Gerretsen Philip, Pollock Bruce G
Faculty of Medicine University of Toronto, Centre for Addiction and Mental Health, Division of Psychiatry, Toronto, Ontario, M5S 2S1, Canada.
Expert Opin Drug Metab Toxicol. 2008 Dec;4(12):1465-78. doi: 10.1517/17425250802560279.
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.
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.
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.
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.
抗抑郁药反应各异的病因仍然不明。衰老以及与年龄相关的疾病增加了老年抑郁症的复杂性和异质性。血清素转运体（5-HTT）是几种抗抑郁药（包括血清素再摄取抑制剂（SSRI））的主要初始作用位点。血清素转运体相关多态性区域（5-HTTLPR）是5-HTT基因SLC6A4中研究最广泛的多态性，被怀疑与老年抑郁症易感性及治疗抵抗有关。
介绍5-HTT基因多态性对老年抑郁症、抗抑郁药反应及药物副作用易感性影响的最新情况。
使用“血清素转运体”“5-HTT”“SERT”“5-HTTLPR”“老年抑郁症”“老年期抑郁”“老年抑郁”“抗抑郁药”及“SSRI”等检索词，对1993年至2008年包含老年抑郁症患者的5-HTT基因变异研究及分析进行了Medline检索。查阅参考文献部分以获取可能被检索策略遗漏的相关文章。
5-HTTLPR可能通过多种方式影响老年抑郁症的治疗反应变异性。间接而言，5-HTTLPR似乎会影响不良反应和不依从的可能性。直接来说，启动子区域可能在治疗初期导致反应变异性，这在一定程度上可由帕罗西汀的基因浓度相互作用来解释。携带S等位基因的受试者药物不良反应风险可能增加，可能需要更高的初始SSRI血浆浓度以实现最大反应。相反，L/L基因型患者即使在较低浓度下也可能有反应。
