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Abstract
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™ 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.
Acknowledgements
This project was supported by Sandra A Rotman Chair in Neuropsychiatry.
Conflict of interest
P Gerretsen has no conflicts of interest to declare.
BG Pollock has received grants or research support from the National Institute of Health. He has served on the advisory board of Forest Laboratories and is a faculty member of the Lundbeck Institute. He is also at present a consultant for Lundbeck and Wyeth. He served as a consultant for Takeda in July 2007.