Depression Is An Inflammatory Response
The last two columns covered new discoveries that relate to depression, including research on dopamine and emerging findings on depression as a movement disorder.
Today’s piece is the “finale” of this particular series. It sketches the outlines of a growing body of research that explores the role of inflammation in depression and its implications for body-mind health.
The Links Between Depression and Inflammation
Multiple studies show strong correlations, and you could even say a causal relationship, between inflammatory markers and depression.
People with major depressive disorder (MDD) exhibit chronically heightened inflammatory responses.
They have a pronounced expression of pro-inflammatory molecules known as cytokines in both their blood and cerebrospinal fluid. Inflammatory molecules common in depression include the interleukins (or IL’s) such as IL-6 and IL-8, tumor necrosis factor (TNF), and c-reactive protein (CRP).
What’s more, this inflammation compromises the dopamine-related reward and movement systems, which leads to the reduced motivation and decreased movement emblematic of depression. (Hence the first two parts of this series, linked above.)
The link to inflammation is especially strong in suicidal depression. In fact, in people who take their own lives have been found to have an increased acute expression of inflammation, including inflammatory genes.
The relationship between inflammation and depression is reciprocal: People with low-grade inflammation have an increased risk of depression.
And that’s not all. In a systematic review and meta-analysis of multiple studies totaling over 6,200 participants, researchers concluded that blocking pro-inflammatory cytokines improves depression.
Anti-inflammatories out-perform placebo interventions (which already has a good record) and aggregate data for antidepressants.
In a subset of people with depression, anti-inflammatories have also enabled antidepressants to work more effectively. This is a great boon: Although antidepressants are life-saving for many, they work only 33% of the time and can sometimes stop working even when they were previously effective.)
Let me add here that depression is not the only “mental illness” strongly linked with inflammation. High levels of inflammatory biomarkers are also elevated in anxiety disorders, bipolar disorder, and PTSD. (More about PTSD in a moment.)
Depression As An Adaptive Response to Inflammation
Depression is still so stigmatized that despite indications to the contrary, modern western culture continues to view it as a brain disorder, a genetic anomaly, or a matter of faulty thought patterns and beliefs. (For more on the “brain disorder” myth, in this article I talked about new research showing that poor health, particularly in the metabolic, hepatic (liver), and immune systems made a greater contribution to mental illness than brain anomalies.)
But let’s continue to consider the possibility that depression is so much more complex than a brain disorder, genetics, or inaccurate beliefs.
In 2020, researchers in the Netherlands Study of Depression and Anxiety tested the relationship between lipopolysaccharides (LPS) markers and depression symptoms. (Some of you may remember this column, which links gut health to brain health via these LPS markers.)
The study looked at 41 subjects with treatment-resistant major depression. They found that LPS-stimulated inflammatory markers were strongly associated with depression symptoms, including:
nervous system hyperarousal (an element of depression)
lack of interest or pleasure in usually pleasurable activities
poor appetite
low concentration
loss of libido
irritability
malaise
social withdrawal
psychomotor slowing, fewer global movements, and reduced sensorimotor performance
Importantly, inflammation was related to the course and presence of these symptoms.
These symptoms of depression mimic the symptoms of physical illness that the medical and research professions call “sickness behaviors.”
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Throughout evolution, particularly when we existed in smaller groups that depended on one another for survival, inflammation and acute illness could wipe out an entire group.
The sickness behaviors in response to inflammation—the ones we also have in depression—have an evolutionary benefit. They helps us conserve the energy needed to fight infection and heal wounds.
And the social avoidance, withdrawal, and other sickness behaviors were forms of “social distancing” that protected the rest of our social group from exposure. (We experienced this need firsthand during the Covid-19 pandemic—though it may have been “programmed out” of some people.)
To reiterate, the sickness behaviors at the heart of depression may be an intelligent, adaptive, evolutionarily-programmed response to high circulating levels of inflammation. This response impacts our motivation, reward, movement, and social connection behaviors in the service of protecting our larger social group.
When we speak of physical illness, this same cascade of symptoms is considered to be evolutionarily adaptive. Why is this not also the case in depression, particularly since the inflammation-depression connection has been building for quite some time?
In much the same way as sickness behaviors do in inflammation and depression, hypervigilance in anxiety disorders helps ensure the group’s protection from attack and exposure to life-threatening injuries or pathogens. For this reason, hypervigilance and excess sensitivity have been called forms of sentinel intelligence. (I love that term so much.)
In people with a history of trauma and posttraumatic stress disorder, those who had a genotype associated with elevated concentrations of the cytokine c-reactive protein had higher rates of PTSD and reported higher severity of symptoms of being overly alert. (This shows that the nervous system responds to elevated levels of “physical” inflammation with an inflammatory—read hyperarousal—response of its own.)
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Science doesn’t yet have a full understanding of inflammation and all the processes involved (such as sleep, the gut, cellular mechanisms like glial cells, the brain, etc.). Perhaps more significantly, the medical field has few nuanced instruments by which to reduce inflammation without rendering the immune system vulnerable to infection.
My take: There are ways to track and begin to address inflammation. In this article I talked about managing inflammation in our enteric nervous system or belly brain. And in this article, I talked about attunement to circadian rhythms and other tools that help reduce our inflammatory burden.
The Social Determinants of Inflammation
Inflammation isn’t just a biological matter. It’s a mind-body issue, which includes our larger social body.
Reducing inflammation also means reducing the influences that contribute to inflammation, including interpersonal and social stress. (This is where we begin to counter the myth that depression is simply a neural, and therefore individual, phenomenon.)
