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Inflammation Drives Susceptibility to Anxiety and Depression

By Roberta Attanasio

Stress and anxiety are part of life — but while a little bit of stress (good stress) may keep us active and alert, and sometimes even motivate us, the long-term type (bad stress) can have negative effects on our health.  Elevated blood pressure and heart disease are just some examples of the so-called “stress-related diseases”. In addition, chronic stress increases the risk of developing depression.

Scientists have known for many years that stress, anxiety and depression are linked to the inflammatory response — our first line of defense against infectious microbes. The link is provided by some of the chemical messengers, or cytokines, involved in this response. Patients with major depressive disorder and post-traumatic stress disorder produce higher levels of the cytokininterleukin 6 (IL-6). Is depression responsible for the increased cytokine levels, or are the increased cytokine levels responsible for the development of depression? Results from a new study published in the scientific journal Proceedings of the National Academy of Sciences (November 11, 2014) help to answer this question.

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Image credit: deviantART, licensed under CC BY-ND 3.0.

The study (Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress) was carried out by researchers at the Icahn School of Medicine at Mount Sinai (and their collaborators), using mice exposed to social stress. The researchers measured levels of IL-6 in mice prior to and after exposure to “repeated social defeat stress” and stress induced by witnessing the defeat of another mice. In experiments that involve repeated social defeat stress, non-aggressive mice are repeatedly subjected to bouts of social defeat by a larger and aggressive mouse placed in the same cage. In experiments based on stress induced by witnessing, mice watch another mouse face a larger, more aggressive mouse through a clear divider — this type of stress is considered purely emotional. When exposed to social stress, some of the non-aggressive mice, the so-called susceptible mice,  develop a clear depressive-like syndrome, which is characterized by long-lasting deficits in social interactions. termed “social avoidance” — mice prefer to spend more time near an empty cage rather than near another mouse.

The researchers found that IL-6 levels are higher in mice more susceptible to stress than in unstressed mice or in mice more resilient to stress. They also found that, in stress-susceptible mice, numbers of white blood cells that release IL-6 are higher than numbers in control groups. Moreover, the researchers found increased levels of IL-6 in two separate groups of human patients diagnosed with treatment-resistant major depressive disorder, thus validating the results obtained with mice. 

In additional experiments, the researchers transplanted a group of mice with white blood cells lacking IL-6, and treated another group of mice with antibodies that block the production of IL-6. Then, they exposed the mice to stress. Their findings show that, in both groups of mice, the development of social avoidance is reduced, suggesting that the emotional response to stress can be generated or blocked by IL-6. Together, results from the study indicate that the levels of IL-6 produced prior to stress exposure may be responsible for susceptibility or resilience to social stress. In other words, increased IL-6 levels may drive the development of depression.

Scott Russo, the leader of the research team, said in a press release: “Interleukin-6 could be a risk factor for the development of depression in vulnerable individuals. We believe our studies could have significant impact on the development of new antidepressant therapeutics that inhibit IL-6, which may reduce stress-induced relapse in patients with major depressive disorder.”

In their paper, the researchers point out that the differences between stress-susceptible and stress-resilient mice are not genetic and might be due, instead, to environmental factors.

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Author: Roberta Attanasio

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19 Comments

  1. “Is depression responsible for the increased cytokine levels, or are the increased cytokine levels responsible for the development of depression?” This is one of those nature vs. nurture/ “chicken or egg” questions that has kept us scratching our heads for a while. There is definitely some evidence that depression and other disorders are cytokine-mediated. According to this research study, cytokines such as IL-1β, IL-6 and γ-IFN play a role in stress and depression. This study states that these cytokines are increased under stress and depressive conditions. Now when discussion stress and depression, there is a general rule that the hormones of the HPA (hypothalamus, pituitary and adrenal gland) axis are involved. The question that I think that should be asked is whether or not hormones such as cortisol and serotonin induce the release of cytokines or does the buildup of cytokines promote the release of these hormones. It is also known that depression is a mental state. Therefore, another question that should be asked is whether or not these cytokines and hormones are playing a direct role in neural modifications whilst being in a state of depression; or is an actual neural change causing these cytokines and hormones to be secreted in excess. I believe in future research, there potentially could be a categorical lining of various cytokine/hormone levels that people associate to with various disorders (stress, depression, suicidal personality, etc.)

