title: Histamine H₁ receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers.
abstract: BACKGROUND
  Histamine H₁ antagonists have hypnotic, appetite-promoting, and sedative effects. The affinities of various antidepressants for histamine receptors have only been partially determined in vitro and animal study. Positron emission tomography (PET) can clarify the in vivo dynamics of antidepressants at histamine receptors.
  
  
  OBJECTIVE
  We performed human PET imaging with [¹¹C]doxepin, a selective PET ligand of the histamine H₁ receptor (H₁R), to study the in vivo affinities of fluvoxamine and mirtazapine for the H₁R.
  
  
  METHODS
  The subjects were five male healthy Japanese volunteers. We performed cross-randomized PET imaging after single oral administration of fluvoxamine (25mg), mirtazapine (15 mg), or placebo. PET data were analyzed by region-of-interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations, using liquid chromatography/tandem mass spectrometry and subjective sleepiness.
  
  
  RESULTS
  The binding potential ratio of mirtazapine in brain cortex was significantly lower than that of fluvoxamine or placebo. Fluvoxamine did not occupy the H₁R, whereas H₁R occupancy (H₁RO) of mirtazapine reached 80-90 % in the cerebral neocortex. In the voxel-by-voxel analysis, the binding potential of mirtazapine was significantly lower than placebo in the dorsolateral prefrontal cortex, lateral temporal cortex, anterior cingulate gyrus, and posterior cingulate gyrus. The H₁RO of mirtazapine depended on the plasma drug concentration (AUC(0-180 min)) and was related to subjective sleepiness.
  
  
  CONCLUSIONS
  Our results demonstrate a low affinity of fluvoxamine and a very high affinity of mirtazapine for the human brain H₁R in vivo. This study provides a basis for investigating the efficacy of new-generation antidepressants in central histamine systems.
authors.affiliation: Department of Psychiatry, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan, h-sato@med.tohoku.ac.jp.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ito
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hiraoka
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shibuya
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Funaki
authors.forename: Ren
authors.initials: R
authors.lastname: Iwata
authors.forename: Hiroo
authors.initials: H
authors.lastname: Matsuoka
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D019540:Area Under Curve; D001921:Brain / Q000378:metabolism; D002853:Chromatography, Liquid; D004311:Double-Blind Method; D004316:Doxepin; D016666:Fluvoxamine / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D008297:Male; D008803:Mianserin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000078785:Mirtazapine; D049268:Positron-Emission Tomography / Q000379:methods*; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D012894:Sleep Stages / Q000187:drug effects; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D000928:Antidepressive Agents; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D004316:Doxepin; D008803:Mianserin; D000078785:Mirtazapine; D016666:Fluvoxamine