title: Norepinephrine transporter occupancy by nortriptyline in patients with depression: a positron emission tomography study with (S,S)-[¹⁸F]FMeNER-D₂.
abstract: Norepinephrine transporter (NET) plays important roles in the treatment of various neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder (ADHD). Nortriptyline is a NET-selective tricyclic antidepressant (TCAs) that has been widely used for the treatment of depression. Previous positron emission tomography (PET) studies have reported over 80% serotonin transporter occupancy with clinical doses of selective serotonin reuptake inhibitors (SSRIs), but there has been no report of NET occupancy in patients treated with relatively NET-selective antidepressants. In the present study, we used PET and (S,S)-[18¹⁸F]FMeNER-D₂ to investigate NET occupancies in the thalamus in 10 patients with major depressive disorder taking various doses of nortriptyline, who were considered to be responders to the treatment. Reference data for the calculation of occupancy were derived from age-matched healthy controls. The result showed approximately 50-70% NET occupancies in the brain as a result of the administration of 75-200 mg/d of nortriptyline. The estimated effective dose (ED₅₀) and concentration (EC₅₀) required to induce 50% occupancy was 65.9 mg/d and 79.8 ng/ml, respectively. Furthermore, as the minimum therapeutic level of plasma nortriptyline for the treatment of depression has been reported to be 70 ng/ml, our data indicate that this plasma nortriptyline concentration corresponds to approximately 50% NET occupancy measured with PET, suggesting that more than 50% of central NET occupancy would be appropriate for the nortriptyline treatment of patients with depression.
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Harumasa
authors.initials: H
authors.lastname: Takano
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Arakawa
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nogami
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Nagashima
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hironobu
authors.initials: H
authors.lastname: Fujiwara
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Kimura
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Fumitoshi
authors.initials: F
authors.lastname: Kodaka
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Takahata
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimada
authors.affiliation: Department of Medical Statistics, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Amane
authors.initials: A
authors.lastname: Tateno
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Yamada
authors.affiliation: Biophysics Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ito
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kawamura
authors.affiliation: Molecular Probe Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Zhang
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Hidehiko
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Neuropsychiatry, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Motoichiro
authors.initials: M
authors.lastname: Kato
authors.affiliation: Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Okubo
authors.affiliation: Clinical Neuroimaging Team, Molecular Neuroimaging Program, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suhara
mesh_terms: D000328:Adult; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D003865:Major Depressive Disorder / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005462:Fluorine Radioisotopes; D006801:Humans; D008297:Male; D008875:Middle Aged; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism*; D009661:Nortriptyline / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding; D013788:Thalamus / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000929:Antidepressive Agents, Tricyclic; D005462:Fluorine Radioisotopes; D050484:Norepinephrine Plasma Membrane Transport Proteins; D009661:Nortriptyline