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Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers

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Abstract

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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Acknowledgments

This study was performed at the Cyclotron and Radioisotope Center, Tohoku University. This work was supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (no. 21650088) and the Japan Society of Technology (“molecular imaging”). We appreciate the technical assistance provided by Y. Ishikawa, S. Watanuki, and K. Takeda in the PET studies.

Sources of support

This work was supported in part by a grant-in-aid for scientific research (no. 21650088 for K. Yanai) from the Japan Society for the Promotion of Science, as well as by a grant from the Japan Society for Technology (“molecular imaging”).

Conflict of interest

No conflicts of interest.

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Authors and Affiliations

  1. Department of Psychiatry, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan

    Hirotoshi Sato, Chihiro Ito & Hiroo Matsuoka

  2. Department of Pharmacology, Tohoku University Graduate School of Medicine, Sendai, 980-8575, Japan

    Hirotoshi Sato, Katsuhiko Shibuya & Kazuhiko Yanai

  3. Cyclotron and Radioisotope Center, Tohoku University, Sendai, 980-8578, Japan

    Manabu Tashiro, Kotaro Hiraoka, Yoshihito Funaki, Ren Iwata & Kazuhiko Yanai

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  1. Hirotoshi Sato
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  2. Chihiro Ito
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Correspondence to Hirotoshi Sato.

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Sato, H., Ito, C., Tashiro, M. et al. Histamine H1 receptor occupancy by the new-generation antidepressants fluvoxamine and mirtazapine: a positron emission tomography study in healthy volunteers. Psychopharmacology 230, 227–234 (2013). https://doi.org/10.1007/s00213-013-3146-1

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