Occupancy of serotonin and norepinephrine transporter by milnacipran in patients with major depressive disorder: a positron emission tomography study with [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2).
Antidepressants used for treatment of depression exert their efficacy by blocking reuptake at serotonin transporters (5-HTT) and/or norepinephrine transporters (NET). Recent studies suggest that serotonin and norepinephrine reuptake inhibitors that block both 5-HTT and NET have better tolerability than tricyclic antidepressants and may have higher efficacy compared to selective serotonin reuptake inhibitors. Previous positron emission tomography (PET) studies have reported >80% 5-HTT occupancy with clinical doses of antidepressants, but there has been no report of NET occupancy in patients treated with antidepressants. In the present study, we investigated both 5-HTT and NET occupancies by PET using radioligands [(11)C]DASB and (S,S)-[(18)F]FMeNER-D(2), in six patients, each with major depressive disorder (MDD), using various doses of milnacipran. Our data show that mean 5-HTT occupancy in the thalamus was 33.0% at 50 mg, 38.6% at 100 mg, 60.0% at 150 mg and 61.5% at 200 mg. Mean NET occupancy in the thalamus was 25.3% at 25 mg, 40.0% at 100 mg, 47.3% at 125 mg and 49.9% at 200 mg. Estimated ED(50) was 122.5 mg with the dose for 5-HTT and 149.9 mg for NET. Both 5-HTT and NET occupancies were observed in a dose-dependent manner. Both 5-HTT and NET occupancies were about 40% by milnacipran at 100 mg, the dose most commonly administered to MDD patients.
Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
Tsuyoshi
T
Nogami
Harumasa
H
Takano
Ryosuke
R
Arakawa
Tetsuya
T
Ichimiya
Hironobu
H
Fujiwara
Yasuyuki
Y
Kimura
Fumitoshi
F
Kodaka
Takeshi
T
Sasaki
Keisuke
K
Takahata
Masayuki
M
Suzuki
Tomohisa
T
Nagashima
Takaaki
T
Mori
Hitoshi
H
Shimada
Hajime
H
Fukuda
Mizuho
M
Sekine
Amane
A
Tateno
Hidehiko
H
Takahashi
Hiroshi
H
Ito
Yoshiro
Y
Okubo
Tetsuya
T
Suhara
D000328:Adult; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001596:Benzylamines / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology; D001931:Brain Mapping; D002250:Carbon Radioisotopes / Q000493:pharmacokinetics; D003521:Cyclopropanes / Q000097:blood / Q000627:therapeutic use*; D003865:Major Depressive Disorder / Q000097:blood / Q000000981:diagnostic imaging* / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D009025:Morpholines / Q000493:pharmacokinetics; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
C506462:2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine; D000928:Antidepressive Agents; D001596:Benzylamines; D002250:Carbon Radioisotopes; D003521:Cyclopropanes; D005462:Fluorine Radioisotopes; D009025:Morpholines; C420885:N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine; D050484:Norepinephrine Plasma Membrane Transport Proteins; D050486:Serotonin Plasma Membrane Transport Proteins; D000078764:Milnacipran