Inflammation and Suicide Study

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Inflammation and Suicide Study

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How the Immune System Influences Suicidality
Inflammatory chemicals can increase the risk of suicide


September 14,2020.


https://www.psychologytoday.com/us/blog ... uicidality

Suicide is the devastating result of complex interactions among multiple factors. To afflicted individuals, psychological pain becomes intolerable, and death seems to be the only option for escaping the pain. The specific biological changes in the brain that produce these overwhelming feelings are not completely understood. New evidence suggests that the immune system plays a significant role .

Clinical depression is the most common psychiatric disorder associated with completed suicides. It is likely that areas of the brain that are functioning abnormally in depression predispose a person to suicidal thinking.

Certain personality traits such as impulsivity may also increase the risk of suicide. This may be especially true in younger individuals. Environmental and social adversity may also contribute to suicidality.

Lena Brundin and colleagues recently published a paper in the journal Neuropsychopharmacology entitled “Role of Inflammation in Suicide: From Mechanism to Treatment.”
As we discussed in our last post, the immune system is intimately involved in brain functioning. In their paper, Brundin and colleagues review a substantial amount of data demonstrating that immune mechanisms can contribute to suicidality.

This evidence is multifaceted. For instance, certain types of medications used to treat cancers by enhancing immune responses increase the risk of depression and suicidal thinking. Specific autoimmune disorders that attack the brain are also associated with increased suicidal behaviors. Multiple sclerosis and lupus are examples of such disorders. The immune system responds to fight infections, and certain brain infections are associated with increased suicidal behaviors.

Traumatic brain disorders are also associated with inflammatory responses in the brain and can lead to behavioral changes including suicidal thinking.


Investigators have found that specific immune-related chemicals that mediate brain inflammatory responses are elevated in persons with suicidal behaviors. Similarly, levels of these chemicals have been shown to be increased in the brains of persons who died from suicide.

Certain medications diminish suicidal thoughts. For example, lithium, a drug helpful in treating bipolar disorder, diminishes the risk of suicide. One of lithium’s biochemical actions is to decrease levels of immune-related chemicals. A very different medication, ketamine, has recently been shown to rapidly diminish depressive symptoms and suicidal thoughts. Ketamine has several effects; one of these is the ability to block some of the chemicals involved in the immune response.

Brundin and colleagues present cogent arguments that immune-related mechanisms can influence suicidal behaviors especially in the context of increased depressive thinking. Stimulating the production of pro-inflammatory chemicals in the brain is associated with increased depressive symptoms (particularly “sickness behaviors” such as dysphoria, sleep pattern changes, appetite changes, and fatigue among others) and suicidal thoughts. On the other hand, decreasing levels of immune chemicals in the brain may be associated with diminished depressive thinking and suicidal thoughts.


Does this mean that medications that block the action of certain immune-related chemicals could have anti-suicidal and anti-depressant properties?


Such medications are currently at various stages of study. Results from such studies are encouraging but preliminary.

Suicidal behavior is a complex phenomenon and cannot be reduced to overly simplistic biochemical explanations. At the same time, it should be no surprise that certain chemical pathways in the brain are involved in this complex behavior.
Medications that interact with these pathways may have the ability to reduce such behaviors and provide a person with the opportunity to more actively participate in therapy. Such a treatment strategy could have the potential to save lives.

This column was written by Eugene Rubin MD, PhD and Charles Zorumski MD.
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Re: Inflammation and Suicide Study

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so we go back in time now to read Lena Brundin ;

Role of Inflammation Suicide: From Mechanisms to Treatment


https://pubmed.ncbi.nlm.nih.gov/27377015/

Abstract

Suicidal behavior is complex and manifests because of a confluence of diverse factors.
One such factor involves dysregulation of the immune system, which has been linked to the pathophysiology of suicidal behavior. This review will provide a brief description of suicidality and discuss the contribution of upstream and downstream factors in the etiology of suicidal behavior, within the contextual framework of inflammation.

The contribution of inflammatory conditions such as traumatic brain injury, autoimmune disorders, and infections to neuropsychiatric symptoms and suicidality is only beginning to be explored.


We will summarize studies of inflammation in the etiology of suicide, and provide a neurobiological basis for different mechanisms by which inflammation might contribute to the pathophysiology. Finally, we will review treatments that affect upstream and downstream pathways related to inflammation in suicidality.
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Re: Inflammation and Suicide Study

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and now we roll forward in time a bit :

Inflammation as a unique marker of suicide ideation distinct from depression syndrome among U.S. adults


https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448785/


Background:


Recent evidence suggests that pro-inflammatory states may be independently associated with the risk of suicidality, above and beyond depression.


