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Safety, Pharmacokinetic, and Positron Emission Tomography Evaluation of Serotonin and Dopamine Transporter Occupancy Following Multiple-Dose Administration of the Triple Monoamine Reuptake Inhibitor BMS-820836
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2015 (English)In: Psychopharmacology, ISSN 0033-3158, E-ISSN 1432-2072, Vol. 232, no 3, 529-540 p.Article in journal (Refereed) Published
Abstract [en]


BMS-820836 is a novel antidepressant that selectively inhibits the reuptake of serotonin, norepinephrine, and dopamine.


This Phase I study assessed safety, tolerability, and pharmacokinetics of multiple daily doses of BMS-820836 in healthy subjects. Central serotonin transporter (SERT) and dopamine transporter (DAT) occupancy were assessed using positron emission tomography and [11C]MADAM or [11C]PE2I, respectively.


Fifty-seven healthy volunteers were enrolled in this double-blind, placebo-controlled, ascending multiple-dose study (ClincalTrials.gov identifier: NCT00892840). Eight participants in seven dose cohorts received oral doses of BMS-820836 (0.1–4 mg) or placebo for 14 days to assess safety, tolerability, and pharmacokinetics. Additionally, SERT and DAT occupancies were evaluated in 4–8 subjects per cohort at 8 h post-dose on Day 10 and 24 h post-dose on Day 15 at anticipated steady-state conditions.


Most adverse events were mild to moderate; there were no serious safety concerns. Median maximum concentrations of BMS-820836 were observed at 4.0–5.5 h post-dose; estimated elimination half-life was 44–74 h. About 80 % striatal SERT occupancy was achieved after multiple doses of 0.5 mg BMS-820836 at both 8 and 24 h post-dose. Striatal DAT occupancy ranged between 14 % and 35 % at 8 h post-dose with a slight decline at 24 h post-dose.


Multiple daily doses of up to 4 mg BMS-820836 appeared to be generally safe and well tolerated in a healthy population. SERT and DAT occupancies were in a range associated with therapeutic efficacy of antidepressants. Together with the pharmacokinetic profile of BMS-820836, the occupancy data support once-daily administration.

Place, publisher, year, edition, pages
Springer Publishing Company, 2015. Vol. 232, no 3, 529-540 p.
Keyword [en]
PET, reuptake inhibitors
National Category
Pharmaceutical Sciences Pharmacology and Toxicology Psychiatry
Research subject
Pharmacokinetics and Drug Therapy
URN: urn:nbn:se:uu:diva-240985DOI: 10.1007/s00213-014-3688-xISI: 000348307000005OAI: oai:DiVA.org:uu-240985DiVA: diva2:777476
Available from: 2015-01-08 Created: 2015-01-08 Last updated: 2015-09-22Bibliographically approved

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Antoni, Gunnar
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Preclinical PET Platform
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