title: Serotonin transporter gene promoter polymorphisms modify the association between paroxetine serotonin transporter occupancy and clinical response in major depressive disorder.
abstract: 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).
  
  
  OBJECTIVE
  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 (20 mg/day). We quantified SERT occupancy with iodine-123-labeled 2beta-carbomethoxy-3beta-(4-iodophenyl)-tropane single-photon emission computed tomography imaging at baseline and after 6 weeks; we genotyped 5-HTTLPR (S, L(G), L(A)).
  
  
  METHODS
  percentage decrease in 17-item Hamilton Depression Rating Scale and response (> or =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 L(A)/L(A) compared with other genotypes, but this difference was nonsignificant (P=0.188).
  
  
  CONCLUSIONS
  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).
authors.affiliation: Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. H.G.Ruhe@AMC.UvA.NL
authors.forename: Henricus G
authors.initials: HG
authors.lastname: Ruhé
authors.forename: Wendy
authors.initials: W
authors.lastname: Ooteman
authors.forename: Jan
authors.initials: J
authors.lastname: Booij
authors.forename: Martin C
authors.initials: MC
authors.lastname: Michel
authors.forename: Martina
authors.initials: M
authors.lastname: Moeton
authors.forename: Frank
authors.initials: F
authors.lastname: Baas
authors.forename: Aart H
authors.initials: AH
authors.lastname: Schene
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000378:metabolism / Q000627:therapeutic use; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D003865:Major Depressive Disorder / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D004027:Diencephalon / Q000000981:diagnostic imaging / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000000981:diagnostic imaging / Q000378:metabolism; D008875:Middle Aged; D017374:Paroxetine / Q000378:metabolism* / Q000627:therapeutic use*; D010597:Pharmacogenetics; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D015899:Tomography, Emission-Computed, Single-Photon
chemical_list: D018687:Antidepressive Agents, Second-Generation; D017931:DNA Primers; D017374:Paroxetine; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human