Depression as a dysfunction of the immune system

Summary: chronic inflammation due to immune system dysregulation, with or without a diagnosed autoimmune disease, plays a fundamental role in chronic depression. This offers sustainable and evidence-based treatments for depression and brain health.The authors of an important paper published in Current Immunology Reviews state:

...current antidepressants do not effectively target all of the pathological processes that are responsible for the major symptoms of depression...However, in recent years greater attention has been directed to the inter-relationship between the brain and peripheral organs (the” body-mind” connection) in which changes in the endocrine and immune systems play a major role in the pathological changes that occur in depression. Thus inflammation is beginning to emerge as a major contributing factor not only to depression and other major psychiatric disorders..."

Two major ways that immune dysfunction promotes depression are emphasized: the direct effect of inflammation on the brain, and the brain effects of the hormonal response to inflammation. Regarding the former:

"...in the past 30 years or so that clinical and experimental evidence has been obtained clearly demonstrating that aspects of both cellular and humoral immunity were dysfunctional in major depression...in particular the pro- and anti-inflammatory cytokines...Such clinical observations suggest that proinflammatory cytokines contribute to the major symptoms of depression and now forms the basis of the inflammation, cytokine or inflammatory response hypothesis of depression."

It's now known that peripherally derived inflammatory cytokines have access to the brain, including areas involved in depression...

"Once in the brain, the proinflammatory cytokines activated both neuronal and non-neuronal (for example, the microglia, astrocytes and oligodendroglia) cells via the nuclear factor-kappa-beta (NF-kB) cascade in a similar manner to that occurring in the peripheral inflammatory response...

Also, the production of serotonin and dopamine is adversely affected by inflammation:

"Recently much attention has been paid to the activation of the tryptophan-kynurenine pathway by these cytokines whereby tryptophan is shunted from the synthesis of serotonin to that of kynurenine...clearly this is an important mechanism whereby serotonergic function is decreased in depression. The activity of the dopaminergic system is also reduced in response to inflammation. For example, IFN reduces the synthesis of dopamine by decreasing the concentration of the co-factor tetrahydrobiopterin (BH4)...As IFN increases the synthesis of nitric oxide by activating the BH4 dependent enzyme nitric oxide synthase in the microglia it seems likely that the reduction in dopaminergic function is linked to the increase in nitric oxide. This gaseous neurotransmitter is known to activate the glutamatergic system which, when this exceeds physiologically limits, enhances apoptosis and neurodegeneration."

In other words, an increase in inflammatory cytokines derails the production of serotonin and dopamine, and activates the excitatory (glutamatergic) system to the point of cell death.Additionally, proinflammatory cytokines activate the HPA (hypothalamo-pituitary-adrenal) axis causing excessive cortisol production which is lethal to brain cells at high levels...

"In addition to the modulation of neurotransmitter function, proinflammatory cytokines contribute to the major symptoms of depression by activating the HPA axis by increasing the release of CRF, thereby contributing to hypercortisolaemia, a feature of major depression. The mechanism whereby the cytokines induce hypercortisolaemia involves a decreased sensitivity of the glucocorticoid receptors thereby leading to glucocorticoid resistance..."

The inflammation model also sheds light on the role of stress in depression:

"...as major depression is often accompanied by inflammatory diseases (such as irritable bowel syndrome, type 2 diabetes, arthritis and autoimmune disorders) that can activate the peripheral and central inflammatory response, it is possible that such inflammatory disorders initiate the inflammatory changes that precipitate depression....[But] it is evident that inflammation also occurs in depressed patients who are not suffering from concurrent inflammatory disorders. Thus the increased vulnerability of depressed patients to psychosocial stress is probably the key factor that leads to the activation of the immune and endocrine axes in depression. It is known, for example, that even the relatively mild acute stress of public speaking causes an increase in NF-kB activity, a key element in the induction of the inflammatory cascade. In this regard, it is also known that patients with major depression frequently show an enhanced responsiveness of IL-6 and NF-kB to an antigen challenge...such changes appear to be associated with activation of the microglia thereby suggestion that the inflammatory changes are also occurring in the brain."

In other words, patients with major depression have a more pronounced inflammatory response to substances to which they are sensitized or allergic to (antigens). This is in addition to an increased immune and hormonal response to psychosocial stress.Of special significance for the use of heart rate variability analysis for evaluation of the autonomic nervous system and therapies that increase parasympathetic tone...