Social systems like patriarchy and systemic racism cause inflammation—not only in their targets (those with less social power) but ultimately also in those who perpetuate these systems.
For example, women represent a whopping 80 (eighty) percent of autoimmune disorders in the U.S. Most common among these are Sjogren’s Syndrome, systemic lupus erythematosus, autoimmune thyroid disease, scleroderma, and myasthenia gravis. (Men, on the other hand, are more likely to do from acute inflammatory reactions such as sepsis.)
This connection is too vast to go into here as an “afterthought” to this column. However, let me offer just one study among a virtual avalanche of others.
This particular study gathered data from 391 African American women participating in the Family and Community Health Study. They used a 13-item index used to assess exposure to racial discrimination over a period of eight years. They measured blood assays of 7 cytokines; the interleukins (IL-1B, IL-2, IL-5, IL-6, IL-17), tumor necrosis factor, and MIP1b (macrophage inflammatory protein 1-b). They found that persistent exposure to discrimination predicted inflammation. Inflammation, in turn, predicted the number of chronic diseases. Racism, they concluded, is a “fundamental cause of health inequalities.”
Some of what we can do is individual, such as improving sleep, gut health, and the quality of our relationships.
But to reduce inflammation on a meaningful level, we also need to address the pandemics of depression, anxiety, chronic pain, and PTSD beyond individual health interventions.
It means addressing the social context of these illnesses by ensuring a more just, equitable, and free society on every level.
Sources:
They have an increased expression of pro-inflammatory molecules: Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews. Immunology, 16(1), 22–34. https://doi.org/10.1038/nri.2015.5
In fact, in people who take their own lives: Miller, A. H., & Raison, C. L. (2016). The role of inflammation in depression: from evolutionary imperative to modern treatment target. Nature reviews. Immunology, 16(1), 22–34. https://doi.org/10.1038/nri.2015.5
What’s more, this inflammation compromises the dopamine-related reward and movement systems: Felger J. C. (2018). Imaging the Role of Inflammation in Mood and Anxiety-related Disorders. Current neuropharmacology, 16(5), 533–558. https://doi.org/10.2174/1570159X15666171123201142
In fact, in people who take their own lives have been found to have an increased acute expression: Tamimou, R., Lumbroso, S., Mouzat, K., & Lopez-Castroman, J. (2022). Genetic variations related to inflammation in suicidal ideation and behavior: A systematic review. Frontiers in psychiatry, 13, 1003034. https://doi.org/10.3389/fpsyt.2022.1003034. See also: Serafini, G., Parisi, V. M., Aguglia, A., Amerio, A., Sampogna, G., Fiorillo, A., Pompili, M., & Amore, M. (2020). A Specific Inflammatory Profile Underlying Suicide Risk? Systematic Review of the Main Literature Findings. International journal of environmental research and public health, 17(7), 2393. https://doi.org/10.3390/ijerph17072393 See also: Brundin, L., Bryleva, E. Y., & Thirtamara Rajamani, K. (2017). Role of Inflammation in Suicide: From Mechanisms to Treatment. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 42(1), 271–283. https://doi.org/10.1038/npp.2016.116
Blocking pro-inflammatory cytokines has been shown to improve: Köhler, O., Benros, M. E., Nordentoft, M., Farkouh, M. E., Iyengar, R. L., Mors, O., & Krogh, J. (2014). Effect of Anti-inflammatory Treatment on Depression, Depressive Symptoms, and Adverse Effects: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Psychiatry, 71(12), 1381–1391. https://doi.org/10.1001/jamapsychiatry.2014.1611
In 2020, researchers in the Netherlands Study of Depression and Anxiety: van Eeden, W. A., van Hemert, A. M., Carlier, I. V. E., Penninx, B. W. J. H., Lamers, F., Fried, E. I., Schoevers, R., & Giltay, E. J. (2020). Basal and LPS-stimulated inflammatory markers and the course of individual symptoms of depression. Translational psychiatry, 10(1), 235. https://doi.org/10.1038/s41398-020-00920-4
In people with a history of trauma and posttraumatic stress disorder: Felger J. C. (2018). Imaging the Role of Inflammation in Mood and Anxiety-related Disorders. Current neuropharmacology, 16(5), 533–558. https://doi.org/10.2174/1570159X15666171123201142
Furthermore, in people from a high-risk urban setting with a history of trauma: Michopoulos, V., Rothbaum, A. O., Jovanovic, T., Almli, L. M., Bradley, B., Rothbaum, B. O., Gillespie, C. F., & Ressler, K. J. (2015). Association of CRP genetic variation and CRP level with elevated PTSD symptoms and physiological responses in a civilian population with high levels of trauma. The American journal of psychiatry, 172(4), 353–362. https://doi.org/10.1176/appi.ajp.2014.14020263
This particular study gathered data from 391 African American women participating in the: Simons, R. L., Lei, M. K., Klopack, E., Zhang, Y., Gibbons, F. X., & Beach, S. R. H. (2021). Racial Discrimination, Inflammation, and Chronic Illness Among African American Women at Midlife: Support for the Weathering Perspective. Journal of racial and ethnic health disparities, 8(2), 339–349. https://doi.org/10.1007/s40615-020-00786-8
For example, women represent a whopping 80 (eighty) percent of: Martínez de Toda, I., González-Sánchez, M., Díaz-Del Cerro, E., Valera, G., Carracedo, J., & Guerra-Pérez, N. (2023). Sex differences in markers of oxidation and inflammation. Implications for ageing. Mechanisms of Ageing and Development, 211, 111797. https://doi.org/10.1016/j.mad.2023.111797