This study assesses whether four indicators of inflammation , circulating levels of C-reactive protein (CRP), white blood cell (WBC) count and immunoglobulin E (IgE), and dietary inflammatory potential, measured using the Dietary Inflammatory Index® (DII), distinguish suicidal ideation (SI) from major depression (MD).

Introduction

Suicide is the 10th leading cause of death in the United States, and incidence has increased over the past 15 years. Suicidal ideation is relatively common, with 4% of adults in the general population reporting suicidal thoughts in the past year (Piscopo et al., 2016). While mood disorders such as major depression (MD) are established risk factors for suicide-related behavior, suicidal ideation and other behaviors (e.g. planning, attempts) also occur outside the context of depression (Miret et al., 2013) suggesting unique mechanisms or processes that may distinguish suicidal ideation from other symptoms of depression.

Activation of inflammatory pathways and MD onset has been replicated in several observational (Berk et al., 2011; Miller et al., 2009) and experimental studies, (Dowlati et al., 2010; Ohgi et al., 2013). However, fewer studies have examined links between inflammatory pathways and suicidal ideation. Prior research suggests an association between neuroinflammation, as measured by microglia activity in the brain, and suicidal thoughts when compared to healthy controls (Setiawan et al., 2015). Other evidence indicates that the kynurenine pathway, which is part of monoamine metabolism and affects glutamate neurotransmission, is a unique mechanism linking inflammation to suicide, distinct from depression (Brundin et al., 2015). Pro-inflammatory conditions may play an upstream role in suicide-related behavior, including neurotropic pathogens, traumatic brain injury and autoimmune disorders (Brundin et al., 2017). In a prospective analysis, those with higher levels of circulating C-reactive protein (CRP), a marker of systemic inflammation, had a greater risk of suicide after 9 years of follow up than those with lower levels of CRP (Batty et al., 2016).

Even less is known concerning whether relationships of inflammatory pathways with suicide-related behavior may be, at least in part, distinct from MD. Only a handful of studies indicate that such relationships exist (Black and Miller, 2015; Brundin et al., 2015; Cáceda et al., 2018; Falcone et al., 2010; O’Donovan et al. 2013). For example, among those with mood disorders, CRP levels are even higher among those with a recent suicide attempt (Loas et al., 2016). Furthermore, the role of external factors, capable of stimulating an inflammatory response, on suicide-related behavior and depressive symptoms is not well established.

Inflammatory signaling is part of the body’s immune system and can be triggered by a wide range of challenges to host defense, including diet (Calder and Yaqoob, 2013) and environmental hazards such as particulate matter (Ma et al., 2017) and pollen (Galli et al., 2008). Different exposures may lead to different patterns of inflammatory activation, for example diet has been linked to inflammatory processes broadly (Minihane et al., 2015), while allergic responses are thought to primarily influence T helper (Th)2 cytokine signaling and reduced innate immune activation (Contoli et al., 2015). Elevated levels of white blood cells (WBC) and C-reactive protein (CRP) have been associated with mortality (Willems et al., 2010) and chronic disease (B. J. Miller et al., 2015), including depression (Chamberlain et al., 2017; Wysokiński and Margulska, 2017). Prior evidence demonstrates that diet can have both pro- and anti-inflammatory properties (Calder and Yaqoob, 2013; Galland, 2010) capable of stimulating pathways associated with neurobiology of mood disorders (Miller et al., 2009). Dietary inflammatory potential, measured using the Dietary Inflammatory Index® (DII), has previously been associated with cardiovascular disease (Garcia-Arellano et al., 2015), multiple types of cancer (Tabung et al., 2016) and depression (Bergmans and Malecki, 2017), but has not been studied in relation to suicide-related behavior. Seasonal pollen peaks have been associated with worsening symptoms of psychiatric disorders (Messias et al., 2010) and increased risk of completed suicide (Qin et al., 2013; Stickley et al., 2017) and suicide attempts (Jeon-Slaughter et al., 2016). However, exposure assessment is limited in prior studies (e.g. ecological design and averaging pollen counts over large geographic areas). Additionally, in a review of the literature (Kõlves et al., 2015), associations between allergies and nonfatal suicide behaviors are mixed, indicating the need for further study.

