# Pediatric Asthma: Where Has Montelukast Gone?
## 4 Montelukast in Pediatric Asthma
### Adverse Reactions  
Despite being traditionally considered as safe, with well-described anti-inflammatory and bronchoprotective activities [48], montelukast may determine adverse events that are mild in most cases [49]. However, the mechanisms and clinical aspects of montelukast-related adverse reactions represent one of the main issues the literature has focused on in the last decade. Many reports have particularly highlighted the occurrence of neuropsychiatric effects ranging from nightmares and sleep disorders to hallucinations, aggressiveness, anxiety, and suicidal ideation [50; 51; 52; 53; 54; 55; 56; 57; 58]. Such manifestations are more common in 4- to 6-year-old children and typically occur within the first ten days after first administration [59]. A detailed characterization of the adverse drug reactions following montelukast therapy was recently provided by a systematic review analyzing 13 studies and almost 7000 treated patients, which confirmed hyperactivity, irritability, anxiety, and sleep disorders as the most widely reported psychiatric manifestations [60]. The increasing awareness of these adverse reactions, their higher frequency in children rather than adults, and the documented negative impact on the patients' quality of life [61] led the FDA to strengthen the existing warnings in 2020 by requiring montelukast to have a boxed warning about serious mental health side effects [62]. The observation of neuropsychiatric events not only during treatment, but also occasionally after montelukast discontinuation [63], and the report of cases with persisting symptoms after drug withdrawal, has stimulated researchers toward the identification of the involved mechanisms. A recent study analyzing montelukast metabolic pathways both in vitro and in mouse models has stressed the role of a metabolite, a montelukastglutathione conjugate, that might be responsible for the decreased glutathione levels in the brain tissue, with a reduction in its protective effect against oxidative stress [64]. Furthermore, montelukast administration in mice has been shown to determine a hypothalamic-pituitary-adrenal axis dysregulation, ultimately entailing altered levels of neurotransmitters, which might induce the observed neuropsychiatric disorders [64]. Although not validated in an experimental model, some drug-gene interactions have also been hypothesized. A wide analysis of 1144 genes interacting with montelukast recently showed that some of them are related to mood disorders. Genes encoding neuropeptide precursors such as hypocretin, affecting depression or serotonin receptors and associated with schizophrenia and suicidality, might be involved in the pathogenesis of neuropsychiatric manifestations [65]. Despite being less frequently reported, several other organs and systems may be involved by adverse reactions following treatment with montelukast. An Italian review of published case reports provided a summary of the potentially harmful effects associated with its administration, even though most of them had been observed in adults [66]. Gastrointestinal symptoms, namely, abdominal pain, nausea, and vomiting may be associated with montelukast administration [60], and a case of hepatotoxicity in a 5-year-old child has been reported [67]. Skin may also be occasionally involved: an 8-year-old girl who had received montelukast for five months developed a widespread erythematous and bullous skin rash, mostly localized at her lower extremities, associated with striking blood and tissue eosinophil [68]. The authors ultimately hypothesized the diagnosis of pemphigus, similar to other drug-induced reported cases [69]. Furthermore, [PERSON] and coworkers described an 11-year-old asthmatic child who presented with spontaneous lower limb bruising while on treatment with montelukast [70]. Such lesions were related to montelukast therapy both because a similar clinical pattern had previously been reported in a young woman [71] and because the resolution of the lesions was observed within a month after drug discontinuation.