title: Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers.
abstract: BACKGROUND
  Histamine H1 antagonists have hypnotic, appetite-promoting, and sedative side effects. Most second-generation antipsychotics have potent antagonistic effects on histamine H1 receptor (H1R). Positron emission tomography (PET) can measure the H1R occupancy (H1RO) in vivo, although there are no reports regarding antipsychotics.
  
  
  OBJECTIVE
  We studied the H1RO of olanzapine and quetiapine in vivo with respect to their plasma concentrations and subjective drowsiness by performing human PET imaging studies with [(11)C]doxepin, a potent PET ligand of H1R.
  
  
  METHODS
  Six healthy Japanese male volunteers were enrolled. Cross-randomized PET imaging was performed after a single oral administration of olanzapine (2.5 mg), quetiapine (25 mg), or placebo. PET data were analyzed by region of interest and voxel-by-voxel analysis. We concurrently measured plasma drug concentrations by liquid chromatography/tandem mass spectrometry and evaluated subjective sleepiness.
  
  
  RESULTS
  The binding potential ratios of olanzapine and quetiapine in the cerebral cortex were significantly lower than that of the placebo. The H1RO values of olanzapine and quetiapine in the cortex were approximately 61-80 and 56-81%, respectively. The binding potential ratios of the drugs were significantly lower than that of the placebo in the dorsolateral prefrontal and lateral temporal cortices, and anterior and posterior cingulate gyri. The H1RO values in the cortex were significantly correlated with subjective sleepiness but not plasma drug concentrations.
  
  
  CONCLUSIONS
  Olanzapine and quetiapine have high H1RO values in the human brain under their clinical minimum doses. This study provides a foundation of the properties by which new-generation antipsychotics block the central histaminergic system in humans.
authors.affiliation: Department of Psychiatry, Tohoku University Graduate School of Medicine, Sendai, 980-8574, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Sato
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ito
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hiraoka
authors.forename: Manabu
authors.initials: M
authors.lastname: Tashiro
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Shibuya
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Funaki
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
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: D000328:Adult; D014150:Antipsychotic Agents / Q000378:metabolism* / Q000494:pharmacology; D001569:Benzodiazepines / Q000378:metabolism* / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004316:Doxepin / Q000378:metabolism / Q000494:pharmacology; D064368:Healthy Volunteers; D006634:Histamine H1 Antagonists / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008297:Male; D000077152:Olanzapine; D049268:Positron-Emission Tomography / Q000379:methods*; D000069348:Quetiapine Fumarate / Q000378:metabolism* / Q000494:pharmacology; D011969:Receptors, Histamine H1 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014150:Antipsychotic Agents; D006634:Histamine H1 Antagonists; D011969:Receptors, Histamine H1; D001569:Benzodiazepines; D004316:Doxepin; D000069348:Quetiapine Fumarate; D000077152:Olanzapine