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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography.

CONTEXT: Serotonin transporters (5-HTT) are regarded as one of the major therapeutic targets of antidepressants. However, there have only been a few studies about 5-HTT occupancy, and in particular, data concerning classical antidepressants are still limited. OBJECTIVE: To investigate the relationship between 5-HTT occupancy and a wide range of antidepressant dosing protocols.Design, Setting, and PARTICIPANTS: Antidepressant occupancies of 5-HTT were measured using positron emission tomography (PET) with [11C](+)McN5652. Twenty-seven healthy volunteers were measured with and without pretreatment with single low doses of antidepressants, and long-term doses were evaluated in 10 patients. Scan data were collected between December 12, 1995, and August 7, 2002, and data were analyzed during the 2001-2002 period at the National Institute of Radiological Sciences (Chiba, Japan).Intervention Four different doses of clomipramine hydrochloride (5-50 mg) and 3 different doses of fluvoxamine maleate (12.5-50 mg) were used for single administration. Long-term doses were 20 to 250 mg per day for clomipramine hydrochloride, and 25 to 200 mg per day for fluvoxamine maleate.Main Outcome Measure Occupancies in the thalamus were calculated using the individual baseline of [11C](+)McN5652 for single-dose studies and 2 long-term-dose studies, and the mean value of healthy volunteers as the baseline for 8 long-term-dose studies. The average data from inactive enantiomers [11C](-)McN5652 were used for the estimation of nonspecific binding. RESULTS: Occupancy of 5-HTT increased in a curvilinear manner. Even 10 mg of clomipramine hydrochloride showed approximately 80% occupancy, which was comparable with that of 50 mg of fluvoxamine maleate. Estimated median effective dose (ED50) of clomipramine hydrochloride was 2.67 mg for oral dose and 1.42 ng/mL for plasma concentration; those of fluvoxamine maleate were 18.6 mg and 4.19 ng/mL, respectively. CONCLUSIONS: Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5-HTT, and dose escalation would have minimal effect on 5-HTT blockade. Ten milligrams of clomipramine hydrochloride was enough to occupy 80% of 5-HTT in vivo.[1]


  1. High levels of serotonin transporter occupancy with low-dose clomipramine in comparative occupancy study with fluvoxamine using positron emission tomography. Suhara, T., Takano, A., Sudo, Y., Ichimiya, T., Inoue, M., Yasuno, F., Ikoma, Y., Okubo, Y. Arch. Gen. Psychiatry (2003) [Pubmed]
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