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    • “The body is one big complex machine that has many parts working together to give an overall response.” Just like you have mentioned, with the release of IL 6 and other cytokines during a stress response, we have the release of many hormones. The “fight or flight” response generated by the systemic pathway during a physiological stress stimulus is responsible for the many hormones that are generated throughout the body. These hormones increase blood pressure, heart rate, metabolism, and airways and pupils also get dilated. All these responses happen because of an emotional or physical form of stress. This is related to your comment on how both the immune system and the autonomic nervous system get activated with response to stress. However, an over activation of both of these responses can lead to many of the “stress- related diseases” that are more common now than ever before.

      http://stresscourse.tripod.com/id11.html

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  2. The study shows that some stress is good in alerting us however; chronic stress is harmful in that it can lead to depression and anxiety. Depression and anxiety are terms that are becoming very common however; the effects on the body and mind are very detrimental. Based on research, this paper summaries how pro-inflammatory cytokines like IL6 are correlated to depression and anxiety. The connection between high plasma levels of IL 6 and depression has opened a wide area of research for inflammatory cytokine intervention. The American Journal of Geriatric Psychiatry has been doing much research for a link between inflammation and many forms of mental decline. In one study, it has been presented that high levels of IL 6 are seen in many elder adults that are having sleep problems. It’s also evident that when stressed about studies or exams, students tend to have hard time sleeping or have no sleep at all the night before an exam. In many situations that involve stress and high levels IL 6, both sleep and memory take a hard hit. In the same journal, another study was done to see the correlations between IL 6 and memory. It was seen that individuals that had higher levels of IL 6 due to stress or anxiety had poor memory. This is also again seen in many college students who cram the night before exams, they are under a lot of stress and therefore, their memory is not working well and they don’t retain as much information. Depression and anxiety might be terms we associate with people who stay at home or away from social gatherings, but in reality we all sense stress and anxiety throughout our life. We just have to realize the effects of stress and anxiety on our sleep and memory and decide if it is a good thing to stress before an exam or any other situation.

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  3. Stress, depression and anxiety are complex medical conditions that researchers are still trying to fully understand. As the study was very informative, explaining the connection between IL-6 levels and depressive symptoms, there could be other factors that affect depression. A recent article by Dr. Kelly Brogan explains how vitamin B12 deficiency has a great impact on the body that can eventually lead to depression. B12 has several important functions that include normal functioning of the brain and nervous system as well as formation of blood. This led to me investigate whether vitamin B12 and cytokine IL-6 have a connection. I did some research and came across this study by Scalabrino et. al that explains how vitamin B12 positively regulates IL-6 in cerebrospinal fluid of rats. Perhaps there may have been low levels of B12 in the mice that were studied by researchers at the Icahn School of Medicine at Mount Sinai. I believe that the relationship between B12 and IL-6 should be further studied in order to successfully control depression or anxiety and its symptoms.

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  4. The results from this study are captivating, especially when considering the amount of individuals whom are diagnosed with depression every year. With the assistance of researchers finding an antidepressant using a therapeutic treatment that inhibits IL-6, we may recognize a reduction in the number of patients whom undergo relapse. Researchers have learned that IL-6 effects depression by repressing the brain-derived neurotrophic factor (BDNF), which is responsible for the survival, growth and differentiation of neurons. Being that it is located in the hippocampus, when IL-6 is upregulated it causes BDNF to undergo downregulation, thereby decreasing the connectivity in the brain, resulting in the individuals depression. IL-6 mediates this morphing of connectivity by altering BDNF function, which consequently leads to a depressive reaction. Therefore, if researchers are able to not only inhibit IL-6, but also prevent BDNF from being altered, then accordingly we will recognize fewer individuals whom suffer from depression.

