Disentangling the Link Between Inflammation and Depression

New research finds little difference in inflammation between people with and without a diagnosis of depression.


There are many theories regarding the cause of depression. Some, such as the “chemical imbalance” theory (which focuses on serotonin), have been debunked. Others, such as the association of emotional distress with traumatic experiences, have been consistently demonstrated. However, one of the more recent potential explanations is the link between brain inflammation and depression.

A new study in The American Journal of Psychiatry aimed to disentangle this link—how well does inflammation explain depression? The researchers found that there was little difference in inflammation between people with and without the depression diagnosis.

The research was led by Cathryn M. Lewis and Carmine M. Pariante at King’s College, London. The study included 26,894 people with a diagnosis of depression and 59,001 people without any psychiatric diagnosis. The participants were all of European ancestry and were obtained through the UK Biobank.

The authors found a statistically significant effect—people with depression did have, on average, slightly higher levels of C-reactive protein (CRP; a marker for inflammation). However, this effect has little explanatory power.

The authors classified a CRP level below 3 mg/L as within the normal range. Above 3 mg/L was considered “low-grade inflammation.”

In the study, 21.2% of people with depression had a CRP >3 mg/L, compared with 16.8% of people without depression. This means that most people with depression (about 80%) had a normal CRP level—compared with a similar 85% of healthy controls.

Additionally, the average CRP level was higher for people with depression—but not by much (2.4 mg/L compared with 2.1 mg/L for controls, which is well below the 3 mg/L cutoff point for “low-grade inflammation”).

Thus, the researchers found that people with depression were just slightly more likely to have low-grade inflammation, but on average, inflammation levels were within the normal range in both groups.

Moreover, after adjusting for clinical and sociodemographic factors—including BMI, smoking, and childhood trauma—the relationship became even less powerful (though it was still technically statistically significant).

Finally, the researchers also used a polygenic risk score (PRS) to determine if the genetic risk for depression was linked to inflammation. They found that once they accounted for BMI and smoking, genetic risk for depression was not linked to inflammation at all.

“The association between the major depression PRS and CRP level disappears when we additionally regress out the effects of BMI and smoking,” the authors write.

Despite these limited—and almost entirely negative—results, the researchers write that they still believe inflammation is a biological cause of depression:

“We suggest that the remaining association between depression and increased inflammation reflects, at least in part, a core biological process and thus possibly a crucial pathogenetic mechanism leading to the depressive phenotype.”



Pitharouli, M. C., Hagenaars, S. P., Glanville, K. P., Coleman, J. R. I., Hotopf, M., Lewis, C. M., & Carmine M. Pariante, C. M. (2021). Elevated C-reactive protein in patients with depression, independent of genetic, health, and psychosocial factors: Results from the UK Biobank. Am J Psychiatry. doi: 10.1176/appi.ajp.2020.20060947 (Link)


  1. Where is the flame of social injustice within the mass of the data? For the Will to Live even if your head has been has suffered at the nands of someone else, the pins and needled of the “fire” imparted from a brain in outrage? How does one entangle the question in linear regressions ad infinitum, when the variables through time, may not even account for how the brain is processing through time?

    As I read your insightful reporting, the questioin became variation and degree of depression being understood through the dimensionality of time and other variables of context stored in memory or being experiences in and of the moment? Where would be the disovery for the role of continuous iimprovement within the individual as well as the surroundign organization?

    Reading your post, the energy was directed to pull a book off the shelf, a good and insightufl read by Donald J. Wheeler, “Understanding Variation: The Key to Managing Chaos.

    What might be creting the grades of depression or exhaltation within the social justice movement of our individual and collective concerns regarding the context of this website and beyond? (To untangle the threads at the threshold perhaps is no less than Dagon losing his head and hands though at what point will the LIGHTS come on within the indvidual with a response that is not to be committed nor drugged?)

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    • I do not know why researchers tend to do this. When I wrote about my own psych studies in college, I was told that if the data does not support the hypothesis, the discussion/conclusion should go on to explain why that may be, even if it runs totally contradictory to our background research. There’s enough literature on why genetic testing for psychiatric issues is a confusing and confounding mess at the moment. Why make a statement like this at the end of an article, again, is beyond me.

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    • If they admit that what they falsely label as an “illness” doesn’t have any biological explanation it would lead them to understand they aren’t practicing medicine. That they’ve been selling stigmatizing and pessimism causing falsehood. Few people will admit they helped cause hundreds of millions of people to become physically addicted to deadly drugs based on self serving lies.

