Endothelial and inflammation markers in schizophrenia and bipolar disorder
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AbstractSchizophrenia and bipolar disorder are complex disorders, with an etiology that involves multiple genes and a variety of environmental risk factors. Despite a high heritability rate, very little is known about the underlying biological mechanisms, but several molecular pathways are probably involved. The diagnostic criteria are descriptive based on partly overlapping symptom profiles and current treatment options only offer symptom relief and are often accompanied with adverse effects. In the recent years, promising results from genetic, molecular as well as epidemiological studies have implicated alterations involving inflammatory mechanisms to be involved in the pathophysiolology of both disorders.
In this project, we investigated the role of inflammation and endothelial markers and their putative involvement in schizophrenia and bipolar disorder pathology. By using a translational approach we explored:
i) the expression of NOTCH4 (a gene within the major histocompatibility complex) previously found to be associated with schizophrenia in genome wide association studies in schizophrenia and bipolar disorder and the association with potential expression quantitative trait loci (eQTL) within the NOTCH4 gene
ii) the role of inflammation in relation to cardiovascular disease (CVD) risk factors associated with second generation antipsychotic treatment
iii) whether inflammation and altered endothelial activity are associated with brain morphology in schizophrenia and bipolar disorder.
The expression of NOTCH4 was significantly increased in patients with bipolar disorder and NOTCH4 expression was associated with three loci within the NOTCH4 gene. Overweight and increased glucose levels were associated with elevated levels of CRP in patients treated with second generation antipsychotics. Von Willebrand factor levels were highly associated with basal ganglia volume across all groups, in particular globus pallidus volume. This association remained significant after adjustment for diagnoses and antipsychotic treatment.
Taken together, the findings support that i) mechanisms related to endothelial activity and inflammation and more specifically the NOTCH4 pathway are involved in bipolar disorder pathophysiology ii) cardiovascular disease risk factors and potentially atherosclerosis induced by second generation antipsychotics may in part be mediated through inflammatory mechanisms iii) and finally that von Willebrand factor, an endothelial marker also known to be involved in inflammation may have a role in the pathophysiological process underlying the enlarged basal ganglia volume seen in schizophrenia.
In summary, the results indicate that endothelial-related inflammation is involved in both disorders but through different molecular mechanisms.
List of papers. The papers are removed from the thesis due to publisher restrictions.
Paper I NOTCH4 Gene Expression is Up-regulated in Bipolar Disorder Ingrid Dieset, Srdjan Djurovic, Martin Tesli, Sigrun Hope, Morten Mattingsdal, Annika Michelsen, Inge Joa, Tor Ketil Larsen, Ingrid Agartz, Ingrid Melle, Jan Ivar Røssberg, Pål Aukrust, Ole A. Andreassen, and Thor Ueland Am J Psychiatry. 2012 Dec 1;169(12):1292-300. doi:10.1176/appi.ajp.2012.11091431
Paper II Cardiovascular risk factors during second generation antipsychotic treatment are associated with increased C-reactive protein Ingrid Dieset, Sigrun Hope, Thor Ueland, Thomas Bjella, Ingrid Agartz, Ingrid Melle, Pål Aukrust, Jan-Ivar Røssberg and Ole A. Andreassen Schizophr Research 2012 Sep; 140(1-3):169-74. doi:10.1016/j.schres.2012.06.040
Paper III Elevated plasma levels of von Willebrand factor is associated with larger basal ganglia volume – relationship to schizophrenia Ingrid Dieset, Unn Kristin Haukvik, Ingrid Melle, Jan Ivar Røssberg, Thor Ueland , Sigrun Hope, Anders M. Dale, Srdjan Djurovic, Pål Aukrust , Ingrid Agartz and Ole A. Andreassen Submitted