Flaming Depression!


Even though the idea that inflammation causes depression is not without validity, things have a tendency to go off the rails when it comes to popular explanations for why this might be the case and what should be done about it.

The truth is it isn’t always possible to make a black and white distinction between symptoms and causes, and this is relevant to the relationship between inflammatory processes and mood disorders like depression or anxiety.

“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 of the symptoms of stress or metabolic suppression go on to promote further interference with metabolism, and because of this it can sometimes be difficult to work out what caused what.

The good news is that if you take a 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 a number of reasons why inflammation is closely associated with depression.

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

“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…”

One recently fashionable suggestion is that an infection of some kind is responsible for the inflammation which then leads to depression. Although this isn’t inconceivable, it’s worth discussing the elements which could be behind the simultaneous promotion of all three of these things and more.

The proper functioning of thyroid metabolism is a central factor protecting against chronic 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.”

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 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…”

Increased adrenalin increases the release of polyunsaturated fats 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.

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

Both low and high blood sugar can cause 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…”

When thyroid function is interfered with, digestion 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 toxic substances such as bacterial endotoxin.

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

Endotoxin can directly promote infection, as well as causing serotonin and nitric oxide levels to rise. Serotonin, nitric oxide and endotoxin can both foster inflammation throughout the intestine, and cause interference with mitochondrial energy systems.

“…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.”

This can result in a reduction in intestinal barrier capability, allowing for these (and other) potentially harmful substances to be released in greater amounts into the system, leading to a more generalized inflammatory state and an increasingly chronic level of 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 there can be a vicious cycle involving inflammatory materials including endotoxin, circulating iron, the polyunsaturated free fatty acids, the prostaglandins and cytokines and rising levels of stress substances including estrogen, nitric oxide and serotonin.

“…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 results in…an increased capacity to produce 5-HT which has previously been shown to…be a potent stimulator of inflammation.”

It can all potentially feed into a chronically blood sugar dysregulated high stress state, increasing susceptibility to many kinds of illness.

Depression is in many ways an energy deficient, hypothermic hibernation-like state, and although the popular belief that serotonin is necessary for happiness is extremely profitable, experimental evidence suggests that high serotonin is a driver of mood instability and 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…”

Misinterpretations (as well as sometimes misrepresentations) regarding the significance of a few important biochemical processes (like viewing serotonin 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…”

Science is now showing that popular antidepressants which increase serotonin levels are not only ineffective in the treatment of depression, they can be responsible for a 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 of improvements in metabolic function makes it more likely that treatment methodologies for depression which end up being counter-productive in the long term 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…”

These kinds of misconceptions add weight to flawed arguments claiming that sugar promotes inflammation and mood related issues and that fish oil is anti-inflammatory and a useful substance in the treatment of depression.

“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…”

Exposure to 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’.

Modern day stressors – including high intake of polyunsaturated fats, greater amounts of radiation and chemical toxins and poisons in the environment, social isolation, authoritarian school and workplace cultures – all have a part to play in relation to susceptibility to infection and inflammation and the the high cortisol high serotonin low energy states common to depression.

Rather than trying to pinpoint one cause, seeing how things that prevent optimal metabolic performance – including symptoms of suppressed metabolism – can be involved in disease promotion in general can make it possible for better approaches to healing to become available.

Looking at ways that chronic inflammation or infection cause depression will be far more worthwhile in the context of an appreciation of things that drive metabolism and protect against stress.

That way it should become more obvious that the treatment of one will usually also be part of the treatment of the others.

It’s a good idea to question whether things proposed for therapy are working in the same basic direction encouraging thyroid function and improving energy metabolism.

This way it doesn’t matter so much whether an infection caused the inflammation which lead to the depression or whether it was the result of some form of ongoing stress, because it will all be helpful information.

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

Association between hypothyroidism and small intestinal bacterial overgrowth.

Mild hypothermia promotes pro-inflammatory cytokine production in monocytes.

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

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.

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

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

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

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

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.

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

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

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

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

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

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

Relationship of Hyperglycemia and Surgical-Site Infection in Orthopaedic Surgery

Association of Hypoglycemia with Mortality for Subjects Hospitalized with Pneumonia

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

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

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.

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

Nitric oxide and virus infection

The Nitric Oxide Theory of Aging Revisited

Increased plasma nitric oxide metabolites in suicide attempters.

Elevated plasma nitrate levels in depressive states.

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



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