Gabriela Hjell1, Attila Szabo2, Lynn Mørch-Johnsen3, René Holst4, Natalia Tesli2, Christina Bell2, Thomas Fischer-Vieler2, Maren Caroline Frogner Werner2, Synve Hoffart Lunding2, Monica Bettina Elkjær Greenwood Ormerod2, Ingrid Torp Johansen2, Ingrid Dieset5, Srdjan Djurovic6, Ingrid Melle2, Thor Ueland7, Ole Andreas Andreassen2, Nils Eiel Steen2, Unn Kristin Haukvik8. 1. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry & Department of Clinical Research, Østfold Hospital, Grålum, Norway. Electronic address: gabriela.hjell@so-hf.no. 2. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 3. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Psychiatry & Department of Clinical Research, Østfold Hospital, Grålum, Norway. 4. Department of Psychiatry & Department of Clinical Research, Østfold Hospital, Grålum, Norway; Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 5. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Division of Mental Health and Addiction, Acute Psychiatric Department, Oslo University Hospital, Oslo, Norway. 6. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. 7. Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway; K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway. 8. NORMENT, Division of Mental Health and Addiction, Oslo University Hospital & Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Adult Psychiatry, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Abstract
OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (β = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (β = 0.06, t = 1.27, p = 0.20), IL-18 (β = 0.05, t = 1.25, p = 0.21), IL-18R1 (β = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.
OBJECTIVE: Agitation is a challenging clinical feature in severe mental disorders, but its biological correlates are largely unknown. Inflammasome-related abnormalities have been linked to severe mental disorders and implicated in animal models of agitation. We investigated if levels of circulating inflammasome-related immune markers were associated with agitation in severe mental disorders. METHODS: Individuals with a psychotic or affective disorder (N = 660) underwent blood sampling and clinical characterization. Plasma levels of interleukin (IL)-18, IL-18 binding protein (IL-18BP), IL-18 receptor 1 (IL-18R1), IL-18 receptor accessory protein (IL-18RAP), and IL-1 receptor antagonist (IL-1RA) were measured. Agitation levels were estimated with the Positive and Negative Syndrome Scale Excited Component. Multiple linear- and logistic regression were used to investigate the associations between agitation and the immune markers, while controlling for confounders. The influence of psychotic and affective symptoms was assessed in follow-up analyses. RESULTS: Agitation was positively associated with IL-18BP (β = 0.13, t = 3.41, p = 0.0007) after controlling for multiple confounders, including BMI, smoking, medication, and substance use. Adjustment for psychotic, manic, and depressive symptoms did not affect the results. There were no significant associations between agitation and the other investigated immune markers (IL-1RA (β = 0.06, t = 1.27, p = 0.20), IL-18 (β = 0.05, t = 1.25, p = 0.21), IL-18R1 (β = 0.04, t = 1.01, p = 0.31), IL-18RAP (odds ratio = 0.96, p = 0.30)). In a subsample (N = 463), we also adjusted for cortisol levels, which yielded unaltered results. CONCLUSION: Our findings add to the accumulating evidence of immune system disturbances in severe mental disorders and suggest the IL-18 system as a part of the biological correlate of agitation independent of affective and psychotic symptoms.