The goal of this study was to use a large, nationally-representative sample of US adults to evaluate the relationship of multiple external inflammatory factors with suicide ideation, both within the context of MD and among those without current depression. Four inflammation-related measures were examined: immunoglobulin E (IgE), C-reactive protein (CRP), white blood cells (WBC), and dietary inflammatory potential. The primary hypothesis was that these four indicators of inflammation would be associated with suicidal ideation, independent of their association with depression.
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Re: Inflammation and Suicide Study

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What’s the Connection Between Brain Inflammation and Suicidal Thoughts?

https://health.usnews.com/health-care/p ... l-thoughts

Over the years, medical research has increasingly pointed an accusatory finger at chronic inflammation as a primary cause of disease. It has been well-established that inflammation may occur throughout the body and that it contributes to atherosclerosis and heart attacks, asthma and diabetes. “There is growing evidence that inflammation in the body may be associated with inflammation in the brain,” says Dr. John H. Krystal, professor and chair of psychiatry at Yale University. And a study released in September has linked brain inflammation[/color] with certain forms of depression and, more specifically, suicidal thinking.

Published in the journal Biological Psychiatry, the study found that patients with major depressive disorder, or MDD, have increased levels of a marker of brain cell activation, a sign of inflammation. The increase in the inflammatory marker was present specifically in patients with MDD who were experiencing suicidal thoughts.

These results may signal a sea change in how some forms of depression are diagnosed and treated.
“The field of medicine has become accustomed to thinking about mental illnesses as if they were dissociated from the processes that produce illness in the major organs of the body,” says Krystal, who also serves as editor of Biological Psychiatry.

“This is an important finding because there are some medications that produce anti-inflammatory effects,” Krystal says. “These medications are currently used to treat illnesses including psoriasis, rheumatoid arthritis, ulcerative colitis and other diseases.” With this new and growing evidence that inflammation, a pathological process that spans body and brain, is not only a signature of more forms of depression, but also contributes to the development of some forms of depression suicidality, perhaps these depression pathways can be targeted by anti-inflammatory treatments, Krystal says.

PET Scans Track Inflammation

In the study, the researchers used a recently developed technique to characterize inflammation in the brain. This technique involves positron emission tomography scan, which records very low doses of a radioactive tracer that binds to a protein expressed when a particular group of immune cells in the brain called microglia are inflamed. “Brain microglia aren’t activated under normal, healthy conditions,” says Dr. Peter S. Talbot, a senior lecturer in psychiatry at the Wolfson Molecular Imaging Centre at the University of Manchester in the U.K. and a co-author of the study. The study found “strong confirmatory evidence for the presence of microglial activation, and hence neuro-inflammation, during a serious depressive episode,” he says. The results, in fact, replicate a prior report that major depressive disorder patients showed evidence of inflammation in three brain regions involved in mood regulation: the anterior cingulate cortex, insula and prefrontal cortex.

Further, Talbot and his colleagues separated the depressed patients into two groups – those with current suicidal thinking and those without – and compared the inflammation levels between the two subgroups. “We found that the elevated levels in the depressed group as a whole was accounted for by those who had suicidal thinking. The subgroup without suicidal thinking didn’t have elevated levels despite having similar scores on depression rating scales,” Talbot says. Krystal believes that this tends to suggest that brain inflammation is a feature of the biology of depression, “particularly among patients who have the more severe forms of depression that are also associated with increased suicide risk.”

Defining the link between depression and inflammation is an active research subject, Talbot says. “I think these findings have the potential to focus future inflammation research more towards the most severe forms of depression, particularly those with prominent suicidal thinking. But they also reinforce the inseparable links between the mind, the brain and the body in depression.

Treating depression effectively will always involve treating the whole person, and if we are to understand and treat inflammation as part of this, it will be vital to use a wide range of broadly anti-inflammatory strategies.”
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Re: Inflammation and Suicide Study

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more background info on suicide ideation and inflammation :

from 2009 :

The Origins of Suicidal Brains

Certain life experiences may lead to brain changes in suicide victims


https://www.scientificamerican.com/arti ... al-brains/

Ultimately, these findings reveal that suicide brains differ from other brains in multiple ways—in other words, “we’re really dealing with some sort of biological imbalance

from 2014 :

The molecular bases of the suicidal brain

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5293539/

Suicide ranks among the leading causes of death around the world, and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal behaviour. Distal factors — such as familial and genetic predisposition, as well as early-life adversity — increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors associate with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain.

This Review explores the key molecular changes associated with suicidality, and presents some promising avenues for future research.



