Effectiveness and Safety of Nebulized Magnesium as Last Line Treatment in Adults with Acute Asthma Attack: A Systematic Review and Meta-Analysis.

BACKGROUND: Asthma is a disease characterized by chronic airway inflammation, however one-third of asthmatic cases did not respond adequately. Inhaled magnesium has been proposed as a treatment for unresponsive asthma cases. However, its role remains controversial. This review evaluates the effectiveness and safety of nebulized magnesium compared to standard therapy (Beta Agonist, Anticholinergic, Corticosteroid) in adults with acute asthma attacks. METHODS: The protocol has been registered in PROSPERO. A literature search was conducted through PubMed/MEDLINE, Cochrane, ProQuest, and Google Scholar, and using the keywords "inhaled magnesium" and "asthma". Manual searches were carried out through data portals. Journal articles included are randomized controlled trials. The assessment risk of bias was performed using Version 2 of the Cochrane risk-of-bias tool for randomized trials. RESULTS: There are five articles included in this review. There is no significant difference in readmission rate and oxygen saturation in the magnesium group compared to control (RR 1; 95% CI 0.92 to 1,08; p= 0,96 and MD 1,82; 95% CI -0.89 to 4.53; p= 0.19, respectively). There is a significant reduction of respiratory rate and clinical severity in magnesium (MD -1,72; 95% CI -3,1 to 0.35; p= 0.01, RR 0.29; 95% CI 0.17 to 0.69; p <0.001, respectively). There was a higher risk of side effects in the magnesium group (HR 1.56; 95%CI 1.05 to 2.32; p= 0.03). However, the side effects are relatively mild such as hypotension and nausea. CONCLUSION: Inhaled magnesium improves the outcome of asthmatic patients, especially in lung function, clinical severity, and respiratory rate. Moreover, inhaled magnesium is safe to be given.

Biologic agents licensed for severe asthma: a systematic review and meta-analysis of randomised controlled trials.

BACKGROUND: Six biologic agents are now approved for patients with severe asthma. This meta-analysis aimed to assess the efficacy and safety of licensed biologic agents in patients with severe asthma, including the recently approved tezepelumab. METHODS: We searched MEDLINE, Embase and CENTRAL to identify randomised controlled trials involving licensed biologics until 31 January 2023. We used random-effects meta-analysis models for efficacy, including subgroup analyses by individual agents and markers of T2-high inflammation (blood eosinophils and fractional exhaled nitric oxide), and assessed safety. RESULTS: 48 studies with 16 350 patients were included in the meta-analysis. Biologics were associated with a 44% reduction in the annualised rate of asthma exacerbations (rate ratio 0.56, 95% CI 0.51-0.62) and 60% reduction of hospitalisations (rate ratio 0.40, 95% CI 0.27-0.60), a mean increase in the forced expiratory volume in 1 s of 0.11 L (95% CI 0.09-0.14), a reduction in asthma control questionnaire by 0.34 points (95% CI -0.46--0.23) and an increase in asthma quality of life questionnaire by 0.38 points (95% CI 0.26-0.49). There was heterogeneity between different classes of biologics in certain outcomes, with overall greater efficacy in patients with T2 inflammation. Overall, biologics exhibited a favourable safety profile. CONCLUSIONS: This comprehensive meta-analysis demonstrated that licensed asthma biologics reduce exacerbations and hospitalisations, improve lung function, asthma control and quality of life, and limit the use of systemic corticosteroids, with a favourable safety profile. These effects are more prominent in patients with evidence of T2 inflammation.

Long-term safety, durability of response, cessation and switching of biologics.

PURPOSE OF REVIEW: Severe asthma patients suffer from decreased quality of life, and increased asthma symptoms, exacerbations, hospitalizations, and risk of death. Biologics have revolutionized treatment for severe asthma. However, with multiple biologic agents now available, clinicians must consider initial selection the long-term effectiveness of biologics. Additionally, patients have overlapping eligibilities and clinicians may consider switching between biologics for improved response. Finally, careful assessment of biologics cessation is needed for severe asthma patients who depend on these add-on therapies for asthma control. RECENT FINDINGS: Evidence for long-term durability and safety varies by biologic agent. In general, initial benefits noted from these agents (ex. exacerbation reduction) is, at minimum, sustained with long term use. Rates of adverse events and serious adverse events, including those requiring cessation of a biologics are low with long term use. Further studies are needed to understand the development of antidrug antibodies but currently their prevalence rates are low. Adverse events and insufficient efficacy are common reasons for biologic cessation or switching. Discontinuation maybe associated with waning of benefits but can be considered in certain situations. Biologic switching can be associated with improved asthma control. SUMMARY: Biologics are safe and effective long-term therapies for the management of asthma. Discontinuation must be carefully considered and if possible avoided. Reasons for insufficient efficacy must be evaluated and if needed, biologic switching should be considered.

