The role of the immune system in the development of anxiety disorders: Towards responsible and sustainable research methods

This thesis examines the role of the immune system in the development of anxiety disorders, focusing on responsible and sustainable research methods. Using various research methods, we have gained insight into the role of the immune system across different aspects of anxiety pathophysiology. The results of our systematic reviews with meta-analyses suggest that the anxiety-reducing effect of SSRIs, the first-line pharmacological treatment of anxiety disorders, can be attributed to the effective reduction of fear generalisation and the general inhibition of fear-related emotions. The reviews furthermore reveal poor study reliability as assessed with bias tools, limiting firm conclusions. This highlights the need for better-designed, preferably human, experimental studies such as those using the anxiety‑potentiated startle test. In addition, we have introduced the adverse outcome pathway (AOP) method into our field of research. Using this method, we systematically mapped the processes linking TNF-α and corticosteroid receptor activation to fear learning problems, thereby studying how the immune system and the HPA axis regulate fear learning processes. These AOPs provide an important starting point for integrating all immune- and stress-related processes in the development of fear learning problems and can help identify potential targets for the treatment of anxiety disorders. For example, these AOPs suggest an important role for the glutamatergic system in explaining how TNF-α and corticosteroid exposure can lead to fear learning problems. Moreover, we demonstrated in a nested case-control study that glucocorticoid use could significantly increase the risk of developing anxiety disorders, as measured by the initiation of SSRI treatment, in patients with rheumatoid arthritis. Although the anti‑inflammatory properties of glucocorticoids were hypothesised to be protective, the findings are consistent with the aforementioned AOP results. Disease severity may confound the observed relationship, but the results still support clinical vigilance for anxiety symptoms in glucocorticoid‑treated patients and motivate replication in other cohorts. Furthermore, this thesis addresses sustainability in academic research. We assessed the current state of sustainability within our university and made recommendations for a more integrated and coordinated approach that is broadly applicable to universities. We propose an integrated top-down and bottom-up approach, combining initiatives and thus emphasising the responsibility and contribution of the entire organisation. Additionally, we present a case study of sustainability implementations in pharmaceutical research laboratories. We provide practical examples for initiating, promoting and integrating laboratory sustainability at a research group and institutional level. These examples aim to foster a culture in which sustainability becomes a normal part of academic work. The application of the three alternative research methods in this thesis has given us new insights into the pathophysiology and potentially the prevention and treatment of anxiety disorders. We have shown that the serotonergic system, the immune system, and the HPA axis all influence specific fear learning processes, most likely via changes in neuroplasticity. Further exploring these interactions will give us better handles for further developing prevention and treatment strategies for anxiety disorders. Of course, these future studies should adhere to the principles of open, responsible, and sustainable research.