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Evaluating the Association of Montelukast Use on Neuropsychiatry-Related Healthcare Utilization and Depression in COVID-19-Hospitalized Veterans: A Nationwide VA Observational Cohort Study

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Abstract

Background

Montelukast’s new boxed warning for neuropsychiatric events questions its use in the setting of coronavirus disease 2019 (COVID-19) due to increased risk for new-onset psychiatric diagnoses.

Objective

We aim to evaluate the impact of using montelukast in patients hospitalized with COVID-19 on neuropsychiatry-related healthcare utilization and depression.

Methods

This retrospective nationwide observational cohort study using the Veterans Health Administration database included patients from January 1, 2020, through July 1, 2021. The treatment cohorts consisted of patients with and without montelukast use prior to COVID-19 hospitalization and matched using propensity score (PS) to two control cohorts: patients with COVID-19-related hospitalization without prior montelukast use and patients with prior montelukast use who were hospitalized for reasons other than COVID-19. The primary outcome of psychiatric hospitalizations at 90 days and 180 days and mental health visits at 180 days were compared using Poisson or negative binomial regression. Secondary outcomes of new-onset depression and new use of antidepressants were analyzed using multivariable logistic regression.

Results

After PS matching, a total of 415 patients were included in COVID-19 with and without montelukast matched cohort and 409 patients in montelukast with and without COVID-19-related hospitalization matched cohorts. For the primary outcomes, inpatient psychiatric hospitalization at 90 days [incidence rate ratio (IRR) 95% CI 1.79 (1.36–2.36)] and 180 days [IRR 95% CI 1.79 (1.32–2.25)] and mental health visits at 180 days [IRR 95% CI 1.72 (1.45–2.03)] were significantly higher in the montelukast with COVID-19 hospitalization group compared with those hospitalized without COVID-19. No difference in primary outcomes were noted in patients hospitalized with COVID-19 with and without use of montelukast. No significant difference was found in the secondary outcomes between either comparator group.

Conclusions

Patients with prior montelukast use who were hospitalized with COVID-19 appeared to have increased rate of neuropsychiatry-related healthcare utilization.

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References

  1. Al-kuraishy HM, Al-Gareeb AI, Almulaiky YQ, et al. Role of leukotriene pathway and montelukast in pulmonary and extrapulmonary manifestations of COVID19: the enigmatic entity. Eur J Pharmacol. 2021. https://doi.org/10.1016/j.ejphar.2021.174196.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Copertino DC, Duarte RRR, Powell TR, et al. Montelukast drug activity and potential against severe acute respiratory syndrome coronavirus 2 (SARSCoV-2). J Med Virol. 2020. https://doi.org/10.1002/jmv.26299.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Khan AR, Misdary C, Yegya-Raman N, et al. Montelukast in hospitalized patients diagnosed with COVID-19. J Asthma. 2021. https://doi.org/10.1080/02770903.2021.1881967.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Wilchesky M, Tranmer G, Grad R. The COvid-19 Symptom MOntelukast trial (COSMO). Identifier NCT04389411. https://clinicaltrials.gov/cr2/show/study/NCT04389411. 2020.

  5. Mera-Cordero F, Bonet-Monne S, Almeda-Ortega J, et al. Double-blind placebo-controlled randomized clinical trial to assess the efficacy of montelukast in mild to moderate respiratory symptoms of patients with long COVID: E-SPERANZA COVID Project study protocol [published correction appears in Trials. 2022 Feb 9;23(1):130]. Trials. 2022;23(1):19. https://doi.org/10.1186/s13063-021-05951-w.

  6. US Food and Drug Administration. Updated information on montelukast (marketed as Singulair): requires boxed warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. 2020. https://www.fda.gov/drugs/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergy-drug. Accessed 12 Jan 2021.

  7. Sansing-Foster V, Haug N, Mosholder A, Cocoros NM, Bradley M, Ma Y, Pennap D, Dee EC, Toh S, Pestine E, Petrone AB, Kim I, Lyons JG, Eworuke E. Risk of psychiatric adverse events among montelukast users. J Allergy Clin Immunol Pract. 2021;9(1):385–93.e12. https://doi.org/10.1016/j.jaip.2020.07.052. 

    Article  CAS  PubMed  Google Scholar 

  8. Taquet M, Geddes JR, Husain M, et al. 6-month neurological and psychiatric outcomes in 236379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021;8:416–27. https://doi.org/10.1016/S2215-0366(21)00084-5.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ettman CK, Abdalla SM, Cohen GH. Prevalence of depression symptoms in US adults before and during the COVID-19 pandemic. Jama Netw Open. 2020;3:e2019686. https://doi.org/10.1001/jamanetworkopen.2020.19686.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Department of Veterans Affairs, Office of Research and Development. COVID-19 Shared Data Resource. https://vhacdwdwhweb100.vha.med.va.gov/phenotype/index.php/COVID-19:Shared_Data_Resource. Accessed 31 Dec 2021.

  11. Glasheen WP, Cordier T, Gumpina R, Haugh G, Davis J, Renda A. Charlson Comorbidity Index: ICD-9 update and ICD-10 translation. Am Health Drug Benef. 2019;12(4):188–97.

    Google Scholar 

  12. Lee SW, Acharya KP. Propensity score matching for causal inference and reducing the confounding effects: statistical standard and guideline of Life Cycle Committee. Life Cycle. 2022;2:e18. https://doi.org/10.54724/lc.2022.e18.

    Article  Google Scholar 

  13. Paljarvi T, Forton J, Luciano S, Herttua K, Fazel S. Analysis of neuropsychiatric diagnoses after montelukast initiation. JAMA Netw Open. 2022;5(5):e2213643. https://doi.org/10.1001/jamanetworkopen.2022.13643.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse propensity scores as weights to directly estimate relative risk and its confidence intervals. Value Health. 2010;13(2):273–7. https://doi.org/10.1111/j.1524-4733.2009.00671.x.

    Article  PubMed  Google Scholar 

  15. Lin YC, Huang MY, Lee MS, et al. Effects of montelukast on M2-related cytokine and chemokine in M2 macrophages. J Microbiol Immunol Infect. 2018;51(1):18–26. https://doi.org/10.1016/j.jmii.2016.04.005.

    Article  CAS  PubMed  Google Scholar 

  16. Coskun AK, Yigiter M, Oral A, et al. The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. Sci World J. 2011;11:1341–56. https://doi.org/10.1100/tsw.2011.122.

    Article  CAS  Google Scholar 

  17. Conti P, Ronconi G, Caraffa A, Gallenga CE, Ross R, Frydas I, et al. Induction of pro-inflammatory cytokines (IL-1 and IL-6) and lung inflammation by Coronavirus-19 (COVI-19 or SARS-CoV-2): anti-inflammatory strategies. J Biol Regul Homeost Agents. 2020;34(2):327.

    CAS  PubMed  Google Scholar 

  18. Qu X, Chen Y, Yin C. Effect of montelukast on the expression of CD4+CD25+ regulatory T cells in children with acute bronchial asthma. Exp Ther Med. 2018;16:2381–6.

    PubMed  PubMed Central  Google Scholar 

  19. Farag AB, Wang P, Ahmed MS, Sadek HA. Identification of FDA approved drugs targeting COVID-19 virus by structure-based drug repositioning. ChemRxiv. 2020.

  20. Benard B, Bastien V, Vinet B, Yang R, Krajinovic M, Ducharme FM. Neuropsychiatric adverse drug reactions in children initiated on montelukast in real-life practice. Eur Respir J. 2017;50(2):1700148.

    Article  PubMed  Google Scholar 

  21. Aldea Perona A, García-Sáiz M, Sanz ÁE. Psychiatric disorders and montelukast in children: a disproportionality analysis of the VigiBase. Drug Saf. 2016;39:69–78. https://doi.org/10.1007/s40264-015-0360-2pmid:26620206.

    Article  CAS  PubMed  Google Scholar 

  22. Kang SO, Min KH, Kim HJ, Kim TH, Kim W, Lee KE. The role of leukotriene modifying agent treatment in neuropsychiatric events of elderly asthma patients: a nested case control study. Asthma Res Pract. 2021;7(1):4. https://doi.org/10.1186/s40733-021-00070-4.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Philip G, Hustad CM, Malice MP, Noonan G, Ezekowitz A, Reiss TF, et al. Analysis of behavior-related adverse experiences in clinical trials of montelukast. J Allergy Clin Immunol. 2009;124:699–706.

