Stratified medicine approaches to identify candidate markers associated with mental health disorders

Abstract

Diagnosis and treatment of depression is based on subjective self-report and clinical judgement, and although antidepressants are beneficial for many patients, there is no empirical measure to determine the most effective treatment for the specific patient. The aim of this thesis was to examine the link between depression and inflammation, by exploring biomarkers and clinical features associated with depression relating to inflammation. Following a review of the literature, five consistently reported upregulated inflammatory proteins associated with depression were investigated in the DISC1 mouse model of major mental illness. Gene expression analysis revealed a decrease in three proteins in the cortex of DISC1 mice compared to wild type. Protein levels, in brain and serum, were then determined using a 10-protein inflammatory panel containing the five primary proteins of interest, revealing only a modest increase in IL-1β levels. Factors influencing antidepressant prescribing in Northern Ireland, and comorbid prescribing rates were then evaluated. Overall 17% of the NI population was prescribed an antidepressant over a one-year period. Females, those over 45 and residents of low socioeconomic areas were more likely to be administered an AD. Also, more AD prescriptions were administered by GPs who were male, and those aged 45+. High rates of mental disorders, including depression, anxiety and suicidal behaviour were reported in first year students recruited to the UU Student Wellbeing study, as well as high rates of co-morbidity between depression and physical health conditions. The composition of the oral microbiome was altered in individuals with depression, with individual bacterial species, known to be opportunistic pathogens, differentially abundant in depressed and healthy individuals. The first evidence suggesting differences in the oral microbiome associated with depression, and further support for a link between dysregulation of the microbiome, immune function and depression. Whole methylome analysis revealed global changes in DNA methylation patterns in females with severe depression compared to healthy controls, and gene ontogeny analysis revealed that genes related to immune function were affected. Genetic analysis, on two commonly studied single nucleotide polymorphisms with depression, 5HTTLPR and BDNF Val66Met, did not reveal an association with depression in this initial modest sample set. Finally, levels of peripheral serum cardiac and inflammatory proteins were measured in a separate clinical sample set of individuals with depression, schizophrenia and healthy controls. Despite modest numbers in this preliminary investigation exploratory statistical analysis uncovered a number of significantly altered proteins, including IL-6 that will be validated in larger sample numbers. In, summary, this thesis provides further support for growing prevalence of mental health disorders and antidepressant use, and for the role of inflammation in the pathology of depression. With further validation, the novel biomarkers identified could be used to assist in diagnosis and treatment selection in depression, which would have a significant impact on its clinical management.

Date of Award	Jun 2018
Original language	English
Sponsors	Department of Education and Learning (DEL)
Supervisor	Tony Bjourson (Supervisor) & Elaine Murray (Supervisor)