Montelukast can cause depression because it blocks leukotriene receptors that exist not only in the airways but also in the brain. The drug was designed to reduce inflammation in the lungs, but it crosses into the central nervous system and interferes with signaling pathways involved in neuroinflammation and immune cell behavior. In 2020, the FDA added its strongest warning, a boxed warning, to montelukast’s label specifically because of mood and behavior changes including depression, suicidal thoughts, and hallucinations.
How Montelukast Reaches the Brain
Montelukast works by blocking a type of receptor called CysLT1, which normally responds to inflammatory molecules called cysteinyl leukotrienes. These receptors are abundant in the lungs, which is why the drug helps with asthma and allergies. But CysLT1 receptors also exist in the brain, expressed on neurons, immune cells called microglia, and support cells called astrocytes.
Animal studies confirm that montelukast does cross the blood-brain barrier and reaches the cerebrospinal fluid and brain tissue, though at much lower concentrations than in the bloodstream. Once there, it blocks leukotriene receptors on microglia, the brain’s resident immune cells. Microglia play a central role in neuroinflammation, and disrupting their signaling may alter the brain’s inflammatory balance in ways that affect mood. The drug also downregulates a receptor called GPR17, another leukotriene target expressed in the brain. Whether montelukast’s psychiatric effects come from directly blocking these brain receptors or from indirect changes to the immune environment remains an open question in the research.
What the Evidence Says About Depression Risk
The relationship between montelukast and depression is more complicated than many people assume. A 2025 meta-analysis published in Frontiers in Pharmacology found that montelukast was associated with an 11% higher risk of anxiety compared to controls. However, the same analysis did not find a statistically significant increase in the risk of depression, suicidal behavior, or self-harm when pooling data across clinical trials.
That doesn’t mean depression doesn’t happen on montelukast. Post-marketing surveillance data, which captures real-world reports from patients and doctors, tells a different story. Thousands of neuropsychiatric adverse events have been reported to safety databases in the U.S., EU, and UK, including depression, suicidal thoughts, and completed suicides. The gap between clinical trial data and real-world reports is likely because trials exclude people with pre-existing psychiatric conditions, run for limited time periods, and may not systematically screen for mood changes. The FDA considered the post-marketing evidence serious enough to mandate the boxed warning.
The Full List of Neuropsychiatric Symptoms
Depression is just one of a broad range of mood and behavior changes linked to montelukast. The FDA’s boxed warning lists the following symptoms to watch for:
- Agitation, aggressive behavior, or hostility
- Depression
- Suicidal thoughts and actions
- Hallucinations
- Anxiety and restlessness
- Vivid or bad dreams
- Trouble sleeping or sleepwalking
- Attention and memory problems
- Disorientation or confusion
- Obsessive-compulsive symptoms
- Irritability
- Tremor, stuttering, or uncontrolled muscle movements
The variety of these symptoms suggests that montelukast’s effects on the brain are not limited to a single neurotransmitter pathway. It appears to broadly alter central nervous system function in susceptible individuals, which is consistent with its interaction with multiple receptor types in the brain.
How Quickly Symptoms Appear and Resolve
Neuropsychiatric symptoms tend to emerge fast. Research shows that 75% of patients who develop mood or behavior changes on montelukast do so within the first two weeks of treatment. This rapid onset aligns with how quickly the drug reaches therapeutic levels in the body.
The good news is that symptoms also tend to resolve quickly after stopping the medication. Case reports describe psychotic symptoms disappearing within two days of discontinuation, and in some cases improvement is almost immediate. This rapid reversibility supports the idea that the drug is directly causing the symptoms rather than triggering an independent psychiatric condition.
Children Face Higher Risk Than Adults
Children are more susceptible to montelukast’s neuropsychiatric effects than adults. In a study of nearly 1,000 pediatric patients, 7.9% experienced a neuropsychiatric event while taking the drug. That’s roughly 1 in 13 children.
The risk climbs sharply for children who already have a psychiatric condition. Kids with a pre-existing diagnosis like ADHD, anxiety, or depression had 4.4 times the odds of experiencing a neuropsychiatric event compared to children with no psychiatric history. Nearly 1 in 5 children (19.3%) with a comorbid psychiatric condition developed symptoms, versus 6.8% of those without one. This makes prior mental health history the most clearly identified risk factor for problems with montelukast, and it’s something worth discussing with a prescriber before starting the medication, particularly for a child.
Why the FDA Added Its Strongest Warning
For years, neuropsychiatric side effects were listed in montelukast’s prescribing information but buried in the fine print. The FDA elevated it to a boxed warning in March 2020 after reviewing accumulating post-marketing reports and concluding that many patients and prescribers were unaware of the risks. The agency also restricted the drug’s use for allergic rhinitis (hay fever), stating that the risk of psychiatric side effects was not justified for a condition with many alternative treatments. For asthma, the FDA still considers montelukast appropriate but advises that the benefits should be weighed carefully against the potential for mood-related side effects.
The practical takeaway is that montelukast remains a useful asthma medication for many people, but anyone taking it should be aware that mood changes can happen quickly, are more likely in children and in people with pre-existing psychiatric conditions, and typically resolve once the drug is stopped.