Such methodological improvements would allow us to confidently draw conclusions from studies on epigenetic modifications linked to suicide and might accelerate the identification of useful biomarkers for increased risk of suicide. In the long-term, this would translate into better management of high-risk patients and improved health outcomes.
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Re: Inflammation and Suicide Study

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Research into changes that occur in the brains of suicide attempters is helping to make sense of tragedy.

Research reveals biological and chemical differences between the brains of people who have attempted suicide and those who are depressed.


https://undark.org/2016/06/28/suicidal- ... epression/


Last week, the American Academy of Pediatrics issued a sobering new finding: Suicide is now the second-leading cause of death among teenagers, with nearly 2,000 taking their own lives annually. That contributes to a rising incidence of suicide among the wider population, which sees roughly 40,000 Americans take their lives each year. In 2014, there were 12.93 suicides per 100,000 people, up from 10.9 in 2005, and the U.S. Centers for Disease Control and Prevention lists suicide as the tenth leading cause of death nationally.

Those facts are known. Far less clear is what characteristics — physical, emotional, psychological — can signal suicide risk. The National Alliance on Mental Illness, an advocacy group, suggests for example that the majority of people who commit suicide suffer from depression or some other diagnosed mental illness. But not all clinically depressed people go on to take their own lives, and comparatively little is known about what distinguishes those who do — once thought to be around 15 percent, but now thought to be somewhere between 2 and 9 percent — and those who don’t.

“Suicide risk can only be reduced, not eliminated,” the AAP researchers noted in their recent report on teen suicide, “and risk factors provide no more than guidance.”

Getting beyond mere guidance, then, would seem to be crucial — and while we may never fully understand what tips someone over the edge, current research suggests that biology may hold at least some answers
.

“Something is happening in the brain of these people,” said Fabrice Jollant, a psychiatrist at McGill University in Montreal. “It’s not doing its job properly.”

Jollant is one of several researchers who have been busy trying to make sense of suicide. His work and that of others has shown major differences between the brains of suicide attempters and depressed individuals who have never attempted suicide. In a 2008 study published in the American Journal of Psychiatry, for example, Jollant found that certain areas of the brain in formerly depressed men who had once attempted suicide reacted more strongly to seeing images of angry faces, compared to men who had a history of major depression, but had never attempted suicide.

“Even though these men were no longer suicidal or depressed, their brain responded very strongly compared to others,” Jollant said. “[The brain] was getting overactivated at angry faces, showing that [it] still responded unnaturally to its environment, even though the patient was healed psychologically.”

Jollant and his team observed that the right lateral orbitofrontal cortex — a region of the brain that is important for encoding the things people care about — lit up more often and more intensely in the men who had attempted suicide, showing they were particularly sensitive to the image. The finding aligns with past research that shows people who attempt suicide tend to react to stress more strongly than others. While healthy individuals can move past a negative experience, someone who is depressed or on the edge of suicide dwells excessively on the situation.

“Angry faces are a signal of social threat; someone’s angry at you,” Jollant explained. “Our interpretation is that [angry faces] are a signal of rejection [and] that’s standing out to these people when it doesn’t to anyone else.”

In an earlier study, Jollant had suicide-attempters participate in a computerized version of what’s known as the Iowa Gambling Task, and found that the decision-making part of their brains was impaired.

In the game, participants were presented with four virtual decks of cards and instructed to select individual cards from any deck of their choosing. Each selected card resulted in winning or losing game money, with a goal of winning as much as possible – but there was a catch: Two decks were stacked to favor small winnings, but even smaller losses, resulting in a net win over the course of the game. The other two decks were tweaked to provide big payoffs, but even greater losses — leading to a net loss in the long run.

Healthy subjects tended to figure out quickly which decks were long-term losers. “Most people test all the options. They lose several times, but at some point they understand that they have to leave those decks alone,” Jollant explaied. “It’s not only risky, it’s disadvantageous.”

But participants who were suicide attempters didn’t seem to distinguish between the decks. They didn’t learn from trial and error, and they continued selecting bad decks throughout the game. “It’s as if their brain isn’t processing the risk,” Jollant said.

MRI scans confirmed that something was amiss. The left lateral orbitofrontal cortex of the brain, which is associated with decision-making, lit up when healthy subjects chose the bad decks. But in suicide attempters, the region was markedly less active. This and past behavioral studies seem to suggest that decision-making is impaired in numerous psychiatric disorders.

