FROM NIGHTMARES TO DEPRESSION: AGE-STRATIFIED NEUROPSYCHIATRIC EFFECTS OF MONTELUKAST

Purpose

To evaluate whether neuropsychiatric adverse drug reactions (ADRs) associated with montelukast demonstrate age-stratified symptom patterns and to examine developmental neurobiological mechanisms that may explain differential vulnerability across pediatric populations. Content: Montelukast, a cysteinyl leukotriene receptor antagonist widely prescribed for asthma and allergic rhinitis, has been associated with neuropsychiatric ADRs including sleep disturbances, agitation, anxiety, depression, and rare psychotic reactions. In 2020, the U.S. Food and Drug Administration issued a boxed warning highlighting serious mental health risks. Pharmacovigilance analyses suggest that these ADRs follow a developmentally patterned presentation. Infants and younger children most frequently exhibit sleep disturbances such as nightmares, night terrors, and insomnia, whereas adolescents more commonly present with internalizing psychiatric symptoms including depression, anxiety, and suicidal ideation. Developmental neurobiology may help explain this pattern. In early childhood, increased blood–brain barrier permeability and immature serotonergic circadian regulatory systems may increase susceptibility to sleep disruption when leukotriene signaling is altered. During adolescence, maturation of corticolimbic circuits involved in emotional regulation—including serotonergic, dopaminergic, and glutamatergic systems—may increase vulnerability to affective symptoms when neuroinflammatory signaling pathways are disrupted.

Methods

A systematic search of PubMed, PMC, and pharmacovigilance databases was conducted for studies examining montelukast-associated neuropsychiatric events across pediatric and adult populations. Twelve key studies published between 2015 and 2025 were identified and synthesized.

Results

Across pharmacovigilance datasets and observational studies, neuropsychiatric ADR reporting was consistently higher in pediatric montelukast users than in adults. Younger children were disproportionately represented in reports of nightmares, night terrors, and insomnia, often emerging within days of treatment initiation. A multicenter pediatric cohort study reported increases in neuropsychiatric symptom reporting from 14.8% at baseline to 34.3% after one month of treatment. A large population-based case-crossover study involving over 160,000 pediatric patients found a 28–38% increased risk of neuropsychiatric events following montelukast exposure. Adolescents more frequently demonstrated internalizing psychiatric symptoms including depression and anxiety. Although some large registry-based studies have reported no significant association between montelukast and neuropsychiatric outcomes, the developmental distribution of symptom types remains relatively consistent across multiple pharmacovigilance datasets.

Importance: Recognition of developmentally patterned neuropsychiatric ADRs has important implications for clinical practice. Sleep disturbances in younger children may represent early warning signs of medication-related central nervous system effects, while mood or behavioral changes may be more prominent in adolescents. Understanding these age-specific vulnerability patterns may improve patient counseling, monitoring, and riskbenefit decision-making when prescribing montelukast in pediatric populations. These findings also highlight the need for prospective age-stratified pharmacoepidemiologic studies to better define neuropsychiatric risk associated with leukotriene receptor antagonists.