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  5. For the first time I read this article, I was wondering where did the IL-6 come from if IL-6 was responsible for the depression. It seems there is no reason that IL-6 is just upregulated and causes depression. So I did some research and was thinking if this was the case. Social stress resulted from repeated defeat by large aggressive mouse is a short term reaction. During the process, a fight or flight reaction is triggered and acetylcholine is released to dialect the blood vessels. The releasing of Ach causes production of nitric oxide. NO also regulates immune response and mimic the situation of inflammation. Under this condition, cytokines are then released. The process repeats during the experiments and constant release of cytokines, IL-6 in this case, leads to the depression, which is a long-term situation comparing with social stress at the first time. Let me know if this is reasonable.

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  6. The symptoms of chronic stress and depression have robust implications on our body, thoughts, feelings, and our behavior. While increased levels of proinflammatory cytokines may contribute to depression, dysregulations in the body manifested by depression may also effect the immune system. Not only is the activity of the immune system affected directly by stress hormones (adrenaline, cortisol), but other symptoms of stress such as lack of sleep and anhedonia may also influence the immune system. For example, lack of deep sleep is common amongst individuals with depression and results in a weakened immune system. Some studies report that sleep deprivation is associated with increased levels of pro-inflammatory cytokines including IL-6 and TFN-α However, studies also note a bi-directional communication between sleep and the immune system. This topic demonstrates how complex the interaction is between chronic stress and immune system functions. Due to the plethora of factors associated with chronic stress/ depression and the immune system, it is difficult to distinguish whether the symptoms of depression influence the alteration in activity of cytokines or whether it’s the alterations in cytokines that manifest the symptoms of chronic stress.

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  7. Like with all good drug targets, I was wondering what would the negative side effects be of inhibiting IL-6. I have found a couple of different studies that look into these side effects. One study shows that the inhibition or complete knock out of IL-6 is linked to obesity and development of Type 2 diabetes Another study shows a impaired immune system. This is something that is to be expected. IL-6 is current a drug target in rheumatoid arthritis which is used as an immune system inhibitor. With a impaired immune system there is a chance of cancer being a issue. All of these factors need to be weighted against the benefits of blocking IL-6 for depression.

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  8. If depression or stress anxiety is causing an increase of Il-6, then this might be due to high levels of Interleukin-6 inhibiting neurotransmitter release, such as dopamine, serotonin, and norepinephrine in the brain.These neurotransmitters are linked to depression, which helps regulate the brains reward and pleasure centers. Depression is a lack/excess activity in many regions of the brain. Some examples of depression in the brain are the hypothalamus, pre-frontal cortex, frontal lobe, and etc. Cytokines are presented everywhere in the body to aid cell signaling. IL-6 is one of the many cytokines that is secreted by T cells and macrophages where trauma is presented. If there is an excess of IL-6, then this might prevent neurotransmitters releasing or causing an overproduction of neurotransmitters. This will stop signals being sent to neurons to decrease the activity of depression.

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  9. While the results of the study provide compelling evidence of IL-6’s involvement in the stress response which contributes to depression, I think we should consider the possibility that it may only be coincidental. Let us take into account one current medicinal therapy widely used at this time, selective serotonin reuptake inhibitors (SSRI). This class of drug is effective at treating major depressive disorder by inhibiting the reuptake of serotonin and thus results in increased levels of serotonin in the brain which elevate mood and affect. Research has shown that people with depression have lower levels of serotonin in the brain according to this Harvard Health article. I believe the researchers should seek a correlation of IL-6 and decreased brain serotonin levels to strengthen their assertions.

