New insight into how omega-3 fatty acids or fish oil supps may reduce depression

[C C]

New insight into how anti-inflammatory effects of omega-3 fatty acids could help reduce depression
https://www.kcl.ac.uk/news/new-insight-i...depression

RELEASE: Research led by King’s College London has, for the first time, shown that when omega-3 polyunsaturated fatty acids (PUFAs) are given to patients with depression they are metabolised into molecules called lipid mediators and the levels of these in the blood are linked to an improvement in symptoms. The research is published today in Molecular Psychiatry.

The omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in oily fish. Researchers from the National Institute of Health Research (NIHR) Maudsley Biomedical Research Centre assessed the effects of high doses of EPA and DHA in lab-grown neurones and then in patients to help clarify how they reduce inflammation and depression. This novel approach allowed the scientists to identify an important molecular mechanism which can help inform the development of potential new treatments involving omega-3 fatty acids for patients with depression.

Lead author Dr Alessandra Borsini, NIHR Maudsley BRC Senior Postdoctoral Neuroscientist at King's College London, said: “Using a combination of laboratory and patient research our study has provided exciting new insight into how omega-3 fatty acids bring about anti-inflammatory effects that improve depression. For some time we have known that omega-3 PUFA can induce anti-depressant and anti-inflammatory effects but, without further understanding of how this happens in the human brain, it has been difficult to develop treatments. Our study has helped shine a light on the molecular mechanisms involved in this relationship which can inform the development of potential new treatments for depression using omega-3 PUFA.” 

Previous research has shown that people with major depressive disorder have higher levels of inflammation in their bodies than those without the disorder. There are currently no proven anti-inflammatory treatment strategies for depression and, although two important omega-3 PUFAs, EPA and DHA, have been shown to provide anti-inflammatory and antidepressant effects, the precise mechanism by which they do this is unknown.

Depression in a dish. The study set out to test the theory that when omega-3 fatty acids are utilised and processed in the body, some of their metabolites (known as lipid mediators) are able to protect the brain from the harmful effects of inflammation. Researchers used a validated in vitro human cell model known as ‘depression in a dish’ that was developed at the NIHR Maudsley Biomedical Research Centre and which uses cells from the hippocampus, a part of the brain fundamental in many cognitive, memory and learning areas thought to be important in depression. Hippocampal cells play an important role in the production of new neurones - neurogenesis.

The study showed that treating human hippocampal cells with EPA or DHA before being exposed to chemical messengers involved in inflammation called cytokines, prevented increased cell death and decreased neurogenesis. Both these impacts had been previously observed in cells exposed to cytokines alone. Further investigation confirmed these effects were mediated by the formation of several key lipid mediators produced by EPA and DHA, namely hydroxyeicosapentaenoic acid (HEPE), hydroxydocosahexaenoic acid (HDHA), epoxyeicosatetraenoic acid (EpETE) and epoxydocosapentaenoic acid (EpDPA), and these were detected for the first time in human hippocampal neurones. Further investigation showed that treatment with an enzyme inhibitor increased the availability of two of these metabolites (EpETE and EpDPA) suggesting a possible way by which future treatments could be optimised.

Professor Anna Nicolaou, professor of Biological Chemistry at the Faculty of Medical and Human Sciences, The University of Manchester, who led the team that measured the lipid mediators using mass spectrometry said: “The lipid mediators that our research identified are broken down in the body relatively quickly, which means they may only be available for a relatively short time. By testing the effect of inhibitors of the enzymes involved in the metabolism of omega-3 PUFA we showed that we can greatly improve how long they can have an effect in the body and ultimately, increase their efficacy. This is very important for the development of new treatments and means that patients could be given higher doses of EPA and DHA together with these enzyme inhibitors to increase the amount of these important compounds in their blood over time.”

