Montelukast and Neuropsychiatric Events: A target trial emulation to quantify adverse reactions and measure the impact of regulatory action

Background Montelukast is a treatment for asthma and seasonal allergic rhinitis, widely used in people aged over 6 months. It is known to cause a wide range of neuropsychiatric side effects, but their frequency of occurrence is uncertain in some instances, and for rare outcomes such as suicide attempt, a causal association has not been established. In 2019 and 2024, the UK Medicines and Healthcare products Regulatory Agency (MHRA) warned prescribers about this problem, but we don t know how impactful this action was. Aims and Objectives The overarching aim is to quantify the risk of neuropsychiatric side effects associated with montelukast therapy in routine clinical care in the UK, and to determine whether regulatory action designed to minimise harm from montelukast has been effective. Specific objectives are: Describe montelukast prescribing patterns in primary care over the last 10 years, including absolute number of patients starting treatment, and % of all eligible asthma patients. Determine the impact of advice and warnings about montelukast from MHRA in 2019 and 2024 on montelukast prescribing patterns. Measure absolute and relative rates of neuropsychiatric signs and symptoms amongst montelukast users compared with similar people with asthma not taking montelukast. Quantify how often montelukast treatment is stopped amongst people presenting with neuropsychiatric signs and symptoms. Methods We will use de-identified patient data from the UK Clinical Practice Research Datalink to meet the study objectives. Feasibility work shows data for ~500,000 montelukast users will be available for the study, making it one of the largest to date in this research area. Initially we will measure the incidence and prevalence of montelukast usage between 2015 and 2024. Using segmented generalised least squares regression, we will determine the impact of MHRA communications on prescribing in 2019 and 2024. Subsequently, we will use recently developed Target Trial Emulation (TTE) methdology to compare outcomes amongst patients with asthma prescribed montelukast with those prescribed alternatives. Outcomes of interest have been developed with our PPI co-applicants and include; sleep disorders (night terrors, dream abnormalities, nightmares, insomnia, somnambulism), hallucinations, anxiety, depression, psychosis, suicidal ideation, suicide attempts and suicide, aggression, obsessive/compulsive behaviour, ADHD and autism. Using the CPRD prescribing data, we will determine points in time when montelukast dose is increased and determine whether this leads to a change in outcome occurrence. We will also measure the rate of montelukast discontinuation following potential neuropsychiatric side effects. Timelines for Delivery Project results will be delivered in 24 months from the start of the study. Anticipated Impact and Dissemination This evidence will impact patient choice and prescribing behaviour in respiratory medicine. Depending on the findings it has clear potential to immediately inform regulatory decision making on the risk/benefit balance of montelukast treatment and current prescribing guidance. It may guide any necessary further regulatory action. Through these mechanisms, the impact of this research will be experienced by individual patients, their families and carers, and the strained health services they are currently reliant on.