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The big impact of stress on the immune system in depression

Stress — it’s a hot topic for discussion. It seems that every day we are confronted with new information on managing it.

The body has many ways to adapt to stress, but one of the most important is the production of cortisol. Each time we have a deadline to meet at work, a public presentation to give, or even have to face our greatest fear (spiders!), cortisol plays a behind-the-scenes role in allowing our body to successfully navigate the challenge ahead.

We know the importance of cortisol to managing stress because a few people, those with a disease that prevents them from producing it, cannot live normally without taking replacement hormones that fill the role of their absent cortisol.

On the flip side, cortisol that becomes elevated due to stress needs to return to a normal level to maintain health. Therefore, cortisol that is either too low or too high can be a problem.

In several long-term illnesses such as rheumatoid arthritis and depression, cortisol levels can change from normal and stay at abnormal levels for a long-time.

In depression, patients with long-term increases in the blood level of cortisol are also often found to have very severe depressive symptoms. At the same time, these depressed patients with high blood cortisol often show changes in the function of their immune systems.

Generally, this is an over-activity of the immune system, leading immune cells to react like there is an infection in the body, but there isn’t. The presence of both increased blood cortisol and altered immune system function in depressed patients has led doctors to question whether there is a link between these two abnormalities: between problems with the way cortisol levels are controlled in depression and the over-activity of the immune system.

Normally, increased cortisol is supposed to put the brakes on the immune system, so having high cortisol and increased immune system activity occurring at the same time in depression is puzzling.

We are very interested in understanding how cortisol and the immune system relate to each in other depression, how this relationship might help us to better understand the causes of depression and how we might use a better understanding of this link between cortisol and the immune system to improve treatments for depressed patients. This is one of the areas of mental health research that we have extensively studied in our lab.

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Over the last 50 or so years, many research studies have looked at how cortisol relates to immune system function in depression.

Overall, these studies tell a story that reads like this — cortisol becomes high in depression and this seems to be associated with increases in the activity of immune cells and the amounts of immune signals, called cytokines, that immune cells produce.

The problem is that the results of these many studies differ from each other in many ways, often due to differences in the patients that were studied, the type of cytokine that was measured and/or the way in which the effects of increased cortisol were measured.

To understand this situation better, we need to look at the overall effect across many studies, using a way to create large groups of patients using data already collected.

This process is known as “meta-analysis”.

What is a meta-analysis?

It begins by finding all of the studies that have been published on the subject of interest, in this case measuring cortisol levels and immune system activity in the same depressed patients, and then using mathematical methods to combine all of the data from the many smaller studies into one large group of patients.

Think of it like the democratic election process. Polls taken early in the campaign are like the small studies that report a specific result from a smaller number of patients. Polls ask a small number of the electorate who they think that they will vote for come election day. Since only a small percentage of the voter population is polled, it is possible that the results found by the pollsters may not truly represent how the election results will turn out. Only by examining the results on election night, or in a larger group of patients in meta-analysis, can the true underlying trends be identified.

We chose to use meta-analysis to examine how cortisol levels relate to immune system function in depression, as it allowed us to determine an answer in a much shorter time frame than we would have if we designed and conducted a large study of our own. Furthermore, the results of meta-analysis can be used to identify important research questions or measurements that should be part of any future larger study.

This helps to make the best use of the money needed to pay for the design and conduct of larger studies whilst also maximizing the potential benefits of these same studies.

So, what did we do?

Using meta-analysis, we combined patients from up to 32 individual studies into one larger group, totalling up to 1,850 depressed patients and 1,232 healthy controls.

We identified a tendency for increased blood cortisol and other effects of increased blood cortisol to accompany increased immune system activity in depressed patients. We can tell this is so because meta-analysis generates a graph that shows how all of the data combined.

In this typical picture of how meta-analysis results are presented, each horizontal line represents a study, and the black diamonds represent the combined groups of patients. The more to the right of the vertical line that the diamond falls, the more cytokines that the depressed patients produced when compared with non-depressed patients.

In what is the key finding of our study, we found that patients with higher cortisol levels (represented by the top-most diamond) tended to produce the most cytokines, while patients with the lowest cortisol levels tended to produce lesser amounts of cytokines (bottom-most diamond).

What’s next?

When we began our meta-analysis, we found many individual studies that showed a strong association between increased blood cortisol and increased immune system activity in depression, but we also found other studies that did not find an association between increased blood cortisol and increased immune system activity in depression.

By combining all of these studies into one larger group of patients, we found the trend that we discussed above. We also found that more studies need to be conducted, most certainly with very large groups of patients, to fully answer our question.

This is important knowledge to have because it helps us to understand that more work in this area is necessary, and it showed us the real picture of the underlying data, a picture that we might have missed if we relied on only a few individual studies.

There is still some way to go until our findings are directly applied to the development of new treatments for depression, but our work has taken important steps toward a better understanding of the link between increased cortisol and cortisol-related effects in depression and the function of the immune system.

We hope that the answers that our study provides will help in the design of new, larger studies that examine this area further and push it toward directly impacting the suffering experienced by depressed patients.


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