Omega-3 metabolites in patients. The study assessed twenty-two patients with major depression who were given either 3 grams of EPA or 1.4 grams of DHA daily for twelve weeks. The lipid metabolites of EPA and DHA were measured in their blood before and after the omega-3 PUFA treatment, along with a score of their depressive symptoms. In both groups of patients, EPA or DHA treatment was associated with an increase in their respective metabolites and a significant improvement in depressive symptoms – an average reduction in symptom scores of 64% and 71% in the EPA and DHA groups respectively. In addition, higher levels of the same metabolites identified in the in vitro experiments were correlated with lower levels of depressive symptoms.

The levels of EPA and DHA used in this study are concentrations that most likely cannot be achieved with dietary consumption of oily fish, a rich source of omega-3 PUFAs, but require therapeutic supplements.

Future Research. The results of the study indicate that the bioactive lipid mediators produced by the breakdown of EPA and DHA in the body could be targeted as a mechanism to reduce depression and inflammation but there is a need to ensure that their effects are prolonged in order for this approach to be successful. Previous research indicates a key enzyme in the omega-3 fatty acid metabolism could be a valid option for drug repurposing and could be used for other inflammation-associated brain disorders, including depression, where at least a sub-group of patients often have chronic levels of inflammation.

Senior author of the paper, Professor Carmine Pariante, NIHR Maudsley BRC Affective Disorders Interface with Medicine Theme Lead said: “There is ever growing interest in the links between the immune system, inflammation and depression but in order to develop new treatments in this area we need to better understand the mechanisms behind these relationships. Our study has provided important insight into how known anti-inflammatory compounds – the omega-3 PUFA – help reduce depression. By identifying and measuring the exact lipid mediators that are involved, identifying the enzyme that prolongs their effects and finding the same lipid mediators in depressed patients treated with omega-3 PUFA and demonstrating improvements in symptoms, we have provided vital information to help shape clinical trials for future therapeutic approaches with omega-3 fatty acids.

“It is important to highlight that our research has not shown that by simply increasing omega-3 fatty acids in our diets or through taking nutritional supplements we can reduce inflammation or depression. The mechanisms behind the associations between depression and omega-3 PUFA are complicated and require further research and clinical trials to fully understand how they work and inform future therapeutic approaches.”

[Magical Realist]

Further evidence that depression is a dysfunctional brain condition and NOT a character flaw.

[Syne]

Further evidence that depression is a dysfunctional brain condition and NOT a character flaw.

No, it doesn't. The study used an extremely small sample of 22 patients, had no control group, and informed consent can invoke a placebo effect (which needs to be controlled for to get significant results).

[Magical Realist]

https://www.nature.com/articles/d41586-018-05261-3

The Inflamed Mind: A Radical New Approach to Depression Edward Bullmore Short (2018)

"Depression affects one in four people at some time in their lives. It is often difficult to treat, in part because its causes are still debated. Psychiatrist Edward Bullmore is an ardent proponent of a radical theory now gaining traction: that inflammation in the brain may underlie some instances. His succinct, broad-brush study, The Inflamed Mind, looks at the mounting evidence.

The book outlines a persuasive case for the link between brain inflammation and depression. Bullmore pleads with the medical profession to open its collective mind, and the pharmaceutical industry to open its research budget, to the idea. He provides a current perspective on how the science of psychiatry is slowly emerging from a decades-long torpor. He sees the start of a shift in the Cartesian view that disorders of the body ‘belong’ to physicians, whereas those of the more ‘immaterial’ mind ‘belong’ to psychiatrists. Accepting that some cases of depression result from infections and other inflammation-causing disorders of the body could lead to much-needed new treatments, he argues.

In 1989, during his clinical training at St Bartholomew’s Hospital in London, Bullmore encountered a patient whom he calls Mrs P, who had severe rheumatoid arthritis. She left an indelible impression. He examined her physically and probed her general state of mind. He reported to his senior physician, with a certain pride in his diagnostic skill, that Mrs P was both arthritic and depressed. Replied the experienced rheumatologist dismissively, given her painful, incurable physical condition, “You would be, wouldn’t you?”

