Histamine H1 receptor occupancy by the new-generation antipsychotics olanzapine and quetiapine: a positron emission tomography study in healthy volunteers

Hirotoshi Sato, Chihiro Ito, Kotaro Hiraoka, Manabu Tashiro, Katsuhiko Shibuya, Yoshihito Funaki, Takeo Yoshikawa, Ren Iwata, Hiroo Matsuoka, Kazuhiko Yanai

研究成果: Article査読

21 被引用数 (Scopus)

抄録

Rationale: 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. Objectives: 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 [11C]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.

本文言語English
論文番号4002
ページ(範囲)3497-3505
ページ数9
ジャーナルPsychopharmacology
232
19
DOI
出版ステータスPublished - 2015 10 1

ASJC Scopus subject areas

  • 薬理学

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