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).

Abstract

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.

• Authors: Tsuyoshi Nogami, Harumasa Takano, Ryosuke Arakawa, Tetsuya Ichimiya, Hironobu Fujiwara, Yasuyuki Kimura, Fumitoshi Kodaka, Takeshi Sasaki, Keisuke Takahata, Masayuki Suzuki, Tomohisa Nagashima, Takaaki Mori, Hitoshi Shimada, Hajime Fukuda, Mizuho Sekine, Amane Tateno, Hidehiko Takahashi, Hiroshi Ito, Yoshiro Okubo, Tetsuya Suhara
• Journal: The international journal of neuropsychopharmacology (Int J Neuropsychopharmacol) Vol. 16 Issue 5 Pg. 937-43 (Jun 2013) ISSN: 1469-5111 [Electronic] England
• PMID: 23067569 (Publication Type: Journal Article)

Chemical References

• 2-(alpha-(2-fluoromethoxyphenoxy)benzyl)morpholine
• Antidepressive Agents
• Benzylamines
• Carbon Radioisotopes
• Cyclopropanes
• Fluorine Radioisotopes
• Morpholines
• N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine
• Norepinephrine Plasma Membrane Transport Proteins
• Serotonin Plasma Membrane Transport Proteins
• Milnacipran

Topics

• Adult
• Antidepressive Agents (therapeutic use)
• Benzylamines (pharmacokinetics)
• Brain (diagnostic imaging, drug effects, pathology)
• Brain Mapping
• Carbon Radioisotopes (pharmacokinetics)
• Cyclopropanes (blood, therapeutic use)
• Depressive Disorder, Major (blood, diagnostic imaging, drug therapy)
• Dose-Response Relationship, Drug
• Female
• Fluorine Radioisotopes (pharmacokinetics)
• Gas Chromatography-Mass Spectrometry
• Humans
• Male
• Middle Aged
• Milnacipran
• Morpholines (pharmacokinetics)
• Norepinephrine Plasma Membrane Transport Proteins (metabolism)
• Positron-Emission Tomography
• Protein Binding (drug effects)
• Serotonin Plasma Membrane Transport Proteins (metabolism)