Pharmacogenetics and the serotonin transporter in late-life depression

Background: The etiologies of variable antidepressant response remain elusive. Aging and age-related illness add to the complexity and heterogeneity of late-life depression. The serotonin transporter (5-HTT) is the principal site of initial action for several antidepressants, including serotonin re-uptake inhibitors (SSRIs). The serotonin transporter-linked polymorphic region (5-HTTLPR) is the most widely studied polymorphism of the 5-HTT gene, SLC6A4, and is suspected of conferring vulnerability to elderly depression and resistance to treatment. Objective: To present an up-to-date account of the influence of 5-HTT polymorphisms on elderly depression, antidepressant response and susceptibility to medication side effects. Method: A Medline (TM) search (1993 - 2008) of 5-HTT gene variation studies and analyses that included elderly depressed subjects was performed using the terms: 'serotonin transporter'; '5-HTT'; 'SERT'; '5-HTTLPR'; 'late-life depression';,elderly depression'; 'geriatric depression'; 'antidepressants' and 'SSRIs'. Reference sections were gleaned for relevant articles that may have been overlooked by the search strategy. Conclusion: 5-HTTLPR may influence treatment response variability in late-life depression in a number of ways. Indirectly, 5-HTTLPR seems to influence the likelihood of adverse effects and non-adherence. Directly, the promoter region may contribute to response variability during the initial stages of treatment, which is explained, in part, by a gene-concentration interaction for paroxetine. Subjects with the S allele may be at an increased risk of adverse drug reactions and may require higher initial SSRI plasma concentrations to maximize response. Conversely, patients with the L/L genotype may respond even at lower concentrations.