title: Regional Differences in Serotonin Transporter Occupancy by Escitalopram: An [11C]DASB PK-PD Study.
abstract: Escitalopram is one of the most commonly prescribed selective serotonin reuptake inhibitors (SSRIs). It is thought to act by blocking the serotonin transporter (SERT). However, its dose-SERT occupancy relationship is not well known, so it is not clear what level of SERT blockade is achieved by currently approved doses.
  
  
  
  To determine the dose-occupancy relationship, we measured serial SERT occupancy using [11C]DASB [3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] positron emission tomography (PET) and plasma drug concentrations after the administration of escitalopram in 12 healthy volunteers. We then built a pharmacokinetic-pharmacodynamic model to characterize the dose-occupancy relationship in the putamen and the dorsal raphe nucleus.
  
  
  
  Escitalopram at approved doses occupied less SERT than expected and the SERT occupancy showed regional effects [occupancy was higher in the dorsal raphe nucleus than in the putamen (p < 0.001)]. The drug concentration when 50 % of receptors are occupied (EC50) value and Hill coefficient were significantly different between the putamen (EC504.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC502.89, Hill coefficient 0.817).
  
  
  
  Higher doses of escitalopram than 20 mg are needed to achieve 80 % or greater SERT occupancy. Higher occupancy by escitalopram in the dorsal raphe nucleus relative to the striatum may explain the delayed onset of action of SSRIs by modulating autoreceptor function. The prevention of the 5-HT1Aautoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects.
authors.affiliation: Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam-si, 13620, Gyeonggi-do, Korea.
authors.forename: Euitae
authors.initials: E
authors.lastname: Kim
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.|Medical Research Council Clinical Sciences Centre, London, W12 0NN, UK.|Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK.
authors.forename: Oliver D
authors.initials: OD
authors.lastname: Howes
authors.affiliation: Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul, 02447, Korea.
authors.forename: Bo-Hyung
authors.initials: BH
authors.lastname: Kim
authors.affiliation: Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea.
authors.forename: Myong-Wuk
authors.initials: MW
authors.lastname: Chon
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea.|Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
authors.forename: Seongho
authors.initials: S
authors.lastname: Seo
authors.affiliation: Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
authors.forename: Federico E
authors.initials: FE
authors.lastname: Turkheimer
authors.affiliation: Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea.|Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
authors.forename: Jae Sung
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea.
authors.forename: Yun-Sang
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea. kwonjs@snu.ac.kr.|Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea. kwonjs@snu.ac.kr.
authors.forename: Jun Soo
authors.initials: JS
authors.lastname: Kwon
mesh_terms: D000328:Adult; D001596:Benzylamines / Q000378:metabolism* / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002250:Carbon Radioisotopes / Q000378:metabolism* / Q000493:pharmacokinetics; D015283:Citalopram / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D049268:Positron-Emission Tomography / Q000379:methods; D011485:Protein Binding / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism* / Q000493:pharmacokinetics; D016037:Single-Blind Method; D055815:Young Adult
chemical_list: D001596:Benzylamines; D002250:Carbon Radioisotopes; D015283:Citalopram; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine