Drug Safety

, Volume 41, Issue 3, pp 253–265 | Cite as

Neuropsychiatric Events Associated with Leukotriene-Modifying Agents: A Systematic Review

  • Sharon W. Y. Law
  • Angel Y. S. Wong
  • Shweta Anand
  • Ian C. K. Wong
  • Esther W. Chan
Systematic Review



Leukotriene-modifying agents (LTMAs) including montelukast, zafirlukast, and zileuton are approved by the US Food and Drug Administration (FDA) for the treatment of asthma and allergic rhinitis. Various neuropsychiatric events (NEs) have been reported; however, the evidence of the association is conflicting. This systematic review investigates the association between NEs and LTMAs by assessing the relevant published literature.


PubMed, EMBASE, MEDLINE, and Cochrane Library were searched using keywords. Studies designed to investigate the association were eligible for inclusion without restriction to any study design or language. The primary outcome was defined as suicidal conditions, while secondary outcomes included all other NEs.


Thirty-three studies were included for a narrative review. Four observational studies did not find a significant association, while ten pharmacovigilance studies using different global databases detected the signals. Notably, some studies suggest that the FDA warning issued in 2008 might have influenced the reporting rate of NEs as a result of increased awareness.


The risk of NEs was not quantified, because of the lack of randomized controlled trials and observational studies investigating the association.


Many pharmacovigilance studies have been conducted to determine the association between NEs and LTMAs, but there is limited evidence from observational studies. High-quality epidemiological studies should be conducted to evaluate the association and quantify the risk, not only in children, but also in adults.



We thank Joseph E. Blais (Centre for Safe Medication Practice and Research) for proofreading the manuscript.

Compliance with Ethical Standards


The study was partially supported by a grant from the Research Grants Council of the Hong Kong Special Administrative Region, China (Project No. HKU 789813).

Conflict of interest

Sharon W.Y. Law, Angel Y.S. Wong, Shweta Anand, Ian C.K. Wong, and Esther W. Chan declare that they have no conflict of interest.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Supplementary material

40264_2017_607_MOESM1_ESM.docx (109 kb)
Supplementary material (DOCX 109 kb)


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • Sharon W. Y. Law
    • 1
  • Angel Y. S. Wong
    • 1
  • Shweta Anand
    • 1
  • Ian C. K. Wong
    • 1
    • 2
  • Esther W. Chan
    • 1
  1. 1.Centre for Safe Medication Practice and Research, Department of Pharmacology and Pharmacy, Li Ka Shing Faculty of MedicineThe University of Hong KongHong Kong SARChina
  2. 2.Research Department of Practice and Policy, School of PharmacyUniversity College LondonLondonUK

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