A novel measure of inflammation in depression

Éimear Foley discusses a recent paper

Inflammation is thought to play a role in depression. According to research that combined information from many studies (i.e., systematic review and meta-analysis), approximately a quarter of all those diagnosed with depression also have consistently higher levels of inflammatory proteins, like C-reactive protein (CRP), in their blood. Large population-based studies and studies using genetic information (i.e., Mendelian Randomization) further suggest that inflammation, particularly an inflammatory protein called interleukin 6 (IL-6), play a key role in causing depression. (You can read more about the role of inflammation in depression in our IEUREKA blog on “Immune cells as biomarkers of depression”.) 

So far, studies examining this relationship between inflammation and depression have only focused on the levels of individual immune proteins in the blood, like IL-6 and CRP. At a cellular level, an inflammatory response is not caused by the activity of one inflammatory protein but rather by the interaction between several proteins working together to trigger a signalling response. Looking at the activity of proteins gives further insight into how these proteins relate to a particular condition, like depression. For this reason, in a recent study, we examined how IL-6 activity relates to symptoms and cognitive performance in people diagnosed with depression.  

How did we measure IL-6 activity? 

IL-6 activity involves the interaction of three main proteins: IL-6, the IL-6 receptor, and glycoprotein 130 (gp130). These proteins interact to trigger or neutralise inflammatory responses.  

We used data from 86 individuals with a diagnosis of depression recruited as part of a randomised clinical trial, The Insight Study. By design, the study recruited roughly equal numbers of participants with low (CRP<3mg/L) and high (CRP>3mg/L) levels inflammation. We measured participants’ blood levels of IL-6, IL-6 receptor, and gp130, and used these values to calculate a ratio score that represents an individuals’ estimated IL-6 activity. This calculation was based on previous research and the exact formula we used for this study can be found in our recently published research paper 

What did we find? 

Relationship with individual inflammatory proteins: 

Our novel marker of IL-6 activity was positively correlated with several individual proinflammatory proteins (IL-6, CRP, soluble IL-6R, and tumour necrosis factor alpha) and negatively correlated with the anti-inflammatory protein, soluble gp130. This suggests that our novel marker is closely related to individual inflammatory proteins and higher levels of our marker do indeed indicate higher levels of inflammation. This is a reassuring result. 

Relationship with symptoms of depression: 

We found that increased IL-6 activity (i.e., higher inflammation) was associated with higher somatic symptoms (e.g., changes in energy, sleep, appetite), fatigue, and depression severity, poorer quality of life, and decreased psychomotor speed (see Figure 1).  

When we compared this novel measure to the results for the individual inflammatory markers often used in immunopsychiatry research (i.e., IL-6 and CRP), we found comparable results. 

 Figure 1. Comparison of the effects of novel IL-6 activity measure and other biomarkers on clinical and cognitive outcomes. 

What does this mean? 

This novel measure of IL-6 activity performs well in comparison to individual inflammatory proteins so often used throughout the field of immunopsychiatry. Studies of individual inflammatory markers have been invaluable in establishing the link between inflammation and depression and have helped further our understanding of the role these proteins play in the development and persistence of depression.  

 The novel marker of inflammation presented in this research paper takes into account multiple proteins at once. It could, therefore, better reflect the actual biological function/action of IL-6. Using this measure in addition to individual proteins in future research may provide unique insights into the role inflammation plays in depression and related psychiatric disorders. 

What next? 

 Next, we need to replicate these findings in much larger, more diverse samples. We also need to perform lab-based experiments to confirm that our novel marker accurately measures IL-6 activity. Lastly, longitudinal studies are required to assess the relationship between IL-6 activity and treatment response, recovery and/or risk of getting depression. 

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