Disentangling the Link Between Inflammation and Depression

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

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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.”

 

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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)

11 COMMENTS

  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?)

    • 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.

    • 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.

    • 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?

  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.

    • 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.

      • 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.

  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?

  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”.

  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:-

    https://www.bps.org.uk/what-psychology/understanding-psychosis-and-schizophrenia

    “..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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