Geriatric Psychiatry Clinic, Mental Health Service Line, Minneapolis VA Medical Center, University of Minnesota Medical School, Minneapolis, MN, USA.
Pharmacogenomics. 2010 Sep;11(9):1305-30. doi: 10.2217/pgs.10.118.
Response to psychiatric medications in later life is highly heterogeneous and complex. Monoaminergic-related polymorphisms may influence medication response and susceptibility to side effects in elderly individuals. Individuals with the lower function short (S) allele of the serotonin transporter gene (SLC6A4) insertion/deletion (indel) promoter polymorphism (5-HTTLPR) have both increased the likelihood of adverse drug events and increased the need for higher antidepressant concentrations to obtain maximum antidepressant response. By contrast, carriers of the higher expression homozygous long allele (L/L) genotype may respond at lower concentrations. The differential role of these polymorphisms appears at early stages of treatment rather than in the final antidepressant outcome. Research findings suggest that the rs25531 SNP may influence functional expression of the L allele. Similarly, a variable number of tandem repeats in the second intron of the serotonin transporter gene may influence the expression of SLC6A4 and the implications of these variants may be influenced by aging. Two polymorphisms, rs2242466 (-182T/C) and rs5569 (1287G/A), in the norepinephrine transporter gene (SLC6A2 or NET) have been associated with antidepressant response. Studies in dopamine-related polymorphisms have focused on associations with neuroleptic-induced movement disorders. The rs1800497 variant (Taq1A) of the dopamine receptor D2 (DRD2) gene located in a noncoding 3´ region may regulate expression of D2 receptors. The rs6280 variant (Ser9Gly) of the dopamine receptor 3 (DRD3) gene may influence the binding affinity of D3 receptors as a result of serine to glycine substitution of the receptor protein. A multicenter collaborative research effort would be an effective strategy to increase sample sizes to further investigate how gene variants impact the pharmacodynamics and pharmacokinetics of psychotropic drugs in elderly persons.
老年人对精神药物的反应高度异质且复杂。单胺能相关的多态性可能会影响老年人对药物的反应和对副作用的易感性。载有较低功能的短（S）等位基因（SLC6A4）插入/缺失（indel）启动子多态性（5-HTTLPR）的 5-羟色胺转运体基因（SLC6A4）的个体，不仅增加了不良药物事件的可能性，而且增加了获得最大抗抑郁反应所需的更高抗抑郁药浓度。相比之下，高表达纯合子长（L/L）基因型的携带者可能会以较低的浓度产生反应。这些多态性的差异作用出现在治疗的早期阶段，而不是在最终的抗抑郁结局中。研究结果表明，rs25531 SNP 可能影响 L 等位基因的功能表达。同样，5-羟色胺转运体基因第二内含子中的可变数目串联重复可能影响 SLC6A4 的表达，这些变体的影响可能会受到年龄的影响。去甲肾上腺素转运体基因（SLC6A2 或 NET）中的两个多态性，rs2242466（-182T/C）和 rs5569（1287G/A），与抗抑郁反应有关。多巴胺相关多态性的研究集中在与神经安定药诱导的运动障碍的关联上。多巴胺受体 D2（DRD2）基因位于非编码 3´ 区域的 rs1800497 变体（Taq1A）可能调节 D2 受体的表达。多巴胺受体 3（DRD3）基因的 rs6280 变体（Ser9Gly）可能通过受体蛋白丝氨酸到甘氨酸取代影响 D3 受体的结合亲和力。多中心合作研究努力将是一种有效的策略，可以增加样本量，以进一步研究基因变体如何影响老年人精神药物的药效学和药代动力学。
