Rationale: 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. Objectives: 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 (25 mg), 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 (AUC0-180 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.
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