Mrs P is a recurring motif, as is the rhetorical question. Bullmore draws on more than two millennia of medical history — from ancient Greek physician Hippocrates to the work of neuroanatomist and 1906 Nobel laureate Santiago Ramón y Cajal — to illustrate his points. At times they seem like intellectual meanderings, but these passages also show how medical science often progresses by means of bold theories that break away from received wisdom.

After his training, Bullmore specialized in psychiatry, and quickly experienced its limitations. He describes his growing awareness of how poorly science has served the field, using the development of selective serotonin reuptake inhibitors (SSRIs) as a prime example.

That long and winding road began with the antibiotic iproniazid. It was discovered through scientific logic: by screening chemicals for their ability to kill Mycobacterium tuberculosis in the test tube and in mice. Iproniazid transformed the treatment of tuberculosis in the 1950s. Patients clawed back from the jaws of death exhibited euphoria — well, you would, wouldn’t you? — and the drug was soon launched as an antidepressant. Soon the theory emerged (based more on supposition than evidence, says Bullmore) that its psychiatric effects were the result of boosting the neurotransmitters adrenaline and noradrenaline. Drug developers began to focus on neurotransmission more broadly.

Prozac (fluoxetine), which boosts serotonin transmission, was launched in the mid-1980s, and many pharmaceutical companies quickly followed with their own SSRIs. It seemed to be the revolution psychiatrists had been waiting for. But it soon emerged that only a modest subset of patients benefited (estimates based on trials vary widely). That is unsurprising in retrospect, with the new appreciation that depression can have many causes. Bullmore holds that the emergence of SSRIs bypassed scientific logic. The serotonin theory, he writes, is as “unsatisfactory as the Freudian theory of unquantifiable libido or the Hippocratic theory of non-existent black bile”. He notes that, after SSRIs failed to live up to the hype, time once again stood still for psychiatry.

Bullmore recalls a teleconference in 2010, when he was working part-time with British pharmaceutical giant GlaxoSmithKline. During the call, the company announced it was pulling out of psychiatry research because no new ideas were emerging. In the following years, almost all of ‘big pharma’ abandoned mental health.

Then a window seemed to open — one that shed a different light on the plight of Mrs P. Some of the textbook certainty that Bullmore had learnt by rote at medical school started to look distinctly uncertain.

In particular, the blood–brain barrier turned out to be less impenetrable than assumed. A range of research showed that proteins in the body could reach the brain. These included inflammatory proteins called cytokines that were churned out in times of infection by immune cells called macrophages. Bullmore pulls together evidence that this echo of inflammation in the brain can be linked to depression. That, he argues, should inspire pharmaceutical companies to return to psychiatry.

It seems unfair that someone struck down by infection should have depression too. Is there a feasible evolutionary explanation? Bullmore hazards that depression would discourage ill individuals from socializing and spreading an infection that might otherwise wipe out a tribe.

Other brain disorders might turn out to be prompted or promoted by inflammation. An exciting link with neurodegenerative diseases, including Alzheimer’s, is also being studied (see Nature 556, 426–428; 2018). But we need to learn from the rollercoaster history of brain research, and keep expectations in check. Beneath his bombastic enthusiasm, Bullmore acknowledges this, too."

[Syne]

A "link between brain inflammation and depression" is only correlation, not causation.

Abstract
This review focuses on those biobehavioral factors that show robust associations with markers of inflammation, including discussion of the following variables: diet, smoking, coffee, alcohol, exercise and sleep disruption. Each of these variables has been assessed in large-scale epidemiological studies, and many in clinical and experimental studies as well. Treatment strategies that target biobehavioral factors have the potential to complement and add to the benefit of anti-inflammatory medicines.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2866374/

As long as there's ample evidence that behavioral factors contribute to inflammation, behavior is a better bet for causation.