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    • I did read that researchers have observed a decrease of IL-6 in serum levels during treatment with the serotonin re-uptake inhibitor drug Fluoxetine (i.e. Prozac). They used a population of 22 people that were inpatients diagnosed with major depression and they treated these patients for 8 weeks with Fluoxetine. Among their immune biomarkers that they studied was IL-6. These researchers found that treatment with the antidepressant Fluoxetine decreased IL-6 concentrations at baseline. But like you said, what about those people with low/- serotonin levels? How does this drug treatment help those with high levels of IL-6 if the therapeutic treatment has nothing to target (i.e. low/- serotonin levels)? I found this paper to support the idea that elevated IL-6 levels act as a key contributor of depressive-like phenotypes Mice were subjected to systemic administration, drug administration directly into the circulatory system, of Fluoxetine in the presence of centrally administered IL-6. These mice did not produce an antidepressant-like response to the fluoxetine. Also, mice that showed an endogenous over-expression of brain IL-6 also did not produce an antidepressant-like response to the treatment like what was observed in the Fluoxetine-treated control mice. Do you think that increased IL-6 levels are negatively regulate serotonin levels? Maybe combination therapy would be necessary where one drug targeted IL-6 levels and the other targeted neurotransmitters.

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      • Thanks for the article, it elaborated more on the relationship between IL-6 and neurotransmitters that I was seeking. To answer your question, I believe it is entirely possible that elevated IL-6 levels may affect brain serotonin levels and that the two act concomitantly to contribute to depression. However, thanks to the article you provided, I now wonder if there are two separate pathways for depression considering that some test subjects demonstrated treatment-resistant depression in the presence of increased IL-6. Do you think increased IL-6 levels contribute to depression through a different mechanism that is independent of serotonin levels? This would make sense given the conclusions of the paper.

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  10. IL-6 has been targeted for drug therapy in inflammatory autoimmune diseases and cancer. Researchers found in clinical studies tocilizumab, an anti-IL-6 receptor antibody, was an effective treatment of rheumatoid arthritis. They also found in the treatment of cancer a combination therapy with IL-6 blockade and conventional drugs is required to be an effective treatment. Autoimmune diseases can also be induced by chronic stress by the up regulation of IL-6. While stress causes the disease, the disease can also cause stress creating a horrible cycle. Individuals caught in this cycle could be considered “vulnerable individuals” to the risk factor of IL-6. Perhaps targeting IL-6 for drug therapy could be useful in preventing both the autoimmune disease progression, and the psychological depression that patients undergo when suffering from autoimmune disease. I think it would be interesting to study autoimmune diseases that are considered to be induced by “environmental factors” and find IL-6 up regulation to be the cause as a result of environmental stress on the individual. It would also be interesting to look at it from a genetics point of view. Maybe individuals are more susceptible to IL-6 up regulation due to environmental stress because of their genetics. Does this susceptibility always exhibit itself in the form of the same disease?

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  11. I think it would be beneficial to look into the dysregulation of inflammation and how it is associated with suicidal behavior since we know there is a direct link to depression. It has been found that high plasma IL-6 levels tend to be a characteristic among individuals of violent suicide attempts. It might be possible for suicidal behavior to be further explained if there is evidence indicating a relation between impulsivity and high levels of IL-6 in the cerebrospinal fluid. It would also be interesting to learn if inflammation is what actually triggers aggression or if it is the aggressive feelings that are the actual cause of inflammation. This could lead to further research to see if there is correlation to the choice of suicide attempt methods.

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  12. A similar study using Il-6 Knockout mice suggests that Il-6 is indeed required to induce stress which can lead to depressive behavior. The group used behavioral tests such as a forced swim test, tail suspension test, and footshock procedure that lead to depressive-like behavior to measure the stress response of wildtype and knockout mice. They also measured Il-6 levels in the hippocampus of wildtype mice following the footshock procedure. What they found was that Il-6 knockout mice exhibited less depressive-like behaviors than wildtype mice. They had reduced despair behavior in the swim and tail suspension tests as well as a resistance to develop learned helplessness. They also found that wildtype mice had increased levels of Il-6 in the hippocampal region following the footshock procedure. This therefore indicates that Il-6 is involved in the development of depression and that higher levels of Il-6 can lead to depressive-like behavior. Whether other cytokines may be involved in depression is yet to be ascertained but I believe that other factors are also involved in addition to Il-6 and their discovery could pave the way to developing better treatments for depression.

