Pharmacogenomic implications of variants of monoaminergic-related genes in geriatric psychiatry

Abstract

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.