellular cholesterol homeostasis to block viral entry

No effect of n-3 long-chain polyunsaturated fatty acid (EPA and DHA) supplementation on depressed mood and cognitive function: a randomised controlled trial.

C/EBPε mediates nicotinamide-enhanced clearance of Staphylococcus aureus in mice

HPA Axis in Major Depression: Cortisol, Clinical Symptomatology, and Genetic Variation Predict Cognition

So depression is an inflammatory disease, but where does the inflammation come from?

Acrolein is increased in Alzheimer’s disease brain and is toxic to primary hippocampal cultures.

Human Monocytes Engage an Alternative Inflammasome Pathway

Neutrophils support lung colonization of metastasis-initiating breast cancer cells

Metabolic syndrome and major depression.

Structural and functional rejuvenation of the aged brain by an approved anti-asthmatic drug

An oxidized metabolite of linoleic acid stimulates corticosterone production by rat adrenal cells.

Study on Subclinical Hypothyroidism and its Association with Various Inflammatory Markers

Associations of salivary cortisol levels with inflammatory markers: the Multi-Ethnic Study of Atherosclerosis

Role of Cytokines in the Pathogenesis and Suppression of Thyroid Autoimmunity

Dengue virus NS1 protein activates cells via Toll-like receptor 4 and disrupts endothelial cell monolayer integrity.

Nitric oxide and virus infection

The Relationship Between Depression and Metabolic Syndrome: Systematic Review and Meta-Analysis Study

Relationships between inflammatory cytokine and cortisol responses in firefighters exposed to simulated wildfire suppression work and sleep restriction

Elevated thyroid stimulating hormone is associated with elevated cortisol in healthy young men and women

The hypoglycemic side of hypothyroidism

The Nitric Oxide Theory of Aging Revisited

Increased plasma nitric oxide metabolites in suicide attempters.

Elevated plasma nitrate levels in depressive states.

Thyroid hormones and the interrelationship of cortisol and prolactin: influence of prolonged, exhaustive exercise.

A critical review of human endotoxin administration as an experimental paradigm of depression

Improvement of blood inflammatory marker levels in patients with hypothyroidism under levothyroxine treatment

Minocycline attenuates lipopolysaccharide (LPS)-induced neuroinflammation, sickness behavior, and anhedonia

Glucose Metabolism in the Insula and Cingulate is affected by Systemic Inflammation in Humans

Inflammation-Induced Anhedonia: Endotoxin Reduces Ventral Striatum Responses to Reward

An fMRI Study of Cytokine-Induced Depressed Mood and Social Pain: The Role of Sex Differences

Inflammation Selectively Enhances Amygdala Activity to Socially Threatening Images

Neural response to emotional stimuli during experimental human endotoxemia.



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