Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review.

BACKGROUND: The United States Food and Drug Administration issued a black box warning on the mental health adverse effects of montelukast in 2020. Age-related effects on the risk of developing specific neuropsychiatric events in montelukast users remain largely unknown. OBJECTIVE: To describe the risk of neuropsychiatric events associated with montelukast in adults and children with asthma. METHODS: A systematic search of all studies investigating neuropsychiatric events in montelukast users was performed in PubMed, the Cochrane Library and Embase from inception to 7 September 2022. Animal studies and conference abstracts were excluded. RESULTS: 59 studies (21 pharmacovigilance studies, four reviews from 172 randomised controlled trials, 20 observational studies, 10 case reports and four case series) evaluating neuropsychiatric events in patients with asthma on montelukast were reviewed. No significant association was shown between montelukast and suicide-related events in six of the observational studies. No association was found for depression as defined by the International Classification of Diseases 10th revision codes in three observational studies and a review of randomised clinical trials. However, findings from four studies using antidepressant prescriptions as the outcome identified significant associations. Consistent with nine pharmacovigilance studies, two large-scale observational studies revealed possible associations of montelukast with anxiety and sleeping disorders in adult patients with asthma, respectively. However, the results were not replicated in two observational studies on children. CONCLUSION: Montelukast is not associated with suicide- and depression-related events in asthma patients. Older adults may be particularly susceptible to anxiety and sleeping disorders.

Meta-analysis of CYP2C19 and CYP2D6 metabolic activity on antidepressant response from 13 clinical studies using genotype imputation.

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. The association of CYP2C19 and CYP2D6 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR=1.46, 95% CI [1.03, 2.06], p=0.033, heterogeneity I2=0%, subgroup difference p=0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19 and CYP2D6, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. CYP2D6 structural variants cannot be imputed from genotype data, limiting inference of pharmacogenetic effects. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Cardiovascular Outcomes in Trials of New Antidiabetic Drug Classes.

Type 2 diabetes is among the most prevalent chronic diseases worldwide and the prevention of associated cardiovascular complications is an important treatment goal. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors are second-line options after metformin, while cardiovascular outcome trials have been conducted to establish the cardiovascular safety of these antidiabetic drug classes. SGLT2 inhibitors have been shown to have the best overall mortality, renal and cardiovascular outcomes. Reduction in hospitalisation for heart failure is particularly consistent. GLP-1 receptor agonists have also showed some benefits, especially in stroke prevention. DPP-4 inhibitors showed neutral effects on cardiovascular outcomes, but may increase the incidence of heart failure. Favourable outcomes observed in trials of SGLT2 inhibitors mean that these should be the preferred second-line option. DPP-4 inhibitors are useful for patients with diabetes at low cardiovascular risk.

Blood lead level and risk of hypertension in the United States National Health and Nutrition Examination Survey 1999-2016.

Lead is a heavy metal without a biological role. High level of lead exposure is known to be associated with hypertension, but the risk at low levels of exposure is uncertain. In this study, data from US NHANES 1999-2016 were analyzed. Adults with blood lead and blood pressure measurements, or self-reported hypertension diagnosis, were included. If not already diagnosed, hypertension was defined according to the AHA/ACC 2017 hypertension guideline. Results were analyzed using R statistics version 3.5.1 with sample weight adjustment. Logistic regression was used to study the association between blood lead level and hypertension. Odds ratio (OR) and 95% confidence interval (95% CI) were estimated. Altogether, 39,477 participants were included. Every doubling in blood lead level was associated with hypertension (OR [95%CI] 1.45 [1.40-1.50]), which remained significant after adjusting for demographics. Using quartile 1 as reference, higher blood lead levels were associated with increased adjusted odds of hypertension (Quartile 4 vs. Quartile 1: 1.22 [1.09-1.36]; Quartile 3 vs. Quartile 1: 1.15 [1.04-1.28]; Quartile 2 vs. Quartile 1: 1.14 [1.05-1.25]). In conclusion, blood lead level is associated with hypertension in the general population with blood lead levels below 5 µg/dL. Our findings suggest that reducing present levels of environmental lead exposure may bring cardiovascular benefits by reducing blood pressure.