Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network

Ryogo Umetsu; Mizuki Tanaka; Yoko Nakayama; Yamato Kato; Natsumi Ueda; Yuri Nishibata; Shiori Hasegawa; Kiyoka Matsumoto; Noriaki Takeyama; Kazuhiro Iguchi; Hiroyuki Tanaka; Eiichi Hinoi; Naoki Inagaki; Masatoshi Inden; Yoshinori Muto; Mitsuhiro Nakamura

doi:10.3389/fphar.2021.764279

Neuropsychiatric Adverse Events of Montelukast: An Analysis of Real-World Datasets and drug-gene Interaction Network

Front Pharmacol. 2021 Dec 20:12:764279. doi: 10.3389/fphar.2021.764279. eCollection 2021.

Authors

Ryogo Umetsu¹, Mizuki Tanaka¹, Yoko Nakayama¹, Yamato Kato¹, Natsumi Ueda¹, Yuri Nishibata¹, Shiori Hasegawa¹, Kiyoka Matsumoto¹, Noriaki Takeyama², Kazuhiro Iguchi³, Hiroyuki Tanaka⁴, Eiichi Hinoi^{2

4}, Naoki Inagaki⁴, Masatoshi Inden⁵, Yoshinori Muto⁶, Mitsuhiro Nakamura¹

Affiliations

¹ Laboratory of Drug Informatics, Gifu Pharmaceutical University, Gifu, Japan.
² Laboratory of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan.
³ Laboratory of Community Pharmacy, Gifu Pharmaceutical University, Gifu, Japan.
⁴ United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan.
⁵ Laboratory of Medical Therapeutics and Molecular Therapeutics, Gifu Pharmaceutical University, Gifu, Japan.
⁶ Department of Functional Bioscience, Gifu University School of Medicine, Gifu, Japan.

Abstract

Montelukast is a selective leukotriene receptor antagonist that is widely used to treat bronchial asthma and nasal allergy. To clarify the association between montelukast and neuropsychiatric adverse events (AEs), we evaluated case reports recorded between January 2004 and December 2018 in the Food and Drug Administration Adverse Event Reporting System (FAERS). Furthermore, we elucidated the potential toxicological mechanisms of montelukast-associated neuropsychiatric AEs through functional enrichment analysis of human genes interacting with montelukast. The reporting odds ratios of suicidal ideation and depression in the system organ class of psychiatric disorders were 21.5 (95% confidence interval (CI): 20.3-22.9) and 8.2 (95% CI: 7.8-8.7), respectively. We explored 1,144 human genes that directly or indirectly interact with montelukast. The molecular complex detection (MCODE) plug-in of Cytoscape detected 14 clusters. Functional analysis indicated that several genes were significantly enriched in the biological processes of "neuroactive ligand-receptor interaction." "Mood disorders" and "major depressive disorder" were significant disease terms related to montelukast. Our retrospective analysis based on the FAERS demonstrated a significant association between montelukast and neuropsychiatric AEs. Functional enrichment analysis of montelukast-associated genes related to neuropsychiatric symptoms warrant further research on the underlying pharmacological mechanisms.

Keywords: drug-gene intraction; enrichment analysis; food and drug administration adverse event reporting system; montelukast; neuropsychiatric adverse events; protein-protein interaction.