Regional Differences in Serotonin Transporter Occupancy by Escitalopram: An [11C]DASB PK-PD Study

• Published in: Clinical pharmacokinetics 2017-04, Vol.56 (4), p.371-381
• Main Authors: Kim, Euitae, Howes, Oliver D., Kim, Bo-Hyung, Chon, Myong-Wuk, Seo, Seongho, Turkheimer, Federico E., Lee, Jae Sung, Lee, Yun-Sang, Kwon, Jun Soo
• Format: Article
• Language: English
• Subjects: Adult; Antidepressants; Behavior disorders; Benzylamines - metabolism; Benzylamines - pharmacokinetics; Brain - diagnostic imaging; Brain - drug effects; Brain - metabolism; Carbon Radioisotopes - metabolism; Carbon Radioisotopes - pharmacokinetics; Citalopram - metabolism; Dose-Response Relationship, Drug; Drug dosages; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Neuroses; Obsessive compulsive disorder; Original Research Article; Pharmacology/Toxicology; Pharmacotherapy; Plasma; Positron-Emission Tomography - methods; Protein Binding - physiology; Serotonin; Serotonin Plasma Membrane Transport Proteins - metabolism; Serotonin Uptake Inhibitors - metabolism; Serotonin Uptake Inhibitors - pharmacokinetics; Single-Blind Method; Studies; Tomography; Young Adult
• ISSN: 0312-5963; 1179-1926
• DOI: 10.1007/s40262-016-0444-x

Background and objective 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. Methods To determine the dose–occupancy relationship, we measured serial SERT occupancy using [ 11 C]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. Results 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 (EC 50 ) value and Hill coefficient were significantly different between the putamen (EC 50 4.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC 50 2.89, Hill coefficient 0.817). Conclusions 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-HT 1A autoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects.