Can montelukast (singulair) exacerbate depression?

Montelukast and Depression: Risk Assessment

Yes, montelukast can exacerbate depression and is associated with serious neuropsychiatric adverse events including depression, anxiety, suicidal thinking and behavior, which led the FDA to issue a black box warning in 2020. 1, 2, 3, 4

FDA Black Box Warning and Regulatory Actions

The FDA's strongest safety warning explicitly states that montelukast carries risks of serious neuropsychiatric events including:

• Suicidal thoughts and actions 1, 2, 3, 4
• Depression (new or worsening) 1, 2, 4
• Anxiety 4
• Sleep disturbances and dream abnormalities 4
• Agitation, aggressive behavior, or hostility 4
• Hallucinations 4

The FDA explicitly states that the benefits of montelukast may not outweigh the risks, especially when disease symptoms are mild and can be adequately treated with other medications. 2, 3

Clinical Evidence on Depression Risk

The evidence regarding montelukast and depression specifically shows:

• Depression was reported in approximately 1% of patients in clinical trials 5
• Depression was the most frequently reported adverse event in the WHO Global database (reporting odds ratio 6.93; 95% CI: 6.5-7.4) 6
• Four studies using antidepressant prescriptions as an outcome identified significant associations with montelukast use 7
• However, three observational studies using ICD-10 depression codes found no association 7

This apparent contradiction exists because studies using antidepressant prescriptions (which capture actual treatment decisions) show associations, while studies using diagnostic codes alone (which may miss subclinical symptoms) do not. 7

Conflicting Evidence and Quality Assessment

The European Respiratory Society acknowledges that evidence of the association between montelukast and neuropsychiatric adverse events is conflicting 1. The most recent and highest quality study addressing this question:

• A 2025 Swedish nationwide cohort study of 74,291 children found no association between montelukast use and neuropsychiatric adverse events (HR 0.99; 95% CI: 0.84-1.16) 8
• However, a 2022 propensity-matched cohort study of 154,946 patients found increased odds of neuropsychiatric outcomes (OR 1.11 for asthma patients, OR 1.07 for allergic rhinitis patients) 9

Despite the conflicting observational evidence, the FDA black box warning takes precedence because it is based on post-marketing surveillance data showing serious outcomes including completed suicides, which cannot be ethically studied in randomized trials. 1, 2, 3

Pre-Treatment Screening Requirements

Before initiating montelukast therapy:

• Screen for pre-existing psychiatric conditions including depression, anxiety, and suicidal ideation 1
• Explicitly discuss neuropsychiatric risks with patients and families, including the potential for suicidal thoughts and behavioral changes 1, 2, 3, 4
• Document that alternative therapies (inhaled corticosteroids for asthma, intranasal corticosteroids for allergic rhinitis) were considered 1, 2, 3

Active Monitoring During Treatment

Patients must be monitored for:

• Mood changes (depression, anxiety, irritability) 1, 4
• Sleep disturbances or dream abnormalities 1, 4
• Behavioral changes (agitation, aggression, restlessness) 1, 4
• Suicidal thoughts or actions 1, 2, 3, 4

Monitor particularly closely during the first weeks of therapy when neuropsychiatric events are most likely to emerge. 2, 3

Immediate Discontinuation Criteria

Discontinue montelukast immediately if the patient develops: 1

• Suicidal thinking or behavior
• New or worsening depression or anxiety
• Agitation or aggressive behavior
• Hallucinations or psychotic symptoms
• Significant sleep disturbances or dream abnormalities

Alternative Therapies to Prioritize

Montelukast should not be used as first-line therapy. 1, 2, 3 Preferred alternatives include:

• For asthma: Inhaled corticosteroids are more effective and safer as first-line therapy for persistent asthma 5, 3
• For allergic rhinitis: Intranasal corticosteroids are more effective than montelukast and lack neuropsychiatric risks 2, 3

The European Respiratory Society recommends montelukast only when patients do not tolerate nasal corticosteroids 1, and the EPOS2020 steering group does not advise adding montelukast to nasal corticosteroids due to lack of demonstrated benefit 5, 2.

Critical Pitfalls to Avoid

• Do not prescribe montelukast for mild disease when safer alternatives are available and appropriate 2, 3
• Do not continue therapy without reassessing risk-benefit if any neuropsychiatric symptoms emerge, even if mild 2, 3
• Do not dismiss patient or family reports of mood changes as unrelated to the medication 4
• Do not assume the drug is safe because the patient has no prior psychiatric history—neuropsychiatric events can occur in patients without pre-existing conditions 4

Special Population Considerations

In children specifically:

• Aggression was reported most frequently (ROR 29.77; 95% CI: 27.5-32.2) 6
• Nightmares are reported frequently in both children and adults 6
• The 2025 Swedish study found no increased risk in children, but this does not negate the FDA warning based on post-marketing surveillance 8