Investigating the molecular underpinnings of major depressive disorder and the utility of biomarkers in the inflammatory cytokine pathway as aids for clinical diagnosis and treatment selection

Major depressive disorder (MDD) is a complex, heterogeneous disorder<br/>characterised by a pathological distortion of emotional mood. There is evidence<br/>of both genetic and environmental risk factors for MDD, and gene-environment<br/>interactions may play a particularly important role. Clinically, MDD is defined by<br/>patients meeting a number of diagnostic criteria. However, the heterogeneous<br/>nature of the disorder can make MDD difficult to diagnose, especially as it<br/>shares close similarities with other psychiatric illnesses such as bipolar disorder.<br/>Another clinical problem is that antidepressants, the first line of treatment for<br/>MDD, are ineffective in a significant proportion of patients. The projects in this<br/>thesis address four aims: (i) the identification of novel gene-environment<br/>interactions which may increase risk for MDD; (ii) the identification of diagnostic<br/>biomarkers for MDD; (iii) the identification of biomarkers for the prediction of<br/>treatment response to antidepressants; and (iv) the identification of<br/>transcriptional changes associated with antidepressant treatment and successful<br/>therapeutic response.<br/>Utilising a model of early life stress in two inbred mouse strains, we<br/>investigated the transcriptional effects of maternal separation. The top stress by<br/>strain interaction was found in the telomerase RNA component gene (Terc). We<br/>also found that a single nucleotide polymorphism in TERC (rs10936599),<br/>previously identified as a predictor of telomere length, interacted with childhood<br/>neglect to predict MDD in a human case-control cohort.<br/>A study investigating differences in the transcription of inflammatory<br/>cytokines in the blood of MDD patients, bipolar disorder patients and controls,<br/>revealed disorder-specific differences in chemokine (C-C motif) ligand 24 and CC<br/>chemokine receptor type 6 which specifically differentiated MDD patients.<br/>Furthermore, we found that transcription of tumour necrosis factor and its targets<br/>in the inflammatory cytokine pathway, and DNA methylation in interleukin-11<br/>could be used to predict antidepressant response amongst MDD patients.<br/>Moreover, transcription of ATP-binding cassette sub-family F member 1 was<br/>found to increase on antidepressant treatment, with the magnitude of change<br/>corresponding to clinical response.

Name dc:type.qualificationname

Doctor of Philosophy

Level dc:type.qualificationlevel

Doctoral Thesis

Grantor dc:publisher.institution

King's College London

Year dc:date.issued

2014

Author dc:creator

• Powell, Tim

Advisors dc:contributor.advisor

• Schalkwyk, Leonard Cornelis
• Mill, Jonathan

Language dc:language

eng

Identifier

oai:kclpure.kcl.ac.uk:studenttheses/c75d417f-13f8-4618-91de-96ce798a8336

OAI identifier oai:identifier

oai:kclpure.kcl.ac.uk:studenttheses/c75d417f-13f8-4618-91de-96ce798a8336