Sustainable research sheds light on how an overactive immune system may increase the risk of anxiety disorders

Although it has become increasingly clear in recent years that the immune system plays an important role in the development of anxiety disorders, the underlying mechanisms are still not fully understood. Laboratory animals are often used to gain a better understanding of the process. Elise Heesbeen, who recently defended her PhD, chose a different approach and applied alternative research methods to generate new insights. Her work shows that brain plasticity, the brain’s ability to form new connections or to strengthen or weaken existing ones, plays a central role.

Anxiety disorders, in which people experience disproportionate fear in response to certain situations, are among the most common mental health conditions worldwide. According to the WHO, approximately 4.4% of the global population currently has an anxiety disorder.

By gaining a better understanding of how the immune system, stress and anxiety are interlinked, Heesbeen hopes to identify new approaches to treating anxiety disorders. “Previous studies show that people are more likely to develop an anxiety disorder when their immune system is activated, for example due to inflammation or an allergic response,” Heesbeen explains. “Animal studies show that stress also increases the risk of developing anxiety disorders.”

SSRIs

Currently, SSRIs are the first-line treatment for anxiety disorders. These medicines increase levels of serotonin, a neurotransmitter that helps transmit signals between nerve cells.

Changes in brain plasticity can make it easier to learn a particular fear, or conversely, more difficult to unlearn it.

Although SSRIs are effective for many patients, they do not work for everyone. “Moreover, it remains unclear exactly how they work, and whether the immune system plays a role in this,” says Heesbeen. “They also often cause side effects, such as insomnia, nausea and sexual dysfunction, like a reduced libido.”

Literature review

That is why Heesbeen conducted a systematic literature review to gain a better understanding of how SSRIs work. She combined the results of a large number of published studies, carried out on laboratory animals, in order to re-analyse them statistically.

“The literature review shows that SSRIs are effective for both acquired and innate forms of anxiety,” Heesbeen explains. “This is probably because SSRIs essentially dampen all emotions, including anxiety. However, this overall blunting of emotions can also be considered an undesirable side effect.”

Visualisation

Heesbeen then used the adverse outcome pathway method to investigate how the immune system may influence the development of acquired anxiety disorders. “This method involves creating a visual overview of all the processes that lead to an adverse outcome. By doing so, you can see what we already know, but also precisely where knowledge is still lacking.”

Brain plasticity

This is how Heesbeen identified how the activation of a protein involved in inflammation can lead to learned fear. Heesbeen: “When the immune system is activated, this leads to a change in brain plasticity. Changes in plasticity can make it easier to learn a particular fear, or conversely, more difficult to unlearn it.”

Heesbeen also conducted an adverse outcome pathway analysis on stress and observed a similar pattern. “When you’re stressed, levels of cortisol, the stress hormone, rise. My research shows that cortisol can also raise the risk of anxiety by affecting brain plasticity.”

According to Heesbeen, this may at least partly explain why some people do develop an anxiety disorder following a particular traumatic event, while others do not. “If your immune system is already overactive, for example due to an allergy, or if you are under significant stress at the time of the event, this may increase the likelihood that it leads to an anxiety disorder.”

Glucocorticoid use

Finally, Heesbeen decided to investigate what happens when people take medication that suppresses the immune system. “People with rheumatoid arthritis are often prescribed anti-inflammatory drugs. We suspected that people taking these drugs would be less likely to develop an anxiety disorder. But the opposite turned out to be true.”

I would like researchers to think more carefully about how they can answer a given question as responsibly as possible.

Heesbeen has an explanation for this finding. “The drugs we studied, glucocorticoids, are very similar to the body’s own cortisol. That may explain why we see that people using them are actually more likely to be prescribed SSRIs. This also fits with the results of my adverse outcome pathway analysis, which shows that elevated cortisol levels can increase the risk of anxiety. We may see different patterns with drugs that suppress the immune system through other mechanisms.”

Alternative treatments

Heesbeen’s findings suggest potential for treatments that focus on brain plasticity. “There are already various experimental treatments designed to influence plasticity. One example is transcranial magnetic stimulation, which uses magnetic fields to stimulate areas of the brain. Psychedelics also have an effect on brain plasticity. These are sometimes already used for post-traumatic stress disorder, but could perhaps be applied more widely.”

Sustainable and responsible

Through her work, Heesbeen demonstrates that new insights can be obtained without additional animal testing.  “I have noticed that other people see what we’re doing and are interested in it as well. And if someone in your department already has experience in this area, it makes it much easier to get started yourself.”

The newly qualified PhD takes a broad view of sustainability in research. For instance, she is one of the driving forces behind the Green Team at the Department of Pharmaceutical Sciences, which is successfully working to make research and teaching there more sustainable. But even beyond her own department, Heesbeen sees significant room for improvement.

“People often stick to established lines of research simply because that’s how they’re used to working,” she explains. “I would like researchers to think more carefully about how they can answer a given question as responsibly as possible. In addition, people often keep it to themselves when a method or experiment does not work, which leads to unnecessary repetition. It would be good if these ‘negative’ results were shared as well.”