John Abel Engh1,2, Thor Ueland3,4,5, Ingrid Agartz6,7,8, Dimitrios Andreou4,7, Pål Aukrust3,4,9, Birgitte Boye10,11, Erlend Bøen11, Ole Kristian Drange12,13,14, Torbjørn Elvsåshagen1, Sigrun Hope1,15, Margrethe Collier Høegh1, Inge Joa16,17, Erik Johnsen18,19,20, Rune Andreas Kroken18,19,20, Trine Vik Lagerberg1, Tove Lekva3, Ulrik Fredrik Malt4, Ingrid Melle1,4, Gunnar Morken12,14, Terje Nærland4,21,22, Vidar Martin Steen19,20,23, Kirsten Wedervang-Resell1, Melissa Auten Weibell16,17, Lars Tjelta Westlye1,24, Srdjan Djurovic20,25, Nils Eiel Steen1,4, Ole Andreas Andreassen1,4. 1. Norwegian Centre for Mental Disorders Research, NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 2. Vestfold Hospital Trust, Division of Mental health and Addiction, Tønsberg, Norway. 3. Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway. 4. Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 5. K.G. Jebsen Thrombosis Research and Expertise Center, University of Troms, Tromsø, Norway. 6. Norwegian Centre for Mental Disorders Research, NORMENT, Institute of Clinical Medicine, University of Oslo, Oslo, Norway. 7. Centre for Psychiatry Research, Department of Clinical Neuroscience, Karolinska Institutet & Stockholm Health Care Services, Stockholm Region, Stockholm, Sweden. 8. Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway. 9. Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway. 10. Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway. 11. Psychosomatic and Consultation-liason Psychiatry, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway. 12. Department of Mental Health, Norwegian University of Science and Technology, NTNU, Trondheim, Norway. 13. Department of Østmarka, Division of Mental Health, St. Olavs University Hospital, Trondheim, Norway. 14. Department of Psychiatry, St Olav University Hospital, Trondheim, Norway. 15. Department of Neuro Habilitation, Oslo University Hospital Ullevål, Oslo, Norway. 16. TIPS, Network for Clinical Research in Psychosis, Stavanger University Hospital, Stavanger, Norway. 17. Network for Medical Sciences, Faculty of Health, University of Stavanger, Stavanger, Norway. 18. Division of Psychiatry, Haukeland University Hospital, Bergen, Norway. 19. University of Bergen, Bergen, Norway. 20. Norwegian Centre for Mental Disorders Research, NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway. 21. K.G. Jebsen Center for Neurodevelopmental Disorders, Oslo, Norway. 22. Department of Rare Disorders and Disabilities, Oslo University Hospital, Oslo, Norway. 23. Dr. Einar Martens Research Group for Biological Psychiatry, Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. 24. Department of Psychology, University of Oslo, Oslo, Norway. 25. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
Abstract
BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.
BACKGROUND: Immune dysfunction has been implicated in the pathogenesis of schizophrenia and other nonaffective psychosis (SCZ), bipolar spectrum disorder (BIP) and major depressive disorder (MDD). The cytokines B cell-activating factor (BAFF) and A proliferation-inducing ligand (APRIL) belong to the tumor necrosis factor (TNF) super family and are essential in orchestrating immune responses. Abnormal levels of BAFF and APRIL have been found in autoimmune diseases with CNS affection. METHODS: We investigated if plasma levels of BAFF and APRIL differed between patients with SCZ, BIP, and MDD with psychotic symptoms (n = 2009) and healthy control subjects (HC, n = 1212), and tested for associations with psychotic symptom load, controlling for sociodemographic status, antipsychotic and other psychotropic medication, smoking, body-mass-index, and high sensitivity CRP. RESULTS: Plasma APRIL level was significantly lower across all patient groups compared to HC (P < .001; Cohen's d = 0.33), and in SCZ compared to HC (P < .001; d = 0.28) and in BIP compared to HC (P < .001; d = 0.37). Lower plasma APRIL was associated with higher psychotic symptom load with nominal significance (P = .017), but not with any other clinical characteristics. Plasma BAFF was not significantly different across patient groups vs HC, but significantly higher in BIP compared to HC (P = .040; d = 0.12) and SCZ (P = .027; d = 0.10). CONCLUSIONS: These results show aberrant levels of BAFF and APRIL and association with psychotic symptoms in patients with SCZ and BIP. This suggest that dysregulation of the TNF system, mediated by BAFF and APRIL, is involved in the pathophysiology of psychotic disorders.
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