Inflammatory profile in schizophrenia and bipolar disorder : Relation to affective state
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AbstractBackground: Schizophrenia and bipolar disorder are debilitating disorders. In addition to classic psychotic and mood symptoms, frequency of cognitive disturbances and mortality from cardiovascular disease are high. Inflammation has been associated with both cognitive disturbances and cardiovascular disease. Recent studies have indicated increased inflammation in patients with severe mental disorders. However, these studies are small and have a limited number of inflammatory markers. This makes it difficult to draw any conclusions about the mechanisms involved. No studies have investigated if inflammatory disturbances differ between schizophrenia and bipolar disorder. Inflammation has been associated with depression and mania, but it is still unclear how it relates to mood symptoms and affective states.
Aims: The aims were to determine if patients with severe mental disorder have high levels of inflammation, if they have a specific inflammatory profile, if inflammatory disturbances differ between schizophrenia and bipolar disorder patients, and if inflammatory profile is associated with mood symptoms or affective state.
Methods: 312 patients from a catchment area were included together with 239 healthy controls. Patients were diagnosed according to DSM-V, and degree of depression and mania was assessed with standard instruments. Four general inflammatory markers were measured: Tumor necrosis factor receptor 1 (TNF-R1), Interleukin 1 receptor antagonist (IL-1Ra), Interleukin 6 (IL-6) and high-sensitivity CRP (hs- CRP). Three specific markers were measured: The platelet related inflammatory marker CD40L ligand (sCD40L), the endothelial related marker von Willebrand factor (vWf) and the calcium related inflammatory marker Osteoprotegerin (OPG). Routine biochemical blood tests and clinical characteristics, which could confound associations, were also assessed.
Results: Patients had a similar immune profile with highly significant increase of TNF-R1, vWf and OPG (p<0.000002, p<0.000002, and p=0.01 respectively). The results were significant also after control for confounding factors. Contrary to expectations, depressed bipolar disorder patients had the lowest levels of inflammation and manic patients had the highest. Degree of depressive mood was also inversely correlated with inflammation, which was significant for OPG (p=0.0003), IL-1Ra (p=0.001) and IL-6 (p= 0.002). Patients in manic state had significantly higher levels of OPG, vWf, IL-1Ra and sTNF-R1. There were no associations between mood and inflammation in schizophrenia.
Discussion: The study indicated that the general inflammatory marker TN-R1, as well as endothelial and calcium related inflammation may play a role in severe mental illness pathology. TNF-R1 has been found to be involved in neuronal plasticity, and related to cognitive dysfunction, which is an important clinical characteristic of the disorders. The results are also in line with recent findings that endothelial dysfunction and calcium metabolism are involved in the pathology. Furthermore, OPG and vWf are risk factors of cardiovascular disease and the high levels in patients may be related to their elevated mortality rates. It has been fairly well documented that inflammation induces typical sickness behavior, with reduced energy, increased sleep and depressive mood. Therefore, it was unexpected that inflammation was increased in the manic state. This suggests that there may be other inflammatory mechanisms involved.
Conclusions: Both bipolar disorder and schizophrenia show increased TNF-R1, OPG and vWf. This immune profile suggests inflammatory disturbances related to neuroplasticity, endothelial function and calcium regulation. In bipolar disorder patients, elevated mood is characterized by high levels of inflammation, while depressed mood is characterized by low. This suggests that inflammatory disturbances may be involved with core psychopathology of bipolar disorder. The study supports that inflammatory disturbances are of importance in severe mental disorders.
List of papers. The papers are removed from the thesis due to copyright restrictions.
List of papers
|Paper I: Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA. Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor. Bipolar Disord 2009 11:726-734. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1111/j.1399-5618.2009.00757.x|
|Paper II: Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA. Osteoprotegerin levels in patients with severe mental disorders. J Psychiatry Neurosci, 2010. 35(5): 304-10. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1503/jpn.090088|
|Paper III: Hope S, Dieseth I , Agartz I, Steen NE, Ueland T, Melle I, Aukrust P, Andreassen OA. Mood states are associated with markers of inflammation and immune activation in bipolar disorder but not in schizophrenia. J Psychiatr Res, 2012. 45(12): 1608-1616. The paper is removed from the thesis in DUO due to publisher restrictions. The published version is available at: https://doi.org/10.1016/j.jpsychires.2011.08.003|