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  13. Levels of IL-6 are also associated with cognitive function in several studies. The article Interleukin-6 predicts short-term global functional decline in the oldest old stated that among a set of inflammatory markers, IL-6 was the best marker for predicting short-term global functioning. An increase in IL-6 level will cause a decrease in global function leading to a lower code on the Global Assessment of Function. The lower the code on the assessment of function the higher the severity. Therefore, person with schizophrenia will have a lower code on the Global Assessment of Function . The article stated that the high levels of IL-6 preceded the decrease of global functions in physical and mental aspect except for symptoms of depression which contradicts the idea that increased level of IL-6 may lead to development of depression in the study Individual differences in the peripheral immune system promote resilience versus susceptibility to social stress . Even though IL-6 may be the main cytokine associated with global functioning and stress, there may be other cytokines involved that produce a synergistic effect when coupled with IL-6. Researchers shouldn’t limit their focus to only IL-6 but also how other cytokines can inhibit or enhance IL-6 activity.

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  14. The researchers believe that only having an increased level of IL-6 may cause depression, but maybe having a decreased level of IL-6 can lead to the development of depression as well. IL-6 and other cytokines are not only important in helping overcome infections in the body, but overcoming issues that effect the brain such as depression. Cytokines at normal levels have a positive impact on the brain by helping forming memories, learning and developing new neurons. I believe that it will be beneficial to research individuals with both a low level of IL-6 and a high level of IL-6 to determine if a certain level of IL-6 is necessary to reduce anxiety and depression. If a specific amount of IL-6 present in the body will help to eliminate the symptoms of depression then it is not beneficial to completely inhibit it. The research should be broaden, as to confirm that the production IL-6 will not at all be necessary to get rid of depression. Maybe the researchers solution is not a one size fits all scenario, but more unique to specific individuals and their genetic makeup.

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  15. It is important to highlight that IL-6 is capable of crossing the blood-brain barrier (BBB) in our bodies in order to cause a cytokine-induced sickness behavior such as depression. By crossing this barrier, IL-6 and other cytokines such as TNF-alpha will affect the function of our central nervous system. How? Researchers have found many direct passages of how cytokines cross the BBB such as simple diffusion. The Blood Brain Barrier and the Role of Cytokines in Neuropsychiatry
    Although the role of cytokines in mental diseases still quite unknown, few studies have shown that these findings could be very helpful to also understand major psychiatric diseases. For example, IL-6 has a powerful effect on neurotransmitter activities that are linked not only with depression but also schizophrenia. This fact caught my attention because schizophrenia is a chronic, severe disease compared to depression and I also thought this was an only an inherited disease. However, our immune system is involved causing this chronic disease and some sources that describe schizophrenia do not even mention that cytokines are also involved. Cytokines in schizophrenia I believe this is due because few people know about these developments that even practicing psychologists and psychiatrist are unaware of the growing revolution in their own field. Therefore, I think is important to do more research about cytokines linked with our CNS in order to inform people such medical professionals to understand schizophrenia and other mental illness.

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  16. Although the researchers suggest that the differences between stress-susceptible and stress-resilient mice may be due to to environmental factors, the group has yet to study every genetic factor that may cause stress/depression. I understand that trying to study every possible genetic and environmental factor would be too difficult of a task, but one genetic factor may be worth looking into: the regulation and expression of the IL-6 receptor.

    The group did a great job by removing the production of IL-6 through a bone marrow transplant and using antibodies to stop the production of IL-6 but never blocked the IL-6 receptor. Both IL-6 and IL-6 receptor are needed for such phenotypes to occur. Absence of IL-6 receptors may still cause stress-resilient mice (among other deficiencies that may be associated with a lack of IL-6 receptor) and over-expression of IL-6 receptors may still cause stress-sensitive mice. If any of these situations or combinations of situations are true, then genetics still does play a role in stress and depression. This could explain any of the few individuals who had depression but did not exhibit increased IL-6 levels because they are genetically predisposed to depression due to increased IL-6 receptors instead of the cytokine itself.

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