The idea that certain biological markers can identify those who are prone to suicide isn’t new. Up until the 1980s, suicide was blamed generally on depression without any real understanding of the underlying neurochemistry. That changed when scientists noticed abnormally low levels of serotonin, a chemical that helps regulate mood, in the brain of individuals who were depressed or had committed suicide.

In a 1976 paper, Marie Asberg, a psychiatrist at the Karolinska Institute in Stockholm, noted that depressed patients with low levels of 5-HIAA, the primary metabolite of serotonin, attempted suicide significantly more often than depressed individuals with higher levels of 5-HIAA. She concluded, “The present investigation, albeit of a preliminary nature and based on a comparatively small sample, indicates that it may prove worthwhile to take biological issues into consideration in attempts to understand, and perhaps ultimately prevent suicide.”

Thus commenced a decades-long focus on serotonin’s association with suicide — though Jollant cautions that the issue is far more complex. “It’s not all about serotonin,” he said. “Yes, the system is implicated with suicide, but there are other factors at play.” Antidepressants — which boost serotonin levels in the brain — don’t work for everyone, for example, and some researchers even doubt their benefits for the severely depressed.

Yogesh Dwivedi, a psychiatrist at the University of Alabama at Birmingham, is among these researchers. In a 2014 overview published in the journal Dialogues in Clinical Neuroscience, Dwivedi suggested that there are observable differences at the cellular — and even molecular — level in the brains of those who commit suicide. Their levels of microRNA — molecules that help regulate gene expression — for example, are much lower than in those who die of natural deaths, Dwivedi observed. They also form entirely different shapes, or networks of microRNA, in the brain.

Dwivedi believes these unique molecular changes, which can appear when someone experiences severe stress at an early age, are one link in the chain of events that leads a person to commit suicide. When he replicated the structures of microRNA he saw in suicide victims in the brains of rodents, the animals themselves became depressed and anxious. “[Micro RNAs] in this form play a distinct role in suicidal behavior,” he said. “They’re another trait of suicide.”

Dwivedi is hoping to create a blood test that can identify these specific microRNA structures. The test could then help physicians identify if a patient is at a higher risk for suicide.
“Scientists are learning more and more that there are very specific changes in the brain of those who commit suicide,” Dwivedi says. “And each of these factors contributes to that fatal decision.”

For all of this, advances in suicide research can seem sluggish — in part because those who are at highest risk are often excluded from studies. This is based on the premise that it would be unethical to allow them to participate in an experimental trial that may not work, instead of giving them already-proven treatment, like counseling or antidepressants.
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Re: Inflammation and Suicide Study

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I had to go back and define it again:


What is Neuroinflammation ?


takes 6 minutes

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Re: Inflammation and Suicide Study

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Five Things to Know About Inflammation and Depression

April 30, 2018


https://www.psychiatrictimes.com/view/f ... depression



Immunologic processes may play a pivotal role in the development and maintenance of psychiatric disorders, opening an entire new avenue for novel strategies to prevent and treat psychiatric disease.


Dr. Milleris William P. Timmie Professor of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, GA.

Understanding the immunological basis of disease has revolutionized the treatment of cancer and autoimmune and inflammatory disorders, benefitting millions of people with breakthrough immunotherapies. We now suspect that immunologic processes may also play a pivotal role in the development and maintenance of psychiatric disorders, opening an entire new avenue for novel strategies to prevent and treat psychiatric disease.

The immunologic processes connected to depression have received the most attention. A vast amount of data supports the hypothesis that the immune system in general and inflammation in particular, represent a pathway to pathology in a significant number of depressed patients. Although the relationship between inflammation and depression may at first glance appear straightforward, this relationship is much richer and more nuanced than is often believed. In hopes of embracing the complexity involved, 5 essential points that represent our current understanding of the field are presented.

Depression is not an inflammatory disorder


Probably the most important lessons that we have learned about inflammation and depression are that depression is not an inflammatory disorder and not every patient with depression has increased inflammation.
Although a multitude of studies have demonstrated increased mean concentrations of a variety of inflammatory markers in depressed patients compared with controls-including reproducible increases in the inflammatory cytokines tumor necrosis factor (TNF), interleukin (IL)-1β, IL-6 and the acute phase protein C-reactive protein (CRP)-there is considerable variability within the depressed population. Indeed, despite the question being asked repeatedly, we do not know the percentage patients in whom inflammation plays a role.