"The mechanism whereby psychological stress influences both the peripheral and central inflammatory cascade is co-ordinated by the autonomic nervous system. Thus the release of noradrenaline and adrenaline following the activation of the sympathetic system results in the activation of both alpha and beta adrenoceptors on immune cells thereby initiating the release of proinflammatory cytokines, via the activation of the NF-kB cascade, particularly on macrophages and monocytes in peripheral blood...Conversely stimulation of the parasympathetic system has the opposite effect on the stress induced inflammatory response...It is possible that the anti-depressant-like action of vagal nerve stimulation, occasionally used to treat resistant depression, is associated with such an anti-inflammatory action."

Brain inflammation associated with depression actually causes the death of brain cells (apoptosis):

"Thus in major depression, the prolonged activation of the inflammatory network in the brain results in a decrease in neurotrophins, leading to reduced neuronal repair, a decrease in neurogenesis, and an increased activation of the glutamatergic pathway that contributes to neuronal apoptosis, oxidative stress and the induction of apoptosis in astrocytes and oligodendrocytes."

On top of all this, inflammation causes the biochemical pathway that produces serotonin from tryptophan to converted to the production of neurotoxins instead through the tryptophan-kynurenine pathway and the production of quinolinic acid.

"As both the cytokines and cortisol are raised in major depression, it is not surprising to find that the tryptophan-kynurenine pathway is increased....Kynurenine hydroxylase metabolises kynurenine first to 3-hydroxykynurenine and then to 3-hydroxyanthranilic acid and quinolinic acid. This pathway is increased in depression and dementia...In chronic depression...the activated microglia produce an excess of the neurotoxin...Furthermore quinolinic acid can cause apoptosis of the astrocytes. This results in a reduction in the metabolic and physical buffer to the neurons that is usually provided by the astrocytes and thereby further exposes the neurons to the neurodegenerative actions of quinolinic acid."

Inflammation in the brain over the long term causes neurodegeneration that appear as brain shrinkage:

"The structural changes observed in the brain of patients with chronic depression lends support to the neurodegenerative hypothesis of depression. It is known that there is a shrinkage of the hippocampus in patients with major depression and a decrease in the number of astrocytes and a neuronal loss in the prefrontal cortex and in the striatum. Such changes could be the consequence of chronic low grade inflammation in which the proinflammatory cytokines, nitric oxide, prostaglandin E2 and other inflammatory mediators play key roles; the cytokines are known to induce the cyclo-oxygenase and nitric oxide sythase pathways in the brain and thereby increase the inflammatory insult. The inhibition of neurotrophin synthesis in the brain by glucocorticoids, and the neurotoxic action of quinolinic acid, add further to the impact of the inflammatory changes."

There are indications that patients who respond poorly to neurotransmitter-manipulating medications have markers for increased inflammation:

"Further evidence for the relationship between inflammation and depression is provided by the observation that depressed patients with a history of partial or lack of response to antidepressant treatments have elevated plasma concentrations of IL-6 and acute phase proteins that persist despite antidepressant treatment. It has been suggested that patients who are resistant to conventional antidepressant treatment possess abnormal alleles of the IL-1 and TNF genes, and possibly for T-cell function."

Moreover, even when there is some relief from a depressed mood or anxiety with these medications...

"...there is abundant clinical evidence that the available antidepressants...are far less effective in treating the memory and cognitive dysfunction (fatigue, psychomotor retardation) that commonly affect middle aged and elderly depressed patients."

There is mounting evidence that modulating inflammation can improve the inflammatory response:

"There are already indications from the clinical literature that TNF antagonists...reduce the symptoms of depression in a variety of patients with autoimmune diseases...the mood state of the patients improving before the signs of improvement of the autoimmune disorder...IL-10, and insulin-like growth factor that has prominent anti-inflammatory activity, have been shown to attenuate the depressive-like behaviour in rodents induced by an inflammatory challenge."

IL-10 is increased by correcting suboptimal levels of vitamin D.

"Perhaps the most obvious step to the reduction of inflammation both centrally and peripherally is to reduce the activity of the prostenoid pathway and thereby reduce the synthesis of inflammatory prostaglandins such as PGE2."

This is exactly what is accomplished by correcting an omega-3 fatty acid deficiency with a low 3:6 ratio.The best chance for a sustainable program for helping depression by treating the inflammation is to determine with the appropriate tests why the excessive inflammation is happening in the first place. Then physiological and sustainable treatments can address those underlying causes properly. That brings up the very large topic of the functional management of autoimmune disease and chronic inflammation, a subject of many posts here and deserving of a weighty textbook. See posts forthcoming in the next week on the role of gastrointestinal inflammation as a contributing cause and treatment target for depression and the effectiveness of the omega-3 fatty acid EPA as a PGE2 reducer for depression.