Benralizumab in children with severe eosinophilic asthma: Pharmacokinetics and long-term safety (TATE study).

BACKGROUND: Benralizumab is an anti-interleukin-5 receptor α monoclonal antibody approved as an add-on maintenance treatment for patients with uncontrolled severe asthma. Prior Phase 3 studies have evaluated benralizumab in patients aged ≥12 years with severe uncontrolled asthma. The TATE study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of benralizumab treatment in children. METHODS: TATE was an open-label, Phase 3 study of benralizumab in children aged 6-11 years from the United States and Japan (plus participants aged 12-14 years from Japan) with severe eosinophilic asthma. Participants received benralizumab 10/30 mg according to weight (<35/≥35 kg). Primary endpoints included maximum serum concentration (Cmax ), clearance, half-life (t1/2 ), and blood eosinophil count. Clearance and t1/2 were derived from a population PK (popPK) analysis. Safety and tolerability were also assessed. RESULTS: Twenty-eight children aged 6-11 years were included, with an additional two participants from Japan aged 12-14 years also included in the popPK analysis. Mean Cmax was 1901.2 and 3118.7 ng/mL in the 10 mg/<35 kg and 30 mg/≥35 kg groups, respectively. Clearance was 0.257, and mean t1/2 was 14.5 days. Near-complete depletion of blood eosinophils was shown across dose/weight groups. Exploratory efficacy analyses found numerical improvements in mean FEV1 , mean ACQ-IA, patient/clinician global impression of change, and exacerbation rates. Adverse events occurred in 22/28 (78.6%) of participants; none led to discontinuation/death. CONCLUSION: PK, PD, and safety data support long-term benralizumab in children with severe eosinophilic asthma, and were similar to findings in adolescents and adults. TRIAL REGISTRATION: ClinicalTrials.gov-ID: NCT04305405.

Adverse events of anti-IL-5 drugs in patients with eosinophilic asthma: a meta-analysis of randomized controlled trials and real-world evidence-based assessments.

BACKGROUND: We aimed to clarify comprehensively the safety profiles of anti-IL-5 drugs and pinpoint potential safety concerns that may arise in their post-marketing phase. METHODS: Two researchers conducted comprehensive searches of PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to September 2022. Additionally, we investigated the FDA AE Reporting System for post-marketing adverse event (AE) reports related to anti-IL-5 drugs. The outcomes fulfilled the proportional reporting rate criteria and the Bayesian confidence propagation neural network. RESULTS: We included 24 published studies in our analysis. The anti-IL-5 treatment group showed an incidence of AEs comparable to the placebo group, and it exhibited a significantly lower frequency of serious AEs. Common AEs were asthma, nasopharyngitis, headache, upper respiratory tract infection (URTI), and bronchitis. The post-marketing data included 28,478 case reports associated with the suspect drugs and 75 suspect safety observations affecting 16 system organ classes. New suspect observations included incomplete therapeutic product effect, URTIs, and pulmonary mass in reports related to mepolizumab. Reports associated with mepolizumab and benralizumab also indicated issues with incorrect technique in device usage and product issues. CONCLUSIONS: Individual anti-IL-5 drugs' safety profiles largely matched their product inserts. We identified issues like improper device usage, product issue, and URTIs as potential concerns for mepolizumab and benralizumab. Additionally, all anti-IL-5 drugs showed signs of incomplete therapeutic effects.

Clinical characteristics of complete responders versus non-complete responders to omalizumab, benralizumab and mepolizumab in patients with severe asthma: a long-term retrospective analysis.

