Antidepressent Response and Gene Expression

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DESCRIPTION (provided by applicant): Depression is estimated to cost 65 billion dollars yearly, whereas any given antidepressant treatment (ADT) is only effective in approximately half of all cases. Despite the obvious need for improvement of ADT, only some progress has been made in understanding the mechanisms of response. Recent evidence has revealed that antidepressant response (ADR) may be dependent upon a polymorphic promoter region in the serotonin transporter (SERT) gene sequence. This polymorphism (5-HTTLPR) is differentially sensitive to several cytokine and kinase signals. Pilot gene chip data has now shown that some of these same cytokine and kinase signals change in the periphery with chronic antidepressant treatment (ADT). This developmental project will enable the initial clinical infrastructure to develop the necessary laboratory and clinical procedures to test the feasibility and application of studying gene expression in the periphery as a function of antidepressant treatment (ADT). The experiment will examine gene expression patterns in lymphocytes using Affymetrix HG-U 133A GeneChip microarrays in 25 depressed patients before and after 8 weeks treatment with s-citalopram, and 10 depressed patients before and after 8 weeks treatment with placebo. RNA from these subjects will be collected in split sample and analyzed for ADT vs. placebo effects in split duplicate. We anticipate that genes that regulate SERT sequestration, transcription factors with differential action at the 5HTTLPR, and sets of co-regulated genes, including those with consensus sequences to the 5HTTLPR 44 base pair polymorphism may be expressed with ADT. Lymphocytes, which express SERT, will be characterized for SERT transport kinetics, which differ with ADT. This will assess the utility of the approach for a future funding proposal to analyze gene expression in those patients, and ultimately study 100 depressed patients phenotyped for ADR and 100 age, sex, and race matched controls.