The difficulty in addressing this question is that the answer depends on the patient population being considered. The more inflammatory risk factors a patient has, the more likely he or she will have inflammation. There are a multitude of factors associated with increased inflammation (Table 1) including treatment resistance. For example, 45% of patients enrolled in a study on treatment resistant depression had a CRP > 3 mg/L, which is considered high inflammation.1

Another pivotal point is that increased inflammation not only occurs in depression but also in multiple other psychiatric diseases including bipolar disorder, anxiety disorders, personality disorders, and schizophrenia. These data suggest that inflammation is transdiagnostic in nature, occurring in subpopulations of patients within a number of psychiatric disorders.

Inflammation has specific effects on the brain and behavior


As we gain more insight into how inflammation affects the brain, it is becoming increasingly clear that there is a surprising specificity on the impact of inflammation on behavior. Such specificity is apparent in the neurocircuits and neurotransmitter systems that appear to be most affected by inflammation both in the context of the administration of inflammatory stimuli or in association with inflammatory markers in patients with depression or other psychiatric disorders (Figure). For example, administration of the inflammatory cytokine interferon (IFN)-α to patients or administration of typhoid vaccination or endotoxin to healthy volunteers has shown that inflammation affects subcortical and cortical brain circuits associated with motivation and motor activity as well as cortical brain regions associated with arousal, anxiety, and alarm.2-4

Similar results have been found in patients with depression where increases in peripheral blood concentrations of the CRP were correlated with decreases in connectivity within motivation and reward circuits involving the ventral striatum and ventromedial prefrontal cortex (vmPFC), that in turn were associated with anhedonia.5 Greater inflammatory responses to stress as reflected by salivary concentrations of soluble TNF receptor 2 have also been correlated with activation of threat assessment circuits in the brain involving the dorsal anterior cingulate cortex (dACC) and insula.6 This latter effect of inflammation on threat and fear-related neurocircuitry may explain the emerging literature on the association of inflammatory markers with suicidal ideation and suicide attempts.7 Indeed, threat sensitivity has been shown to independently predict suicide risk, and data suggest that increased inflammatory markers may be preferentially associated with depressed patients who have attempted suicide.7,8

In terms of the neurotransmitter systems involved, inflammation reduces the availability of monoamines by increasing the expression and function of the presynaptic reuptake pumps (transporters) for serotonin, dopamine, and norepinephrine and by reducing monoamine synthesis and release by decreasing enzymatic co-factors such as tetrahydrobiopterin.1,2 Cytokine-induced decreases in basal ganglia dopamine release have been observed in humans and directly correlated with reduced motivation in laboratory animals.1,2

Inflammation also decreases relevant monoamine precursors by activating the enzyme indoleamine 2,3 dioxygenase, which breaks down tryptophan, the primary precursor for 5-HT, into kynurenine. Activated microglia can convert kynurenine into quinolinic acid, which can lead to excessive glutamate, an excitatory amino acid neurotransmitter. Excessive glutamate can lead to decreased brain-derived neurotrophic factor (BDNF) and excitotoxicity. Increased CRP has been directly correlated with increased glutamate in the basal ganglia of patients with depression.9 Finally, based on the inhibitory effects of inflammation on monoamine metabolism and BDNF, it is not surprising that inflammation is associated with a poor response to conventional antidepressants, whose efficacy relies in part on increasing monoamine availability and inducing BDNF and neurogenesis.

The immunology of inflammation in depression is only beginning to be understood

Our understanding of the immunology underlying inflammation in depression is limited to a small number of human studies in addition to animal studies. Thus, the relative contribution of innate and adaptive immune responses is unknown. One might suspect from the inflammatory mediators that are increased in the blood of depressed patients (eg, TNF, IL-1β and IL-6) that the primary drivers of inflammation in depression involve monocytes and activation of the innate immune response. Consistent with this notion is a recent report of increased perivascular monocytes/macrophages and monocyte chemoattractant protein (MCP)-1, a protein that attracts monocytes to the tissues in postmortem brain samples of presumably depressed suicide victims.10

Findings from animal studies also suggest that stress-induced increases in catecholamines stimulate the release of monocytes from the bone marrow.2 Once in the blood, these monocytes encounter danger- or microbial-associated molecular patterns derived from stress-induced alterations in metabolism or microbial products from the gut that in turn activate inflammatory signaling pathways such as nuclear factor κB (BF-κB) leading to TNF and IL-6 as well as the imflammasome, which leads to the production of IL-1. TNF in turn has been shown to activate microglia to produce MCP-1, attracting monocytes to the brain notably in areas that regulate fear and anxiety including the amygdala.11 Recent data indicate that chronic social stress in laboratory animals can also lead to permeability in the blood – brain barrier that allows peripheral inflammatory signals including IL-6 to enter the brain in regions relevant to motivation and reward.12 Consistent with these laboratory animal data, peripheral blood immune cells from depressed patients have shown evidence of activation of both nuclear factor κB and the inflammasome.13