BACKGROUND: Some patients with severe asthma may benefit from treatment with biologics, but evidence has been mostly collected from randomized controlled trials (RCTs), in which patients' characteristics are different from those encountered in asthma patients in the real-world setting. The aim of this study was to describe the clinical features of complete responders versus non-complete responders to long-term treatment with biologics in patients with severe asthma attended in routine daily practice. METHODS: Data of a cohort of 90 patients with severe asthma who were treated with biologics (omalizumab, benralizumab, and mepolizumab) for at least 12 months and were followed up to March 2022. Data recorded included clinical characteristics and effectiveness of treatment (exacerbation, Asthma Control Test [ACT] score, lung function, use of maintenance oral corticosteroids [mOCS]), FeNO, and blood eosinophils at baseline, at 12 months, and at the end of follow-up. Complete response is considered if, in addition to not presenting exacerbations or the use of mOCS, the ACT score was >20 and, the FEV1 >80% predicted. RESULTS: An improvement in all asthma control parameters was observed after 12 months of treatment and a mean follow-up of 55 months. After 12 months of treatment 27.2% of patients met the criteria of complete response and this percentage even increased to 35.3% at the end of follow-up. Long-term complete response was associated to better lung function with mepolizumab and omalizumab treatment and to less previous exacerbations in the benralizumab group. The main cause of not achieving a complete response was the persistence of an airflow obstructive pattern. CONCLUSIONS: This study shows that omalizumab, benralizumab, and mepolizumab improved the clinical outcomes of patients with severe asthma in a clinic environment with similar effect sizes to RCTs in the long term follow-up. Airflow obstruction, however, was a predictor of a non-complete response to biologics.

Treatment with anti-IgE and anti-IL-5 biologics significantly improved clinical outcomes in severe asthma patients.The rate of complete responders of 27.2% at 12 months even increased to 35.3% at the end of a mean follow-up of 55 months.The persistence of an airflow obstructive pattern was the main cause of the failure to achieve complete response.

Resolvin and lipoxin metabolism network regulated by Hyssopus Cuspidatus Boriss extract in asthmatic mice.

Resolvin (Rv) and lipoxin (Lx) play important regulative roles in the development of several inflammation-related diseases. The dysregulation of their metabolic network is believed to be closely related to the occurrence and development of asthma. The Hyssopus Cuspidatus Boriss extract (SXCF) has long been used as a treatment for asthma, while the mechanism of anti-inflammatory and anti-asthma action targeting Rv and Lx has not been thoroughly investigated. In this study, we aimed to investigate the effects of SXCF on Rv, Lx in ovalbumin (OVA)-sensitized asthmatic mice. The changes of Rv, Lx before and after drug administration were analyzed based on high sensitivity chromatography-multiple response monitoring (UHPLC-MRM) analysis and multivariate statistics. The pathology exploration included behavioral changes of mice, IgE in serum, cytokines in BALF, and lung tissue sections stained with H&E. It was found that SXCF significantly modulated the metabolic disturbance of Rv, Lx due to asthma. Its modulation effect was significantly better than that of dexamethasone and rosmarinic acid which is the first-line clinical medicine and the main component of Hyssopus Cuspidatus Boriss, respectively. SXCF is demonstrated to be a potential anti-asthmatic drug with significant disease-modifying effects on OVA-induced asthma. The modulation of Rv and Lx is a possible underlying mechanism of the SXCF effects.

"Patient remodeling" as a consequence of uncontrolled and prolonged OCS use in severe asthma: how biologic therapy can reverse a dangerous trend.

INTRODUCTION: Asthma is a chronic inflammatory disease that can lead to airways remodeling. Despite their well-known side-effects, oral corticosteroids (OCS) continue to be used to reduce exacerbations and control asthma symptoms in many patients. CASE STUDY: We describe two cases of uncontrolled severe asthma characterized by systemic clinical consequences of prolonged OCS use, such as diabetes, weight gain, and osteoporosis. RESULTS: Both patients were treated with Dupilumab. During follow-up both patients showed an improvement in asthma control and were able to gradually taper the OCS dose, thus reducing the clinical burden associated with hypercortisolism. CONCLUSION: Dupilumab was able to control both the inflammatory-induced "airway remodeling" as well as the OCS-induced "patient remodeling".

Short-acting ß2-agonist prescriptions in patients with asthma: findings from the South Korean cohort of SABINA III.

BACKGROUND/AIMS: Despite short-acting ß2-agonist (SABA) overuse being associated with poor asthma outcomes, data on SABA use in South Korea is scarce. Herein, we describe prescription patterns of SABA and other asthma medications in patients from the South Korean cohort of the SABA use IN Asthma (SABINA) III study. METHODS: This study included patients with asthma aged ≥ 12 years, who had ≥ 3 consultations with the same healthcare provider, and medical records containing data for ≥ 12 months prior to the study visit. Patients were classified by investigator-defined asthma severity (per 2017 Global Initiative for Asthma recommendations) and practice type (primary or specialist care). Data on disease characteristics, asthma treatments, and clinical outcomes in the 12 months before the study visit were collected using electronic case report forms. RESULTS: Data from 476 patients (mean age, 55.4 years; female, 63.0%) were analyzed. Most patients were treated by specialists (83.7%) and had moderate-to-severe asthma (91.0%). Overall, 7.6% of patients were prescribed ≥ 3 SABA canisters (defined as over-prescription). In patients prescribed SABA in addition to maintenance therapy, 47.4% were over-prescribed SABA. Most patients (95.4%) were prescribed a fixed-dose combination of an inhaled corticosteroid and a long-acting ß2-agonist as maintenance therapy. Although asthma was well-controlled/partly-controlled in 91.6% of patients, 29.6% experienced ≥ 1 severe asthma exacerbation. CONCLUSION: SABA over-prescription was reported in nearly 50% of patients prescribed SABA in addition to maintenance therapy, underscoring the need to align clinical practices with the latest evidence-based recommendations and educate physicians and patients on appropriate SABA use.

Biological Drugs for the Treatment of Uncontrolled Severe Asthma in Children.

The introduction of biological drugs for the treatment of severe allergic asthma in children, almost twenty years ago, had a substantial impact on both the pathology's clinical course and the quality of life of the patients who receive treatment. Over the years, several molecules have been developed that inhibit molecular targets involved in the pathogenesis of the asthmatic disease. Biological drugs demonstrate a significant improvement in several key clinical parameters in patients with severe asthma. In this review, we provide a concise summary of the evidence on biological therapy for children and adolescents with severe asthma.

Dual biologics therapy in a patient with severe asthma and chronic urticaria: a case report and review of the literature.

INTRODUCTION: The data on the use of dual biologics are scant, but a topic of current interest. CASE STUDY: In this report, the treatment regimen of a patient with two T helper 2 pathway-related comorbidities, severe asthma, and chronic spontaneous urticaria, was presented. RESULTS: Both urticaria and asthma symptoms of the patient could not be controlled entirely with monotherapy while both diseases could be controlled after omalizumab-mepolizumab dual treatment. No adverse events were observed after 6 months of dual biologics use. CONCLUSION: This report supports other publications in the literature involving the use of dual biologics and provides a summary of the literature.

Safety and efficacy of benralizumab in elderly subjects with severe asthma.

INTRODUCTION: The prevalence of asthma in adults >65 years old is approximately 12-14%, and 10% have severe asthma. A higher mortality rate is observed in subjects with asthma >65 years old and especially >80 years old. OBJECTIVE: To analyze the effectiveness and safety of at least three doses of benralizumab in a subgroup of elderly subjects (>65 years old) with uncontrolled severe eosinophilic asthma in real-life conditions. METHODS: This was a retrospective multicenter study (AUTOBENRA study) conducted in 9 hospitals that included 72 patients aged >18 years old with uncontrolled severe asthma based on the Spanish Asthma Guidelines who were treated with at least three doses of benralizumab, self-administered at home since before April 30, 2021. The recruitment period ended on October 1, 2021. Written consent was obtained before the study commencement. In this subanalysis, we compared the results between patients >65 years old and patients <65 years old. RESULTS: A total of 72 subjects with severe asthma were screened, and 54 were included (MD: 57.3 ± 10 years old). There were 12 subjects aged >65 years old [MD: 69.8 ± 4.3 years old (minimum: 65 years old; maximum: 83 years old)]. Subjects >65 years old experienced statistically significant improvement in lung function, ACT and mini-AQLQ with benralizumab. Additionally, 9 patients (75%) experienced no asthma exacerbation (p = 0.0047), half (3/6) were able to stop OCS (p = 0.08), and no adverse effects with benralizumab were reported during the 20 months of follow-up. CONCLUSIONS: In patients aged >65 years old, benralizumab was an effective and safe therapy for severe eosinophilic asthma in our study, with no significant differences from the younger subgroup. This is especially important since they are a group with numerous comorbidities, medications and worse quality of life.

Is the assessment of asthma treatment efficacy sufficiently comprehensive?

The goal of asthma guideline therapy is to achieve disease control, by minimizing impairment and decreasing the risk of exacerbations and adverse effects of the disease and its treatment. The primary objective of most clinical trials of biologics for severe asthma is a reduction in exacerbation rate. Recently, studies with patients at the lower guideline steps have also selected exacerbation reduction as a primary objective. These trials in patients with milder disease frequently demonstrate statistically significantly fewer exacerbations, but their power calculations reflect larger sample size and smaller effect size. Exacerbations have a precise consensus definition, although a minimal clinically important difference has not been established. Reduction of exacerbations in severe asthma is commonly 10-fold greater than in mild disease. Further, reduction in exacerbations is not always associated with reduced impairment. If superior control is the objective, both domains should demonstrate consistent and parallel improvement. The disconnect may reflect the need for alternative tools for measurement of impairment or, possibly, different therapeutic mechanisms of action. Determining response to biologics or discussion of disease remission requires assessing symptoms that may occur daily rather than focusing on exacerbations that occur once or twice a year for patients at the highest steps of care according to the guidelines.

An efficacy and safety evaluation of montelukast + fluticasone propionate vs. fluticasone propionate in the treatment of cough variant asthma in children: a meta-analysis.

PURPOSE: This study aimed to evaluate the efficacy and safety of montelukast (Mon) + fluticasone propionate (Flu) versus Flu in the treatment of cough variant asthma (CVA) in children. METHODS: Eligible documents were selected from various databases. Weighted mean difference (WMD) and 95% confidence interval (CI) were used to evaluate continuous variables, and categorical variables were evaluated using risk ratio (RR) and 95% CI. Heterogeneity analysis was performed using Cochran's Q test and I2 statistics, followed by sensitivity analysis and publication bias evaluation. RESULTS: Nine studies were included, and Flu + Mon was found to significantly improve the total effective rate and reduce cough recurrence compared to Flu. The cough remission and disappearance times in the Mon + Flu group were significantly lower than those in the Flu group. FEV1% recovery in the Mon + Flu group was significantly better than that in the Flu group. CONCLUSION: Mon + Flu is effective and safe for the treatment of CVA in children.

Progress in diagnosis and treatment of difficult-to-treat asthma in children.

At present, medications containing inhaled corticosteroids (ICS-containing) are the keystones of asthma treatment. The majority of asthmatic children can significantly improve clinical outcomes with little worsening by standardized inhaled glucocorticoid treatment, but there is still a small proportion of children who are unable to achieve good symptom control even after the maximum standardized treatment, known as 'children with difficult-to-treat asthma (DA)'. The high heterogeneity of DA makes therapy challenging and expensive, which poses a serious risk to children's health and makes it extremely difficult for clinical physicians to accurately identify and treat children with DA. This article reviews the definition, evaluation, and treatment of this asthma in order to provide a reference for optimal clinical decision-making.

Improvement in severe asthma patients receiving biologics and factors associated with persistent insufficient control: a real-life national study.

BACKGROUND: Biological therapies have revolutionized the treatment of severe asthma with type 2 inflammation. Although such treatments are very effective in reducing exacerbation and the dose of oral steroids, little is known about the persistence of symptoms in severe asthma patients treated with biologics. PURPOSE: We aim to describe asthma control and healthcare consumption of severe asthma patients treated with biologics. DESIGN: The Second Souffle study is a real-life prospective observational study endorsed by the Clinical Research Initiative in Severe Asthma: a Lever for Innovation & Science Network. METHODS: Adults with a confirmed diagnosis of severe asthma for at least 12 months' duration were enrolled in the study. A self-administered questionnaire including the Asthma Control Questionnaire (ACQ), Asthma Quality of Life Questionnaire (AQLQ) and a compliance evaluation test was given to the patients. Healthcare consumption within 12 months prior to enrolment was documented. In patients receiving biologics, doctors indicated whether the patients were biologic responders or non-responders. RESULTS: The characteristics of 431 patients with severe asthma were analysed. Among them, 409 patients (94.9%) presented asthma with type 2 inflammation (T2 high) profile, and 297 (72.6%) patients with a T2 high phenotype were treated with a biologic. Physicians estimated that 88.2% of patients receiving biologics were responders. However, asthma control was only achieved in 25.3% of those patients (ACQ > 0.75). A high proportion of patients (77.8%) identified as responders to biologics were not controlled according to the ACQ score. About 50% of patients continue to use oral corticosteroids either daily (25.2%) or more than three times a year for at least three consecutive days (25.6%). Gastro-oesophageal Reflux Disease (GERD) and Obstructive Sleep Apnoea syndrome (OSA) were identified as independent factors associated with uncontrolled asthma. CONCLUSION: Although a high proportion of severe asthma patients respond to biologics, only 25.3% have controlled asthma. GERD and OSA are independent factors of uncontrolled asthma.

Expert Consensus on SABA Use for Asthma Clinical Decision-Making: A Delphi Approach.

PURPOSE OF REVIEW: A modified Delphi process was undertaken to provide a US expert-led consensus to guide clinical action on short-acting beta2-agonist (SABA) use. This comprised an online survey (Phase 1), forum discussion and statement development (Phase 2), and statement adjudication (Phase 3). RECENT FINDINGS: In Phase 1 (n = 100 clinicians), 12% routinely provided patients with ≥4 SABA prescriptions/year, 73% solicited SABA use frequency at every patient visit, and 21% did not consult asthma guidelines/expert reports. Phase 3 experts (n = 8) reached consensus (median Likert score, interquartile range) that use of ≥3 SABA canisters/year is associated with increased risk of exacerbation and asthma-related death (5, 4.75-5); SABA use history should be solicited at every patient visit (5, 4.75-5); usage patterns over time, not absolute thresholds, should guide response to SABA overuse (5, 4.5-5). Future asthma guidelines should include clear recommendations regarding SABA usage, using expert-led thresholds for action.

A risk of serious anaphylatic reactions to asthma biologics: a pharmacovigilance study based on a global real-world database.

Asthma is a chronic inflammatory condition that affects the lung airways. Chronic use of oral glucocorticoids in patients with severe asthma is associated with several adverse events (AEs). Biologics (omalizumab, benralizumab, mepolizumab, reslizumab, and dupilumab) have been developed as alternative therapies for the treatment of asthma. In this study, we aimed to evaluate the risk of anaphylactic reactions associated with these five biologics based on a large global database. We utilized individual case reports from the Uppsala Monitoring Center from January 1968 to December 29, 2019. A disproportionality analysis was performed over all drugs and monoclonal antibodies. Anaphylactic reactions were defined according to the "anaphylactic reaction" of the standardized MedDRA queries. Contrary to dupilumab, omalizumab, benralizumab, and mepolizumab demonstrated positive signals related to anaphylactic reactions over all drugs and monoclonal antibodies. Reslizumab, which represented only 315 cases of all AEs, requires more reports to determine its association with anaphylactic reactions. More anaphylactic reactions have been identified than are known, and most cases (96.2%) are reported to be serious. Our findings indicate that omalizumab, benralizumab, and mepolizumab for asthma treatment are associated with a high risk of anaphylactic reactions; thus, more careful monitoring in the post-administration period is recommended.

The Risk of Neuropsychiatric Adverse Events With Use of Leukotriene Receptor Antagonists in Patients With Asthma: Analysis of Korea's National Health Insurance Sharing Service Database.

BACKGROUND: Montelukast, a selective leukotriene receptor antagonist, is a commonly prescribed allergy medication but its potential association with neuropsychiatric adverse events is concerning. OBJECTIVE: To analyze Korea's National Health Insurance System claims records to identify the risk of neuropsychiatric adverse events in patients with asthma treated with montelukast. METHODS: This retrospective population-based study analyzed the National Health Insurance claims records of the entire Korean population between 2008 and 2015. We compared the risk of neuropsychiatric adverse events among patients with asthma using inhaled corticosteroids and/or long-acting ß2-agonists with montelukast or pranlukast and those not using leukotriene receptor antagonists (control group). RESULTS: There was no increased risk of the composite outcome of all measured neuropsychiatric adverse events in patients with asthma who were prescribed montelukast or pranlukast compared with those who were not. However, montelukast use was associated with an increased risk of hallucinations (inverse probability treatment weighting hazard ratio, 1.45; 95% CI, 1.07-1.96) and attention problems (inverse probability treatment weighting hazard ratio, 1.24; 95% CI, 1.01-1.52). Significant negative hazards for disorientation, anxiety, stress reactions, and somatic symptoms were observed in the montelukast group. When grouped by sex, the risk of hallucinations and attention problems was higher in men prescribed montelukast compared with the controls. CONCLUSIONS: We did not observe an increase in all neuropsychiatric adverse events in the leukotriene receptor antagonist-treated group; however, an increased risk of hallucinations and attention problems was observed in those taking montelukast, regardless of the medication administration period.