Depressive disorders (DD) are a leading cause of disability worldwide and display diverse symptoms including anhedonia, melancholia, decreased concentration, sleep and appetite disturbances, and suicidal thoughts and acts. Current available medications are still ineffective for more than 30% of patients, suggesting DD are multi-faceted heterogeneous disorders. Despite intense research, as yet there are no widely used biological diagnostic tests for DD. Since DD are likely a manifestation of both genetic and environmental factors, gene expression of peripheral blood leukocyte allows for a non-invasive means to evaluate trait- and state-dependent neurophysiological dysregulation. In this dissertation, we employed real-time quantitative polymerase chain reaction (qPCR) to evaluate differences between healthy controls and patients with medication-refractory depression, for a panel of candidate genes previously implicated in depression as well as novel genes implicated in related neurological disorders. Chapter 1 begins with an overview of the multiple domains involved in depression and of previous literature findings evaluating protein and gene expression. Chapter 2 describes one of our studies of gene expression of a small panel of 14 genes involved in the immune and stress response in 19 patients with medication-refractory depression, before and following symptom improvement, compared to 20 healthy controls. We found that patients displayed trait- and state-dependent dysregulation in immune cytokines IL-10 and IL-6, transcription factor NFkB1, the serotonin receptor HTR1D, GABAA modulator DBI, and the adrenergic receptors ADR2A and ADRB1. Furthermore, the dopamine receptor DRD4, the glucocorticoid receptor NR3C1, and SULT1A1 displayed acute changes following treatment, though no differences were observed Pretreatment. In Chapter 3, we describe another gene expression study with results using a larger sample size (42 patients and 38 controls) and an expanded gene panel (46 genes) that includes candidate genes from diverse biological pathways. In this study, we found upregulation of IL-10 and IL-6 as well as dysregulation in the amyloid precursor protein, neuregulin-1, and several ion channels that have roles in anxiety, pain, and fatigue. Finally, Chapter 4 summarizes results from both studies and discusses future research into promising biomarkers and novel mechanisms of depression.
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