Despite evidence that monocytes and the innate immune response play a pivotal role in effects of inflammation on the brain, there is growing evidence to suggest that T cells and the adaptive immune response may also be involved.14 Decreased anti-inflammatory T regulatory cells and increased hyperinflammatory Th17 cells have been described in depressed patients and animal models of depression.13-15 Moreover, T cells and their production of IL-4 have been associated with resilience to stress and depression in laboratory animal models.1,14,16 These data are especially intriguing given recent characterization of the lymphatic system within CNS that allows the T cells to patrol the brain.17 Whether inflammatory responses are primarily driven by innate immune responses and monocytes versus the adaptive immune response and T cells will have profound implications for immunotherapeutic targeting of the immune system to treat depression.

Inflammation is related to treatment response


A major advantage of a pathophysiologic process that is believed to largely emanate from the periphery and spread to the brain is the opportunity to use blood tests to identify specific individuals for treatment targeting and ultimately precision care. Indeed, inflammatory markers alone or in combination have been shown to predict treatment response to conventional antidepressants and psychotherapy as well as advanced treatment strategies such as ketamine and anti-cytokine immunotherapy.13,18 Unfortunately, these studies are post hoc in nature, and no study has yet to prospectively assign patients with one or more level of inflammatory marker to a given treatment and predict response.

The greatest challenge is to determine which inflammatory marker(s) exhibits the greatest predictive value, while also being readily available for clinical application. Findings suggest that individuals with a CRP >1mg/L, which is the cut off for moderate inflammation, were less likely to respond to SSRIs.19,20 High CRP was also shown to predict response to the anti-inflammatory drug infliximab, an inhibitor of TNF.1 Given the relative availability of CRP in clinics and hospitals throughout the US and elsewhere, it may be that until other data are available, clinicians can use CRP as a general yardstick for inflammatory load.

There has been recent interest in identifying inflammation directly in the brain of depressed patients using positron emission tomography to identify activated microglia reflected by upregulation of the translocator protein (TSPO).21 Although there has been an assumption that increased TSPO binding signals neuroinflammation, the TSPO ligand is not able to distinguish microglia that are activated to perform important neuroprotective and neuroregulatory functions from microglia that are inflammatory. Therefore, these ligands are not ready for prime time, and results from the published literature using TSPO ligands should be interpreted with caution.

Therapeutic implications are imminent


Clearly, there is much to be learned about the relationship between depression and inflammation. Nevertheless, the most exciting aspects of this work are the clear therapeutic implications ranging from blocking inflammation to targeting the downstream effects of inflammation on neurotransmitter systems and neurocircuits to implementing lifestyle interventions that reduce inflammation (Table 2).

Several clinical trials are underway using immunotherapies that target TNF and IL-6. In each instance, a precision medicine approach is being taken: individuals with increased inflammation of CRP >3 mg/L are being treated. Whether targeting these cytokines versus targeting T cell-derived cytokines such as IL-17 is more efficacious and for whom remains to be determined. In addition, studies have suggested that both minocycline, which blocks microglial activation, and inhibitors of the inflammatory mediator cyclooxygenase (COX)-2 have antidepressant efficacy.18 However, more data are needed, given that precision targeting of patient populations with high inflammation has not been incorporated into the clinical trial design of these studies. Based on the impact of inflammation on dopaminergic and glutamatergic pathways, drugs that enhance dopamine signaling or block glutamate receptors may be especially relevant for patients with depressive symptoms and increased inflammation.

References:

1. Raison CL, Rutherford RE, Woolwine BJ, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA Psychiatry. 2013;70:31-41.

2. Capuron L, Pagnoni G, Drake DF, et al. Dopaminergic mechanisms of reduced basal ganglia responses to hedonic reward during interferon alfa administration. Arch Gen Psychiatry. 2012;69:1044-1053.

3. Eisenberger NI, Berkman ET, Inagaki TK, et al. Inflammation-induced anhedonia: endotoxin reduces ventral striatum responses to reward. Biol Psychiatry. 2010;68:748-754.

4. Harrison NA, Voon V, Cercignani M, et al. A neurocomputational account of how inflammation enhances sensitivity to punishments versus rewards. Biol Psychiatry. 2016;80:73-81.

