Antidepressant-induced adverse effects are common, occur early on in treatment and affect adherence. This thesis aims to gain a greater understanding of genetic markers involved in antidepressant-induced adverse effects. This will include: (i) clarifying the role of the most widely studied polymorphism in this area, the serotonin transporter linked polymorphic region (5-HTTLPR), on discontinuation from antidepressant treatment; (ii) improving our understanding of the adverse effects induced by two pharmacologically different antidepressants; and (iii) examining whether genetic markers can be used to guide antidepressant choice by reducing the risk of experiencing adverse effects. A systematic review and meta-analysis (total n=4309) was performed to investigate the effect of 5-HTTLPR on discontinuation from antidepressant treatment. Data from the GENPOD trial (n=601) were analysed to investigate the adverse effects induced by citalopram or reboxetine. Genetic data from GENPOD were analysed to identify genetic markers that had a differential effect on antidepressant-induced adverse effects. This involved both a genome-wide approach with an independent replication sample and a candidate gene approach. A meta-analysis of previous studies provided no evidence that 5-HTTLPR was associated with discontinuation from SSRls in Europeans. Antidepressant-induced dizziness and the total number of adverse effects were associated with discontinuation in the GENPOD trial. Reports of physical symptoms were high when patients were medication free and adverse effects reduced with time. No genetic markers differentially predicted the occurrence of antidepressant-induced adverse effects. 5-HTTLPR did not identify individuals at higher risk for discontinuation of antidepressant treatment, however larger sample sizes are required before its clinically utility can be excluded. Although adverse decreased with time they were still commonly reported throughout the trial. Distinguishing between physical symptoms of depression and adverse effects remains a challenge. At present, pharmacogenetics cannot be used to guide clinical practice in terms of the occurrence of antidepressant-induced adverse effects. The establishment of consortia collecting standardised data and conducting pooled analyses across large datasets may further research in this area.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:686641 |
| Date | January 2014 |
| Creators | Crawford, Andrew Alexander |
| Publisher | University of Bristol |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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