Inflammation Drives Depression

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Move over serotonin, inflammation is the new target of depression treatment

Is inflammation a bad thing? Not necessarily: Inflammation helps the cells of the immune system fight infections and repair injuries. Like many things, however, the key to inflammation is balance – not too much, and not too little. Too little inflammation allows infections and illnesses to run amuck, whereas too much inflammation can cause pain, tissue damage, immune dysfunction, and even depression.[1] That’s right: inflammation is a significant cause of depression and other mood disorders.

What the research says about inflammation, CRP, and depression

A study published this summer has confirmed the link between inflammation and depression.[2] Pulling data from the UK Biobank, the researchers considered the health factors of 26,894 people with a lifetime diagnosis of major depressive disorder (MDD) as compared to 59,001 healthy controls.

Various causes of inflammation were considered, including genetic, environmental, lifestyle, and medical factors, and blood samples were collected from the participants to measure their levels of C-reactive protein (CRP), a marker of inflammation.

Blood CRP levels were found to be significantly higher in those with depression relative to those without the condition. The authors also found that eating and smoking habits had more to do with depression-related inflammation than genetics – meaning that there’s a lot we can do to improve our mental health.

Eating and smoking habits had more to do with depression-related inflammation than genetics.

This was by no means the first study to illuminate the link between inflammation and depression:

A 2019 systematic literature review and meta-analysis of 37 studies – including 13,541 patients with depression and 155,728 control patients – found that about one fourth (25%) of those with depression had blood test results consistent with low-grade inflammation (defined as CRP >3 mg/L), and over half had mildly elevated CRP levels (defined as CRP >1 mg/L). The authors also found that low-grade inflammation was much more prevalent in the depressed patients as compared to healthy controls, confirming that inflammation and depression often go hand-in-hand.[3]

A 2019 clinical trial shines light on the nuances of inflammation and depression.[4] This study considered the participants’ blood levels of high-sensitivity CRP (hs-CRP) in addition to their body mass index (BMI) and questionnaire responses. The study participants included 102 patients with treatment-resistant major depressive disorder (MDD) experiencing depression at the time of the study, 48 patients with MDD who were treatment-responsive (and thus not experiencing depression at the time), 48 unmedicated patients with “regular” depression (not MDD), and 54 healthy controls.

Quelling inflammation may be the key to treating stubborn cases of MDD.

Hs-CRP was found to be elevated in those with MDD, especially in patients with treatment-resistant MDD. After controlling for BMI, the hs-CRP levels were still significantly elevated in the people with treatment-resistant MDD as compared to the healthy controls – but not in the patients with treatment-responsive MDD or unmedicated “regular” depression.

The authors conclude that that patients with MDD “…have a distinctive clinical profile that might be responsive to second-line treatment with anti-inflammatory drugs,” suggesting that quelling inflammation may be the key to treating stubborn cases of MDD.

Other markers of inflammation

A meta-analysis published in 2020 considered not only CRP levels, but also other markers of inflammation, namely interleukins 3, 6, 12, and 18 (IL-3, IL-6, IL-12, and IL-18, respectively), serum soluble interleukin 2 (sIL-2R), and tumor necrosis factor alpha (TNFα).[5] One hundred and seven (107) studies were included in the analysis, including data from 5,166 patients with depression and 5,083 control patients. The levels of all of the inflammatory markers assessed were significantly higher in those with depression than in the non-depressed controls. Those with depression were also found to have reductions in the anti-inflammatory marker interleukin 4 (IL-4), further confirming that depression is a pro-inflammatory state.

All of the inflammatory markers assessed were significantly higher in those with depression than in the non-depressed controls.

But is it really necessary to check all of these inflammatory markers when hunting for the cause of a patient’s depression? Perhaps not: A 2020 study comparing plasma (blood) and cerebrospinal fluid (CSF) levels of CRP, IL-6, TNF, and interleukin-1 beta (IL-1β) concludes that blood CRP alone is a good enough marker for assessing inflammation in both the periphery (in the blood) and in the central nervous system. The researchers conclude that testing CRP alone may help guide the treatment of patients with MDD.[6]

How does inflammation cause depression?