5. Felger JC, Li Z, Haroon E, et al. Inflammation is associated with decreased functional connectivity within corticostriatal reward circuitry in depression. Mol Psychiatry. 2016;21:1358-1365.

6. Slavich GM, Way BM, Eisenberger NI, et al. Neural sensitivity to social rejection is associated with inflammatory responses to social stress. Proc Natl Acad Sci USA. 2010;107:14817-14822.

7. Brundin L, Bryleva EY, Thirtamara Rajamani K. Role of inflammation in suicide: from mechanisms to treatment. Neuropsychopharmacol. 2017;42:271-283.

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trader32176
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Re: Inflammation and Suicide Study

Post by trader32176 »

An inflammatory profile linked to increased suicide risk

15 March 2019

https://www.sciencedirect.com/science/a ... 2718320512

Highlights

• We identified a distinct immunobiological profile linked to cross-diagnostic suicide risk in women with mood disorders, attending a psychiatric outpatient clinic.

• We analyzed a high number of biological analytes and subjected the data to robust statistical models to understand inflammatory factors in their composite biological networks.

• Granulocyte mediated immune reactions may potentially be central among the biological mechanisms triggering suicidal ideation and behavior.

Background

Suicide risk assessments are often challenging for clinicians, and therefore, biological markers are warranted as guiding tools in these assessments. Suicidal patients display increased cytokine levels in peripheral blood, although the composite inflammatory profile in the subjects is still unknown. It is also not yet established whether certain inflammatory changes are specific to suicidal subjects. To address this, we measured 45 immunobiological factors in peripheral blood and identified the biological profiles associated with cross-diagnostic suicide risk and depression, respectively.

Methods

Sixty-six women with mood and anxiety disorders underwent computerized adaptive testing for mental health, assessing depression and suicide risk. Weighted correlation network analysis was used to uncover system level associations between suicide risk, depression, and the immunobiological factors in plasma. Secondary regression models were used to establish the sensitivity of the results to potential confounders, including age, body mass index (BMI), treatment and symptoms of depression and anxiety.
Results

The biological profile of patients assessed to be at increased suicide risk differed from that associated with depression. At the system level, a biological cluster containing increased levels of interleukin-6, lymphocytes, monocytes, white blood cell count and polymorphonuclear leukocyte count significantly impacted suicide risk, with the latter two inferring the strongest influence. The cytokine interleukin-8 was independently and negatively associated with increased suicide risk. The results remained after adjusting for confounders.

Limitations

This study is cross-sectional and not designed to prove causality.

Discussion


A unique immunobiological profile was linked to increased suicide risk.The profile was different from that observed in patients with depressive symptoms, and indicates that granulocyte mediated biological mechanisms could be activated in patients at risk for suicide.
trader32176
Posts: 1755
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Re: Inflammation and Suicide Study

Post by trader32176 »

Suicidal ideation and suicide attempts: associations with sleep duration, insomnia, and inflammation

2020 Apr 23

https://pubmed.ncbi.nlm.nih.gov/32321599/


Abstract

Background: Sleep disturbance has been consistently identified as an independent contributor to suicide risk. Inflammation has emerged as a potential mechanism linked to both sleep disturbance and suicide risk. This study tested associations between sleep duration, insomnia, and inflammation on suicidal ideation (SI) and history of a suicide attempt (SA).

Methods: Participants included 2329 adults with current or remitted depression and/or anxiety enrolled in the Netherlands Study of Depression and Anxiety. Sleep duration, insomnia, past week SI, and SA were assessed with self-report measures. Plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α were obtained.

Results: Short sleep duration (⩽6 h) compared to normal sleep duration (7-9 h) was associated with reporting a prior SA, adjusting for covariates [adjusted odds ratio (AOR) 1.68, 95% CI 1.13-2.51]. A higher likelihood of SI during the past week was observed for participants with long sleep duration (⩾10 h) compared to normal sleep duration (AOR 2.22, 95% CI 1.02-4.82), more insomnia symptoms (AOR 1.44, 95% CI 1.14-1.83), and higher IL-6 (AOR 1.31, 95% CI 1.02-1.68). Mediation analyses indicated that the association between long sleep duration and SI was partially explained by IL-6 (AOR 1.02, 95% CI 1.00-1.05).

Conclusions: These findings from a large sample of adults with depression and/or anxiety provide evidence that both short and long sleep duration, insomnia symptoms, and IL-6 are associated with the indicators of suicide risk. Furthermore, the association between long sleep duration and SI may operate through IL-6.
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