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

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Abstract

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-HT1A autoreceptor-mediated negative feedback could be a strategy for accelerating the clinical antidepressant effects.

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Acknowledgments

We thank June Hee Lee, Seong A Shin and Boeun Lee for their kind assistance.

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Authors and Affiliations

  1. Department of Neuropsychiatry, Seoul National University Bundang Hospital, Seongnam-si, 13620, Gyeonggi-do, Korea

    Euitae Kim

  2. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, London, SE5 8AF, UK

    Oliver D. Howes & Federico E. Turkheimer

  3. Medical Research Council Clinical Sciences Centre, London, W12 0NN, UK

    Oliver D. Howes

  4. Imperial College London, Hammersmith Hospital Campus, London, W12 0NN, UK

    Oliver D. Howes

  5. Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul, 02447, Korea

    Bo-Hyung Kim

  6. Department of Psychiatry, Seoul National University College of Medicine, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea

    Myong-Wuk Chon & Jun Soo Kwon

  7. Department of Brain and Cognitive Sciences, College of Natural Sciences, Seoul National University, 28 Yeongon-dong, Chongno-gu, Seoul, 03080, Korea

    Seongho Seo, Jae Sung Lee & Jun Soo Kwon

  8. Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul, 03080, Korea

    Seongho Seo, Jae Sung Lee & Yun-Sang Lee

Authors
  1. Euitae Kim
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Corresponding author

Correspondence to Jun Soo Kwon.

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Funding

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Korean Government (MSIP) (no. NRF-2015R1A5A7037676) and Grant No. 14-2014-007 from the SNUBH Research Fund. Dr. Oliver Howes was funded by the Medical Research Council-UK (no. MC-A656-5QD30), the Maudsley Charity (no. 666), the Brain and Behavior Research Foundation, Wellcome Trust (no. 094849/Z/10/Z) and the National Institute for Health Research (NIHR) Biomedical Research Centre at the South London and Maudsley NHS Foundation Trust and King’s College London.

Conflicts of interest

Kim E. has participated in speaker meetings organized by Otsuka. Howes O.D. has received investigator-initiated research funding from, and/or participated in advisory/speaker meetings organized by, Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Kwon J.S. has received investigator-initiated research funding from Otsuka and has participated in advisory/speaker meetings organized by Jansenn, Otsuka and Dainippon Sumitomo Pharma. Kim B.-H., Chon M.-W., Turkheimer F.E., Lee J.S., Lee Y.-S., and Seo S. have no conflicts of interest. Neither the authors nor their families have been employed by, or have holdings/a financial stake in, any biomedical company.

Ethical approval

This study was conducted in observance with the Declaration of Helsinki after the study protocol was approved by the Institutional Review Board of Seoul National University Hospital.

Informed consent

Written informed consent was obtained from all individual participants included in the study.

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Kim, E., Howes, O.D., Kim, BH. et al. Regional Differences in Serotonin Transporter Occupancy by Escitalopram: An [11C]DASB PK-PD Study. Clin Pharmacokinet 56, 371–381 (2017). https://doi.org/10.1007/s40262-016-0444-x

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