      Their social, egotistical, and financial status are more important than the people they pretend caring about.

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    • Thank you Miranda for introducing expanding my vocabulary and perhaps typing skills. I wish my ability to proof and type could be better. One is challenged to ask if the mind is flat and void of time? And the more important question might be how could a citizen be mistreated so poorly, where the rights as understood by the practioner/researcher’s limited interaction with a patient? Even the assumptions that frame the research are in need of an examination, to help focus the “language” of today. But I wonder if we are communicating in a spoken sense or a typing sense in and of conscious/unconscious awareness?

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  2. It’s interesting information about CRP but doesn’t really prove anything about inflammation generally.

    Inflammation in Lyme disease is associated with specific interleukins and not CRP, for one example. And at least in my own case, there’s a very clear correlation between a rise in physical symptoms which are obviously inflammatory in nature (hot, swollen, red joints, for example) and associated neuropsychiatric distress. The nervous system effects are what take me down – headaches, sleep disturbance and cognitive difficulties, especially conversational abilities. Then there’s the lovely resting bitch face as a result of facial palsy and parathesia. There is the shooting pain that appears to be mostly nerve related. And perhaps the depression is just be an effect of “not looking sick” and being assumed by others of being capable of things and having to navigate their inability to understand and make space for what’s actually going on. Or even to care or ask if I’m ok. People act like being intelligent is all you need to overcome any obstacles. I’m exhausted of the misabling.

    So I don’t know if it’s inflammation or not but I know that whether or not any particular study supports that hypothesis, it’s the only thing that makes any sense. Neuroborelliosis isn’t sufficiently explanatory on its own. And controlling for trauma may be muddying the results. As if someone with a history of trauma can’t get sick. I forgot I’m actually superwoman and impervious to illness since I have a history of trauma.

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    • This is a really good point.

      Both cytokines and macrophages interact with microglia in the brain and CNS. This may be enough to trigger depression and social anxiety. It fits with evolutionary biology – an environemental or pathogenic stressor may trigger anti-social behaviours long before any symptoms manifest. Like an early warning system, in lieu of physical pain.

      The types of immune insults which instigate cytokine activity don’t necessarily cause elevated CRP despite, as you say, modulating cytokine expression. IL-6 and TNF-α for example. In fact, many protozoan parasites (implicated in many MH disorders) subvert the host immune system by dampening inflammatory markers, but this doesn’t mean they aren’t pathogenic.

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      • Oh hey, it’s always a pleasant surprise when someone knows what I’m talking about. Most doctors don’t seem to understand how various microbes modulate immune response as a survival mechanism. So a negative test is a negative test despite an obvious clinical diagnosis.

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  3. This is something i never understand: The operating of ‘scientific endeavour’ on a religious mode:

    Is not science the great explorer indifferent to preconceived belief?

    Is there any science that can be truly trusted nowadays?
    And where are the true sincere researchers?

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  4. It’s occurred to me that a lot of “depression”, is closely linked to “anxiety” (which most people experience, at one level or another).

    My epipheny was that it was possible to do something about anxiety. Without this discovery, I would never have successfully withdrawn from “medication”.

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  5. Thank you Peter.

    I’ve seen the inflammation(/depression) idea circulating quite a bit and I was wondering what was in it.

    From The British Psychological Society:-


    “..The problems we think of as ‘psychosis’ – hearing voices, believing things that others find strange, or appearing out of touch with reality – can be understood in the same way as other psychological problems such as anxiety or shyness…”

    In my own personal experience this is true – its not a theory. This is the way forward.

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  6. Hmmm. I’m not an expert on the design of studies, how the participants are chosen. However, I think a discussion about design of the study and other possible ways to design a study would be helpful.
    Also, it is unclear whether adjusting for certain factors should be interpreted to mean that patients with diagnosed inflammatory conditions were not selected for the study.
    Whatever, the field of immunology has clearly shown that inflammation impacts the Central Nervous System. Sickness behavior looks like depression.
    For those who think vitamins are worthless for depression, Hormone Vitamin D has been shown to lower inflammation of the CNS. However, obesity seems to reduce the benefit by locking up the Vitamin D in stored fat. Obese people have higher levels of inflammation. bmcneurosci.biomedcentral.com/articles/10.1186/s12868-017-0400-1
    Nutritional supplements make such a difference on the immune system that when you prepare to have allergy testing done, the prep requires that you limit the amounts of those anti-inflammatory supplements because they do tamp down the immune response that is being investigated. The immune response produces inflammation.

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      • Actually, inflammation in depression is caused by different sources. According to Dr Uma Naidoo, a Harvard psychiatrist, 2 hours of stress is enough to cause dysbiosis. Dysbiosis causes inflammation and mast cell activation and mast cells produce histamine. Depressed people have more gut bacteria that produce histamine and a stronger immune response to chemicals produced by bacteria and this also causes inflammation. Histamine H4 receptors are highly expressed on mast cells where their stimulation exacerbates histamine and cytokine generation.

        Inflammation causes leaky intestines which cause the translocation of intestinal products to the brain and activation of TLRs. This causes inflammation and histamine production in the brain and activation of the HPA Axis and microglia. Inflammation can’t be controlled because of low Vit D.

        My guess is that HISTAMINE will end up being a critical player in the pathology of depression. Go ahead, bet me.

        “spikes in brain histamine following stress likely drive neurochemical changes in monoaminergic systems. Indeed, elevated histamine can result in increased activation of H3 heteroreceptors on 5HT terminals in the hippocampus, resulting in blunting of neuronal serotonin release and producing a reduction in extracellular serotonin.”

        Histamine may also be an important regulator of antidepressant efficacy because it regulates Norepinephrine, serotonin, and Dopamine release in the prefrontal cortex

        Inflammation-Induced Histamine Impairs the Capacity of Escitalopram to Increase Hippocampal Extracellular Serotonin

        Suicidal patients are deficient in vitamin D, associated with a pro-inflammatory status in the blood

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    • I worked as a Study Coordinator in Clinical Research so to answer your question about how subjects are chosen. They have to meet the inclusion/exclusion criteria. For example, the inclusion criteria might say subjects need to be people who are depressed and have never taken an antidepressant. Or it can say they want people who have failed 3 antidepressants and they will receive a new drug to see if it helps. It depends what they’re trying to prove.
      You also choose people who can come to the visits (or make arrangements so they can) and are willing to get the tests, X-rays, etc needed for the study.

      Some studies are more difficult to enroll. For example if it’s a rheumatoid arthritis study and you need to take the pt off the anti inflammatory they are taking and let them flare before you give them the new drug, it’s going to be hard to find people who want to do that.

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  7. Furthermore, I don’t understand the polarization re: causes of depression. Yes, social -emotional factors cause depression and even psychosis in some people. I would think that sub-groups of people will differ in their resilience to depression and in their predisposing factors. Some people are just more sensitive , emotionally and/or physically. The polarization about the causes of depression is troubling. I’ll try not to let it get me down.

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  8. Here’s an excerpt from a study on Depression in Women and Vitamin D3 which is anti-inflammatory. See source at bottom.


    There appears to be good prof that early-life lack of VD may be a physiological trigger for depression development at a later period in women’s life. It may be that VD at non-optimal levels is no longer neuroprotective, perhaps because of the loss of its antioxidant or anti-inflammatory effects, making it more vulnerable to emerging neuropsychiatric diseases such as affective-related disorders. VD deficiency has been associated with poorer mental health, depression and psychotic disorders, as well as chronic physical problems. However, the factual basis that VD is a potential cause rather than the consequence of depression is lacking, although there is some evidence that VD deficiency in development may be relevant to the risk of psychosis.

    In general, several clinical randomized trials are strongly recommended to investigate the interaction between the repletion of VD stores and affective-related states, especially, depression. Moreover, these trials should contain healthy and non-healthy women in different life periods and from different race/ethnicity. While impressive gains have been made by researchers to clarify the neurobiology of depression, the contradictory data from clinical and preclinical studies underscore that interpersonal, as well as non-personal variables, may promote polymorphism of depressive disorders, which should be considered as the pathophysiological basis for several different forms of treatment. For studying the critical role of VD in depression, research also needs to consider these factors in designing any future research with the aim of treating depression./www.ncbi.nlm.nih.gov/pmc/articles/PMC7327938/
    Curr Neuropharmacol. 2020 Apr; 18(4): 288–300.
    Published online 2020 Apr. doi: 10.2174/1570159X17666191108111120
    PMCID: PMC7327938
    PMID: 31701847
    Vitamin D and Depression in Women: A Mini-review
    Mohamed Said Boulkrane,1 Julia Fedotova,1,2,* Valentina Kolodyaznaya,1 Vincenzo Micale,3 Filippo Drago,3 Annemieke Johanna Maria van den Tol,4 and Denis Baranenko1

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