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

Psychopharmacology (Berl). 2015 Oct;232(19):3497-505. doi: 10.1007/s00213-015-4002-2. Epub 2015 Jul 7.


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 [(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.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Antipsychotic Agents / metabolism*
  • Antipsychotic Agents / pharmacology
  • Benzodiazepines / metabolism*
  • Benzodiazepines / pharmacology
  • Brain / drug effects
  • Brain / metabolism*
  • Cross-Over Studies
  • Double-Blind Method
  • Doxepin / metabolism
  • Doxepin / pharmacology
  • Healthy Volunteers
  • Histamine H1 Antagonists / metabolism
  • Histamine H1 Antagonists / pharmacology
  • Humans
  • Male
  • Olanzapine
  • Positron-Emission Tomography / methods*
  • Quetiapine Fumarate / metabolism*
  • Quetiapine Fumarate / pharmacology
  • Receptors, Histamine H1 / metabolism*
  • Young Adult


  • Antipsychotic Agents
  • Histamine H1 Antagonists
  • Receptors, Histamine H1
  • Benzodiazepines
  • Doxepin
  • Quetiapine Fumarate
  • Olanzapine