Montelukast Can Cause Depression and Other Neuropsychiatric Events in Pediatric Patients
Yes, montelukast can cause depression and a range of neuropsychiatric adverse events in children, which is why the FDA issued a Boxed Warning in March 2020, and current guidelines now list it only as an alternative therapy with explicit caution. 1, 2
Regulatory Position and Guidelines
The 2020 National Asthma Education and Prevention Program guidelines explicitly note that montelukast has limited availability for use in the United States following the FDA's Boxed Warning 1. Montelukast is now relegated to "alternative" therapy status (not preferred) across all pediatric age groups for asthma management, reflecting the serious nature of these concerns 1.
The FDA drug label does not specifically list depression as a known adverse effect in its standard sections, but the existence of the Boxed Warning (issued March 2020) indicates the agency's serious concern about neuropsychiatric events 2.
Evidence of Neuropsychiatric Risk
Recent Large-Scale Studies Show Conflicting Results
The evidence presents a complex picture:
Most recent high-quality evidence (2025) from a Swedish nationwide cohort study of 74,291 children found no increased risk of neuropsychiatric adverse events compared to LABA users (HR 0.99,95% CI 0.84-1.16) 3. This included no increased risk specifically for depression (HR 1.16,95% CI 0.70-1.95) or anxiety (HR 0.79,95% CI 0.54-1.14) 3.
However, a 2025 prospective cohort study from 31 pediatric centers found that neuropsychiatric symptoms increased dramatically from 14.8% to 34.3% after just 1 month of montelukast treatment (p<0.001), with significant increases in depressive mood, anxiety, behavioral problems, and sleep disorders 4. This study specifically noted that concomitant antihistamine use increased the risk 4.
Pharmacovigilance Data Consistently Shows Signal
Multiple pharmacovigilance analyses have detected disproportionate reporting:
- A 2016 VigiBase analysis of 2,630 pediatric cases found suicidal behavior was over-represented across all age groups, with information component values reaching 5.01 in children 5
- Completed suicides were reported more frequently in children (IC 3.15) than in the general population (IC 1.95) 5
- Depression/anxiety were the main symptoms in children aged 2-11 years 5
- A Swedish analysis found psychiatric ADRs appeared in 48% of cases in children ≤3 years old, with 80% occurring within 1 week of starting treatment 6
Mechanistic Evidence
Recent mechanistic studies (2022,2025) provide biological plausibility:
- Montelukast interferes with glutathione detoxification in the brain and dysregulates neurotransmitter pathways, particularly those regulating the hypothalamic-pituitary-adrenal axis 7
- Animal studies demonstrate montelukast induces depression-like behaviors through oxidative stress and inflammatory responses, with elevated hippocampal IL-1β and serum corticosterone 8
- These mechanisms suggest children may be more vulnerable due to their developing nervous systems 7
Clinical Implications
When to Avoid Montelukast
Do not use montelukast as first-line therapy in pediatric patients. Inhaled corticosteroids are preferred at all treatment steps 1.
Avoid montelukast entirely in children with:
- Pre-existing psychiatric conditions
- Family history of depression or suicide
- Concurrent antihistamine use (increases risk) 4
- Age ≤3 years (higher vulnerability) 6
If Montelukast Must Be Used
When montelukast is prescribed as alternative therapy:
- Inform caregivers explicitly about neuropsychiatric risks including depression, anxiety, sleep disturbances, behavioral changes, and suicidal ideation
- Monitor within the first week - 80% of psychiatric ADRs occur within 7 days of initiation 6
- Discontinue immediately if any neuropsychiatric symptoms emerge
- Reassess at 1 month - significant symptom increases occur by this timepoint 4
Common Pitfalls
- Assuming safety in young children: Infants and toddlers ≤3 years show high rates of psychiatric ADRs (48% in one series) 6
- Missing early symptoms: Sleep disorders, nightmares, and behavioral changes may precede more serious depression or suicidal ideation 5, 6
- Ignoring drug interactions: Concurrent antihistamines significantly increase neuropsychiatric risk 4
- Continuing despite mild symptoms: Even "minor" mood changes warrant immediate discontinuation given the risk of progression to suicidal behavior 5
Reconciling Contradictory Evidence
The 2025 Swedish registry study 3 showing no increased risk contradicts pharmacovigilance data 4, 5, 6 and mechanistic studies 7, 8. This likely reflects:
- Selection bias: Registry studies may miss acute, early-onset events if patients discontinue quickly
- Detection bias: Spontaneous reporting captures severe, recognized events better than routine clinical data
- Population differences: The prospective cohort 4 specifically enrolled patients starting montelukast, while registry studies 3 include prevalent users who tolerated initial exposure
Given the FDA Boxed Warning, mechanistic plausibility, consistent pharmacovigilance signals, and availability of safer alternatives (inhaled corticosteroids), the precautionary principle mandates treating montelukast as carrying real neuropsychiatric risk in children, including depression.