C-reactive protein (CRP), tumor necrosis factor (TNF), interleukin-1β (IL-1β), and interleukin-6 (IL-6) seem to be the inflammatory markers most reliably elevated in blood of people with depression. But why and how does inflammation cause depression?

Inflammation and depression were once part of our evolutionary response to infections and injuries.

It is thought that inflammation and depression were once part of our evolutionary response to infections and injuries, forcing us to rest and stay in one place and rest. This response helped us recover faster and avoid further pathogen exposure or compounded injury. In today’s world of sanitation and advanced medicine, however, we are left with the symptom of depression as a byproduct of inflammation.[7]

Once the inflammatory cascade is activated – whether it be by stress, infection, heavy metals or other toxins, alcohol, poor dietary choices, sleep deprivation, a weak gut microbiome, poor digestive integrity, or other cause of inflammation – the peripheral inflammatory response gets transmitted to the brain, where it impacts the neurotransmitters serotonin, dopamine, and glutamate. Inflammation also affects kynurenine pathway, a cascade of reactions that generates the neurotoxic (toxic to the nervous system) metabolite quinolinic acid. These responses alter the circuitry of the nervous system, thus derailing motivation, decreasing joy, affecting motor activity, and driving anxiety and alarm.[8]

This may explain why autoimmune diseases and chronic infections (conditions associated with ongoing inflammation) are proven risk factors for mood disorders like depression.[9]

Interestingly, it has been noted that the development of depressive and anxiety-like behavior in stressed mice can be mediated by the activation of cells that produce the anti-inflammatory agent IL-4 around the brain and spinal cord.[10]

A mother’s prenatal depression can cause inflammation in her child for at least a quarter of a century after birth.

Does inflammation cause depression, or does depression cause inflammation? The two seem to be birds of a feather, according to a prospective longitudinal cohort study of pregnant women with depression and their children. One hundred three (103) young adult offspring were assessed by the researchers, who found that in utero exposure to prenatal depression was associated with significant elevations in the children’s hs-CRP levels at age 25. This elevation in hs-CRP was independent of child abuse or depression in the offspring, suggesting that a mother’s prenatal depression can cause inflammation in her child for at least a quarter of a century after birth.[11]

The heart of depression: association with heart disease

The authors of a 2019 wondered if there is a connection between coronary heart disease (CHD) and depression, as both conditions are associated with inflammation.[12] They found (perhaps unsurprisingly) that elevated hs-CRP levels were associated with depression severity in those with CHD. Even in those CHD patients who did not have depression at the beginning of the study, elevations in hs-CRP predicted the future onset of clinically-significant depression within the three-year study period.

A family history of heart disease was associated with a 20% increased risk of depression.

In another exploration of CHD and depression, researchers conducted a population-based cohort study, analyzing data from 367,703 unrelated middle-aged participants who were of European ancestry.[13] They found that a family history of heart disease was associated with a 20% increased risk of depression.

The authors wanted to understand if the connection between CHD and depression was on account of genetics or environmental factors. Upon considering the patients’ genetic risk factors for CHD, they found that the genes strongly associated with CHD were not associated with depression. Specifically, the authors calculated the “genetic risk score” of CHD for the patients, and found that an increase of just one standard deviation of the genetic risk score resulted in a 71% increase in CHD risk – but only a 1% increase the risk of depression.

What CHD and depression have in common are environmental causes of inflammation – and not genetics.

The researchers did report, however, that increased levels of triglycerides (a type of cholesterol linked with blood sugar), IL-6, and CRP were all likely implicated in depression. In short, the analysis suggests that what CHD and depression have in common are environmental causes of inflammation – and not genetics. That’s good news: it means we can control our mental well being through healthy life practices.

Conclusion

It has become clear in recent years that inflammation increases the risk of depression, and that CRP and/or hs-CRP blood levels can be used to assess inflammation severity. Fortunately, the research does not seem to support the theory of a strong genetic influence on that inflammation. Rather, we can have control over our CRP levels, our bodies, and even our minds through healthy lifestyle choices.

Stay tuned for Part 2 of this article, in which we explore the things you can do to help fight inflammation and thus lower the risk of depression.

References

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