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

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 [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. 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 (EC₅₀) value and Hill coefficient were significantly different between the putamen (EC₅₀ 4.30, Hill coefficient 0.459) and the dorsal raphe nucleus (EC₅₀ 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.