[Magical Realist]

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658985/

The Role of Inflammation in Depression and Fatigue
Chieh-Hsin Lee1 and Fabrizio Giuliani1,2,*

Abstract
"Depression and fatigue are conditions responsible for heavy global societal burden, especially in patients already suffering from chronic diseases. These symptoms have been identified by those affected as some of the most disabling symptoms which affect the quality of life and productivity of the individual. While many factors play a role in the development of depression and fatigue, both have been associated with increased inflammatory activation of the immune system affecting both the periphery and the central nervous system (CNS). This is further supported by the well-described association between diseases that involve immune activation and these symptoms in autoimmune disorders, such as multiple sclerosis and immune system activation in response to infections, like sepsis. Treatments for depression also support this immunopsychiatric link. Antidepressants have been shown to decrease inflammation, while higher levels of baseline inflammation predict lower treatment efficacy for most treatments. Those patients with higher initial immune activation may on the other hand be more responsive to treatments targeting immune pathways, which have been found to be effective in treating depression and fatigue in some cases. These results show strong support for the hypothesis that depression and fatigue are associated with an increased activation of the immune system which may serve as a valid target for treatment. Further studies should focus on the pathways involved in these symptoms and the development of treatments that target those pathways will help us to better understand these conditions and devise more targeted treatments."
===============================================================
Depression: Not an Inflammatory Disease, but Inflammation Plays a Huge Role
October 27, 2018
Allison Inserro


Conferences | Psych Congress

What is the role of inflammation in major depressive disorder (MDD)? In a session called “What’s Hot: An Inflammatory Take on the Immune System in Psychiatry,” Charles L. Raison, MD, from the University of Wisconsin, Madison, presented recent findings in this area, including how subgroups of depressed individuals show increased levels of inflammatory biomarkers.

What is the role of inflammation in major depressive disorder (MDD)? In a session called “What’s Hot: An Inflammatory Take on the Immune System in Psychiatry,” Charles L. Raison, MD, from the University of Wisconsin, Madison, presented recent findings in this area, including how subgroups of depressed individuals show increased levels of inflammatory biomarkers.

These findings are sometimes misinterpreted to mean that MDD is an inflammatory condition, but that would be incorrect, he said. The topic is more complex than that, he added.

“Inflammation is becoming surprisingly relevant in clinical treatment,” said Raison, the director of clinical and translational research at the Usona Institute. Calling inflammation a relic left over from the time of earliest human development, he said it is now fueled by lifestyle, with a propensity to go haywire. But for evolutionary purposes, “inflammation was all that stood between a person from near certain death from infection,” he said.

Major depression is not an inflammatory disorder, he said—if it were, you would want to give an anti-inflammatory to every depressed person.

With that, however, there are caveats, which Raison delved into by presenting what he called a series of “thought experiments” and reviewing previous studies.

There is no doubt, he said, that inflammatory pathways in the brain interact with every system in the body. As a result, people might vary in their sensitivity to that or may have different vulnerabilities when it comes to effects on depression.

What if inflammation is only relevant for a subgroup of people with depression? Early on, Raison and his colleagues theorized that since people given interferon-alpha became depressed, reductions in depressive symptoms would correlate with reductions in inflammatory biomarkers. In other words, people with depression and high inflammation would respond to an intervention, but people who are depressed but are not inflamed would not.

In 1 study, 60 patients with treatment-resistant depression were randomized to receive either 3 infusions of the tumor necrosis factor (TNF) infliximab or a salt water placebo for 12 weeks. To Raison’s shock, salt water beat infliximab.

That was the study that proved that depression was not an inflammatory disorder, but they still had another theory that if inflammation was high, those patients would be the ones to respond to treatment. That was true in the salt water study—it was the high inflammation group that did respond to infliximab. He called this a “great mystery.”

“If major depression is a brain disorder, so the brain is broken, how can it be that turning off the signal from the body can undepress people?” he said.

This may mean that the brain is reacting to signals from the environment that a problem exists, he said. It may also suggest that inflammation may not also be bad for everyone, yet “inflammation can be a road into depression.”

“Don’t come up to the mike and ask me, ‘where does that cut-off begin?’” he told his audience. “There’s no answer to that.”

Inflammation's role in treatment

Raison reviewed several studies pointing to the role that increased inflammation has in inhibiting treatment response.

In 1 study, 102 patients with treatment-resistant MDD had higher levels of C-reactive protein (CRP), and patients who failed 3 or more trials had higher TNF, soluble TNF receptor 2, and interleukin-6 compared with individuals with 0 or 1 trial.

In another study, chronic inflammation from infection increased the rate of MDD and reduced the responsiveness of antidepressants, and another study showed inflammation reduced response to psychotherapy.

All of this information is useful only if it can help guide treatment decisions, and to that end, Raison showed results from a study that found that patients with high CRP levels responded better to the selective serotonin reuptake inhibitor (SSRI) escitalopram then they did to the tricyclic antidepressant nortriptyline.

In another study, bupropion added to an SSRI improved treatment response for those whose CRP levels were equal or greater than 1 mg/L. In fact, that was one of Raison’s takeaways—inflammatory biomarkers can help guide treatment, such as by adding a drug like bupropion to an SSRI.

There are also inflammatory differences by gender, he said, which can probably be explained by the role of inflammation in evolution during female childbearing years, during which “women paid a higher reproductive cost.” Inflammation reduces fertility, impairs lactation, and directs energy away from reproduction. Women may be more likely to develop depression because social withdrawal reduced exposure to pathogens, so women were able to survive with less inflammation and still avoid death from infection, he said."

https://www.ajmc.com/view/depression-not...-huge-role

[Syne]

Again, "both have been associated with increased inflammatory activation" still doesn't provide any evidence of causation. Saying inflammation, that is shown to have behavior as a causal factor, is associated with depression, if anything, also points to behavior as a cause.

[Magical Realist]

https://www.medicalnewstoday.com/articles/288715

Severe depression linked with inflammation in the brain

Clinical depression is associated with a 30% increase of inflammation in the brain, according to a new study published in JAMA Psychiatry.

The new study is the first to find definitive evidence of inflammation in the brain of depressed patients.

Inflammation is the immune system’s natural response to infection or disease. The body often uses inflammation to protect itself, such as when an ankle is sprained and becomes inflamed, and the same principle also applies to the brain. However, too much inflammation is unhelpful and can be damaging.

Increasingly, evidence is suggesting that inflammation may drive some depressive symptoms, such as low mood, loss of appetite and reduced ability to sleep.

What the new study set out to investigate was whether inflammation is a driver of clinical depression independent of other physical illness.

Researchers from the Centre for Addiction and Mental Health’s (CAMH) Campbell Family Mental Health Research Institute in Toronto, Canada, used positron emission tomography (PET) to scan the brains of 20 patients with depression and 20 healthy control participants.

In particular, the team closely measured the activation of microglia – immune cells that play a key role in the brain’s inflammatory response

The PET scans showed significant inflammation in the brains of the people with depression, and the inflammation was most severe among the participants with the most severe depression. The brains of people who were experiencing clinical depression exhibited an inflammatory increase of 30%.

Previous studies have examined markers of inflammation in the blood of depressed people, in an attempt to solve the “chicken or egg” debate of whether inflammation is a consequence of or contributor to major depression.

For instance, in 2012, a study conducted by Duke University Medical Center researchers and published in Biological Psychiatry found an association between the number of cumulative depressive episodes experienced by study participants and increased levels of an inflammation marker in their blood called C-reactive protein (CRP).

“Our results support a pathway from childhood depression to increased levels of CRP, even after accounting for other health-related behaviors that are known to influence inflammation. We found no support for the pathway from CRP to increased risk for depression,” said Duke study leader Dr. William Copeland.

The Duke team concluded that depression, therefore, is more likely to contribute to inflammation in the body as opposed to arising as a consequence of inflammation.

Medical News Today did not have access to data on whether the patients in the CAMH study exhibited brain inflammation prior to developing depression or after symptom onset. However, the CAMH researchers claim that their study is the first to find definitive evidence of inflammation in the brains of depressed patients.

Should future depression therapies target inflammation?

“This finding provides the most compelling evidence to date of brain inflammation during a major depressive episode,” says senior author Dr. Jeffrey Meyer, who holds a Canada Research Chair in the neurochemistry of major depression. He adds:

“This discovery has important implications for developing new treatments for a significant group of people who suffer from depression. It provides a potential new target to either reverse the brain inflammation or shift to a more positive repair role, with the idea that it would alleviate symptoms.”

Severe depression affects 4% of the general population. However, more than half of people with major depression do not respond to antidepressants. Dr. Meyer suggests that future studies should investigate the possible impact of anti-inflammatory drugs on depression symptoms.

“Depression is a complex illness and we know that it takes more than one biological change to tip someone into an episode,” says Dr. Meyer. “But we now believe that inflammation in the brain is one of these changes and that’s an important step forward.”

[Syne]

Severe depression linked with inflammation in the brain

For the umpteenth time, "linked with" is correlation, not causation.

Clinical depression is associated with a 30% increase of inflammation in the brain, according to a new study published in JAMA Psychiatry.

So all people with a 30% increase of inflammation and zero people without any inflammation in the brain exhibit depression? No? Then it's not causative, hence "associated."

Increasingly, evidence is suggesting that inflammation may drive some depressive symptoms, such as low mood, loss of appetite and reduced ability to sleep.

"Suggesting" and "may" are hedge words when there's zero evidence of causation.

What the new study set out to investigate was whether inflammation is a driver of clinical depression independent of other physical illness.

Researchers from the Centre for Addiction and Mental Health’s (CAMH) Campbell Family Mental Health Research Institute in Toronto, Canada, used positron emission tomography (PET) to scan the brains of 20 patients with depression and 20 healthy control participants.

20 is an even smaller sample size than your previous 22.

In particular, the team closely measured the activation of microglia – immune cells that play a key role in the brain’s inflammatory response

The PET scans showed significant inflammation in the brains of the people with depression, and the inflammation was most severe among the participants with the most severe depression. The brains of people who were experiencing clinical depression exhibited an inflammatory increase of 30%.

So, if truly "independent of other physical illness", is this still a predictor of such physical illness and they just found 20 patients who had yet to display any symptoms of these illnesses? You know, controlling for other possible factors.

For instance, in 2012, a study conducted by Duke University Medical Center researchers and published in Biological Psychiatry found an association between the number of cumulative depressive episodes experienced by study participants and increased levels of an inflammation marker in their blood called C-reactive protein (CRP).

“Our results support a pathway from childhood depression to increased levels of CRP, even after accounting for other health-related behaviors that are known to influence inflammation. We found no support for the pathway from CRP to increased risk for depression,” said Duke study leader Dr. William Copeland.

So why didn't the CAMH study control for "other health-related behaviors that are known to influence inflammation?"

The Duke team concluded that depression, therefore, is more likely to contribute to inflammation in the body as opposed to arising as a consequence of inflammation.

Ah, because when you do, you find that "depression is more likely to contribute to inflammation in the body as opposed to arising as a consequence of inflammation."

Medical News Today did not have access to data on whether the patients in the CAMH study exhibited brain inflammation prior to developing depression or after symptom onset. However, the CAMH researchers claim that their study is the first to find definitive evidence of inflammation in the brains of depressed patients.

So no way to determine causation in the CAMH study.


One of these days you might actually learn how to read scientific articles and papers, rather than just seeking to confirm your bias.

[Magical Realist]

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

Five Things to Know About Inflammation and Depression
April 30, 2018
Andrew H. Miller, MD
Psychiatric Times, Vol 35 No 4, Volume 35, Issue 4


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.

Dr Miller reports no conflicts of interest concerning the subject matter of this article."