    Article  CAS  PubMed  Google Scholar 

  24. Schumock GT, Stayner LT, Valuck RJ, Joo MJ, Gibbons RD, Lee TA. Risk of suicide attempt in asthmatic children and young adults prescribed leukotriene-modifying agents: a nested case-control study. J Allergy Clin Immunol. 2012;130(2):368–75. https://doi.org/10.1016/j.jaci.2012.04.035.

    Article  PubMed  Google Scholar 

  25. Nersesjan V, Fonsmark L, Christensen R, et al. Neuropsychiatric and cognitive outcomes in patients 6 months after COVID-19 requiring hospitalization compared with matched control patients hospitalized for non–COVID-19 illness. JAMA Psychiat. 2022;79(5):486–97. https://doi.org/10.1001/jamapsychiatry.2022.0284.

    Article  Google Scholar 

  26. Fernandéz A, Pinto-Meza A, Bellón JA, et al. Is major depression adequately diagnosed and treated by general practitioners? Results from an epidemiological study. Gen Hosp Psychiatry. 2010;32:201–9. https://doi.org/10.1016/j.genhosppsych/2009.11.015.

    Article  PubMed  Google Scholar 

  27. Murphy D, Williamson C, Baumann J, Busuttil W, Fear NT. Exploring the impact of COVID-19 and restrictions to daily living as a result of social distancing within veterans with pre-existing mental health difficulties. BMJ Mil Health. 2022;168(1):29–33. https://doi.org/10.1136/bmjmilitary-2020-001622.

    Article  PubMed  Google Scholar 

  28. Hill ML, Nichter B, Na PJ, Norman SB, Morland LA, Krystal JH, Pietrzak RH. Mental health impact of the COVID-19 pandemic in U.S. military veterans: a population-based, prospective cohort study. Psychol Med. 2021. https://doi.org/10.1017/S0033291721002361.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported using resources and facilities at the VA Informatics and Computing Infrastructure (VINCI), VA HSR RES 13-457. Additionally, the study was conducted with the resources and support of Salem VA Medical Center and Veterans Health Administration. This work was supported using resources from the Department of Veterans Affairs (VA) Centralized Interactive Phenomics Resource (CIPHER). This study was supported using data from the VA COVID-19 Shared Data Resource and CDW Database [US Department of Veterans Affairs. 172VA10P2: VHA Corporate Data Warehouse–VA. 79 FR 4377. Updated (the last date of your record search). Accessed December 12, 2022.]. We would like to thank Dr. Emily Halsey for the additional review of this manuscript.

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Authors and Affiliations

  1. Salem Veterans Affairs HealthCare System, 1970 Roanoke Blvd, Salem, VA, 24153, USA

    Tanvi Patil, Michelle Radtke, Joseph Smigiel, Natalie Savona, Bush Kavuru & Anuradha Sekhri

  2. Central Western Massachusetts Veterans Affair Health Care System, 421 N Main St, Leeds, MA, 01053, USA

    Jasper Jade Raguindin

Authors
  1. Tanvi Patil
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Corresponding author

Correspondence to Tanvi Patil.

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Funding

The study did not receive any special grant or funding from agencies in public, commercial or not-for profit sectors

Conflict of interest

None of the authors have any conflict to disclose. The results of this study do not represent the views of federal government or Veterans Health Administration.

Ethics approval

This study was conducted in accordance with the 1964 Declaration of Helsinki and was reviewed and exempted by the Institutional Review Board of Salem VA Health Care System.

Consent to participate

Informed consent was waived due to the retrospective nature of the study.

Consent for publication

Not applicable.

Availability of data and material

Data cannot be shared publicly because it involves sensitive human subject data as per Veterans Health Administration Policy. The data that support the findings of this study are available from the VA. VA data are made available to researchers behind the VA firewall with an approved VA study protocol.

Code availability

Not applicable.

Authors’ contributions

First author (Dr. Patil) contributed significantly to the conception, data extraction and analysis, synthesis, and writing of the final manuscript. Second author (Dr. Raguidin) contributed significantly to the conception, design, synthesis, and writing of the initial draft of the manuscript. All other authors contributed toward the design and intellectual review of the final manuscript.

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Patil, T., Raguindin, J.J., Radtke, M. et al. Evaluating the Association of Montelukast Use on Neuropsychiatry-Related Healthcare Utilization and Depression in COVID-19-Hospitalized Veterans: A Nationwide VA Observational Cohort Study. Clin Drug Investig 43, 605–619 (2023). https://doi.org/10.1007/s40261-023-01292-5

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