Immunopsychiatry from a transdiagnostic perspective : the immunometabolic interplay

Background/Objective: Psychiatric disorders are common and they significantly impact quality of life. It has been proposed that inflammatory processescontribute to the emergence of psychiatric disorders. In addition to inflammation, disturbances in metabolic pathways have been seen in individuals with various psychiatric disorders. At the interface between inflammation and metabolism stands the Nod-like receptor 3 (NLRP3) inflammasome, which is anintracellular protein complex responsible for cleaving members of the interleukin-1(IL-1) to their active forms. The overall aim of this thesis project was tounderstand the interplay between metabolism and inflammation in a transdiagnostic cohort of individuals with severe psychiatric disorders. Methods: Patients with severe psychiatric disorder (n=39) and age- and sexmatched healthy controls (n=39) were included in the studies. Psychiatric diagnoses, comorbidities, severity, and functioning were measured using a numberof validated assessment scales. Biological parameters, such as circulating immune markers, gene expression, and metabolites were analyzed using electrochemiluminescence immunoassay, qPCR, and UHPLC-MSMS, respectively. Results: The results revealed that in individuals with psychiatric disorders, immune cells were primed in regard to the NLRP3 inflammasome, with elevatedinflammasome-related cytokine levels, regardless of diagnosis. In addition, positive metabolic inflammasome regulators, such as lactic acid, serine, and glutamine were significantly higher in the patients; the main metabolic pathwaysthat were affected included arginine and proline metabolism and tryptophan metabolism. A number of these parameters also correlated with the patients’ disease severity. Lastly, the patients as a group displayed transdiagnosticchanges in immune–lipid pathways. In particular, strong associations could beobserved between two triglycerides and one ether phospholipid, with the inflammatory markers osteopontin and IL-1Ra.