Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder

Background In major depressive disorder, selective serotonin reuptake inhibitors target the serotonin transporter (SERT). Their response rates (30-50%) are modified by SERT promotor polymorphisms (5-HTTLPR). Objectives To quantify the relationship between SERT occupancy and response, and whether 5-HTTLPR is a modifier. Methods Drug-free depressed outpatients (n=49; both sexes; aged 25-55 years), received paroxetine (20mg/day). We quantified SERT occupancy with iodine-123-labeled 2 beta-carbomethoxy-3 beta-(4-iodophenyl)-tropane single-photon emission computed tomography imaging at baseline and after 6 weeks; we genotyped 5-HTTLPR (S, L(G), L(A))- Primary outcomes: percentage decrease in 17-item Hamilton Depression Rating Scale and response (>= 50% decrease of 17-item Hamilton Depression Rating Scale). Results A significant positive relationship between SERT occupancy and clinical response existed only in the L(A)/L(A) genotype (P<0.002). Relative to paroxetine serum concentrations maximal midbrain SERT occupancy was numerically higher for LA/LA compared with other genotypes, but this difference was nonsignificant (P=0.188). Conclusion Higher SERT occupancy is only associated with more clinical improvement in the L(A)/L(A) genotype. We hypothesize that the L(A)/L(A) carriers have a more dynamic serotonergic system, which seems more responsive to selective serotonin reuptake inhibitors. (ISRCTN trial register ISRCTN44111488; http://www.trialregister.nl/ trialreg/admin/rctview.asp?TC=193). Pharmacogenetics and Genomics 19:67-76 (C) 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins.